Condensed aminohydrothiazine derivative

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of general formula:

or its pharmaceutically acceptable salt wherein the ring A represents a phenyl group which can contain 1-3 substitutes specified in a group of substitutes, or a thienyl group which can contain 1-3 substitutes specified in a group of substitutes α; L represents a single bond or a group of formula -NRC CO- (wherein Re represents a hydrogen atom), the ring B represents C6-14 aryl group which can contain 1-3 substitutes specified in a group of substitutes α, or a 5-10-member heterocyclic group which can contain 1-3 substitutes specified in a group of substitutes α; the X, Y, Z , R1 and R2 , R3, R4, R5 and R6 radical values are presented in cl.1 of the patent claim which possess an effect of Aβ protein production inhibition or an effect of BACE1 inhibition.

EFFECT: preparing the compound which is applicable as a preventive or therapeutic agent for neurodegenerative disease caused by Aβ.

13 cl, 35 tbl, 285 ex

 

The technical field to which the invention relates

The present invention relates to condensed derived aminopiperidine and its pharmaceutical use. More specifically, the present invention relates to condensed derived aminopiperidine, which has the effect of inhibiting the production of β-amyloid protein (hereinafter designated as Aβ) or the effect of inhibition of enzyme cleavage of beta-site of the protein precursor of amyloid-β type 1 (enzyme, hereinafter designated as BACE1 or beta secretase) and is effective in the treatment of neurodegenerative disease caused by Aβ protein, in particular dementia, Alzheimer's disease, down's syndrome or the like, and pharmaceutical compositions containing condensed derived aminopiperidine as the active component.

Background of invention

Alzheimer's is a disease characterized by degeneration and loss of neurons and the formation of senile plaques and neurofibrillary degeneration. Currently, Alzheimer's disease treated only by symptomatic therapy with the use of funds to reduce symptoms, a typical representative of which is an inhibitor of acetylcholinesterase and fundamental drug with estvo, inhibiting the progression of the disease is still not created. You must develop a way of controlling the causes of pathology in order to create the fundamental remedy for the treatment of Alzheimer's disease.

It is believed that Aβ proteins as metabolites of amyloid protein precursor (hereinafter designated as APP) are strongly involved in the processes of degeneration and loss of neurons and the onset of symptoms of dementia (see, for example, non-patent documents 3 and 4). Aβ proteins contain as main components Aβ40, consisting of 40 amino acids, and Aβ42, which additionally contains 2 amino acids at the C-end. It is known that Aβ40 and Aβ42 have a high aggregation ability (see, for example, non-patent document 5) and are the main components of senile plaques (see, for example, non-patent documents 5, 6 and 7). It is also known that Aβ40 and Aβ42 have a high mutation in the genes APP and presenilin, which is observed in family form of Alzheimer's disease (see, for example, non-patent documents 8, 9 and 10). Therefore, it is expected that the combination of lowering the production of Aβ40 and Aβ42, is for Alzheimer's disease inhibitor development or prophylactic agent.

Aβ is produced in the cleavage of APP by beta secretases (BACE1) and then gamma secretases. Therefore, attempts have been made to create the inhibitor is in the gamma secretase and beta secretase, in order to inhibit the production of Aβ. Already known inhibitors of beta-secretase described in the following patent documents 1-13 and non-patent documents 1 and 2, and the like. In particular, in patent document 1 describes a derived aminopiperidine and the compounds having inhibitory activity against BACE1.

Patent document 1: WO 2007/049532

Patent document 2: US 3235551

Patent document 3: US 3227713

Patent document 4: JP-A-09-067355

Patent document 5: WO 01/87293

Patent document 6: WO 04/014843

Patent document 7: JP-A-2004-149429

Patent document 8: WO 02/96897

Patent document 9: WO 04/043916

Patent document 10: WO 2005/058311

Patent document 11: WO 2005/097767

Patent document 12: WO 2006/041404

Patent document 13: WO 2006/041405

Non-patent document 1: Journal of Heterocyclic Chemistry, vol. 14, p. 717-723 (1977).

Non-patent document 2: Journal Organic Chemistry, vol. 33, p. 3126-3132 (1968).

Non-patent document 3: Klein WL, and seven others, Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests molecular basis for reversible memory loss, Proceeding National Academy of Science USA 2003, Sep 2; 100 (18), p. 10417-10422.

Non-patent document 4: Nitsch RM, and sixteen others, Antibodies against β-amyloid slow cognitive decline in Alzheimer's disease, Neuron, 2003, May 22; 38, p. 547-554.

Non-patent document 5: Jarrett JT, and two others, The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimer's disease, Biochemistry, 1993, 32 (18), p. 4693-4697.

Non-patent document is NT 6: Glenner GG, and one other, Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein, Biochemical and biophysical research communications, 1984, May 16, 120 (3), p. 885-890.

Non-patent document 7: Masters CL, and five others, Amyloid plaque core protein in Alzheimer disease and Down syndrome, Proceding National Academy of Science USA, 1985, Jun, 82 (12), p. 4245-4249.

Non-patent document 8: Gouras GK, and eleven others, Intraneuronal Aβ42 accumulation in human brain, American Journal of Pathology, 2000, Jan, 156 (1), p. 15-20.

Non-patent document 9: Scheuner D, and twenty others, Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease, Nature Medicine, 1996, Aug, 2 (8), p. 864-870.

Non-patent document 10: Forman MS, and four others, Differential effects of the swedish mutant amyloid precursor protein on β-amyloid accumulation and secretion in neurons and nonneuronal cells, The Journal of Biological Chemistry, 1997, Dec 19, 272 (51), p. 32247-32253.

Disclosure of the invention

Problems to be solved by the invention of

The aim of the present invention is to provide a condensed derived aminopiperidine, which is a compound that is different from the derived aminopiperidine and compounds having BACE1 inhibitory activity described in patent document 1, and which inhibits Aβ production or inhibits BACE1 and applicable as a preventive or therapeutic agent from calling protein Aβ neurodegenerative diseases, a typical example of which is dementia Alzheimer's, and Pharma is eticheskoe application.

In accordance with the present invention include:

[1] a Compound represented by the formula (I):

[Formula 1]

or its pharmaceutically acceptable salt or MES, where

ring A represents a C6-14aryl group, which may contain 1-3 substituent selected from the group of substituents α, 5-6-membered heteroaryl group which may contain 1-3 substituent selected from the group of substituents α, or 9-10-membered benzododecinium heterocyclic group, which may contain 1-3 substituent selected from the group of substituents α,

L represents a single bond, an oxygen atom, a group of the formula-NReCO- (where Rerepresents a hydrogen atom or a C1-6alkyl group, which may contain 1-3 substituent selected from the group of substituents α), a group of the formula-NReSO2- (where Rerepresents a hydrogen atom or a C1-6alkyl group, which may contain 1-3 substituent selected from the group of substituents α), a group of the formula-NRe- (where Rerepresents a hydrogen atom or a C1-6alkyl group, which may contain 1-3 substituent selected from the group of substituents α), C1-6alkylenes group, which may contain 1-3 substituent selected from the group of Deputy who nd α, C2-6alkynylamino group, which may contain 1-3 substituent selected from the group of substituents α, or C2-6alkynylamino group, which may contain 1-3 substituent selected from the group of substituents α,

ring B represents a C3-8cycloalkyl group, which may contain 1-3 substituent selected from the group of substituents α, C6-14aryl group, which may contain 1-3 substituent selected from the group of substituents α, or 5-10-membered heterocyclic group, which may contain 1-3 substituent selected from the group of substituents α,

X represents a single bond or C1-3alkylenes group, which may contain 1-3 substituent selected from the group of substituents α,

Y represents a single bond, -NRY- (where RYrepresents a hydrogen atom, a C1-6alkyl group, which may contain 1-3 substituent selected from the group of substituents α, C1-6alkylcarboxylic group, which may contain 1-3 substituent selected from the group of substituents α, C6-14arylcarbamoyl group, which may contain 1-3 substituent selected from the group of substituents α, C1-6alkylsulfonyl group, which may contain 1-3 substituent selected from the group of substituents α, C6-14arylsulfonyl groups who, which may contain 1-3 substituent selected from the group of substituents α, C6-14aryl group, which may contain 1-3 substituent selected from the group of substituents α, or 5-10-membered heterocyclic group, which may contain 1-3 substituent selected from the group of substituents α), an oxygen atom, a sulfur atom, sulfoxide or sulfon,

Z represents a single bond, C1-3alkylenes group, which may contain 1-3 substituent selected from the group of substituents α, or C2-3alkynylamino group, which may contain 1-3 substituent selected from the group of substituents α,

R1and R2each independently represents a hydrogen atom, a C1-6alkyl group, which may contain 1-3 substituent selected from the group of substituents α, C1-6alkylcarboxylic group, which may contain 1-3 substituent selected from the group of substituents α, C6-14arylcarbamoyl group, which may contain 1-3 substituent selected from the group of substituents α, C1-6alkylsulfonyl group, which may contain 1-3 substituent selected from the group of substituents α, C6-14arylsulfonyl group, which may contain 1-3 substituent selected from the group of substituents α, 3-10-membered carbocyclic group which may contain 1-3 will replace the La, selected from the group of substituents α, or 5-10-membered heterocyclic group, which may contain 1-3 substituent selected from the group of substituents α, and

R3, R4, R5and R6independently represent a hydrogen atom, a halogen atom, a hydroxy-group, C1-6alkyl group, which may contain 1-3 substituent selected from the group of substituents α, C1-6alkoxygroup, which may contain 1-3 substituent selected from the group of substituents α, 3-10-membered carbocyclic group which may contain 1-3 substituent selected from the group of substituents α, or 5-10-membered heterocyclic group, which may contain 1-3 substituent selected from the group of substituents α, or

R4and R6together may form a ring represented by the formula (II):

[Formula 2]

where Y, Z, R5and R3are as defined above, and Q represents an oxygen atom, methylene group or ethylene group

[the group of substituents α: a hydrogen atom, halogen atom, hydroxy-group, a nitrogroup, C1-6allylthiourea, C6-14aryl group, a C6-14aryloxyalkyl group, C6-14arylcarbamoyl group, cyano, C3-8cycloalkanes, C3-8cycloalkyl group, C3-8cycloalkyl Agrippa, sulfonylamino (where sulfonylamino may be substituted C1-6alkyl group), C2-6Alchemilla group, which may contain 1-3 substituent selected from the group of substituents β, C2-6Alchemilla group, which may contain 1-3 substituent selected from the group of substituents β, carnemolla group which may be substituted by one or two C1-6alkyl groups, C1-6alkoxygroup, which may contain 1-3 substituent selected from the group of substituents β, C1-6alkyl group which may contain 1-3 substituent selected from the group of substituents β, and a 5-10 membered heterocyclic group, which may contain 1-3 substituent selected from the group of substituents β,

the group of substituents β: halogen atom, cyano, hydroxy-group, C1-6alkoxygroup, C1-6alkyl group, a C3-8cycloalkyl group and oxoprop];

[2] the Compound or its pharmaceutically acceptable salt or MES item [1] above, where X represents a methylene, which may contain 1-2 substituent selected from the group of substituents α;

[3] the Compound or its pharmaceutically acceptable salt or MES item [1] or [2] above, where Y is a single bond and Z represents a C1-3alkylene, which may contain 1-3 replace the I, selected from the group of substituents α;

[4] the Compound or its pharmaceutically acceptable salt or MES item [1] or [2] above, where Y represents an oxygen atom and Z represents a C1-3alkylene, which may contain 1-3 substituent selected from the group of substituents α;

[5] the Compound or its pharmaceutically acceptable salt or MES item [1] or [2] above, where Y represents an oxygen atom and Z represents a single bond;

[6] the Compound or its pharmaceutically acceptable salt or MES item [1] or [2] above, where Y is-NRY- (where RYrepresents a C1-6alkyl group, which may contain 1-3 substituent selected from the group of substituents α, C1-6alkylcarboxylic group, which may contain 1-3 substituent selected from the group of substituents α, C6-14arylcarbamoyl group, which may contain 1-3 substituent selected from the group of substituents α, C6-14arylsulfonyl group, which may contain 1-3 substituent selected from the group of substituents α, C6-14aryl group, which may contain 1-3 substituent selected from the group of substituents α, or 5-10-membered heterocyclic group, which may contain 1-3 substituent selected from the group of substituents α), sulfur atom, sulfoxide isosulfan and Z represents a single bond, C1-3alkylene, which may contain 1-3 substituent selected from the group of substituents α;

[7] the Compound or its pharmaceutically acceptable salt or MES according to any one of items [1]to[6] above, where L represents a single bond, a group of the formula-NReCO- (where Rerepresents a hydrogen atom or a C1-6alkyl group, which may contain 1-3 substituent selected from the group of substituents α) or a group of the formula-NReSO2- (where Rerepresents a hydrogen atom or a C1-6alkyl group, which may contain 1-3 substituent selected from the group of substituents α);

[8] the Compound or its pharmaceutically acceptable salt or MES according to any one of items [1]to[6] above, where L represents a single bond, an oxygen atom, a C1-6alkylenes group, which may contain 1-3 substituent selected from the group of substituents α, C2-6alkynylamino group, which may contain 1-3 substituent selected from the group of substituents α, or C2-6alkynylamino group, which may contain 1-3 substituent selected from the group of substituents α;

[9] the Compound or its pharmaceutically acceptable salt or MES according to any one of items [1]to[6] above, where L represents a group of formula-NReCO- (where Rerepresents a hydrogen atom or a C1-6lilou group, which may contain 1-3 substituent selected from the group of substituents α);

[10] the Compound or its pharmaceutically acceptable salt or MES according to any one of items 1-9, which is selected from the following compounds:

1) (+)-N-{3-[(4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl]-4-forfinal}-5-chloropyridin-2-carboxamid,

2) (+)-N-{3-[(4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl]-4-forfinal}-5-chloropyridin-2-carboxamid,

3) N-{3-[(4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl]-4-forfinal}pyridine-2-carboxamide,

4) N-{3-[(4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl]-4-forfinal}-5-herperidin-2-carboxamid,

5) N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,

6) N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformatsiei-2-carboxamid,

7) N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-formatexpiry-2-carboxamid,

8) N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,

9) N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-formatexception-2-carboxamid,

10) N-[3-((4aS*,7aS*)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,

11) N-[3-(4aS*,7aS*)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformatsiei-2-carboxamid,

12) N-[3-((4aS*,7aS*)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-chloropyridin-2-carboxamid,

13) N-[3-((7S*,7aS*)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-formatexpiry-2-carboxamid,

14) N-[3-((4aS*,8aS*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,

15) N-[3-((4aS*,8aS*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-deformatsiei-2-carboxamid,

16) N-[3-((4aS*,8aS*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-chloropyridin-2-carboxamid,

17) (+)-N-[3-((4aR*,6S*,7aS*)-2-amino-6-methoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,

18) (+)-N-[3-((4aR*,6R*,7aS*)-2-amino-6-methoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,

19) (+)-N-[3-((4aR*,9aS*)-2-amino-4a,5,6,7,8,9-hexahydro-4H-cyclohepta[d][1,3]thiazin-9a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,

20) N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-methoxyphenyl]-5-chloropyridin-2-carboxamid,

21) N-[3-((4aS*,7aS*)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamid,

22) (4aR*,7aS*)-7a-[3-(2-herperidin-3-yl)phenyl]-6-phenyl-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-ylamine,

23) (4aR*,7aS*)-7a-[3-(2-herperidin-3-yl)phenyl]-6-pyrimidine-2-yl-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,]thiazin-2-ylamine,

24) N-[3-((4aS*,5R*,7aS*)-2-amino-5-methyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,

25) N-[3-((4aS*,5R*,7aS*)-2-amino-5-methyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamid,

26) N-[3-((4aS*,8aS*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-formatexpiry-2-carboxamid,

27) N-[3-((4aS*,5R*,7aS*)-2-amino-5-ethyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformatsiei-2-carboxamid,

28) N-[3-((4aS,5S,7aS)-2-amino-5-vermeil-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamid,

29) N-[3-((4aS,5S,7aS)-2-amino-5-vermeil-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-formatexpiry-2-carboxamid,

30) N-[3-((4aS*,5S*,7aS*)-2-amino-5-vermeil-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,

31) N-[3-((4aS*,5S*,8aS*)-2-amino-5-vermeil-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,

32) N-[3-((4aS*,5S*,8aS*)-2-amino-5-vermeil-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-formatexpiry-2-carboxamid,

33) N-[3-((4aS*,5S*,8aS*)-2-amino-5-vermeil-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-chloropyridin-2-carboxamid,

34) N-[3-((4aS*,6S*,7aS*)-2-amino-6-methoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carb is camid,

35) N-[3-((4aR*,6R*,7aS*)-2-amino-6-methoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamide and

36) N-[3-((4aR*,6S*,7aS*)-2-amino-6-fluoro-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamide;

[11] a Pharmaceutical composition comprising the compound or its pharmaceutically acceptable salt or MES according to any one of items [1]to[10] above as an active ingredient;

[12] the Pharmaceutical composition according to paragraph [11] above for inhibiting the production of β-amyloid protein;

[13] the Pharmaceutical composition according to paragraph [11] above for the inhibition of enzyme cleavage of beta-site of the protein precursor of β-amyloid type 1 (BACE1);

[14] the Pharmaceutical composition according to any one of items [11]to[13] above for the treatment of neurodegenerative diseases and

[15] the Pharmaceutical composition according to paragraph [14] above, where the specified neurodegenerative disease is dementia Alzheimer's disease or down's syndrome.

Further explains the meaning of the symbols, terms and the like, used in this description, and provides a detailed description of the present invention.

In this specification, the structural formula of the compound may be a suitable way to represent any isomer. However, the present invention includes all isomers and isomeric mixture, such as geometries is their isomers, which can be formed in connection with the structure of the compound, optical isomers, the formation of which is based on the presence of asymmetric carbons, stereoisomers and tautomers. The present invention is not limited to the description chosen for reasons of convenience, chemical formulas, and may include any of the isomers or a mixture thereof. Thus, the connection of the present invention may be of the molecule in the asymmetric carbon atom and can exist as optically active compound or racemate, and the present invention includes without limitation as optically active compound, and the racemate. Although there may be crystalline polymorphs connection, the connection is just not limited and may be in the form of single crystal or a mixture of single crystals. The connection may be an anhydride or a hydrate. Any of these forms are included in the claims of this specification.

"Halogen atom" in the present description refers to a fluorine atom, chlorine atom, bromine atom, iodine atom or the like, and preferably represents a fluorine atom or a chlorine atom.

"C1-6alkyl group" refers to an alkyl group containing 1-6 carbon atoms. Preferred examples of the group include unbranched or branched alkyl groups such as methyl group is and, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, tert-bucilina group, n-pencilina group, isopentyl group, neopentyl group, n-exilda group, 1-methylpropyl group, 1,2-dimethylpropylene group, 1-ethylpropyl group, 1-methyl-2-ethylpropyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 2-ethylbutyl group, 1,3-dimethylbutyl group, 2-methylpentyl group and 3-methylpentyl group. More preferably, this group is a methyl group, ethyl group or n-through the group.

"C2-6Alchemilla group" refers to alkenylphenol group containing 2-6 carbon atoms. Preferred examples of the group include unbranched or branched alkeneamine groups such as vinyl group, allyl group, 1-protanilla group, Isopropenyl group, 1-butene-1-ilen group, 1-butene-2-ilen group, 1-butene-3-ilen group, 2-butene-1-ilen group and 2-butene-2-ilen group.

"C2-6Alchemilla group" refers to alkenylphenol group containing 2-6 carbon atoms. Preferred examples of the group include unbranched or branched alkyline group, t is the cue as etinilnoy group, 1-proponila group, 2-proponila group, Butyrina group, puntinella group and hexylamine group.

"C1-6alkoxygroup" refers to an alkyl group containing 1-6 carbon atoms in which one hydrogen atom is replaced by an oxygen atom. Examples of the group include a methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, sec-butoxypropyl, tert-butoxypropyl, n-phenoxypropan, isobutoxy, sec-phenoxypropan, tert-phenoxypropan, n-hexachrome, isohexadecane, 1,2-DIMETHYLPROPANE, 2-ethylpropoxy, 1-methyl-2-ethylpropoxy, 1-ethyl-2-methylpropoxy, 1,1,2-trimethylpropyl, 1,1-Dimethylbutane, 2,2-Dimethylbutane, 2-ethylbutane, 1,3-Dimethylbutane, 2-methylphenoxy, 3-methylphenoxy and hexyloxy.

"C1-6allylthiourea" refers to an alkyl group containing 1-6 carbon atoms in which one hydrogen atom is replaced by a sulfur atom. Examples of the group include metalcorp, ethylthiourea, n-PropertyGroup, isopropylthio, n-butylthiourea, isobutylthiazole, tert-butylthiourea, n-intelligroup, isopentype, pointertype, n-vexillographer and 1-methylpropionate.

"C1-6alkylsulfonyl group" refers to an alkyl group containing 1-6 carbon atoms, in which one hydrogen atom is replaced by sulfonyloxy group. Examples of groups include methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylphenyl group, n-butylsulfonyl group, isobutylamino group, tert-butylsulfonyl group, n-pentylaniline group, isopentenyladenine group, neopentylglycol group, n-hexylaniline group and 1-methylpropylsulfonic group.

"C1-6acylcarnitine group" refers to an alkyl group containing 1-6 carbon atoms in which one hydrogen atom is replaced by a carbonyl group. Preferred examples of the group include acetyl group, propionyl group and butyryloxy group.

"C6-14aryl group" refers to an aromatic cyclic hydrocarbon group containing 6-14 carbon atoms. Examples of the group include phenyl group, naftalina group and untilnow group. Phenyl group is particularly preferred.

"C7-12kalkilya group" refers to a group containing 7 to 12 carbon atoms in which the aromatic hydrocarbon cycle, such as a phenyl group or naftalina group, substituted C1-6alkyl group. Examples of the group include benzyl group, fenetylline group, phenylpropyl group and nattily the optimum group. Benzyl group is particularly preferred.

"C6-14aryloxyalkyl group" refers to a group in which oxycarbonyl associated with aromatic hydrocarbon cyclic group containing 6-14 carbon atoms. Preferred examples of the group include phenoxycarbonyl group, naphthalocyanine group and antioxidatively group. Vinyloxycarbonyl group is more preferred.

"C6-14arylcarbamoyl group" refers to a group in which a carbonyl group linked to an aromatic hydrocarbon cyclic group containing 6-14 carbon atoms. Preferred examples of the group include benzoyloxy group and naftolin group. Benzoline group is more preferred.

"C6-14arylsulfonyl group" refers to a group in which sulfonylurea group linked to an aromatic hydrocarbon cyclic group containing 6-14 carbon atoms. Preferred examples of the group include benzosulfimide group and naphthylmethyl group. Benzolsulfonat group is more preferred.

"C3-8cycloalkyl group" refers to a cyclic alkyl group containing 3-8 carbon atoms. Preferred examples of the group include cyclopropyl group, cyclobutyl group is, cyclopentyloxy group, tsiklogeksilnogo group, cycloheptyl group and cyclooctyl group.

"C3-8cycloalkanes" refers to a cyclic alkyl group containing 3 to 8 carbon atoms in which one hydrogen atom is replaced by an oxygen atom. Examples of the group include cyclopropane, cyclobutanes, cyclopentamine, cyclohexamide, cycloheptylamine and cyclooctylamine.

"C3-8cycloalkylation" refers to a cyclic alkyl group containing 3 to 8 carbon atoms in which one hydrogen atom is replaced by a sulfur atom. Examples of the group include cyclopropylamino, cyclobutylamine, cyclopentylamine, cyclohexylprop, cycloheptylamine and cyclooctylamine.

"5-10-Membered heterocyclic group" refers to a cyclic group containing a heteroatom and having a total of 5-10 members. Preferred examples of the group include piperidinyloxy group, pyrrolidinyl group, sepanlou group, atenilol group, piperazinilnom group, 1,4-diazepino group, morpholinyl group, thiomorpholine group, pyrrolidino group, imidazolidinyl group, pyrazolidine group, pyridinyl group, pyridazinyl group, pyrimidinyl group, personilnya group, triazolyl group, triazinyl group tetrazolyl group, isoxazolyl group, oxazolidinyl group, oxadiazolyl group, isothiazolinone group, thiazolidine group, thiadiazolyl group, follow group, thienyl group, hyalinella group, athinodorou group, benzofuranyl group, benzopyranyl group, benzimidazolyl group, benzothiazolyl group, benzisothiazolinone group, indolinyl group, isoindolyl group, romanello group, isopropanolol group, 1,3-dioxindole group and 1,4-doxytetracycline group.

"5-6-Membered heteroaryl group" refers to the "5-to 10-membered heterocyclic group", which is an aromatic cyclic group containing a heteroatom and having a total of 5-6 members. Examples of groups include pyrrolidinyl group, imidazolidinyl group, pyrazolidine group, pyridinyl group, pyridazinyl group, pyrimidinyl group, personilnya group, triazolyl group, triazinyl group, tetrazolyl group, isoxazolyl group, oxazolidinyl group, oxadiazolyl group, isothiazolinone group, thiazolidine group, thiadiazolyl group, follow group and thienyl group.

"9-10-Membered benzododecinium heterocyclic group" refers to the "5-to 10-membered heterocyclic group", which is a cyclic group, includes the soup of the heteroatom and having a total of 9-10 members, condensed with a benzene ring. Preferred examples of the group include indolinyl group, isoindolyl group, romanello group, isopropanolol group, 1,3-dioxindole group and 1,4-doxytetracycline group.

"3-10-Membered carbocyclic group" refers to a carbocyclic group having a total of 3-10 members. Preferred examples of the group include cyclopropyl group, cyclobutyl group, cyclopentyl group, tsiklogeksilnogo group, cycloheptyl group, cyclooctyl group, Spiro[3,4]octanediol group, deganello group, indenolol group, 1-acenaphthylene group, Cyclopentasiloxane group, benzocyclobutene group, indenolol group, tetrahydronaphthyl group, 6,7,8,9-tetrahydro-5H-benzocycloheptene group and 1,4-dihydronaphthalene group.

"C1-6Allenova group" refers to a divalent group obtained by removing any one hydrogen atom from C1-6alkyl group"defined above. Examples of the group include methylene group, 1,2-ethylene group, 1,1-ethylene group, 1,3-propylene group, tetramethylene group, pentamethylene group and hexamethylene group.

"C2-6alkenylamine group" refers to a divalent group obtained by removing any one atom bodoro is and "C 2-6alkenylphenol group"defined above. Examples of groups include 1,2-vanilinovoi group (ethenylene group), propenylidene group, butenylamine group, pentesilea group and hexadecanoyl group.

"C2-6akinlana group" refers to a divalent group obtained by removing any one hydrogen atom from C2-6alkenylphenol group"defined above. Examples of groups include ethynylene group, propylene group, butilyenov group, pentylindol group and hexylamino group.

Examples of "C1-3alkalinous group include methylene group, ethylene group and propylene group.

Examples of "C2-3alkenylamine groups include 1,2-vanilinovoi group (atenololbuy group) and propenylidene group.

Examples of "C2-3alkynylamino group" include ethynylene group and propylene group.

Examples of sulfonylamino, which may be substituted C1-6the alkyl group in sulfonylamino (where sulfonylamino may be substituted C1-6alkyl group)"include methylsulfonylamino, arilsulfonilglitsinov and ethylsulfonylimidazo.

"The group of substituents α" refers to a hydrogen atom, halogen atom, hydroxy-group, a nitrogroup, C1-6allylthiourea, C6-14ariline the group, C6-14aryloxyalkyl group, C6-14arylcarbamoyl group, cyano, C3-8cycloalkene, C3-8cycloalkyl group, C3-8cycloalkylation, sulfonylamino (where sulfonylamino may be substituted C1-6alkyl group), C2-6alkenylphenol group, which may contain 1-3 substituent selected from the group of substituents β, C2-6alkenylphenol group, which may contain 1-3 substituent selected from the group of substituents β, carbamoyl group which may be substituted by one or two C1-6alkyl groups, C1-6alkoxygroup, which may contain 1-3 substituent selected from the group of substituents β, C1-6alkyl group, which may contain 1-3 substituent selected from the group of substituents β, and a 5-10 membered heterocyclic group, which may contain 1-3 substituent selected from the group of substituents β.

"The group of substituents β" refers to a halogen atom, a cyano, a hydroxy-group, C1-6alkoxygroup, C1-6alkyl group, a C3-8cycloalkyl group and oxoprop.

Condensed derived aminopiperidine formula (I) in accordance with the present invention may be a pharmaceutically acceptable salt. Specific examples of pharmaceutically acceptable the th salts include inorganic salts (such as sulfates, nitrates, perchlorates, phosphates, carbonates, bicarbonates, hydrohloride, hydrochloride, hydrobromide and hydroiodide), organic carboxylates (such as acetates, oxalates, maleate, tartratami, fumarate and citrate), organic sulfonates (such as methanesulfonate, triftoratsetata, econsultancy, bansilalpet, toluensulfonate and camphorsulfonate), salt, amino acids (such as aspartate and glutamate), salts of Quaternary amines, alkali metal salts (such as sodium salts and potassium salts), and salts of alkaline earth metals (such as magnesium salt and calcium salt).

Condensed derived aminopiperidine formula (I) or pharmaceutically acceptable salt according to the present invention may be a MES. Examples of MES include hydrate.

The compound (I) is not limited to a specific isomer, and includes all possible isomers (such as keto-enol isomer, Imin-adaminaby isomer, diastereoisomer, optical isomer and rotamer) and racemates. For example, the compound (I), where R1represents hydrogen, includes the following tautomers.

[Formula 3]

Condensed derived aminopiperidine formula (I) according to the present invention preferably is a compound of formula (I), where X represents a methylene which could contain 1-2 substituent, selected from the group of substituents α. The compound of formula (I), where Y is a single bond and Z represents a C1-3alkylene, which may contain 1-3 substituent selected from the group of substituents α; where Y represents an oxygen atom and Z represents a C1-3alkylene, which may contain 1-3 substituent selected from the group of substituents α; or where Y represents an oxygen atom and Z represents a single bond is particularly preferred.

Condensed derived aminopiperidine formula (I) according to the present invention preferably is a compound of formula (I), where L represents a single bond, a group of the formula-NReCO- (where Rerepresents a hydrogen atom or a C1-6alkyl group, which may contain 1-3 substituent selected from the group of substituents α) or a group of the formula-NReSO2- (where Rerepresents a hydrogen atom or a C1-6alkyl group, which may contain 1-3 substituent selected from the group of substituents α) or where L represents a single bond, an oxygen atom, a C1-6alkylenes group, which may contain 1-3 substituent selected from the group of substituents α, C2-6alkynylamino group, which may contain 1-3 substituent selected from gruppesamtale α, or C2-6alkynylamino group, which may contain 1-3 substituent selected from the group of substituents α. Connection, where L represents a group of formula-NReCO- (where Rerepresents a hydrogen atom or a C1-6alkyl group, which may contain 1-3 substituent selected from the group of substituents α), is especially preferred.

Preferred compounds of the present invention include the following compounds:

1) (+)-N-{3-[(4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl]-4-forfinal}-5-chloropyridin-2-carboxamid,

2) (+)-N-{3-[(4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl]-4-forfinal}-5-chloropyridin-2-carboxamid,

3) N-{3-[(4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl]-4-forfinal}pyridine-2-carboxamide,

4) N-{3-[(4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl]-4-forfinal}-5-herperidin-2-carboxamid,

5) N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,

6) N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformatsiei-2-carboxamid,

7) N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-formatexpiry-2-carboxamid,

8) N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-canop ridin-2-carboxamid,

9) N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-formatexception-2-carboxamid,

10) N-[3-((4aS*,7aS*)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,

11) N-[3-((4aS*,7aS*)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformatsiei-2-carboxamid,

12) N-[3-((4aS*,7aS*)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-chloropyridin-2-carboxamid,

13) N-[3-((7S*,7aS*)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-formatexpiry-2-carboxamid,

14) N-[3-((4aS*,8aS*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,

15) N-[3-((4aS*,8aS*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-deformatsiei-2-carboxamid,

16) N-[3-((4aS*,8aS*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-chloropyridin-2-carboxamid,

17) (+)-N-[3-((4aR*,6S*,7aS*)-2-amino-6-methoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,

18) (+)-N-[3-((4aR*,6R*,7aS*)-2-amino-6-methoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,

19) (+)-N-[3-((4aR*,9aS*)-2-amino-4a,5,6,7,8,9-hexahydro-4H-cyclohepta[d][1,3]thiazin-9a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,

20) N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-methoxyp the Nile]-5-chloropyridin-2-carboxamid,

21) N-[3-((4aS*,7aS*)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamid,

22) (4aR*,7aS*)-7a-[3-(2-herperidin-3-yl)phenyl]-6-phenyl-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-ylamine,

23) (4aR*,7aS*)-7a-[3-(2-herperidin-3-yl)phenyl]-6-pyrimidine-2-yl-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-ylamine,

24) N-[3-((4aS*,5R*,7aS*)-2-amino-5-ethyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,

25) N-[3-((4aS*,5R*,7aS*)-2-amino-5-ethyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamid,

26) N-[3-((4aS*,8aS*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-formatexpiry-2-carboxamid,

27) N-[3-((4aS*,5R*,7aS*)-2-amino-5-ethyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformatsiei-2-carboxamid,

28) N-[3-((4aS,5S,7aS)-2-amino-5-vermeil-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamid,

29) N-[3-((4aS,5S,7aS)-2-amino-5-vermeil-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-formatexpiry-2-carboxamid,

30) N-[3-((4aS*,5S*,7aS*)-2-amino-5-vermeil-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,

31) N-[3-((4aS*,5S*,8aS*)-2-amino-5-vermeil-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,

32) N-[3-((4aS*,5S*,8aS*)-2-amino-5-vermeil-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-AZ the naphthalene-8a-yl)-4-forfinal]-5-formatexpiry-2-carboxamid,

33) N-[3-((4aS*,5S*,8aS*)-2-amino-5-vermeil-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-chloropyridin-2-carboxamid,

34) N-[3-((4aS*,6S*,7aS*)-2-amino-6-methoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamid,

35) N-[3-((4aR*,6R*,7aS*)-2-amino-6-methoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamide and

36) N-[3-((4aR*,6S*,7aS*)-2-amino-6-fluoro-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamide.

The following describes methods for obtaining the compounds of formula (I) [hereinafter referred to as compound (I); a compound represented by a formula described in the same way] or its pharmaceutically acceptable salt according to the present invention.

The compound represented by formula (I):

[Formula 4]

(where the ring A, ring B, R1, R2, R3, R4, R5, R6, L, X, Y, and Z are as defined above), or an intermediate compound synthesized, for example, General methods of obtaining 1-15 described below.

"Leaving group" in the initial compound used for obtaining the compound (I) of the present invention, can be any leaving group that is used for the reaction of nucleophilic substitution. Preferred examples of the ear is of the present group include a halogen atom, C1-6alkylsulfonates, which can be substituted for the above group of substituents α, and arylsulfonate, which can be substituted for the above group of substituents α. Specific examples of leaving groups include chlorine atom, bromine atom, iodine atom, methysulfonylmethane, triftormetilfullerenov and p-toluensulfonate.

1.A common way of obtaining 1:

[Formula 5]

In this diagram, R7represents a C1-6alkyl group such as methyl group or ethyl group, a C7-12aracelio group such as benzyl group, or the like, LV is a leaving group and represents, for example, halogen atom (such as chlorine atom, bromine atom or iodine atom), for example, or sulfonyloxy, such as methanesulfonamido, p-toluensulfonate or triftormetilfullerenov (represented in the diagram as TfO), and ring A, R3, R4, R5, R6, Y and Z are as defined above.

A common way of obtaining 1 is a method of obtaining compound (1-7), which is an intermediate compound in the synthesis of compounds (I) of the present invention, obtained from the compound (1-1) as the source substance by conducting several is tady from stages 1-1 to the stage 1-6.

The compound (1-1) can be a commercially available product used as it is, can also be obtained from a commercially available product by a method known to a person skilled in the art and, in addition, can be obtained by the method described in the examples get in the "Examples"section.

Stage 1-1:

This stage is the stage of obtaining the compound (1-2) triftormetilfullerenov compounds (1-1).

The reaction at this stage can be carried out under the same conditions, which are usually used in the reaction of triftormetilfullerenov carbonyl compounds (such as the conditions described in J. Org. Chem., 57, 6972-6975 (1992), Tetrahedron Letters., 40, 8133-8136 (1999) and Tetrahedron., 61, 4128-4140 (2005)).

In particular, the compound (1-2) can be obtained by the action of base on the compound (1-1), and then by the interaction of the compounds, for example, N-phenyltrichlorosilane or triftormetilfullerenov anhydride. This reaction can be carried out by one or more equivalents of base to compound (1-1) in an organic solvent, such as, for example, a simple ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, benzene or toluene. Examples of the base include sodium hydride, LDA (diisopropylamide lithium), bis(trimethylsilyl)amide lithium, diisopropylate the amine, pyridine and 2,6-lutidine. The reaction time is not particularly limited, and it is usually from 5 minutes to 24 hours, preferably from 5 minutes to 12 hours. The reaction temperature is usually from -100°C to room temperature, and more preferably from -78°C to room temperature.

Stage 1-2:

This stage is the stage of obtaining the compound (1-3) by the reaction of a combination of compound (1-2) using a transition metal.

This reaction can be carried out under the conditions normally used in the reaction combinations using a transition metal (such as a Suzuki reaction-Miyaura or response style).

Examples of reactions using organoboron reagent as the ORGANOMETALLIC compound include a reaction that is described in documents such as Tetrahedron: Asymmetry 16 (2005) 2, 528-539 and Org. Lett. 6 (2004) 2, 277-279. Examples of reactions using ORGANOTIN reagent include the reaction described in this document, as Tetrahedron 61 (2005) 16, 4128-4140. Examples of reactions using tsinkorganicheskih reagent as the ORGANOMETALLIC compound include a reaction that is described in this document, as Tetrahedron 61 (2005) 16, 4128-4140. ORGANOMETALLIC catalyst used in this reaction are not particularly limited. Preferable examples of the ORGANOMETALLIC catalyst include tetrakis(trifinio the fin)palladium(0), dichlorobis(triphenylphosphine)palladium(II)dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II), bis(tert-butylphosphine)palladium(0), palladium(II) acetate and [1,3-bis(diphenylphosphino)propane]Nickel(II). The amount of the ORGANOMETALLIC catalyst is about 0.001 to 0.1 equivalent with respect to the original substances. ORGANOMETALLIC compound is not particularly limited. Preferable examples of the ORGANOMETALLIC compound include ORGANOTIN reagents, such as aritri-n-botillo, and organoboron reagents, such as arylboronic acid. The amount of ORGANOMETALLIC compound is one to five equivalents relative to the original substances. The solvent used in this reaction is not particularly limited, but he would not slow down the reaction. Preferred examples of the solvent include benzene, toluene, xylene, N,N-dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, 1,4-dioxane, acetonitrile and propionitrile. The reaction temperature is not particularly limited, and it usually is, for example, within the temperature cooling with ice to the boiling point of the solvent under reflux, and preferably from room temperature to the boiling point of the solvent under reflux. The reaction time is not particularly limited, and it is about the commonly from 0.5 to 48 hours, preferably from 0.5 to 24 hours.

Better result, such as increased output can be achieved by the implementation of this reaction in the presence of a base. Such a base is not particularly limited. Preferred examples of the base include such bases as sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate and their solutions, and triethylamine.

Stage 1-3:

This stage is the stage of obtaining alcohol compounds (1-4) by restoring the ester compounds (1-3). Alcohol compound (1-4) can be obtained from the ester compound (1-3) in a manner known to a person skilled in the technical field.

Examples of the reducing agent used in this reaction include alumoweld lithium borohydride lithium and diisobutylaluminum. The reaction temperature is not particularly limited, and it is usually in the range from -78°C to the boiling point of the solvent under reflux, and preferably from -78°C to room temperature. The solvent used in this reaction is not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. Preferred examples of the solvent include tetrahydrofuran, diethyl ether, toluene and dichloromethane.

Stage 1-4:

This stage is the stage of obtaining the compound (1-5) by converting the hydroxyl group of the compound (1-4) in the stretching group.

Examples of leaving groups include halogen atoms (such as chlorine atom, bromine atom and iodine atom) and sulfonyloxy, such as methanesulfonamido, p-toluensulfonate and triftormetilfullerenov.

The reaction can be carried out under the same conditions, which are usually used in the reaction for the conversion of the hydroxyl group in such a leaving group. If the leaving group is a halogen atom, the compound (1-5) can be obtained by reacting compound (1-4), for example, thionyl chloride, tierbroker, tribromide phosphorus or tetrachloroethylthio. The solvent used in this reaction is not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. Preferred examples of the solvent include benzene, toluene, xylene, dichloromethane and chloroform. The reaction temperature is usually in the range from -78°C to the boiling point of the solvent under reflux, and preferably the temperature of the cooling with ice to the boiling point of the solvent under reflux. The reaction time is not particularly limited, and it is usually from 5 minutes to 48 hours, preferably from 5 minutes to 12 hours.

If the leaving group is sulfonyloxy, that is EDINENIE (1-5) can be obtained by reacting compound (1-4), for example, methanesulfonamido, p-toluensulfonate or triftormetilfullerenov anhydride.

The solvent used in this reaction is not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. Preferred examples of the solvent include tetrahydrofuran, toluene, xylene, dichloromethane, chloroform, and N,N-dimethylformamide. The reaction temperature is usually in the range from -78°C to the boiling point of the solvent under reflux, and preferably from -78°C to room temperature. A positive result, such as increased output can be achieved by adding a base. Used the base is not particularly limited, if only it didn't slow the reaction. Preferred examples of the base include sodium carbonate, potassium carbonate, triethylamine, pyridine and diisopropylethylamine.

Stage 1-5:

This stage is the stage of obtaining compounds (1-6) from the compound (1-5). Derived thiourea (1-6) can be obtained from the compounds (1-5) in a manner known to a person skilled in the technical field.

In particular, the compound (1-6) can be obtained, for example, by reacting the compound (1-5) with thiourea in a solvent. This reaction can be carried out by one or more EC is ivalent thiourea on the compound (1-5) in an organic solvent, such as, for example, ethanol, 1-propanol, 2-propanol, 1-butanol, tetrahydrofuran, 1,4-dioxane or N,N-dimethylformamide. The reaction time is not particularly limited, and it is usually from 5 minutes to 24 hours, preferably from 5 minutes to 12 hours. The reaction temperature is usually in the range from 0°C to 150°C, and more preferably from room temperature to 100°C.

Stage 1-6:

This stage is a method of obtaining compound (1-7) by cyclization of compound (1-6) acid.

The reaction solution is not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. For example, the reaction may be carried out by the action of a suitable acid in an amount of one equivalent to a large excess of the compound (1-6) in the presence or in the absence of a solvent, such as benzene, toluene or dichloromethane. In addition, the acid can also be used as solvent. Examples of the acid include sulfuric acid, triperoxonane acid, methanesulfonate acid, triftormetilfullerenov acid and mixtures thereof. The reaction time is not particularly limited, and it is usually from 1 to 72 hours, preferably from 1 to 48 hours. The reaction temperature is usually in the range of temperature cooling with ice to a temperature of the boiling process is Italia under reflux.

The amino group in the compound (1-7) can be converted to the appropriate group-NR1R2in the formula (I)in which R1and R2are substituted, an additional interaction of the compound (1-7) with a corresponding halide or the like, such as C1-6alkylhalogenide, C1-6alkylhalogenide, C6-14arylcarboxamide, C1-6alkylsulfonate, C6-14arylsulfonate, 3-10-membered carbocyclic halide or a 5-10 membered heterocyclic halide.

2.A common way to obtain 2:

Method 2A:

[Formula 6]

In this diagram, ring A, R3, R4, R5, R6, Y and Z are as defined above.

A common way to obtain 2 consists of the above method 2A and method described below, 2B. Method 2A is a method of obtaining compounds of General formula (1-4), which is an intermediate compound in the synthesis of compounds (I) of the present invention, obtained from the compound (2-1) as the source substance by conducting several stages from stage 2A-1 to stage 2A-3.

The compound (2-1) may be commercially available product used as it is, can also be obtained from a commercially available product by a method known to the expert in question is the field of technology, and, in addition, can be obtained by the method described in the examples get in the "Examples"section.

Stage 2A-1:

This stage is the stage of obtaining the compound (2-2) from the compound (2-1). This reaction can be carried out under the same conditions, which are usually used in the synthesis reaction of the compound (2-2) of carbonyl compounds (such as the conditions described in J. Org. Chem., 47, 3597-3607 (1982)).

Stage 2A-2:

This stage is the stage of synthesizing the compound (2-3) from the compound (2-2) as the original substances using the production method, described above (stage 1-2).

Stage 2A-3:

This stage is the stage of obtaining alcohol compounds (1-4) recovery of the aldehyde compound (2-3).

Alcohol compound (1-4) can be obtained from the aldehyde compound (2-3) in a manner known to a person skilled in the art. Examples of the reducing agent used in this reaction include sodium borohydride, cyanoborohydride sodium and triacetoxyborohydride sodium. The reaction temperature is not particularly limited, and it is usually in the range from -78°C to the boiling point of the solvent under reflux, and preferably from -20°C to room temperature. The solvent used in this reaction is not particularly limited, but he would not have slowed down the reaction and allow what was the original substance dissolved therein to a certain extent. Preferred examples of the solvent include methanol, ethanol, tetrahydrofuran, simple ether, toluene and dichloromethane.

Method 2B:

[Formula 7]

In this diagram, ring A, R3, R4, R5, R6, R7, Y and Z are as defined above.

As described above in method 2B, the compound (1-4) can also be obtained by converting compound (1-3) in the compound (2-4) and the recovery of the compounds.

The compound (1-3) can be obtained from the commercially available product of the General method of obtaining 1 can also be obtained by the method described in the examples get in the "Examples"section.

Stage 2B-1:

This stage is the stage of obtaining the compound (2-4) alkaline hydrolysis of the compound (1-3).

The reaction can be carried out under the same reaction conditions, which are described, for example, in J. Med. Chem., 33 (9), 2621-2629 (1990).

In particular, the compound (2-4) can be obtained by adding a base such as sodium hydroxide, to a solution of compound (1-3), stirring the mixture for several hours to one day and then the processing solution of acid, such as, for example, a solution of acetic acid.

The solvent used in this reaction is not particularly limited, but he would not slow down the reaction and allowed the original substance of rest ratesa it to a certain extent. Examples of the solvent include methanol, ethanol, 2-propanol, tetrahydrofuran and 1,4-dioxane. Used the base is not particularly limited, and preferably it represents, for example, sodium hydroxide, potassium hydroxide or lithium hydroxide. The amount of base is from one equivalent to a large excess and preferably 1 to 20 equivalents relative to the compound (1-3). The reaction time is not particularly limited, and it is usually 1 to 24 hours, preferably 1-6 hours. The reaction temperature is not particularly limited, and it is usually in the range from room temperature to the boiling point of the solvent under reflux.

Stage 2B-2:

This stage is the stage of obtaining compounds (1-4) reconnection (2-4).

The compound (1-4) can be obtained by converting compound (2-4) in a mixed acid anhydride and then the interaction of the mixed acid anhydride with sodium borohydride. The mixed acid anhydride can be synthesized by a method known to a person skilled in the art. The synthesis is accomplished by the interaction of the compound (2-4) with CHLOROFORMATES, such as ethylchloride, in the presence of a base, such as, for example, triethylamine. Use one to two equivalent chloroformiate and the base relative to the compound (2-4). the reaction temperature ranges from -30°C to room temperature, preferably from -20°C to room temperature.

Stage of the interaction between the mixed anhydride of the acid with a reducing agent such as sodium borohydride, is performed, for example, by reaction in a solvent such as tetrahydrofuran or 1,2-dimethoxyethane, or in the mixed solution of the solvent and water. A reducing agent such as sodium borohydride is used in an amount of one equivalent to a large excess relative to the mixed anhydride of the acid.

The reaction time is not particularly limited, and it is usually from 0.5 to 48 hours, preferably from 0.5 to 24 hours. The reaction temperature is not particularly limited, and it is usually in the range from -78°C to the boiling point of the solvent under reflux, and preferably from -20°C to room temperature. The solvent used in this reaction is not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. Preferred examples of the solvent include tetrahydrofuran and simple ether.

3.A common method of obtaining 3:

[Formula 8]

In this diagram, ring A, R1, R2, R3, R4, R5, R6X, Y, Z and ring B are as defined above.

General method for the preparation of 3 represents a method of obtaining connection is in the General formula (I) according to the present invention, where L represents-NHCO -, and R1and R2represent hydrogen atoms from the compound (3-1) as the source substance by conducting several stages from stage 3-1 to stage 3-4.

The compound (3-1) can be obtained from the commercially available product of the above described General method of obtaining 1 or a combination of three ways: a General method of obtaining 1, a General method of obtaining 2 and common way of getting 4, and can also be obtained by the method described in the examples get in the "Examples"section. Each of the compounds (3-4) and (3-5) may be commercially available product used as it is, can also be obtained from a commercially available product by a method known to a person skilled in the art and, in addition, can be obtained by the method described in the examples get in the "Examples"section.

Stage 3-1:

This stage is the stage of obtaining the compound (3-2) tert-butoxycarbonylamino amino group of compound (3-1), when R1and R2both represent hydrogen.

The reaction can be carried out under the same conditions, which is usually used in tert-butoxycarbonylamino of amino compounds, such as the conditions described in this document such as T. W. Green and P. G. M. Wuts, "Protective Groups in Organic Chemistry, Second Edition", John Wiley & Sons (1991), p. 327-330. The compound (3-2) mo is et to be obtained, for example, by reacting the compound (3-1) with di-tert-BUTYLCARBAMATE using triethylamine as a base in a solvent such as tetrahydrofuran.

Stage 3-2:

This stage is the stage of obtaining the compound (3-3) from the compound (3-2).

The compound (3-3) synthesize the restoration of nitrocompounds (3-2) method of synthesis known to a person skilled in the art. Examples of the method include restoration by catalytic hydrogenation using a catalyst based on a noble metal such as Raney Nickel, palladium, ruthenium, rhodium or platinum. In this case, it is preferable, for example, the reduction of iron in neutral conditions using ammonium chloride.

Stage 3-3:

This stage is the stage of obtaining the compound (3-6) condensation of the compound (3-3) with compound (3-4) using a condensing agent. Alternatively, this stage is the stage of obtaining the compound (3-6) condensation of the compound (3-3) with compound (3-5) by carrying out the acylation reaction.

The condensation reaction of the compound (3-3) with compound (3-4) using a condensing agent may be carried out under the same conditions as commonly used conditions are described in the following documents. Examples of known SP is soba include examples, described by Rosowsky, A.; Forsch, R. A.; Moran, R. G.; Freisheim, J. H.; J. Med. Chem., 34 (1), 227-234 (1991), Brzostwska, M.; Brossi, A.; Flippen-Anderson, J. L.; Heterocycles, 32 (10), 1968-1972 (1991), and Romero, D. L.; Morge, R. A.; Biles, C.; Berrios-Pena, N.; May, P. D.; Palmer, J. R.; Johnson, P. D.; Smith, H. W.; Busso, M.; Tan, C.-K.; Voorman, R. L.; Reusser, F.; Althaus, I. W.; Downey, K. M.; So, A. G.; Resnick, L.; Tarpley, W. G., Aristoff, P. A.; J. Med. Chem., 37 (7), 998-1014 (1994).

The compound (3-3) can be a free form or salt.

The solvent in this reaction is not particularly limited, but he would not slow down the reaction. Examples of the solvent include tetrahydrofuran, 1,4-dioxane, ethyl acetate, methyl acetate, dichloromethane, chloroform, N,N-dimethylformamide, toluene and xylene. Examples of the condensing agent include CDI (N,N'-carbonyldiimidazole), Bop (hexaphosphate 1H-1,2,3-benzotriazol-1 iloxi(three(dimethylamino))phosphonium), WSC (hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), DCC (N,N-dicyclohexylcarbodiimide), diethylphosphoramidite, PyBOP (hexaphosphate benzotriazol-1-yloxytris(pyrrolidino)phosphonium) and EDC·HCl (hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide). The compound (3-4) is used in an amount of one equivalent to a large excess relative to the compound (3-3). If necessary, may be added an organic base, such as triethylamine, in an amount of one equivalent to a large excess.

The reaction time is not particularly limited, and it is usually from 0.5 to 48 hours, preferably from 0.5 to 24 hours. The reaction temperature varies according to whether the starting material, solvent and the like, and its not particularly limited. Preferred is a temperature within the temperature cooling with ice to the boiling point of the solvent under reflux.

The compound of formula (I) according to the present invention, where at least one of R1and R2represents a C1-6alkyl group, which may contain 1-3 substituent selected from the group of substituents α, C1-6alkylcarboxylic group, which may contain 1-3 substituent selected from the group of substituents α, C6-14arylcarbamoyl group, which may contain 1-3 substituent selected from the group of substituents α, C1-6alkylsulfonyl group, which may contain 1-3 substituent selected from the group of substituents α, C6-14arylsulfonyl group, which may contain 1-3 substituent selected from the group of substituents α, 3-10-membered carbocyclic group which may contain 1-3 substituent selected from the group of substituents α, or 5-10-membered heterocyclic group, which may contain 1-3 substituent selected from the group of substituents α, can be obtained by the additional interaction of the compound (I-a)obtained by the General method of obtaining 3 compliance is adequate by halogen, such as C1-6alkylhalogenide.

Alternatively, a group-NHCO - group L in the compound (I-a) according to the present invention can be transformed into the group-NReCO- (where Rerepresents a C1-6alkyl group, which may contain 1-3 substituent selected from the group of substituents α) additional interaction of the compound (I-a)obtained by the General method for the preparation of 3, with a corresponding halide, such as C1-6alkylhalogenide.

The compound of formula (I) according to the present invention, where L represents-NReSO2-can be obtained using the corresponding sulphonylchloride instead of the compound (3-4) or (3-5)used in the General method of obtaining 3.

In a General method of obtaining 3 connection (3-6) can also be obtained from compound (3-3) (3-4) in the manner described in the following alternative method (1) or (2).

An alternative method (1):

The compound (3-6) can be obtained by converting compound (3-4) in a mixed acid anhydride and then the interaction of the mixed acid anhydride with the compound (3-3). The mixed acid anhydride can be synthesized by methods known to the person skilled in the art. The synthesis is performed, for example, by reacting the compound (3-4) CHLOROFORMATES, such as ethylchloride, Pris the accordance of the base, such as triethylamine. Use one to two equivalent chloroformiate and the base relative to the compound (3-4). The reaction temperature ranges from -30°C to room temperature, preferably from -20°C to room temperature.

The stage of condensation of the mixed acid anhydride with the compound (3-3) is performed, for example, by reacting the mixed acid anhydride with the compound (3-3) in a solvent such as dichloromethane, tetrahydrofuran or N,N-dimethylformamide. The compound (3-3) is used in an amount of one equivalent to a large excess relative to the mixed anhydride of the acid.

The reaction time is not particularly limited, and it is usually from 0.5 to 48 hours, preferably from 0.5 to 12 hours. The reaction temperature ranges from -20°C to 50°C and preferably from -20°C to room temperature.

An alternative method (2):

The compound (3-6) can be obtained by converting compound (3-4) in the activated ester and then the interaction of the activated complex ester with the compound (3-3). Stage produce an activated complex ester is performed, for example, by reacting the compound (3-4) with an activating reagent for the synthesis of ester in a solvent such as 1,4-dioxane, tetrahydrofuran or N,N-dimethylformamide, in the presence of a condensing agent such as DCC. An example of the activating reagent for the synthesis of ester include N-hydroxysuccinimide. Use one to 1.5 equivalents of an activating reagent for the synthesis of ester and condensing agent relative to the compound (3-4). The reaction time is not particularly limited, and it is usually from 0.5 to 48 hours, preferably from 0.5 to 24 hours.

The reaction temperature ranges from -20°C to 50°C, preferably from -20°C to room temperature.

The stage of condensation of the activated complex ester with the compound (3-3) is performed, for example, by reacting an activated complex with ether compound (3-3) in a solvent such as dichloromethane, tetrahydrofuran or N,N-dimethylformamide. The compound (3-3) is used in an amount of one equivalent to a large excess relative to the activated complex ester. The reaction time is not particularly limited, and it is usually from 0.5 to 48 hours, preferably from 0.5 to 24 hours. The reaction temperature ranges from -20°C to 50°C, preferably from -20°C to room temperature.

In this reaction, acylation of the compound (3-6) can be obtained from compounds (3-3) and (3-5) in a manner known to a person skilled in the technical field.

Examples of the base used in this reaction include triethylamine, pyridine, potassium carbonate and diisopropylethylamine. The reaction temperature is not particularly limited, and it is usually in the range from -78°C to the temperature to the singing of the solvent under reflux, and preferably from -20°C to room temperature. The solvent used in this reaction is not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. Preferred examples of the solvent include tetrahydrofuran, simple ether, toluene and dichloromethane.

Stage 3-4:

This stage is the stage of obtaining the compound (I-a) conducting a reaction of removal of the tert-butoxycarbonyl protective group of the compound (3-6).

The reaction can be carried out under the same conditions, which are usually used in the reaction, removal of the tert-butoxycarbonyl protective groups, such as the conditions described in this document such as T. W. Green and P. G. M. Wuts, "Protective Groups in Organic Chemistry, Second Edition", John Wiley & Sons (1991), p. 327-330. The compound (I-a) can be obtained, for example, by reacting triperoxonane acid with the compound (3-6) in a solvent such as dichloromethane.

4.A common way to obtain 4:

[Formula 9]

In this diagram, ring A, R1, R2, R3, R4, R5, R6X, Y and Z are as defined above.

General method 4 is a method of obtaining compounds of General formula (3-1), which is an intermediate compound in the synthesis of compounds of the present invention and COI the box is used in a General way to obtain 3, obtained from compound (4-1) as the source material stage 4-1.

The compound (4-1) can be obtained from the commercially available product of the General method of obtaining 1, the General method of obtaining 5 or a combination of the common way obtain a 1 and a common method of obtaining 2 and can also be obtained by the method described in the examples get in the "Examples"section.

Stage 4-1:

This stage is the stage of obtaining the compounds (3-1) by the reaction of nitration of the compound (4-1). In this reaction nitration of the compound (3-1) can be obtained from the compounds (4-1) by a method known to a person skilled in the art. Examples nitrouse agent used in this reaction include a mixture of potassium nitrate/sulfuric acid and fuming nitric acid/acetic anhydride. The reaction temperature is not particularly limited, and it is usually from -20°C to room temperature.

5.A common way to obtain 5:

[Formula 10]

This diagram Prt represents a protective group, such as benzoline group, acetyl group or 8-fluorenylmethoxycarbonyl group (Fmoc group), and ring A, R3, R4, R5, R6, Y and Z are as defined above.

A common way of obtaining 5 represents a method of obtaining compound (1-7, which is an intermediate compound in the synthesis of compounds (I) of the present invention, obtained from the compound (5-1) as the source substance by conducting several stages from stage 5-1 to the stage 5-7.

The compound (5-1) can be obtained from the commercially available product of the following common way of getting 6 or 7, can also be obtained from a commercially available product by a method known to a person skilled in the art and, in addition, can be obtained by the method described in the examples get in the "Examples"section.

Stage 5-1:

This stage is the stage of obtaining the compound (5-2) aksamitowana compounds (5-1).

The reaction at this stage can be carried out under the same conditions, which are usually used in the reaction of oxymorphine carbonyl compounds, such as the conditions described in Org. Lett. 9 (2007) 5, 753-756, Tetrahedron: Asymmetry 5 (1994) 6, 1018-1028 and Tetrahedron 54 (1998) 22, 5868-5882.

In particular, the compound (5-2) can be obtained, for example, by reacting the compound (5-1) with hydroxylamine or hydroxylamine salt such as hydroxylamine hydrochloride or hydroxylamine sulfate) in the presence of a base or without base.

The solvent used in this reaction is not particularly limited, but he would not slow down the reaction. Preferred examples dissolve the El include organic solvents, such as ethanol, methanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and dichloromethane, and mixtures of these solvents and water. Examples of the base include sodium acetate, pyridine, sodium hydroxide, cesium hydroxide, barium hydroxide and 2,6-lutidine. The reaction time is not particularly limited, and it is usually from 5 minutes to 24 hours, preferably from 5 minutes to 12 hours. The reaction temperature is usually in the range from -20°C to the boiling point of the solvent under reflux, and more preferably from 0°C to the boiling point of the solvent under reflux.

Stage 5-2:

This stage is the stage of obtaining the compound (5-3) conversion of the compound (5-2) in the nitrile oxide approach derived and performing the reaction of 1,3-dipolar cycloaddition reactions with olefinic fragment in the same molecule.

The reaction at this stage can be carried out under the same conditions, which are usually used in the reaction of 1,3-dipolar cycloaddition, such as the conditions described in this document, as Org. Lett. 9 (2007) 5, 753-756, Tetrahedron: Asymmetry 5 (1994) 6, 1018-1028 and Tetrahedron 54 (1998) 22, 5868-5882. Examples of the reagent for the conversion of compounds of the oxime in nitriloside include N-chlorosuccinimide and sodium hypochlorite. The solvent used in this reaction is not particularly limited, but he would not have slowed down the reactions is. Preferred examples of the solvent include dichloromethane, chloroform, benzene, toluene, xylene, N,N-dimethylformamide, tetrahydrofuran and 1,4-dioxane. The reaction temperature is not particularly limited, and it is usually in the range of temperature cooling with ice to the boiling point of the solvent under reflux. The reaction time is not particularly limited, and it is usually from 0.5 to 48 hours, preferably from 0.5 to 24 hours.

Better result, such as increased output can be achieved by the implementation of this reaction in the presence of a base. Such a base is not particularly limited. Examples of the base include such bases as sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate and their solutions, and triethylamine and pyridine.

Stage 5-3:

This stage is the stage of obtaining the compound (5-4) by an additional interaction abilitiesa reagent (including heterocyclic) or Grignard reagent (including heterocyclic) with compound (5-3).

The reaction at this stage can be carried out, for example, under the same conditions as described in J. Am. Chem. Soc. 2005, 127, 5376-5383, Bull. Chem. Soc. Jpn., 66, 2730-2737 (1993) and SYNLETT. 2004, No. 8, pp 1408-1413.

Abilitiy reagent (including heterocyclic) or a Grignard reagent (including heterocyclic) can be obtained by a method known to the person skilled in the art. In particular, the corresponding abilitiy reagent (including heterocyclic) or arimany reagent (including heterocyclic) can be obtained, for example, exchange of the halogen-metal between arylalkenes and commercially available ORGANOMETALLIC reagent, such as alkyllithium reagent, such as n-, sec - or tert-utility, or a Grignard reagent, such as isopropylacrylamide, or metal magnesium.

The solvent used at this stage, is changed in accordance with the original substance and the reagent, and its not particularly limited, but he would not slow down the reaction, allowed the original substance dissolved therein to a certain extent and always was inert during the reaction. Preferred examples of the solvent include organic solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene and toluene, and mixed solvents. The reaction time is not particularly limited, and it is usually 0.1 to 48 hours, preferably 0.1 to 12 hours. The reaction temperature varies according to whether the starting material, the reagent and the like, and its support preferably low, for example, -78°C, to minimize the formation of by-product.

Positive results such as increased output, ponie the TES reaction time, can be achieved, for example, the addition of TMEDA (tetramethylethylenediamine), HMPA (hexamethylphosphoramide) or a Lewis acid such as a complex of boron TRIFLUORIDE-diethyl ether (BF3·OEt2) as an additive.

Stage 5-4:

This stage is the stage of obtaining compound (5-5) by the reaction of reductive cleavage of N-O link connection (5-4).

The reaction of the reductive cleavage of N-O bond may be carried out in conditions using, for example, a mixture of zinc-acetic acid, a metal catalyst, such as hydrogen-platinum oxide, or lithium aluminum hydride.

The reaction using zinc, such as a mixture of the zinc-acetic acid, can be carried out, for example, under the same conditions as described in J. Org. Chem. 2003, 68, 1207-1215 and Org. Lett. 7 (2005) 25, 5741-5742. Examples of the acid include acetic acid, formic acid and chloride-hydrogen acid. The solvent used in this reaction is not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. Examples of the solvent include methanol, ethanol, 1,4-dioxane, THF and water. The above acid can also be used as solvent. The reaction temperature is in the range usually from -20°C to the boiling point of the solvent treatment is essential refrigerator, and preferably the temperature of the cooling with ice to the boiling point of the solvent under reflux. The reaction time is not particularly limited, and it is usually from 5 minutes to 48 hours, preferably from 5 minutes to 24 hours.

Reaction using a metal catalyst, such as hydrogen oxide of platinum, can be carried out, for example, under the same conditions as described in Tetrahedron: Asymmetry 5 (1994) 6, 1018-1028 and Tetrahedron, Vol. 53, No. 16, pp 5752-5746, 1997. The compound (5-5) can be obtained, for example, by hydrogenation of the compound (5-4) using platinum oxide as a catalyst in a solvent such as methanol.

The reaction using lithium aluminum hydride can be carried out, for example, under the same conditions as described in Bull. Chem. Soc. Jpn., 66, 2730-2737 (1993). The compound (5-5) can be obtained, for example, by reduction of compound (5-4) using lithium aluminum hydride in a solvent such as simple air.

Stage 5-5:

This stage is the stage of obtaining compound (5-6) from compound (5-5). Derived thiourea (5-6) can be obtained from compound (5-5) in a manner known to a person skilled in the technical field.

If the protective group is benzoline group, the compound (5-6) can be obtained at this stage by reacting compound (5-5) with benzoylisothiocyanate rastvoritele, such as dichloromethane or toluene. This reaction can be carried out, for example, under the same conditions as described in J. Org. Chem. 1994, 59, 1911-1917. The solvent used in this reaction is not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. Examples of the solvent include dichloromethane, chloroform, toluene, methanol, ethanol, 1,4-dioxane and THF. The reaction temperature is usually in the range from -20°C to the boiling point of the solvent under reflux, and preferably the temperature of the cooling with ice to the boiling point of the solvent under reflux. The reaction time is not particularly limited, and it is usually from 5 minutes to 48 hours, preferably from 5 minutes to 24 hours.

If the protective group is 8-fluorenylmethoxycarbonyl group (Fmoc group), the compound (5-6) can be obtained at this stage by reacting compound (5-5) with fluorenylmethoxycarbonyloxy in a solvent such as dichloromethane or toluene. This reaction can be carried out, for example, under the same conditions as described in J. Org. Chem. 1998, 63, 196-200. The solvent used in this reaction is not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. When the minimum level of the solvent include dichloromethane, chloroform, toluene, methanol, ethanol, 1,4-dioxane and THF. The reaction temperature is usually in the range from -20°C to the boiling point of the solvent under reflux, and preferably the temperature of the cooling with ice to the boiling point of the solvent under reflux. The reaction time is not particularly limited, and it is usually from 5 minutes to 48 hours, preferably from 5 minutes to 24 hours.

Stage 5-6:

This stage is a way of obtaining compound (5-7) by cyclization of compound (5-6).

In this reaction, the compound (5-6) can be subjected to cyclization in different conditions obtaining compounds (5-7) by selection of the protective group of the compound (5-6).

If the protective group is, for example, the Fmoc group or benzoline group, the compound (5-7) can be obtained in this reaction by heating compound (5-6) in a solvent such as methanol, in the presence of acid, such as, for example, concentrated chloride-hydrogen acid. The solvent used in this reaction is not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. Examples of the solvent include solvents such as methanol, ethanol, 1-propanol and water, mixed solvents and acid used as solvent. Rea is tion can be carried out by the action of a suitable acid in an amount of one equivalent to a large excess, in the presence or in the absence of such a solvent. Examples of acids include concentrated chloride-hydrogen acid, Hydrobromic acid, sulfuric acid, triperoxonane acid, methanesulfonate acid, triftormetilfullerenov acid and mixtures thereof. The reaction time is not particularly limited, and it is usually from 0.5 to 72 hours, preferably from 0.5 to 24 hours. The reaction temperature is usually within the temperature cooling with ice to the boiling point of the solvent under reflux.

If the protecting group is Fmoc group or benzoline group, the compound (5-7) can be obtained in an alternative way 1 interaction of the compound (5-6) with triftormetilfullerenov anhydride in a solvent such as dichloromethane, in the presence of a base, such as pyridine. This reaction can be carried out under the same conditions, as described in Chem Bio Chem. 2005, 6, 186-191. The solvent used in this reaction is not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. Examples of the solvent include solvents such as dichloromethane, 1,2-dichloroethane, THF, 1,2-dimethoxyethane and toluene, and mixed solvents. The reaction can be carried out using 1 to 20 equivalents of a suitable base in such a solvent. The examples and the use of the base include pyridine, 2,6-lutidine, sodium carbonate, potassium carbonate and mixtures thereof. The reaction time is not particularly limited, and it is usually from 0.5 to 24 hours, preferably from 0.5 to 12 hours. The reaction temperature is usually from -78°C to room temperature.

If the protective group is benzoline group, the compound (5-7) can be obtained in an alternative way 2 the interaction of the compound (5-6) with triphenylphosphine and tetrabromide carbon (or bromine) in a solvent such as dichloromethane. Reaction conditions are the same as conditions of the synthesized primary alcohol, which are known to the person skilled in the technical field.

Stage 5-7:

This stage is a method of obtaining compound (1-7) removing the protective group of the compound (5-7). The compound (1-7) can be obtained in terms of removing the protection, well-known specialist in this field of technology.

If the protective group is, for example, the Fmoc group, the compound (1-7) can be obtained in the same conditions, which is usually used in the removal of the protective group of the amino compounds (such as the conditions described in this document such as T. W. Green and P. G. M. Wuts, "Protective Groups in Organic Chemistry, Third Edition", John Wiley & Sons, p. 506-507 and J. Org. Chem. 1998, 63, 196-200). In this reaction, the compound (1-7) can be obtained, for example, by reacting compounds (5-7) with excess amine, such ka is pyrrolidin, in a solvent such as acetonitrile. The solvent used in this reaction is not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. Examples of the solvent include dichloromethane, THF and acetonitrile. The reaction can be carried out by the action of a suitable base in an amount of one equivalent to a large excess in the presence of such a solvent. Examples of the base include piperidine, morpholine, pyrrolidine, TBAF and DBU. The reaction time is not particularly limited, and it is usually from 0.5 to 72 hours, preferably from 0.5 to 24 hours. The reaction temperature is usually in the range of temperature cooling with ice to the boiling point of the solvent under reflux.

Positive results such as increased output and reduced reaction time can be achieved, for example, the introduction of Colnago compounds such as 1-octanethiol, as an additive.

If the protective group is benzoline group, the compound (1-7) can be obtained in this reaction, for example, by heating the compounds (5-7) in a solvent such as methanol, in the presence of a base such as DBU. This reaction can be carried out, for example, under the same conditions as described in Synth. Commun. 32 (2), 265-272 (2002). The solvent used in isoamyl in this reaction, not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. Examples of the solvent include solvents such as methanol, ethanol and 1-propanol. The reaction can be carried out using 1 to 20 equivalents of a suitable base in such a solvent. Examples of the base include DBU. The reaction time is not particularly limited, and it is usually from 0.5 to 24 hours, preferably from 0.5 to 12 hours. The reaction temperature is usually in the range from room temperature to the boiling point of the solvent under reflux.

6.A common way of obtaining 6:

[Formula 11]

This diagram Prt2is a primary hydroxylamino group, R8represents a C1-6alkyl group, and Z, R3, R4, R5, R6, R7and LV are as defined above.

A common way of obtaining 6 represents a method of obtaining compound (6-4), which is compound (5-1), serving as the starting material for the General method of obtaining 5, where Y represents an oxygen atom.

Each of the compounds (6-1), (6-2), (6-5), (6-7) and (6-9) may be commercially available product used as it is, can also be obtained from the com the Cesky available product by the way well-known specialist in this field of technology, and, in addition, can be obtained by the method described in the examples get in the "Examples"section.

Stage 6-1:

This stage is the stage of obtaining the compound (6-3) by reacting the compound (6-1) with compound (6-2).

This reaction can be carried out under the same conditions, which are usually used in the reaction of O-alkylation of an alcohol compound such as the conditions described in Tetrahedron Lett. 46 (2005) 45, 7751-7755). In this reaction, the compound (6-3) can be obtained, for example, by adding a base such as sodium hydride, to a solution of compound (6-1) in THF obtaining alkoxide and then by the interaction of the alkoxide with the compound (6-2). The solvent used in this reaction is not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. Examples of the solvent include solvents such as THF, DMF and dimethylsulfoxide. The reaction can be carried out by the action of 1-3 equivalents of a suitable base in the presence of such a solvent. Examples of the base include sodium hydride, potassium hydride and tert-butoxylate. The reaction time is not particularly limited, and it is usually from 0.5 to 72 hours, preferably from 0.5 to 12 hours. The reaction temperature is usually from 0°C to 50°C.

Better result, such as increased output can be achieved in this reaction the addition of salts, such as tetrabutylammonium iodide.

Stage 6-2:

This stage is the stage of obtaining the aldehyde compound (6-4) by the oxidation of an alcohol compound (6-3). Aldehyde compound can be obtained from the alcohol connection method known to a person skilled in the technical field.

Examples of known oxidation method used in this reaction include oxidation in Turn, the oxidation Corey-Kim oxidation by Moffatt, PCC oxidation, PDC oxidation, oxidation by Dess-Martin oxidation using complex SO3the pyridine and TEMPO oxidation.

The solvent used in this reaction is not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. Examples of the solvent include dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane and chloroform.

The reaction temperature is not particularly limited, and it is usually in the range from -78°C to the boiling point of the solvent under reflux, and preferably from -78°C to room temperature. The reaction time is not particularly limited, and it is usually from 0.5 to 48 hours, preferably from 0.5 to 24 hours.

Stage 6-3:

This stage is the stage of synthesizing the compound (6-6) from the compound (6-5) as the original substances using the production method, described above (stage 6-1).

Stage 6-4:

This stage is the stage of obtaining compound (6-4) unprotect acetamino group connection (6-6).

This reaction can be carried out under the same conditions, which is usually used when removing the protection of the aldehyde group, such as the conditions described in this document such as T. W. Green and P. G. M. Wuts, "Protective Groups in Organic Chemistry, Third Edition", John Wiley & Sons, P. 293-329.

Stage 6-5:

This stage is the stage of synthesizing the compounds (6-8) from the compound (6-7) as the original substances using the production method, described above (stage 6-1).

Stage 6-6:

This stage is the stage of obtaining the compound (6-3) removing hydroxylamino group of compounds (6-8). Hydroxylamino group to be used at this stage is not particularly limited.

This reaction can be carried out under the same conditions, which is usually used in the removal of the protective group for an alcohol, such as the conditions described in this document such as T. W. Green and P. G. M. Wuts, "Protective Groups in Organic Chemistry, Third Edition", John Wiley & Sons, P. 17-245.

Stage 6-7:

This stage is the stage of synthesizing the compound (6-3) is connected to the I (6-9) as the original substances using the production method, described above(stage 1-3) or (stage 2B-1 and 2)).

7.A common way to obtain 7:

[Formula 12]

In this diagram, R9represents a C1-6alkyl group, or two R9together may form a ring, the Prt3represents a protective group, such as 2,4-dimethoxybenzyl group, and Z, R3, R4, R5, R6Z and LV are as defined above.

A common way to obtain 7 is a method of obtaining compound (7-5), which is compound (5-1), serving as the starting material for the General method of obtaining 5, where Y represents a nitrogen atom.

Each of the compounds (7-1) and (7-3) may be commercially available product used as it is, can also be obtained from a commercially available product by a method known to a person skilled in the art and, in addition, can be obtained by the method described in the examples get in the "Examples"section.

Stage 7-1:

This stage is the stage of obtaining the compound (7-2) protection of the amino group of the compound (7-1).

This reaction can be carried out under the same conditions, which is usually used in the protection of amino groups, such as the conditions described in this document such as T. W. Green and P. G. M. Wuts, "Protective Groups in Organic Chemistry, Third Edition", John Wiley & Sons, P.494-572 and J. Med. Chem. 2007, 50, 5493-5508.

Stage 7-2:

This stage is the stage of obtaining compound (7-4) by the reaction of N-alkylation of compound (7-2) of the compound (7-3).

This reaction can be carried out under the same conditions, which are usually used in the reaction of N-alkylation of compound (7-2) (such as the conditions described in J. Med. Chem. 2007, 50, 5493-5508). In this reaction, the compound (7-4) can be obtained, for example, by adding a base such as powdered sodium hydroxide, to a solution of compound (7-2) in toluene, and then the interaction of the mixture with the compound (7-3). The solvent used in this reaction is not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. Examples of the solvent include solvents such as toluene, THF, DMF and dimethylsulfoxide. The reaction can be carried out by the action of 1-5 equivalents of a suitable base in the presence of such a solvent. Examples of the base include sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride and tert-butoxylate. The reaction time is not particularly limited, and it is usually from 0.5 to 72 hours, preferably from 0.5 to 24 hours. The reaction temperature is usually from -20°C to 100°C.

Better result, such as increased output, can the be achieved in a given reaction by adding salt, such as tetrabutylammonium iodide.

Stage 7-3:

This stage is the stage of obtaining compound (7-5) unprotect acetamino group of the compound (7-4).

This reaction can be carried out under the same conditions, which is usually used when removing the protection of the aldehyde group, such as the conditions described in this document such as T. W. Green and P. G. M. Wuts, "Protective Groups in Organic Chemistry, Third Edition", John Wiley & Sons, P. 293-329.

8.A common way to obtain 8:

[Formula 13]

This diagram Prt represents a protective group, such as benzoline group, acetyl group or 8-fluorenylmethoxycarbonyl group (Fmoc group), the Prt3represents a protective group, such as 2,4-dimethoxybenzyl group, and ring A, R3, R4, R5and R6are as defined above.

A common way to obtain 8 represents a stage of the method of obtaining compounds of General formula (8-7) and (8-8), which are intermediate compounds for the synthesis of compound (I) of the present invention in a General way to obtain 5, where Y represents a nitrogen atom and Z represents a single bond. These compounds can be obtained from compound (8-1) as the source substance by carrying out stages shown above.

The compound (8-1) can be private and available product used as it is, can also be obtained from a commercially available product by a method known to a person skilled in the art and, in addition, can be obtained by the method described in the examples get in the "Examples"section. The compound (8-2) can be obtained from a commercially available product by a method known to a person skilled in the art and, in addition, can be obtained by the method described in the examples get in the "Examples"section.

Stage 8-1:

This stage is the stage of obtaining compound (8-3) by reacting the compound (8-1) with compound (8-2). This reaction can be carried out under the same conditions, which are usually used in the reaction of N-alkylation of amino compounds (such as the conditions described in J. Med. Chem. 2002, 45, 3794-3804 and J. Med. Chem. 2000, 43, 3808-3812). In this reaction, the compound (8-3) can be obtained, for example, the interaction of the compound (8-1) with compound (8-2) in a solvent such as dichloromethane, in the presence of a base, such as N,N-diisopropylethylamine. The solvent used in this reaction is not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. Examples of the solvent include dichloromethane, THF, acetonitrile and DMF. The reaction can be carried out by the action of 1-10 equivalents of the right reasons in this solvent. Examples of the base include N,N-diisopropylethylamine, triethylamine, sodium carbonate and potassium carbonate. The reaction time is not particularly limited, and it is usually from 0.5 to 72 hours, preferably from 0.5 to 12 hours. The reaction temperature is usually from temperature cooling with ice up to 50°C.

Stage 8-2:

This stage is the stage of obtaining compound (8-4) aksamitowana connection (8-3).

The reaction at this stage can be carried out under the same conditions, which are usually used in the reaction of oxymorphine carbonyl compounds, such as the conditions described in J. Med. Chem. 2002, 45, 3794-3804 and J. Med. Chem. 2000, 43, 3808-3812.

In particular, the compound (8-4) can be obtained, for example, by reacting compound (8-3) with hydroxylamine or hydroxylamine salt such as hydroxylamine hydrochloride or hydroxylamine sulfate) in the presence of a base or without base. The solvent used in this reaction is not particularly limited, but he would not slow down the reaction. Preferred examples of the solvent include organic solvents such as ethanol, methanol, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and dichloromethane, and mixtures of these solvents and water. Examples of the base include sodium carbonate, potassium carbonate, sodium acetate, pyridine, hydrocentre, the cesium hydroxide, barium hydroxide and 2,6-lutidine. The reaction time is not particularly limited, and it is usually from 5 minutes to 24 hours, preferably from 5 minutes to 12 hours. The reaction temperature is usually in the range from 0°C to the boiling point of the solvent under reflux, and more preferably from room temperature to the boiling point of the solvent under reflux.

Stage 8-3:

This stage is the stage of obtaining compound (8-5) by introducing Aksenovo connection (8-4) in the reaction of 1,3-dipolar cycloaddition.

The reaction at this stage can be carried out under the same conditions, which are usually used in the reaction of 1,3-dipolar cycloaddition, such as the conditions described in J. Org. Chem. 1993, 58, 4538-4546 and Tetrahedron Letters, Vol. 29, No. 41, pp 5312-5316.

In particular, the compound (8-5) can be obtained, for example, by boiling under reflux solution of the compound (8-4) in toluene solvent. The solvent used in this reaction is not particularly limited, but he would not slow down the reaction. Preferred examples of the solvent include organic solvents such as toluene, xylene and chlorobenzene. The reaction time is not particularly limited, and it is usually from 5 minutes to 24 hours, preferably from 5 minutes to 12 hours. The reaction temperature is usually within 0°C to the boiling point of the solvent under reflux, and more preferably from room temperature to the boiling point of the solvent under reflux.

Positive results such as increased output and reduced reaction time, can be achieved by adding a Lewis acid such as zinc chloride, in the form of supplements.

Positive outcomes such as reduced reaction time and increased output can be obtained by carrying out this reaction using microwave reactor.

Stage 8-4:

The compound (8-6) can be synthesized from compound (8-5) using a series of methods shown in the above-described method of obtaining from ((stage 5-4) to (stage 5-6)).

Stage 8-5:

This stage is the stage of synthesizing the compound (8-7) from compound (8-6) as the original substances using the production method, described above (stage 5-7).

Stage 8-6:

This stage is the stage of obtaining compounds (8-8) removing the protection of the amino group of compound (8-6). Aminosidine group to be used at this stage is not particularly limited. If Prt3represents, for example, 2,4-dimethoxybenzyl group, this stage can be carried out under the same conditions, which are usually used (such as the conditions described in this document, as Tetrahedron Vol. 47, No. 26, pp 4591-4602, 1991). If Dunn is stage Prt 3represents a 2,4-dimethoxybenzyl group, the solvent used at this stage is not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. For example, the solvent in the reaction of the first stage may be methylene chloride or chloroform, and the solvent in the reaction of the second stage may be methanol. The reaction temperature at this stage is usually from 0°C to room temperature. The reaction time at this stage is not particularly limited, and it is usually from 0.5 to 24 hours, preferably from 0.5 to 12 hours.

9.A common way to obtain 9:

[Formula 14]

This diagram L1represents a single bond or C1-6alkylenes group in compounds (9-3) and (9-4) and represents a single bond or C1-4alkylenes group in compounds (9-5) and (9-6), L represents a single bond, an oxygen atom, a C1-6alkylenes group, C2-6alkenylamine group or a C2-6alkynylamino group, Alk represents a C1-6alkyl group, and ring A, ring B, R3, R4, R5, R6, Y, Z and LV are as defined above.

A common way to obtain 9 is a method of obtaining the compound (I-b) of General formula (I) according to the present image is ateneu, where L represents a single bond, an oxygen atom, a C1-6alkylenes group, C2-6alkenylamine group or a C2-6alkynylamino group, and R1and R2represent hydrogen atoms from the compound (9-1) as the starting material holding shown above stages.

The compound (9-1) can be obtained from the commercially available product of the General method of obtaining 1, the General method of obtaining 5 or a combination of the common way obtain 1 and method 2B of the common way obtain a 2 and can also be obtained by the method described in the examples get in the "Examples"section. Each of the compounds (9-3)and (9-4)and (9-5)and (9-6) and (9-7) may be commercially available product used as it is, can also be obtained from a commercially available product by a method known to a person skilled in the art and, in addition, can be obtained by the method described in the examples get in the "Examples"section.

Stage 9-1:

This stage is the stage of obtaining compound (9-2) di-tert-butoxycarbonylamino compounds (9-1). This reaction can be carried out under the same conditions, which is usually used in tert-butoxycarbonylamino amide compounds such as the conditions described in T. W. Green and P. G. M. Wuts, "Protective Groups in Organic Chemistry, Third Edition", John Wiley & Sons, p. 642-643 and J. Org. Chem. 2005, 70, 2445-2454. EDINENIE (9-2) can be obtained, for example, by reacting the compound (9-1) with di-tert-BUTYLCARBAMATE using 4-dimethylaminopyridine as a base in a solvent such as THF.

The solvent used in this reaction is not particularly limited, but he would not slow down the reaction. Preferred examples of the solvent include organic solvents such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, DMF and acetonitrile, and their mixed solvents. Examples of the base include triethylamine, 4-dimethylaminopyridine, DBU, and mixtures thereof. The base is used in an amount of from a catalytic amount to excess, and more preferably 0.1 to 5 equivalents relative to compound (9-1). Di-tert-BUTYLCARBAMATE used in an amount of two equivalents to an excess, and more preferably 2 to 10 equivalents relative to compound (9-1). The reaction time is not particularly limited, and it is usually from 5 minutes to 24 hours, preferably from 5 minutes to 12 hours. The reaction temperature is usually in the range from -20°C to the boiling point of the solvent under reflux, and more preferably from 0°C to the boiling point of the solvent under reflux.

Stage 9-2:

This stage is the stage of obtaining compounds (9-8) reaction of a combination of compound (9-2) with the the group (9-3), (9-4)and (9-5)and (9-6) (9-7) using a transition metal. This reaction can be carried out under the conditions normally employed in the reaction mix using a transition metal (such as a Suzuki reaction-Miyaura, the reaction Steele, the reaction Sonogashira, the reaction Hake or the reaction of Buchwald etc. using kilowog simple ether).

Examples of the reaction the Suzuki-Miyaura include reactions described in texts such as J. Org. Chem. 2007, 72, 7207-7213, J. Am. Chem. Soc. 2000, 122, 4020-4028 and J. Org. Chem. 2007, 72, 5960-5967. Examples of combination reaction on the still include the reaction described in this document, as J. Am. Chem. Soc. 1990, 112, 3093-3100. Examples of the reaction Sonogashira include reactions described in texts such as J. Org. Chem. 2007, 72, 8547-8550 and J. Org. Chem. 2008, 73, 234-240. Examples of the Heck reaction include a reaction that is described in this document, as J. Am. Chem. Soc. 2005, 127, 16900-16911. Examples of the reaction of Buchwald etc. using kilowog simple ether include reaction described in this document, as Buckwald, S. L. et al., J Am Chem Soc (1999) 121 (18), 4369-4378. ORGANOMETALLIC catalyst used in this reaction are not particularly limited. Preferable examples of the ORGANOMETALLIC catalyst include metal catalysts such as tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II)dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II), bis(tert-b is telespin)palladium(0), the palladium(II) acetate and [1,3-bis(diphenylphosphino)propane]Nickel(II), and mixtures of these metal catalysts. The amount of the ORGANOMETALLIC catalyst is about 0.001 to 0.5 equivalent relative to the original substances. The amount used of the compound (9-3)and (9-4)and (9-5)and (9-6) (9-7) are not particularly limited, and it is generally 1-5 equivalents relative to compound (9-2). The solvent used in this reaction is not particularly limited, but he would not slow down the reaction. Preferred examples of the solvent include benzene, toluene, xylene, N,N-dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile and propionitrile. The reaction temperature is not particularly limited, and it is usually in the range of temperature cooling with ice to the boiling point of the solvent under reflux, and preferably, for example, from room temperature to the boiling point of the solvent under reflux. The reaction time is not particularly limited, and it is usually from 0.5 to 48 hours, preferably from 0.5 to 24 hours.

Better result, such as increased output can be achieved by the implementation of this reaction in the presence of a base or salt. This(second) base or salt is not particularly limited. A preferred example of the base or salt include a base or salt, as sodium carbonate, potassium carbonate, barium hydroxide, cesium carbonate, potassium phosphate, potassium fluoride and their solutions, and triethylamine, N,N-diisopropylethylamine, lithium chloride and copper iodide(I).

Stage 9-3:

This stage is the stage of synthesizing the compound (I-b) from compound (9-8) as the original substances using the production method, described above (stage 3-4).

The compound of formula (I) according to the present invention, where at least one of R1and R2represents a C1-6alkyl group, which may contain 1-3 substituent selected from the group of substituents α, C1-6alkylcarboxylic group, which may contain 1-3 substituent selected from the group of substituents α, C6-14arylcarbamoyl group, which may contain 1-3 substituent selected from the group of substituents α, C1-6alkylsulfonyl group, which may contain 1-3 substituent selected from the group of substituents α, C6-14arylsulfonyl group, which may contain 1-3 substituent selected from the group of substituents α, 3-10-membered carbocyclic group which may contain 1-3 substituent selected from the group of substituents α, or 5-10-membered heterocyclic group, which may contain 1-3 substituent selected from the group of substituents α, can be obtained additional is the principal interaction of the compound (I-b), the General method of obtaining 9, with a corresponding halide, such as C1-6alkylhalogenide.

10.A common way of obtaining 10:

[Formula 15]

In this diagram, ring A, ring B, R3, R4, R5, R6, Z, Y, L1, L and LV are as defined above.

A common way of obtaining 10 is a method of obtaining the compound (I-b) of General formula (I) according to the present invention, where L represents a single bond, and R1and R2represent hydrogen atoms from the compound (10-1).

The compound (10-1) can be obtained from the commercially available product of the General method of obtaining 1, the General method of obtaining 5 or a combination of the common way obtain 1 and method 2B of the common way obtain a 2 and can also be obtained by the method described in the examples get in the "Examples"section.

Stage 10-1:

This stage is the stage of obtaining the compound (10-2) benzyloxycarbonylamino compound (10-1).

The reaction can be carried out under the same conditions, which is usually used in benzyloxycarbonylamino of amino compounds, such as the conditions described in this document such as T. W. Green and P. G. M. Wuts, "Protective Groups in Organic Chemistry, Third Edition", John Wiley & Sons, p. 531-537. The compound (10-2) can be obtained, for example, by interaction with the organisations (10-1) benzylchloride in a mixed solvent of 1,4-dioxane and saturated sodium bicarbonate solution.

Stage 10-2:

This stage is the stage of synthesizing the compound (I-b) from compound (10-2) as the original substances using the same method as the Suzuki reaction-Miyaura described in the above method of obtaining (stage 9-2).

The compound of formula (I) according to the present invention, where at least one of R1and R2represents a C1-6alkyl group, which may contain 1-3 substituent selected from the group of substituents α, C1-6alkylcarboxylic group, which may contain 1-3 substituent selected from the group of substituents α, C6-14arylcarbamoyl group, which may contain 1-3 substituent selected from the group of substituents α, C1-6alkylsulfonyl group, which may contain 1-3 substituent selected from the group of substituents α, C6-14arylsulfonyl group, which may contain 1-3 substituent selected from the group of substituents α, 3-10-membered carbocyclic group which may contain 1-3 substituent selected from the group of substituents α, or 5-10-membered heterocyclic group, which may contain 1-3 substituent selected from the group of substituents α, can be obtained by the additional interaction of the compound (I-b)obtained by the General method of obtaining 10, with a corresponding halide, such as C 1-6alkylhalogenide.

11.A common way to obtain 11:

[Formula 16]

In this diagram, ring A, ring B, R3, R4, R5, R6, L1, L, LV, Alk and Prt3are as defined above.

A common way to obtain 11 is a General method of obtaining 9 when in the General formula Y represents a nitrogen atom and Z represents a single bond. This method is a method of obtaining compound (11-4), which is an intermediate compound in the synthesis of compounds (I) of the present invention, obtained from the compound (11-1).

The compound (11-1) can be obtained from the commercially available product of the General method of obtaining 5 or the General method of obtaining 8 and can also be obtained by the method described in the examples get in the "Examples"section.

Stage 11-1:

This stage is the stage of synthesizing the compound (11-2) from the compound (11-1) as the original substances using the production method, described above (stage 9-1).

Stage 11-2:

This stage is the stage of synthesizing the compound (11-3) from compound (11-2) as the original substances using the production method, described above (stage 9-2).

Stage 11-3:

This stage is the stage of obtaining compound (11-4 removing the protection of the amino group of compound (11-3). Aminosidine group to be used at this stage is not particularly limited. If, for example, the Prt3represents a 2,4-dimethoxybenzyl group, this stage can be carried out under the same conditions, which are usually used (such as the conditions described in this document, as Tetrahedron Vol. 47, No. 26, pp 4591-4602, 1991). At this stage, if Prt3represents a 2,4-dimethoxybenzyl group, you may be charged one Boc protective group simultaneously with the removal of 2,4-dimethoxyaniline protective group. If at this stage Prt3represents a 2,4-dimethoxybenzyl group, the solvent used at this stage is not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. For example, the solvent in the reaction of the first stage may be methylene chloride or chloroform, and the solvent in the reaction of the second stage may be methanol. The reaction temperature at this stage is usually from 0°C to room temperature. The reaction time at this stage is not particularly limited, and it is usually from 0.5 to 24 hours, preferably from 0.5 to 12 hours.

12.A common way to obtain 12:

[Formula 17]

In this diagram, ring A, ring B, R3, R4, R5, R6, Y, Z, L and LV are the one whom they as specified above.

A common way to obtain 12 is a method of obtaining the compound (I-b) of General formula (I) according to the present invention, where L represents a single bond, and R1and R2represent hydrogen atoms from the compound (9-2).

The compound (9-2) can be obtained from the commercially available product of the General method of obtaining 9 and can also be obtained by the method described in the examples get in the "Examples"section. The compound (12-2) can be a commercially available product used as it is, can also be obtained from a commercially available product by a method known to a person skilled in the art and, in addition, can be obtained by the method described in the examples get in the "Examples"section.

Stage 12-1:

This stage is the stage of obtaining the compound (12-1) reaction of a combination of compound (9-2) using a transition metal.

The reaction at this stage can be carried out under the same conditions, which are usually used in the reaction combinations using transition metal, such as the conditions described in Org. Lett. 2007, Vol. 9, No. 4, 558-562 and Bioorg. Med. Chem, 14 (2006) 4944-4957. In particular, the compound (12-1) can be obtained, for example, by reacting compound (9-2) with bis(pinacolato)DIBORANE in the conditions of heating in a solvent such ka is DMF, in the presence of a catalyst, such as potassium acetate or dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium (II).

ORGANOMETALLIC catalyst used in this reaction are not particularly limited. Preferable examples of the ORGANOMETALLIC catalyst include metal catalysts such as dichlorobis(triphenylphosphine)palladium(II)dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II), bis(tert-butylphosphine)palladium(0), palladium(II) acetate and [1,3-bis(diphenylphosphino)propane]Nickel(II). The amount of the ORGANOMETALLIC catalyst is about 0.001 to 0.5 equivalent relative to the original substances. The solvent used in this reaction is not particularly limited, but he would not slow down the reaction. Preferred examples of the solvent include benzene, toluene, xylene, N,N-dimethylformamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile and propionitrile. The reaction temperature is not particularly limited, and it is, for example, is usually in the range of temperature cooling with ice to the boiling point of the solvent under reflux, and preferably from room temperature to the boiling point of the solvent under reflux. The reaction time is not particularly limited, and it is usually from 0.5 to 72 hours, before occhialino from 0.5 to 24 hours.

Better result, such as increased output can be achieved by the implementation of this reaction in the presence of a base. Such a base is not particularly limited. Preferred examples of the base include such grounds as potassium acetate, sodium acetate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium fluoride, triethylamine and N,N-diisopropylethylamine.

Stage 12-2:

This stage is the stage of synthesizing the compound (12-3) from the compound (12-1) as the original substances using the production method, described above (stage 9-2).

Stage 12-3:

This stage is the stage of synthesizing the compound (I-b) from compound (12-3) as a starting substance, using the production method, described above (stage 3-4).

The compound of formula (I) according to the present invention, where at least one of R1and R2represents a C1-6alkyl group, which may contain 1-3 substituent selected from the group of substituents α, C1-6alkylcarboxylic group, which may contain 1-3 substituent selected from the group of substituents α, C6-14arylcarbamoyl group, which may contain 1-3 substituent selected from the group of substituents α, C1-6alkylsulfonyl group, which may contain 1-3 to cover the El, selected from the group of substituents α, C6-14arylsulfonyl group, which may contain 1-3 substituent selected from the group of substituents α, 3-10-membered carbocyclic group which may contain 1-3 substituent selected from the group of substituents α, or 5-10-membered heterocyclic group, which may contain 1-3 substituent selected from the group of substituents α, can be obtained by the additional interaction of the compound (I-b)obtained by the General method of obtaining 12, with a corresponding halide, such as C1-6alkylhalogenide.

13.A common way to obtain 13:

[Formula 18]

In this diagram, ring A, ring B, R3, R4, R5, R6, Y and Z are as defined above.

A common way to obtain 13 is a method of obtaining the compound (I-a) of General formula (I) according to the present invention, where L represents-NHCO -, and R1and R2represent hydrogen atoms from the compound (12-1).

The compound (12-1) can be obtained from the commercially available product of the General method of obtaining 12 and may also be obtained by the method described in the examples get in the "Examples"section.

Stage 13-1:

This stage is the stage of obtaining the compound (13-1) by reacting the compound (12-1) with azide three is in the presence of a copper catalyst.

The reaction at this stage can be carried out, for example, under the same conditions as described in Org. Lett. 2007, Vol. 9, No. 5, 761-764 and Tetrahedron Lett. 2007, 48, 3525-3529. In particular, the compound (13-1) can be obtained, for example, the interaction of the compound (12-1) with sodium azide at room temperature using a solvent, such as methanol, in the presence of a catalyst such as copper acetate(II).

The catalyst used in this reaction are not particularly limited. Preferred examples of the catalyst include metal catalysts such as copper acetate(II)sulfate copper(II)iodide copper(I) chloride copper(I). The amount used of the catalyst is not particularly limited, and it is usually about 0.1 to 0.5 equivalent relative to the original substances. The solvent used in this reaction is not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. Preferred examples of the solvent include methanol, N,N-dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, propionitrile and dichloromethane. The reaction temperature is not particularly limited, and it is, for example, is usually in the range of temperature cooling with ice to the boiling point of the solvent under reflux, and preferably from to matnog temperature up to the boiling point of the solvent under reflux. The reaction time is not particularly limited, and it is usually from 0.5 to 100 hours, preferably from 1 to 72 hours.

Better result, such as increased output can be achieved by the implementation of this reaction in the atmosphere of oxygen.

Stage 13-2:

This stage is the stage of obtaining compound (13-2) recovery etidocaine (13-1). The reaction at this stage can be carried out, for example, under the same conditions as described in J. Org. Chem. 2003, 68, 4693-4699. In particular, the compound (13-2) can be obtained, for example, by dissolving the compound (13-1) in a solvent such as methanol, and the interaction of the resulting solution with sodium borohydride.

Stage 13-3:

This stage is the stage of synthesizing the compound (13-3) from compound (13-2) as the original substances using the production method, described above (stage 3-3).

Stage 13-4:

This stage is the stage of synthesizing the compound (I-a) from compound (13-3) as the original substances using the production method, described above (stage 3-4).

The compound of formula (I) according to the present invention, where at least one of R1and R2represents a C1-6alkyl group, which may contain 1-3 substituent selected from the group of substituents α, C1-6ancillary niloy group, which may contain 1-3 substituent selected from the group of substituents α, C6-14arylcarbamoyl group, which may contain 1-3 substituent selected from the group of substituents α, C1-6alkylsulfonyl group, which may contain 1-3 substituent selected from the group of substituents α, C6-14arylsulfonyl group, which may contain 1-3 substituent selected from the group of substituents α, 3-10-membered carbocyclic group which may contain 1-3 substituent selected from the group of substituents α, or 5-10-membered heterocyclic group, which may contain 1-3 substituent selected from the group of substituents α, can be obtained by the additional interaction of the compound (I-a)obtained by the General method of obtaining 13, with a corresponding halide, such as C1-6alkylhalogenide.

Alternatively, -NHCO - group L in the compound (I-a) according to the present invention can be transformed into the group-NReCO- (where Rerepresents a C1-6alkyl group, which may contain 1-3 substituent selected from the group of substituents α) additional interaction of the compound (I-a)obtained by the General method of obtaining 13, with a corresponding halide, such as C1-6alkylhalogenide.

The compound of formula (I) according to the present invention, where L represents-N eSO2-can be obtained using the corresponding derived sulphonylchloride instead of the compound (3-4) or (3-5)used in a General way to obtain 13.

14.A common way to obtain 14:

[Formula 19-1]

[Formula 19-2]

In this diagram, ring A, ring B, R3, R4, R5, R6, L, Z, Prt3and LV are as defined above; ring D represents a C6-14aryl group, which may contain 1-3 substituent selected from the group of substituents α, or 5-6-membered heteroaryl group which may contain 1-3 substituent selected from the group of substituents α; R10represents a C6-14aryl group, which may contain 1-3 substituent selected from the group of substituents α, 5-10-membered heterocyclic group, which may contain 1-3 substituent selected from the group of substituents α, C3-8cycloalkyl group, which may contain 1-3 substituent selected from the group of substituents α, C1-6alkyl group, which may contain 1-3 substituent selected from the group of substituents α, or 3-10-membered carbocyclic group which may contain 1-3 substituent selected from the group of substituents α; R11and R1 each independently represents a hydrogen atom, a C6-14aryl group, which may contain 1-3 substituent selected from the group of substituents α, 5-10-membered heterocyclic group, which may contain 1-3 substituent selected from the group of substituents α, C3-8cycloalkyl group, which may contain 1-3 substituent selected from the group of substituents α, C1-6alkyl group, which may contain 1-3 substituent selected from the group of substituents α, or 3-10-membered carbocyclic group which may contain 1-3 substituent selected from the group of substituents α, or R11and R12together may form a ring; R13represents a C6-14aryl group, which may contain 1-3 substituent selected from the group of substituents α, 5-10-membered heterocyclic group, which may contain 1-3 substituent selected from the group of substituents α, C3-8cycloalkyl group, which may contain 1-3 substituent selected from the group of substituents α, C1-6alkyl group, which may contain 1-3 substituent selected from the group of substituents α, or 3-10-membered carbocyclic group which may contain 1-3 substituent selected from the group of substituents α; and R14represents a C7-12aracelio group which may with erati 1-3 substituent, selected from the group of substituents α.

A common way to obtain 14 is a method of obtaining the compounds (I-c)-(I-g) of General formula (I) according to the present invention, where Y represents a nitrogen atom and R1and R2represent hydrogen atoms from the compound (14-1).

The compound (14-1) can be obtained from the commercially available product of the General method of obtaining 5, a common method of obtaining 8, a common way to obtain 9, a common method of obtaining 10, a common method of obtaining 11, a common way of getting 12 or a combination and may also be obtained by the method described in the examples get in the "Examples"section.

Each of the compounds (14-3), (14-4), (14-5), (14-6), (14-7), (14-8) and (14-9) may be commercially available product used as it is, can also be obtained from a commercially available product by a method known to a person skilled in the art and, in addition, can be obtained by the method described in the examples get in the "Examples"section.

Stage 14-1:

This stage is the stage of obtaining the compound (14-2) removing the protection of the amino group of compound (14-1).

The reaction can be carried out under the same conditions, which is usually used in the removal of the protective group of amino compounds, such as the conditions described in this document such as T. W. Green and P. G. M. Wuts, "Protective Groups in Organic Chemisty, Third Edition", John Wiley & Sons, P. 494-572.

Aminosidine group to be used at this stage is not particularly limited. If Prt3represents, for example, 2,4-dimethoxybenzyl group, this stage can be carried out under the same conditions as commonly used terms (such as the conditions described in this document, as Tetrahedron Vol. 47, No. 26, pp 4591-4602, 1991). Can be charged one Boc protective group simultaneously with the removal of 2,4-dimethoxyaniline protective group. The solvent used at this stage is not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. For example, the solvent in the reaction of the first stage may be methylene chloride or chloroform, and the solvent in the reaction of the second stage may be methanol. The reaction temperature at this stage is usually from 0°C to room temperature. The reaction time at this stage is not particularly limited, and it is usually from 0.5 to 24 hours, preferably from 0.5 to 12 hours.

If Prt3represents benzyloxycarbonyloxy group, the compound (14-2) can be obtained by removing protection from compound (14-1) by hydrogenation using palladium on carbon as catalyst in a solvent such as, for example, alcohol.

Stage 14-2:

This stage is the fast stage of synthesizing the compound (I-c) from the compound (14-2) as the original substances using the production method, described above(stage 3-3) and (stage 3-4)).

Stage 14-3:

This stage is the stage of synthesizing the compound (I-d) using the production method, described above (stage 3-4), after the reaction of reductive amination of the compound (14-2) of the compound (14-5).

The reaction of reductive amination can be carried out under the same conditions, which are usually used in the reaction of reductive amination between the carbonyl compound and aminoguanidinium. The reaction of recovery at this stage is not particularly limited. Examples of reduction reaction includes the reaction of reductive amination using a reducing agent such as boranova or borhydride compound. Examples of the reaction of reductive amination using borhydride complex compounds include the method described in this document, as J. Org. Chem. 1996, 61, 3849. Examples borhydride complex compounds, which can be used include sodium borohydride, cyanoborohydride sodium and triacetoxyborohydride sodium.

If borhydride compound used as a reducing agent, the solvent is not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. Concrete at the career of the solvent, which can be used include methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide, dichloromethane and 1,2-dichloroethane. Better result, such as increased output can be obtained by the implementation of this reaction in the presence of acid. This acid is not particularly limited. Preferred examples of the acid include mineral acids, such as chloride-hydrogen acid, organic acids such as acetic acid and a Lewis acid such as zinc chloride, a complex of boron TRIFLUORIDE-diethyl ether and tetraisopropoxide titanium(IV).

Stage 14-4:

This stage is the stage of synthesizing the compound (I-e) using the production method, described above (stage 3-4), after sulfonylamine amino group of the compound (14-2). For sulfanilamide reaction known to a person skilled in the art is a reaction using the derived sulphonylchloride.

Stage 14-5:

This stage is the stage of synthesizing the compound (I-f) using the production method, described above (stage 3-4), after reaction of the combination between the compound (14-2) and compound (14-7) or (14-8). At this stage use the reaction, such as a combination of using the complex of the transition metal or the like, or nucleophilic aromatic substitution (SNAr who eacce).

The reaction mix at this stage can be carried out, for example, under the same conditions as described in Org. Lett. 2007, Vol. 9, No. 5, 761-764 and Org. Lett. 2003, Vol. 5, No. 23, 4397-4400. In particular, the reaction mix can be carried out by reacting the compound (14-2) with compound (14-7) at a temperature ranging from room temperature to 50°C using a solvent, such as dichloromethane, in the presence of molecular sieves 4A, and a catalyst such as copper acetate(II).

The catalyst used in this reaction are not particularly limited. Preferred examples of the catalyst include metal catalysts such as copper acetate(II)sulfate copper(II)iodide copper(I) chloride copper(I). The amount used of the catalyst is not particularly limited, and it is usually about 0.1 to 0.5 equivalent relative to the original substances. The solvent used in this reaction is not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. Preferred examples of the solvent include N,N-dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, propionitrile and dichloromethane. The reaction temperature is not particularly limited, and it is usually in the range of temperature cooling with ice to a temperature of Ki is possible solvent under reflux, and preferably, for example, from room temperature to the boiling point of the solvent under reflux. The reaction time is not particularly limited, and it is usually from 0.5 to 100 hours, preferably from 1 to 72 hours.

Better result, such as increased output can be achieved by the implementation of this reaction in the atmosphere of oxygen.

When this stage is a reaction mix using the complex of the transition metal or the like as a catalyst, the reaction can be carried out using the compound (14-2) (14-8), which is derived helgaleena, derived heteroarylboronic derived aryloxypropanolamine or derived heteroskedasticityconsistent, under the same conditions as commonly used terms (such as the conditions described in this document, as Org. Lett. 2002, Vol. 4, No. 4, 581). Derived helgaleena, derived heteroarylboronic derived aryloxypropanolamine or derived heteroskedasticityconsistent used at this stage may be a commercially available product used as it is, and can also be obtained from a commercially available product by a method known to a person skilled in the art. PR is the measure of the complex transition metal, used at this stage include dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0), Tris(dibenzylideneacetone)palladium(0) and a complex copper-diol ligand. In this reaction may also be added phosphorus ligand (such as preferably triphenylphosphine, tri-o-tolylphosphino, three-tert-butylphosphine, 2,2'-bis(diphenylphosphino)-1,1 binaphthyl or 1,1'-bis(diphenylphosphino)ferrocene)in order to obtain positive results (such as low reaction temperature, reduced reaction time and increased output). If the complex of the transition metal is palladium complex, the reaction at this stage is preferably carried out in an atmosphere of nitrogen or argon. The solvent used at this stage is not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. For example, if you used the complex of the transition metal is palladium complex may be used N,N-dimethylformamide, N-methyl-2-pyrrolidone, 1,4-dioxane, toluene, xylene or the like. If the complex of the transition metal is copper-diol complex, it can be used 2-propanol or the like. The reaction temperature at this stage is usually in the range from room temperature to the temperature of the boiling point of the solvent under reflux. The reaction time at this stage is not particularly limited, and it is usually from 0.5 to 72 hours, preferably from 0.5 to 24 hours.

If this stage is a nucleophilic aromatic substitution (SNAr reaction), the reaction can be carried out using the compound (14-2) (14-8), which is derived helgaleena, derived heteroarylboronic derived aryloxypropanolamine or derived heteroskedasticityconsistent, in the presence of a base under the same conditions as commonly used terms. Derived helgaleena, derived heteroarylboronic derived aryloxypropanolamine or derived heteroskedasticityconsistent used at this stage may be a commercially available product used as it is, and can also be obtained from a commercially available product by a method known to a person skilled in the art. Nucleophilic aromatic substitution (SNAr reaction)used at this stage may be carried out under the same conditions as commonly used conditions (such as conditions in accordance with methods described in documents such as Org. Prep. Proced. int. 39 (2007) 4, 399-402, Bioorg. Med. Chem. Lett. 15 (2005) 9, 2409-2413 and Bioorg. Med. Chem. Lett. 15 (2005) 3, 719-723). The solvent used is at this stage, not particularly limited, but he would not slow down the reaction and allowed the original substance dissolved therein to a certain extent. Examples of the solvent which can be used include N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide and acetonitrile. Used the base at this stage is not particularly limited. Examples of the base include potassium carbonate, sodium carbonate, sodium hydride and tetrabutylammonium. It is preferable to use potassium carbonate, sodium carbonate and tetrabutylammonium. The reaction temperature at this stage is usually in the range from room temperature to the boiling point of the solvent under reflux. The reaction time at this stage is not particularly limited, and it is usually from 0.5 to 24 hours, preferably from 0.5 to 12 hours.

Stage 14-6:

This stage is the stage of synthesizing the compound (I-g) from the compound (14-2) as the original substances using the production method, described above(stage 8-1) and (stage 3-4)).

The compound of formula (I) according to the present invention, where at least one of R1and R2represents a C1-6alkyl group, which may contain 1-3 substituent selected from the group of substituents α, C1-6alkylcarboxylic group, which may contain 1-3 will replace the La, selected from the group of substituents α, C6-14arylcarbamoyl group, which may contain 1-3 substituent selected from the group of substituents α, C1-6alkylsulfonyl group, which may contain 1-3 substituent selected from the group of substituents α, C6-14arylsulfonyl group, which may contain 1-3 substituent selected from the group of substituents α, 3-10-membered carbocyclic group which may contain 1-3 substituent selected from the group of substituents α, or 5-10-membered heterocyclic group, which may contain 1-3 substituent selected from the group of substituents α, can be obtained for more interaction with any of the compounds (I-c)-(I-g), obtained by the General method of obtaining 14, with a corresponding halide, such as C1-6alkylhalogenide.

The compound of formula (I) according to the present invention obtained in the manner described above, can be optionally converted into a pharmaceutically acceptable salt in the traditional way. Salt can be obtained in a manner that appropriately combined methods commonly used in the chemistry of organic synthesis, and the like. Specific examples of the method include neutralization titration of the free solution of the compound of the present invention the acid solution. The connection formula is (I) of the present invention can, if necessary, convert to MES, exposing the connection known in itself salvadoraceae reaction.

Condensed derived aminopiperidine or its pharmaceutically acceptable salt or MES according to the present invention has a very high inhibitory effect against Aβ production or effect of inhibition of BACE1 and is very useful(Oh) as a preventive or therapeutic agent for a neurodegenerative disease caused by Aβ, a typical example of which is dementia Alzheimer's disease.

Condensed derived aminopiperidine or its pharmaceutically acceptable salt or MES according to the present invention can be obtained in the form of a dosage form in the traditional way. Preferred examples of dosage forms include tablets, coated tablets, such as tablets, film-coated tablets sugar coated microspheres, granules, powders, capsules, syrups, lozenges, inhalants, suppositories, solutions for injections, ointments, eye drops, nose drops, ear drops, poultices and lotions.

These solid preparations such as tablets, capsules, granules and powders may contain usually 0.01-100 wt.%, preferably 0.1 to 100 wt.%, condensed derived aminopiperidine or in pharmaceutical preparations is automatic acceptable salt or MES according to the present invention as the active component.

For the manufacture of dosage forms, the active ingredient in the traditional way is mixed with the components that are commonly used as materials for pharmaceutical preparations, and add the most commonly used excipient, baking powder, binder, grease, dye and corrigent, and add, if necessary, for example, a stabilizer, an emulsifier, a substance that facilitates absorption, surfactant, pH Adjuster, preservative and antioxidant. Examples of such components include animal and vegetable oils such as soybean oil, beef tallow and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane and solid paraffin; essential oils, such as octyldodecanol and isopropylmyristate; higher alcohols, such as cetosteatil alcohol and beganovic alcohol; silicone resins; silicone oils; surfactants such as esters of polyoxyethylene and fatty acids, ester sorbitan and fatty acid ester of glycerol and fatty acids, esters of polyoxyethylenesorbitan and fatty acids, polyoxyethylene hydrogenated castor oil and the block the copolymer of polyoxyethylene and polyoxypropylene; water-soluble polymers such as hydroxyethylcellulose, polyacrylic acid, carboxyvinyl the second polymer, the polyethylene glycol, polyvinylpyrrolidone and methyl cellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropyleneglycol and sorbitol; sugars such as glucose and sucrose; inorganic powders such as silicic anhydride, aluminum silicate and magnesium aluminum silicate, and distilled water. The examples used excipient include lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose and silicon dioxide. Examples of binders include polyvinyl alcohol, simple, polyvinyl ether, methylcellulose, ethylcellulose, Arabian gum, tragakant, gelatin, shellac, hypromellose, hydroxypropylcellulose, polyvinylpyrrolidone, block-copolymer polypropylenglycol and polyoxyethylene and meglumin. Examples of the powder include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin and calcium carboxymethylcellulose. Examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica, and hydrogenated vegetable oil. Examples of the coloring matter used include dyes that are acceptable for pharmaceutical PR the preparations. The examples used corrigent include cocoa powder, menthol, mpasm (empasm), peppermint oil, borneol and cinnamon powder. It is obvious that these components are not limited to these additives.

For example, the preparation for oral administration obtained by adding condensed derived aminopiperidine or its pharmaceutically acceptable salt or MES according to the present invention as an active ingredient, excipient and, if necessary, binder, baking powder, lubricants, coloring matter, corrigent and the like, and then converting the mixture into a powder, microspheres, granules, tablets, coated tablets, capsules or the like in a traditional way. Obviously, tablets or granules may optionally be fitted with a suitable coating, such as a sugar coating.

For example, the syrup or the preparation for injection is obtained by adding a pH regulator, a solubilizer, isotonic means and the like and, if required, solubilizers tools, stabilizer and the like in the traditional way. The preparation for injection can be a pre-prepared solution or powder as such or powder containing a suitable additive, which is dissolved before use. The preparation for injection outstanging usually 0.01-100 wt.%, preferably 0.1 to 100 wt.% the active component. In addition, the liquid preparation for oral administration, such as suspension or syrup may contain usually 0.01-100 wt.%, preferably 0.1 to 100 wt.% the active component.

For example, the preparation for external use can be obtained by any conventional method without particular limitations. As the material for the base can be used any of the many materials commonly used to obtain a pharmaceutical preparation, quasilikelihood tools, cosmetics or the like. Examples of the material for the base include materials such as animal and vegetable oils, mineral oils, essential oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, clay minerals and distilled water. If necessary, can be added a pH regulator, antioxidant, helatoobrazovatel, preservative and fungicide, coloring matter, flavoring substance, or the like. In addition, if necessary, can be mixed components, such as component, having the effect of inducing differentiation, power flow, bactericide, anti-inflammatory agent, an activator of cells, vitamin, amino acids which, humectant and keratolytic agent.

Dose condensed derived aminopiperidine or its pharmaceutically acceptable salt or MES according to the present invention as an active ingredient change, for example, in accordance with the degree of symptoms, age, sex, body weight, method of administration, type of salt and the particular form of the disease. Usually the active ingredient is administered orally to an adult in an amount of about 30 μg to 10 g, preferably from 100 μg to 5 g, and more preferably from 100 μg to 1 g per day or impose an adult by injection of from about 30 μg to 1 g, preferably 100 μg to 500 mg and more preferably from 100 μg to 300 mg per day as single dose or in divided doses, respectively.

The best option of carrying out the invention

The present invention is described in more detail below with reference to examples, sample receiving and sample tests. However, the present invention is not limited to this. Abbreviations used in the examples are conventional abbreviations known to the person skilled in the art. Some abbreviations are shown below:

THF: tetrahydrofuran

DMF: N,N-dimethylformamide

TFUCK: triperoxonane acid

EDC·HCl: hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

ptsh: p operativnaya thin-layer chromatography

LC-MS: liquid chromatography-mass spectrometry

PyBOP: hexaphosphate benzotriazol-1-yloxytris(pyrrolidino)phosphonium

Pd2DBA3: Tris(dibenzylideneacetone)dipalladium

Pd(t-Bu3P)2: bis(tri-tert-butylphosphine)palladium

Chemical shifts in the spectrum of proton nuclear magnetic resonance recorded in δ units (ppm) relative to tetramethylsilane and the binding constants are recorded in Hertz (Hz). Types of signals in the spectrum labeled with: singlet, d: doublet, t: triplet, ush.: widened.

"Room temperature" in the following examples and the examples of the preparation usually refers to a temperature in the range from about 10°C to about 35°C. "%" means " wt.%, if not specified otherwise.

Example obtain 1

Synthesis of tert-butyl (±)-[(4aR*,8aS*)-8a-(5-amino-2-forfinal)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

[Formula 20]

(1)Synthesis of ethyl 2-triftoratsetilatsetonom-1 enecarboxylate

Diisopropylethylamine (38,0 ml) was added to a solution of ethyl 2-oxocyclohexanecarboxylate (8.00 g) in dichloromethane (100 ml) in a nitrogen atmosphere at -78°C. After stirring at the same temperature for 10 minutes was added triftormetilfullerenov anhydride (8,80 ml). The mixture was stirred overnight while gradually warming to room temperature. The mixture was washed with water and ZAT is m twice washed with 5% citric acid solution (150 ml). The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain specified in the connection header in the form of the crude product (15.5 g). The crude product was used for next reaction without further purification.

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.33 (t, J=7.2 Hz, 3H), of 1.66 (m, 2H), 1,78 (m, 2H), 2.40 a (m, 2H), 2,48 (m, 2H), 4,28 (kV, J=7.2 Hz, 2H).

(2)Synthesis of ethyl 2-(2-forfinal)cyclohex-1 enecarboxylate

Ethanol (100 ml) was added to a solution of ethyl 2-triftoratsetilatsetonom-1 enecarboxylate obtained in the example of a 1-(1) (17.0 g)in toluene (200 ml). Was added 2-ftorhinolonovy acid (7,74 g) and tetrakis(triphenylphosphine)palladium (1.60 g). Added 1 n solution of sodium carbonate (55,3 ml), after which the reaction atmosphere was replaced with nitrogen. The reaction solution was heated up to 80°C and was stirred for eight hours. After bringing to room temperature, the excess ethanol is evaporated under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (10.5 g).

1H is the Mr (400 MHz, CDCl3) δ (ppm): of 0.87 (t, J=7.2 Hz, 3H), of 1.75 (m, 4H), of 2.36 (m, 2H), 2,46 (m, 2H), 3,89 (kV, J=7.2 Hz, 2H), 6,99-was 7.08 (m, 3H), 7,22 (m, 1H).

(3)Synthesis of [2-(2-forfinal)cyclohex-1-enyl]methanol

Alumoweld lithium (1.90 g) was placed in a distillation flask was added THF (300 ml) in an ice bath. A solution of ethyl 2-(2-forfinal)cyclohex-1 enecarboxylate obtained in example obtain 1-(2) (10.3 g)in THF (100 ml) was added dropwise to the reaction solution at the same temperature and the mixture was stirred for one hour. Sequentially added to the reaction solution, water (1.90 ml), 5 n sodium hydroxide solution (1.90 ml) and water (5,70 ml). Addition was added anhydrous magnesium sulfate, followed by extraction with ethyl acetate. The insoluble substance was separated by filtration and the filtrate was concentrated under reduced pressure to obtain specified in the connection header (8,88 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,22 (dt, J=2.0 a, 5,2 Hz, 1H), 1,75 (ush., 4H), 2,25 (ush., 2H), 2,30 (ush., 2H), 3,86 (d, J=5,2 Hz, 2H),? 7.04 baby mortality (t, J=9,2 Hz, 1H), 7,08-7,13 (m, 2H), 7,22 (m, 1H).

(4)Synthesis of 1-(2-Cormeilles-1-enyl)-2-fermental

N,N-Diisopropylethylamine (14.7 ml) was added to a solution of [2-(2-forfinal)cyclohex-1-enyl]methanol obtained in example obtain 1-(3) (8,88 g), in dichloromethane (300 ml). Methanesulfonanilide (4,00 ml) was added dropwise to the reaction solution in an ice bath. The reaction solution pic is upendo was heated to room temperature and was stirred overnight. To the reaction solution was added water, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on a column of silica gel with obtaining specified in the connection header (5,88 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,75 (USS, 4H), and 2.27 (m, 4H), 3,89 (USS, 2H), 7.03 is-7,29 (m, 4H).

(5)Synthesis of hydrochloride of 2-[2-(2-forfinal)cyclohex-1-animetal]estimacion

The thiourea (2,09 g) was added to a solution of 1-(2-Cormeilles-1-enyl)-2-fervently obtained in example obtain 1-(4) (5,88 g), in ethanol (200 ml). The reaction solution was heated up to 80°C and was stirred for 270 minutes. The thiourea (399 mg) was added to the reaction solution, followed by stirring at the same temperature for one hour. After cooling to room temperature the solvent is evaporated under reduced pressure. To the residual syrup was added diethyl ether and ethyl acetate. White solid was besieged by ultrasonic treatment. After sedimentation at room temperature for 30 minutes to remove the supernatant. Then the solid is washed with diethyl ether and again removing the supernatant. The obtained solid substance was dried at ponie nom pressure obtaining specified in the connection header (6,38 g).

1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.69 in (s, 4H), 2,20 (s, 2H), 2,21 (s, 2H), 3,60 (s, 2H), 7,17 (dt, J=2.0 a, 7,6 Hz, 1H), 7,24 (m, 2H), 7,38 (m, 1H), 9,04 (USS, 3H).

(6)Synthesis of (±)-(4aR*,8aS*)-8a-(2-forfinal)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-ylamine

Hydrochloride of 2-[2-(2-forfinal)cyclohex-1-animetal]estimacion obtained in example obtain 1-(5) (6,38 g), was dissolved in TFOC (32,0 ml) under cooling with ice and triftormetilfullerenov acid (6,40 ml) was added dropwise at the same temperature. The reaction solution was stirred overnight while gradually warming to room temperature. The reaction solution was poured into ice, diluted with diethyl ether and then neutralized with sodium bicarbonate. The reaction mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to get crude product. The crude product was purified by chromatography on a column with NH-silica gel with obtaining specified in the connection header (4,58 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,47 of-1.83 (m, 7H), and 2.26 (m, 1H), 2,52 (DD, J=2,8, 12.0 Hz, 1H), 2,70 (DDD, J=4,0, 6,8, 12.0 Hz, 1H), 2,86 (DD, J=4,4, and 12.4 Hz, 1H), 7,01 (DDD, J=1,2, 8,0, to 12.8 Hz, 1H), was 7.08 (dt, J=1,2, 7,6 Hz, 1H), 7,21 (m, 1H), 7,28 (dt, J=2,0, 8.0 Hz, 1H).

(7)Synthesis of tert-butyl (±)-[(4aR*,8aS*)-8a-(2-fluoro-5-nitrophenyl)-4a,5,6,7,8,8a-hexage the on-4H-benzo[d][1,3]thiazin-2-yl]carbamate

The compound obtained in example obtain 1-(6) (3.50 g)was added to concentrated sulfuric acid (25,0 ml) in an ice bath. To the reaction solution was added dropwise fuming nitric acid (specific gravity: 1,53, 800 μl), followed by stirring at the same temperature for 30 minutes. The reaction mixture was poured on ice and neutralized 5 N. solution of sodium hydroxide. The obtained solid substance was collected by filtration through a glass filter and washed with water. The solid was dissolved in a mixed solvent of THF and ethyl acetate and the solution was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate evaporated under reduced pressure at room temperature or below to obtain an intermediate compound in the form of the crude reaction product. To a solution of the crude product in THF (100 ml) was added triethylamine (9,20 ml). To the reaction solution was added di-tert-BUTYLCARBAMATE (8,64 g), followed by stirring for two days. A saturated solution of sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column with a specification of the gel with obtaining specified in the connection header (4,70 d).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1.55V (s, 9H), 1,65-of 1.88 (m, 7H), of 2.23 (m, 1H), 2,55 (DD, J=2,8, to 12.8 Hz, 1H), and 2.83 (m, 2H), 7.23 percent (m, 1H), to 8.20 (m, 2H).

(8)Synthesis of tert-butyl (±)-[(4aR*,8aS*)-8a-(5-amino-2-forfinal)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

To a solution of the compound obtained in the example of a 1-(7) (58,0 mg), in methanol (14,5 ml) was added 10% palladium on carbon (15.8 mg). The atmosphere of the reaction system was replaced with hydrogen, followed by stirring at room temperature for two hours. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure to get crude product specified in the connection header (58,0 mg). The crude product was used for next reaction without further purification.

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.53 (s, 9H), 1,64-to 1.87 (m, 7H), to 2.35 (m, 1H), 2,47 (DD, J=2,8, to 12.8 Hz, 1H), 2,88 (m, 2H), to 3.64 (s, 2H), 6,54 (m, 2H), 6,85 (m, 1H).

Example of getting 2

Synthesis of tert-butyl [(4aR*,8aS*)-8a-(5-amino-2-forfinal)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

[Formula 21]

(1)Synthesis of tert-butyl (+)-[(4aR*,8aS*)-8a-(2-fluoro-5-nitrophenyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

The compound obtained in the example of a 1-(7) (80.0 mg), optically separated using CHIRALPAK™ OJ-H production Daicel Chemical Industries, Ltd. (2 cm ×25 cm, mobile phase: hexane:ethanol = 8:2, flow rate: 20 ml/min). Components having a retention time from 9,38 to 18.3 minutes, collected by obtaining specified in the connection header. The same operation was repeated to obtain specified in the title compound (433 mg, >99% ee) of racemate (1,00 g).

(2)Synthesis of tert-butyl [(4aR*,8aS*)-8a-(5-amino-2-forfinal)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

The solution dithionite sodium (923 mg) in water (20,0 ml) was added dropwise to a solution of the compound obtained in the example of a 2-(1) (433 mg)in ethanol (100 ml) at room temperature. The reaction solution was stirred for 30 minutes and the ethanol is then evaporated under reduced pressure at room temperature or below. The residue was neutralized with sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on a column with NH-silica gel with obtaining specified in the title compound (111 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.53 (s, 9H), 1.57 in-2,05 (m, 7H), a 2.36 (dt, J=4,4, 14.4 Hz, 1H), 2,47 (DD, J=2,8, and 12.4 Hz, 1H), 2,84 (m, 1H), 2,90 (DD, J=4.0 a, and 12.4 Hz, 1H), to 3.64 (s, 2H), 6,55 (m, 2H), 6,85 (m, 1H).

Example of getting 3

Synthesis of tert-butyl (-)-[(4aR*,7aS*)-7a-(5-and the Ino-2-forfinal)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

[Formula 22]

(1)Synthesis of ethyl 2-triftoratsetilatsetonom-1 enecarboxylate

N,N-Diisopropylethylamine to 27.2 ml) was added to a solution of ethyl 2-oxo-cyclopentanecarboxylate (5,00 g) in dichloromethane (100 ml) at -78°C for 10 minutes. Triftormetilfullerenov anhydride (of 5.92 ml) was added dropwise to the reaction solution at the same temperature. The reaction solution was stirred overnight while gradually warming to room temperature. To the reaction mixture was added water, then twice washed with 5% citric acid solution (150 ml). The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and to the filtrate was added toluene (200 ml). Dichloromethane is evaporated under reduced pressure at room temperature or below with obtaining the solution specified in the header of the compound in toluene. The connection used for the next reaction without further purification.

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.33 (t, J=6.0 Hz, 3H), 2,02 (m, 2H), 2,72 (m, 4H), 4,27 (kV, J=6.0 Hz, 2H).

(2)Synthesis of ethyl 2-(2-forfinal)cyclopent-1-enecarboxylate

2-Ferbinteanu acid (4,48 g) and tetrakis(triphenylphosphine)palladium (740 mg) was added to a solution of ethyl 2-triftoratsetilatsetonom-1 enecarboxylate obtained in example of preparation of 3-(1)in toluene is. Then added to the reaction solution ethanol (100 ml) and 1 n sodium carbonate solution (32 ml), and then replaced the reactionary atmosphere of nitrogen. The reaction solution was heated to 85°C and was stirred overnight. The reaction solution was cooled to room temperature, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (7,60 g).

ESI-MS; m/z 235 [M+H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,06 (t, J=7.2 Hz, 3H), 2,02 (m, 2H), and 2.83 (t, J=7,6 Hz, 4H), of 4.05 (q, J=7.2 Hz, 2H),? 7.04 baby mortality (m, 1H), 7,10 (dt, J=1,2, 7.2 Hz, 1H), 7,19-7,29 (m, 2H).

(3)Synthesis of [2-(2-forfinal)cyclopent-1-enyl]methanol

A solution of ethyl 2-(2-forfinal)cyclopent-1-enecarboxylate obtained in example of preparation of 3-(2) (7,60 g)in THF (100 ml) was added dropwise to a suspension of lithium aluminum hydride (1,34 g) in THF (300 ml) in an ice bath. The reaction solution was stirred at the same temperature for one hour. Then was added dropwise water (1.35 ml), 5 n sodium hydroxide solution (1.35 ml) and water (of 4.05 ml) in an ice bath. To the obtained reaction mixture was added anhydrous magnesium sulfate, followed by extraction with ethyl acetate. The reaction mixture is filtered through celite and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (6.50 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,34 (dt, J=1,6, 5.8 Hz, 1H), 2,00 (m, 2H), 2,65 (m, 2H), 2,75 (m, 2H), 4,15 (d, J=5.8 Hz, 2H), 7.03 is-7,27 (m, 4H).

(4)Synthesis of 1-(2-hlormetilsilatran-1-enyl)-2-fermental

N,N-Diisopropylethylamine (17,2 ml) was added to a solution of [2-(2-forfinal)cyclopent-1-enyl]methanol obtained in example of preparation of 3-(3) (6.50 g)in dichloromethane (300 ml) in an ice bath. Methanesulfonanilide (2,88 ml) was added to the reaction solution at the same temperature. Then the reaction solution was heated to room temperature and was stirred overnight. To the reaction mixture was added water, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (of 7.23 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,02 (m, 2H), to 2.67 (m, 2H), 2,77 (m, 2H), 4,11 (s, 2H), 7,07 (m, 1H), 7,15 (m, 1H), 7.23 percent-7,30 (m, 2H).

(5)Synthesis of (±)-(4aR*,7aS*)-7a-(2-forfinal)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine

The thiourea (2,60 g) was added to a solution of 1-(2-hlormetilsilatran-1-enyl)-2-fervently obtained in example of preparation of 3-(4) (7.20 g), the ethanol (100 ml) and the mixture was stirred at the boil under reflux for five hours. The reaction solution was cooled to room temperature and evaporated under reduced pressure the solvent. The residual syrup was washed with heptane, and then dried under reduced pressure. Triperoxonane acid (50,0 ml) and triftormetilfullerenov acid (10.0 ml) was added to the residue in an ice bath. Then the reaction mixture was heated to room temperature and was stirred for four days. The reaction solution was poured into ice, diluted simple ether and then neutralized with sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by chromatography on a column with NH-silica gel with obtaining specified in the connection header (to 4.98 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,69-of 1.95 (m, 5H), 2,62 (m, 1H), 2,74 (DD, J=4.0 a, and 12.4 Hz, 1H), 2,77 (m, 1H), equal to 2.94 (DD, J=3,2, and 12.4 Hz, 1H), 7,00 (DDD, J=1,6, 8,4, to 12.8 Hz, 1H), to 7.09 (DDD, J=1,2, of 7.2 and 7.6 Hz, 1H), 7,20 (m, 1H), 7,33 (DDD, J=2,0, an 8.4, and 8.8 Hz, 1H).

(6)Synthesis of tert-butyl (±)-[(4aR*,7aS*)-7a-(2-fluoro-5-nitrophenyl)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

The compound obtained in example of preparation of 3-(5) (1,00 g), was dissolved in sulfuric acid (6,00 ml) in an ice bath. Fuming nitric acid (215 μl, specific gravity: 1,53) was added what about the drops to the reaction solution at the same temperature, followed by stirring for 30 minutes. The reaction mixture was poured on ice and neutralized 5 N. solution of sodium hydroxide. The obtained solid substance was collected by filtration through a glass filter and then was dissolved in a mixed solvent of THF and ethyl acetate. The solution was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate evaporated under reduced pressure to obtain an intermediate compound. The triethylamine (2,77 ml) and di-tert-BUTYLCARBAMATE (2,47 g) was added to a solution of intermediate compound in THF (50 ml) followed by stirring for two days. A saturated solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (1,00 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.53 (s, 9H), 1,80-of 2.16 (m, 5H), 2,52 (m, 1H), was 2.76 (m, 1H), 2,97 (m, 2H), 7,22 (m, 1H), to 8.20 (m, 1H), 8,25 (m, 1H).

(7)Synthesis of tert-butyl (±)-[(4aR*,7aS*)-7a-(5-amino-2-forfinal)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

A saturated solution of ammonium chloride (2.10 ml) and iron powder (905 mg) was added to a solution of compounds poluchennogo is in the sample preparation of 3-(6) (800 mg), in ethanol (21,0 ml) and the mixture was stirred at the boil under reflux for 30 minutes. The reaction solution was cooled to room temperature and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column with NH-silica gel with obtaining specified in the title compound (545 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): is 1.51 (s, 9H), 1,87-of 2.08 (m, 5H), 2,62 (m, 1H), 2,70 (DD, J=4,4, of 14.0 Hz, 1H), to 3.02 (DD, J=3,4, of 14.0 Hz, 1H), 3,03 (m, 1H), 3,63 (s, 2H), 6,55 (m, 1H), 6,59 (DD, J=2,6, 7,0 Hz, 1H), 6,85 (DD, J=8,4, 12.0 Hz, 1H).

(8)Synthesis of tert-butyl (-)-[(4aR*,7aS*)-7a-(5-amino-2-forfinal)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

The compound obtained in example of preparation of 3-(7) (50 mg), optically separated using CHIRALPAK™ AD-H production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 9:1, flow rate: 20 ml/min), and the components with retention time from 17.1% to 22.8 minutes was collected. This operation was repeated to obtain specified in the title compound (200 mg, >99% ee) from 500 mg of the racemate.

Example 4

Synthesis of tert-butyl [(4aR*,8aS*)-8a-(3-AMINOPHENYL)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

[Formula 23]

(1)Synthesis of 2-(3-nitrophenyl)cyclohex-1-interbanded

Ethanol (11,1 ml) was added to a solution of 2-branikloks-1-encebollada (2,22 g) in toluene (22,2 is l). To the mixture was added 3-nitrophenylarsonic acid (2,34 g), tetrakis(triphenylphosphine)palladium (270 mg) and 1 n sodium carbonate solution (14,0 ml). The atmosphere of the reaction system was replaced with nitrogen. Then the reaction solution was stirred at the boil under reflux for three hours. The reaction solution was cooled to room temperature, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by chromatography on a column of silica gel with obtaining specified in the header of the compound (2.00 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): to 1.76 (m, 2H)and 1.83 (m, 2H), 2,39 (m, 2H), has 2.56 (m, 2H), 7,58 (m, 2H), 8,14 (m, 1H), 8,24 (m, 1H), 9,46 (s, 1H).

(2)Synthesis of [2-(3-nitrophenyl)cyclohex-1-enyl]methanol

The heptahydrate of cerium chloride (1.22 g) was added to a mixed solution of 2-(3-nitrophenyl)cyclohex-1-interbanded obtained in example 4-(1) (630 mg)in methanol (60,0 ml) and THF (20,0 ml) in an ice bath. Sodium borohydride (130 mg) was added to the reaction solution at the same temperature, followed by stirring for 30 minutes. A saturated solution of ammonium chloride was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed us is placed a solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to get crude product. The crude product was purified by chromatography on a column with NH-silica gel with obtaining specified in the title compound (610 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.28 (t, J=5,2 Hz, 1H), 1.77 in (m, 4H), 2,30 (s, 4H), 3,93 (d, J=5,2 Hz, 2H), 7,50 (m, 2H), 8,04 (m, 1H), 8,11 (dt, J=2,0, 7.2 Hz, 1H).

(3)Synthesis of 1-(2-Cormeilles-1-enyl)-3-nitrobenzene

N,N-Diisopropylethylamine (of 3.64 ml) was added to a solution of [2-(3-nitrophenyl)cyclohex-1-enyl]methanol obtained in example 4-(2) (1,67 g), in dichloromethane (109 ml) in an ice bath. Then was added dropwise methanesulfonanilide (668 μl). The reaction mixture was heated to room temperature and was stirred overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (1.56 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,78 (m, 4H), 2,32 (s, 4H), 3,86 (s, 2H), 7,54 (t, J=7,6 Hz, 1H), 7,60 (m, 1H), 8,10 (m, 1H), 8,15 (m, 1H).

(4)Synthesis of hydrochloride of 2-[2-(3-n is trienyl)cyclohex-1-animetal]estimacion

The thiourea (495 mg) was added to a solution of 1-(2-Cormeilles-1-enyl)-3-nitrobenzene obtained in example 4-(3) (1.56 g)in ethanol (71,6 ml) and the mixture was stirred at the boil under reflux for four hours. The reaction solution was cooled to room temperature and then evaporated under reduced pressure the solvent. The residual solid was washed with ether to obtain specified in the connection header (2,04 g).

1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1,70 (s, 4H), 2,22 (s, 2H), 2,30 (s, 2H), 3,68 (s, 2H), 7,65 (dt, J=1,2, 7,6 Hz, 1H), 7,71 (t, J=8.0 Hz, 1H), 7,99 (t, J=2.0 Hz, 1H), 8,19 (DDD, J=1,6, and 2.4, and 8.4 Hz, 1H), 9,02 (USS, 3H).

(5)Synthesis of (±)-(4aR*,8aS*)-8a-(3-nitrophenyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-ylamine

Triftormetilfullerenov acid (1,00 ml) was added to a solution of the hydrochloride of 2-[2-(3-nitrophenyl)cyclohex-1-animetal]estimacion obtained in example 4-(4) (2,04 g), in TFOC (10.0 ml) in an ice bath. The reaction solution was heated to room temperature, followed by stirring overnight. Triftormetilfullerenov acid (1,00 ml) was additionally added to the reaction solution, followed by stirring for two days. After confirming completion of the reaction, the reaction mixture was carefully poured into a mixed solution of saturated sodium bicarbonate solution and simple live on the ice is Noah bath. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with a saturated solution of sodium bicarbonate and a saturated solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to get crude product. The crude product was purified by chromatography on a column with NH-silica gel with obtaining specified in the connection header (1,62 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,47 is 1.86 (m, 8H), of 2.23 (DDD, J=4,0, 6,4, and 11.6 Hz, 1H), of 2.51 (DD, J=2,8, 12.0 Hz, 1H), 2,78 (DD, J=4,4, 12.0 Hz, 1H), of 4.45 (s, 2H), 7,49 (t, J=8.0 Hz, 1H), to 7.67 (DDD, J=1,2, of 2.0, 8.0 Hz, 1H), 8,08 (DDD, J=1,2, and 2.4, 8.0 Hz, 1H), 8,19 (t, J=2.0 Hz, 1H).

(6)Synthesis of tert-butyl (±)-[(4aR*,8aS*)-8a-(3-nitrophenyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

The triethylamine (is 3.08 ml) was added to a solution of the compound obtained in example 4-(5) (1,62 g)in THF (30,0 ml). Di-tert-BUTYLCARBAMATE (1,33 g) was added to the reaction solution, followed by stirring at room temperature for three days. The reaction solution was concentrated under reduced pressure. The residue was purified by chromatography on a column with NH-silica gel with obtaining specified in the title compound (2.28 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,46-of 1.95 (m, 8H), and 1.54 (s, 9H), 2,46 (m, 1H), 2,48 (DD, J=2,4, 13,2 Hz, 1H), 2,74 (DD, J=44, of 12.8 Hz, 1H), EUR 7.57 (t, J=8.0 Hz, 1H), of 7.70 (d, J=8.0 Hz, 1H), 8,18 (m, 2H).

(7)Synthesis of tert-butyl (-)-[(4aR*,8aS*)-8a-(3-nitrophenyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

The compound obtained in example 4-(6) (70.0 mg)was dissolved in ethanol (1.2 ml) and optically separated using CHIRALPAK™ OJ-H production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 8:2, flow rate: 20 ml/min). Components having a retention time of from 12.0 to 21,51 minutes, collected by obtaining specified in the header (-)-isomer. This operation was repeated to obtain specified in the header (-)-isomer (144 mg) of 290 mg of the original substance.

(8)Synthesis of tert-butyl [(4aR*,8aS*)-8a-(3-AMINOPHENYL)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

A saturated solution of dithionite sodium (879 mg) was added to a solution of tert-butyl (-)-[(4aR*,8aS*)-8a-(3-nitrophenyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate (395 mg) in ethanol (20 ml) at room temperature. After stirring at room temperature for 10 minutes was additionally added to the reaction solution of ethanol (10 ml). After stirring at room temperature for five minutes was further added water (10 ml). The reaction solution was heated to 40°C and was stirred for 30 minutes. After confirming completion of the reaction, the reaction solution was cooled to room temperature, the Excess of ethanol in the reaction solution is evaporated under reduced pressure and then the aqueous layer was extracted with ethyl acetate. The organic layer was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column with NH-silica gel with obtaining specified in the title compound (110 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.53 (s, 9H), 1,61 of 1.99 (m, 8H), of 2.38 (DD, J=2,4, 13,2 Hz, 1H), 2,39 (m, 1H), 2,89 (DD, J=4,8, 13,2 Hz, 1H), 3,74 (s, 2H), 6,60 (m, 2H), 6,66 (d, J=8,4 Hz, 1H), 7,15 (t, J=7,6 Hz, 1H).

Example of getting 5

Synthesis of tert-butyl (-)-[(4aR*,8aS*)-8a-(5-amino-2,3-differenl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

[Formula 24]

(1)Synthesis of ethyl 2-(2,3-differenl)cyclohex-1 enecarboxylate

Specified in the title compound (675 mg) was obtained from ethyl 2-triftoratsetilatsetonom-1 enecarboxylate obtained in the example of a 1-(1) (1,00 g)and 2,3-diftorhinolonom acid (627 mg) according to the method of example obtain 1-(2).

1H-NMR (400 MHz, CDCl3) δ (ppm): to 0.92 (t, J=7.2 Hz, 3H), of 1.76 (m, 4H), of 2.34 (m, 2H), 2,46 (m, 2H), 3,92 (kV, J=7.2 Hz, 2H), PC 6.82 (m, 1H), 7,02 (m, 2H).

(2)Synthesis of [2-(2,3-differenl)cyclohex-1-enyl]methanol

Specified in the title compound (490 mg) was obtained from ethyl 2-(2,3-differenl)cyclohex-1 enecarboxylate obtained in example obtain 5-(1) (675 mg), matched with the accordance with the method of example obtain 1-(3).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,19 (dt, J=1,6, 5.8 Hz, 1H), about 1.75 (m, 4H), 2,24 (m, 2H), 2,30 (m, 2H), 3,86 (d, J=5.8 Hz, 2H), 6.87 in (m, 1H),? 7.04 baby mortality (m, 2H).

(3)Synthesis of 1-(2-Cormeilles-1-enyl)-2,3-diferente

Specified in the title compound (588 mg) was obtained from [2-(2,3-differenl)cyclohex-1-enyl]methanol obtained in example obtain 5-(2) (490 mg), in accordance with the method of example obtain 1-(4).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1.77 in (s, 4H), 2,29 (USS, 4H), 3,85 (s, 2H), of 6.96 (m, 1H), 7,07 (m, 2H).

(4)Synthesis of hydrochloride of 2-[2-(2,3-differenl)cyclohex-1-animetal]estimacion

Specified in the title compound (635 mg) was obtained from 1-(2-Cormeilles-1-enyl)-2,3-diferente obtained in example obtain 5-(3) (588 mg), and thiourea (193 mg) in accordance with the method of example obtain 1-(5).

1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1,67 (s, 4H), 2,19 (s, 2H), 2,20 (s, 2H), 3,62 (s, 2H), 6,97 (m, 1H), 7,22 (m, 1H), 7,38 (m, 1H), 8,99 (s, 3H).

(5)Synthesis of (±)-(4aR*,8aS*)-8a-(2,3-differenl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-ylamine

Specified in the title compound (447 mg) was obtained from hydrochloride of 2-[2-(2,3-differenl)cyclohex-1-animetal]estimacion obtained in example obtain 5-(4) (635 mg), in accordance with the method of example obtain 1-(6).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,48-of 1.81 (m, 7H), 2,22 (m, 1H), 2,55 (DD, J=2,8, 12.0 Hz, 1H), 2,66 (m, 1H), 2,87 (DD, J=4,4, 12.0 Hz, 1H), of 4.45 (s, 2H), 7,03 (m, 3H).

(6)Synthesis of tert-butyl (±)-[(4aR*,8aS*)-8a-(2,3-debtor-5-nitrophenyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

Specified in the title compound (530 mg) was obtained from (±)-(4aR*,8aS*)-8a-(2,3-differenl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-ylamine obtained in example obtain 5-(5) (420 mg), in accordance with the method of example obtain 1-(7).

1H-NMR (400 MHz, CDCl3) δ (ppm): and 1.54 (s, 9H), 1,54-1,90 (m, 7H), 2,19 (m, 1H), 2,58 (DD, J=2,8, to 12.8 Hz, 1H), and 2.79 (m, 1H), 2,82 (m, 1H), with 8.05 (m, 2H).

(7)Synthesis of tert-butyl (±)-[(4aR*,8aS*)-8a-(5-amino-2,3-differenl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

Specified in the title compound (174 mg) was obtained from tert-butyl (±)-[(4aR*,8aS*)-8a-(2,3-debtor-5-nitrophenyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in example obtain 5-(6) (530 mg), in accordance with the method of example the preparation of 3-(7).

ESI-MS; m/z 398 [M+H].

1H-NMR (400 MHz, CDCl3) δ (ppm): and 1.54 (s, 9H), 1,63-of 1.92 (m, 7H), 2,31 (m, 1H), of 2.51 (DD, J=2,4, of 12.8 Hz, 1H), 2,81 (m, 1H), 2,92 (DD, J=4,0, to 12.8 Hz, 1H), and 3.72 (s, 2H), 6,29 (m, 1H), 6.42 per (DDD, J=2,8, 6,0, 11.2 Hz, 1H).

(8)Synthesis of tert-butyl (-)-[(4aR*,8aS*)-8a-(5-amino-2,3-differenl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

tert-Butyl (±)-[(4aR*,8aS*)-8a-(5-amino-2,3-differenl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in example obtain 5-(7) (150 mg), optically separated using CHIRALPAK™ AD-H production Daicel Chemica Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 8:2, flow rate: 20 ml/min). Components having a retention time from 9,13 up to 12.4 minutes, collected by obtaining specified in the title compound (42 mg).

An example of obtaining 6

Synthesistert-butyl (±)-[(4aR*,7aS*)-7a-(5-amino-2-methoxyphenyl)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

[Formula 25]

(1)Synthesistert-butyl (±)-[(4aR*,7aS*)-7a-(2-methoxy-5-nitrophenyl)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

To a solution of the compound obtained in example of preparation of 3-(6) (97 mg)in methanol (2.0 ml) was added a 28% solution of sodium methoxide in methanol (100 ml). The reaction solution was stirred at room temperature for one hour and stirred at 45°C for five hours. The reaction solution was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (to 75.8 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1.50 in (s, 9H), 1,75-of 2.36 (m, 6H), 2,82-only 2.91 (m, 1H), 3,13-up 3.22 (m, 1H), 3,22-3,29 (m, 1H), a 4.03 (s, 3H), 7,02 (d, J=9,2 Hz, 1H), 8,14 (d, J=2,8 Hz, 1H), 8,23 (DD, J=9,2, 2.8 Hz, 1H).

(2)Synthesistert-butyl (±)-[(4aR*,7aS*)-7a-(5-amino-2-methoxyphenyl)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

Iron (83,1 mg) and a saturated solution of ammonium chloride (168 μl) on balali to a solution of compounds received in the sample receiving 6-(1) (75,8 mg)in ethanol (1,68 ml). The reaction solution was heated under reflux at an ambient temperature of 100°C for 20 minutes. After cooling to room temperature was added to the reaction solution in ethyl acetate. The insoluble substance was filtered. To the filtrate was added water, followed by extraction with ethyl acetate. The organic layer was concentrated. The residue was purified by chromatography on NH-silica gel with obtaining specified in the title compound (50 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1.50 in (s, 9H), 1,78-of 2.15 (m, 5H), 2,49-2,61 (m, 1H), 2,67-to 2.74 (DD, J=13,1, a 4.3 Hz, 1H), 3,09-and 3.16 (DD, J=13,1, a 4.3 Hz, 1H), 3,16-of 3.25 (m, 1H), 3,42-3,54 (USS, 2H), 3,79 (s, 3H), 6,59-6,62 (m, 2H), 6.73 x-6,77 (m, 1H).

Example of getting 7

Synthesis of tert-butyl (-)-[(4aR*,9aS*)-9a-(5-amino-2-forfinal)-4,4a,5,6,7,8,9,9a-octahydrocyclopenta[d][1,3]thiazin-2-yl]carbamate

[Formula 26]

(1)Synthesis of methyl 2-(2-forfinal)cyclohepta-1 enecarboxylate

Specified in the title compound (10.2 g) was obtained from methyl 2-triftoratsetilatsetonom-1 enecarboxylate obtained in accordance with example obtain 1-(1) (16.0 g), and 2-ftorhinolonovy acid (4,50 g) in accordance with the method of example obtain 1-(2).

ESI-MS; m/z 249 [M+H].

(2)Synthesis of [2-(2-forfinal)cyclohepta-1-enyl]methanol

Specified in the header connection (4,50 who) was obtained from methyl 2-(2-forfinal)cyclohepta-1 enecarboxylate, obtained in example obtain 7-(1) (10.2 g), in accordance with the method of example obtain 1-(3).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,21 (dt, J=2.0 a, 6,0 Hz, 1H), 1.56 to to 1.67 (m, 4H), of 1.84 (m, 2H), 2,46 (m, 4H), to 3.89 (m, 2H),? 7.04 baby mortality (m, 1H), to 7.09 (m, 2H), 7,21 (m, 1H).

(3)Synthesis of 1-chloromethyl-2-(2-forfinal)cycloheptene

Specified in the title compound (1.56 g) was obtained from [2-(2-forfinal)cyclohepta-1-enyl]methanol obtained in example obtain 7-(2) (2.10 g), in accordance with the method of example obtain 1-(4).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,55 by 1.68 (m, 4H)and 1.83 (m, 2H), 2,46 (m, 4H), to 3.92 (d, J=3.2 Hz, 2H), 7,05 (DDD, J=1,6, 8,0, 9.6 Hz, 1H), 7,11 (dt, J=1,2, 7.2 Hz, 1H), 7,20 (dt, J=2,0, 7.2 Hz, 1H), 7,26 (m, 1H).

(4)Synthesis of hydrochloride of 2-[2-(2-forfinal)cyclohepta-1-animetal]estimacion

Specified in the header of the connection (for 2.01 g) was obtained from 1-chloromethyl-2-(2-forfinal)cycloheptene obtained in example obtain 7-(3) (1.56 g)and thiourea (507 mg) in accordance with the method of example obtain 1-(5).

1H-NMR (400 MHz, DMSO-d6) δ (ppm): and 1.54 (m, 4H), 1.77 in (m, 2H), is 2.37 (m, 4H), of 3.65 (m, 2H), 7,11 (dt, J=2,0, 7.2 Hz, 1H), 7,19 (m, 1H), 7.23 percent (m, 1H), 7,35 (m, 1H), 8,99 (s, 3H).

(5)Synthesis of (±)-(4aR*,9aS*)-9a-(2-forfinal)-4,4a,5,6,7,8,9,9a-octahydrocyclopenta[d][1,3]thiazin-2-ylamine

Specified in the title compound (1.35 g) was obtained from hydrochloride of 2-[2-(2-forfinal)cyclohepta-1-animetal]estimacion obtained in example obtain 7-(4) (2.00 g), in accordance with the JV is by way of example, obtain 1-(6).

ESI-MS; m/z 279 [M+H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,48-1,89 (m, 9H), 2.40 a (m, 1H), 2,50 (DD, J=3,6, 12.0 Hz, 1H), 2,65 (m, 1H), 2,77 (DD, J=3,6, 12.0 Hz, 1H), 7,00 (DDD, J=1,6, 8,0, to 12.8 Hz, 1H), 7,07 (dt, J= 1,6 and 7.6 Hz, 1H), 7,17-7,24 (m, 2H).

(6)Synthesis of tert-butyl (±)-[(4aR*,9aS*)-9a-(2-fluoro-5-nitrophenyl)-4,4a,5,6,7,8,9,9a-octahydrocyclopenta[d][1,3]thiazin-2-yl]carbamate

Specified in the header connection (to 1.83 g) was obtained from (±)-(4aR*,9aS*)-9a-(2-forfinal)-4,4a,5,6,7,8,9,9a-octahydrocyclopenta[d][1,3]thiazin-2-ylamine obtained in example obtain 7-(5) (1.35 g), in accordance with the method of example obtain 1-(7).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,50-to 1.98 (m, 9H), and 1.54 (s, 9H), of 2.38 (m, 1H), 2,53 (DD, J=3.2, and to 12.8 Hz, 1H), 2,70 (3,2, 9.6 Hz, 1H), 2,82 (m, 1H), 7.23 percent (m, 1H), 8,19 (m, 2H).

(7)Synthesis of tert-butyl (±)-[(4aR*,9aS*)-9a-(5-amino-2-forfinal)-4,4a,5,6,7,8,9,9a-octahydrocyclopenta[d][1,3]thiazin-2-yl]carbamate

Specified in the header connection (1,36 g) was obtained from tert-butyl (±)-[(4aR*,9aS*)-9a-(2-fluoro-5-nitrophenyl)-4,4a,5,6,7,8,9,9a-octahydrocyclopenta[d][1,3]thiazin-2-yl]carbamate obtained in example obtain 7-(6) (1,83 g), in accordance with the method of example the preparation of 3-(7).

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.53 (s, 9H), 1,57 of 1.99 (m, 9H), of 2.45 (m, 2H), and 2.83 (m, 2H), to 3.64 (s, 2H), 6,53 (m, 2H), 6,84 (m, 1H).

(8)Synthesis of tert-butyl (-)-[(4aR*,9aS*)-9a-(5-amino-2-forfinal)-4,4a,5,6,7,8,9,9a-octahydrocyclopenta[d][1,3]thiazin-2-yl]carbamate

tert-Butyl (±)-[(4aR*,9aS*)-9a-(5-amino-2-forfinal)-4,4a,5,6,7,8,9,9a-octahydrocyclopenta[d[1,3]thiazin-2-yl]carbamate, obtained in example obtain 7-(7) (140 mg), optically separated using CHIRALPAK™ AD-H production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 8:2, flow rate: 10 ml/min). Components having a retention time from 14,3 to 17.9 minutes, collected by obtaining specified in the title compound (60 mg).

Example obtain 8

Synthesis of tert-butyl (-)-[(4aS*,8aS*)-8a-(5-amino-2-forfinal)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

[Formula 27]

(1)Synthesis of oxime 3-aryloxypropanolamine

The solution containing oxacillin (the 5.45 ml) in dichloromethane (130 ml)was cooled to -78°C under nitrogen atmosphere. A solution containing dimethyl sulfoxide (4,85 ml) in dichloromethane (5 ml)was added dropwise to the reaction solution at the same temperature. After stirring at the same temperature for 10 minutes to the reaction solution was added dropwise a solution containing 3-allylacetate-1-ol (4,99 g) in dichloromethane (5 ml). After stirring at the same temperature for one hour to the reaction solution was added triethylamine (20.4 ml). The cooling bath was removed. The reaction solution was heated to room temperature and was stirred at room temperature for one hour. To the reaction solution was added saturated aqueous solution of ammonium chloride is separated organic layer. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (100 ml) and water (10 ml). Sodium acetate (12 g) and hydroxylamine sulfate (8,02 g) was added to the reaction solution at room temperature. The reaction solution was stirred at room temperature for 15 hours. Then was added a saturated solution of sodium chloride and ethyl acetate and the separated organic layer. The organic layer was again washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (5.5 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,47-2,52 (m, 1H), 2,65-2,70 (m, 1H), to 3.58-3,62 (m, 2H), 3,98-4,01 (m, 2H), 5,17-5,22 (m, 1H), 5,24-5,31 (m, 1H), 5,85-5,96 (m, 1H), 6,86 (t, J=5,2 Hz, 0,5H), to 7.50 (t, J=5.6 Hz, 0,5H).

(2)Synthesis of (±)-3a,4,6,7 there-tetrahydro-3H-pyrano[4,3-c]isoxazol

5% Solution of sodium hypochlorite (63,2 ml) was added to the solution containing the compound obtained in example obtain 8-(1) (5.5 g)in dichloromethane (200 ml) at room temperature and the mixture was stirred is at room temperature for four hours. Water and sodium bisulfite (10 g) was added to the reaction solution, followed by stirring at room temperature for 10 minutes. The organic layer was separated and washed with a saturated solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (3.33 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,47-of 2.56 (m, 1H), 2,73 (DD, J=2,8, of 14.0 Hz, 1H), 3,23-3,47 (m, 3H), of 3.73 (DD, J=2,4, 10.4 Hz, 1H), 4.26 deaths (DD, J=2,4, 11.2 Hz, 1H), 4,34 (DD, J=6,8, and 10.8 Hz, 1H), 4,47 (DD, J=8,0, to 10.8 Hz, 1H).

(3)Synthesis of (±)-(3aS*,7aS*)-7a-(2-forfinal)hexahydropyrazino[4,3-c]isoxazol

A solution of n-utility in hexane (2.77 M; 18,9 ml) was added dropwise to a solution containing 2-bramptonbest (being 9.61 g) in a mixture of tetrahydrofuran/toluene (35 ml/115 ml)in nitrogen atmosphere at -78°C. the Reaction solution was stirred at the same temperature for one hour. The complex of boron TRIFLUORIDE-diethyl ether (6.6 ml) was added dropwise to the solution containing the compound obtained in example obtain 8-(2) (3.33 g)in toluene (235 ml) in nitrogen atmosphere at -78°C. the Previously obtained solution of 2-formanilide was added dropwise to the reaction solution at the same temperature. After stirring at the same temperature during the one hour to the reaction solution was added an aqueous solution of ammonium chloride and the reaction solution was heated to room temperature. To the reaction solution were added water and ethyl acetate and the separated organic layer. The organic layer was washed with a saturated solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated and the residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (5.1 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,90-1,95 (m, 1H), 2,42-of 2.50 (m, 1H), 3,05-3,11 (m, 1H), 3,54-of 3.60 (m, 1H), 3,67-a 3.87 (m, 4H), 3,98 (DD, J=4,8, 12.0 Hz, 1H), 7,07 (DD, J=8,0, 12.0 Hz, 1H), 7,14-7,19 (m, 1H), 7,27-7,32 (m, 1H), 7,73-7,78 (m, 1H).

(4)Synthesis of (±)-[(3R*,4S*)-4-amino-4-(2-forfinal)tetrahydropyran-3-yl]methanol

Zinc powder (19.1 g) was added to the solution containing the compound obtained in example obtain 8-(3) (5,1 g)in acetic acid (130 ml) at room temperature. The reaction solution was stirred at room temperature for 16 hours. The insoluble substance was separated by filtration through celite and the filtrate was concentrated. To the residue was added ethyl acetate and sodium bicarbonate solution and separated the organic layer. The organic layer was washed with a saturated aqueous solution of sodium chloride. The organic layers additionally were extracted from the aqueous layer four times with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. Neretva imoe substance was separated by filtration and the filtrate was concentrated under reduced pressure to obtain specified in the title compound (5.1 g).

1H-NMR (CDCl3) δ (ppm): 1,45 (d, J=14,0 Hz, 1H), 2,52-of 2.58 (m, 1H), 2,62-2,70 (m, 1H), 3,54 (d, J=4.0 Hz, 2H), 3,89-of 3.96 (m, 4H), 7,07 (DD, J=8,0, 12.0 Hz, 1H), 7,15-7,19 (m, 1H), 7,26-7,31 (m, 1H), EUR 7.57-to 7.61 (m, 1H).

(5)Synthesis of (±)-9H-fluoren-9-ylmethyl({[(3R*,4S*)-4-(2-forfinal)-3-(hydroxymethyl)tetrahydro-2H-Piran-4-yl]amino}carbonothioyl)carbamate

Fluorenylmethoxycarbonyl (7,02 g) was added to the solution containing the compound obtained in example obtain 8-(4) (5,1 g), in dichloromethane (100 ml) and the mixture was stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (there is a 10.03 g).

1H-NMR (CDCl3) δ (ppm): 1,64-1,66 (USM, 1H), 2,45-2,55 (USM, 1H), 2,59-to 2.67 (m, 1H), 3,49-3,52 (USM, 1H), 3,67-a 3.87 (m, 4H), 4,00-Android 4.04 (m, 2H), 4,24-4,27 (m, 1H), 4,50-4,59 (m, 2H), 7,05 (DDD, J=1,2, 8,0, to 12.8 Hz, 1H), 7,13-7,17 (m, 1H), 7,26-7,46 (m, 6H), 7,56-to 7.59 (m, 2H), 7,79 (d, J=8.0 Hz, 2H), of 7.96 (USS, 1H), 10,6 (USS, 1H).

(6)Synthesis of (±)-(4aS*,8aS*)-8a-(2-forfinal)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-ylamine

Concentrated chloride-hydrogen acid (5 ml) was added to the solution containing the compound obtained in example obtain 8-(5) (10 g)in methanol (200 ml) and the reaction solution was boiled under reflux for two hours. The reaction solution was cooled to room temperature and to is centered under reduced pressure. To the residue was added ethyl acetate and saturated sodium bicarbonate solution and separated the organic layer. The organic layer was concentrated under reduced pressure. The residue was dissolved in acetonitrile (200 ml). To the solution was added piperidine (20 ml) followed by stirring at room temperature for two hours. The reaction solution was concentrated and the residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (3,17 g).

1H-NMR (CDCl3) δ (ppm): 1,65 (d, J=13,2 Hz, 1H), 2,53 (DD, J=2,8, to 12.8 Hz, 1H), 2,65-by 2.73 (m, 1H), 2,87 (DD, J=4,4, and 12.4 Hz, 1H), 2,98-3,10 (m, 1H), 3,69-of 3.80 (m, 3H), 3,88 (DD, J=4,4, to 10.8 Hz, 1H), 4,55 (USS, 2H),? 7.04 baby mortality (DD, J=8,0, to 12.8 Hz, 1H), 7,09-7,13 (m, 1H), 7,21-to 7.32 (m, 2H).

(7)Synthesis of tert-butyl (±)-[(4aS*,8aS*)-8a-(2-fluoro-5-nitrophenyl)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

Fuming nitric acid (682 μl) was added dropwise to a solution of the compound obtained in example obtain 8-(6) (2,08 g), concentrated sulfuric acid (30 ml) under cooling with ice. After stirring the reaction solution at the same temperature for 30 minutes the reaction solution was poured into ice water. The reaction mixture was podslushivaet 5 N. solution of sodium hydroxide. Was added to a mixture of chloroform and separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate. Insoluble substance CTD is ranged by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (120 ml). The triethylamine (6.6 ml) and di-tert-BUTYLCARBAMATE (6.5 g) was added to the solution and the mixture was stirred at room temperature for 17 hours. To the reaction solution was added a saturated solution of sodium chloride and ethyl acetate and the separated organic layer. The organic layer was dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (4.7 g).

ESI-MS; m/z 412 [M++H].

1H-NMR (CDCl3) δ (ppm): of 1.53 (s, 9H), 1,64 is 1.70 (m, 1H), 2,52-2,62 (m, 2H), and 2.79 (DD, J=3,6, 13,2 Hz, 1H), 3,05-3,15 (USM, 1H), 3,60-3,93 (m, 4H), 7,22-7,28 (m, 1H), 8,18 is 8.22 (m, 2H).

(8)Synthesis of tert-butyl (±)-[(4aS*,8aS*)-8a-(5-amino-2-forfinal)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

Iron powder (5,28 g) and a saturated aqueous solution of ammonium chloride (18.6 ml) was added to a solution of the compound obtained in example obtain 8-(7) (4.7 g)in ethanol (150 ml). The reaction solution was boiled under reflux for 30 minutes and then was added iron powder (5,28 g). The reaction solution was further heated under reflux for 30 minutes and then was added iron powder (5,28 g). The reaction solution was further heated with about the military refrigerator for 30 minutes and then cooled to room temperature. The reaction solution was diluted with ethyl acetate and the insoluble substance was separated by filtration through celite. The filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate and a saturated aqueous solution of sodium chloride and separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated under reduced pressure to obtain specified in the connection header (3,48 g).

ESI-MS; m/z 382 [M++H].

1H-NMR (CDCl3) δ (ppm): of 1.53 (s, 9H), 1,55-of 1.66 (m, 1H), 2,48 (DD, J=2,8, and 9.2 Hz, 1H), 2,72-of 2.81 (m, 1H), 2,92 (DD, J=4,0, 13,2 Hz, 1H), 3,09-3,13 (m, 1H), 3,66 (s, 2H), 3,71-of 3.94 (m, 4H), 6,53-6,59 (m, 2H), to 6.88 (DD, J=8,0, 12.0 Hz, 1H).

(9)Synthesis of tert-butyl (-)-[(4aS*,8aS*)-8a-(5-amino-2-forfinal)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

The compound obtained in example obtain 8-(8) (75 mg), optically separated using CHIRALPAK™ AD-H production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 7:3, flow rate: 10 ml/min), and the components with retention time from 31,8 up to 38.3 minutes, was collected. This operation was repeated to obtain specified in the title compound (444 mg, >99% ee) from 1 g of the racemate.

ESI-MS; m/z 382 [M++H].

1H-NMR (CDCl3) δ (ppm): of 1.53 (s, 9H), 1,55-of 1.66 (m, 1H), 2,48 (DD, J=2,8, and 9.2 Hz, 1H), 2,72-of 2.81 (m, 1H), 2,92 (DD, J=4,0, 13,2 Hz, 1H), 3,09-3,13 (m, 1H), 3,66 (s, 2H), 3,71-of 3.94 (m, H), 6,53-6,59 (m, 2H), to 6.88 (DD, J=8,0, 12.0 Hz, 1H).

Example of getting 9

Synthesis of tert-butyl [(4aS*,7aS*)-7a-(5-amino-2-forfinal)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

[Formula 28]

(1)Synthesis alliancehealth.com

The solution containing oxalicacid cases (27.3 ml) in dichloromethane (600 ml)was cooled to -78°C under nitrogen atmosphere. A solution containing dimethyl sulfoxide (24.3 ml) in dichloromethane (50 ml)was added dropwise to the reaction solution at the same temperature. After stirring at the same temperature for 10 minutes to the reaction solution was added dropwise a solution containing 2-allylacetate (25 g) in dichloromethane (50 ml)at the same temperature. After stirring at the same temperature for one hour to the reaction solution was added triethylamine (102 ml). The cooling bath was removed. The reaction solution was heated to room temperature and was stirred at room temperature for one hour. To the reaction solution was added saturated aqueous solution of ammonium chloride. The organic layer was separated and washed with saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol(500 ml) and water (50 ml). Sodium acetate (60,2 g) and hydroxylamine sulfate (40,2 g) was added to the reaction solution at room temperature. The reaction solution was stirred at room temperature for 15 hours. Then added water and ethyl acetate and the separated organic layer. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (13,2 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 4,00-Android 4.04 (m, 2H), 4.09 to-4,11 (m, 1H), 4,35 (d, J=3.6 Hz, 1H), to 5.21-5.25 in (m, 1H), 5,27 to 5.35 (m, 1H), 5,85-5,95 (m, 1H), 6,92 (t, J=4.0 Hz, 0.5 H), 7,51 (t, J=5.6 Hz, 0,5H).

(2)Synthesis of (±)-3a,4-dihydro-3H,6H-furo[3,4-c]isoxazol

5% sodium hypochlorite Solution (170 ml) was added to the solution containing the compound obtained in the example of a 9-(1) (13,2 g)in dichloromethane (400 ml) at room temperature and the mixture was stirred at room temperature for six hours. Water and sodium bisulfite (of 7.95 g) was added to the reaction solution, followed by stirring at room temperature for 10 minutes. Then separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (4.8 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): the 3.65 (DD, J=9,2, 8.0 Hz, 1H), 4,00 (DD, J=12,0, 8.0 Hz, 1H), 4,17-the 4.29 (m, 2H), 4,40-of 4.49 (m, 2H), 4,59 (DD, J=9,2, 8.0 Hz, 1H).

(3)Synthesis of (±)-(3aS*,6aS*)-6a-(2-forfinal)tetrahydrofuro[3,4-c]isoxazol

2.77 M solution of n-utility in hexane (30,7 ml) was added dropwise to a solution containing 2-bramptonbest (15.6 g) in a mixture of tetrahydrofuran/toluene (50 ml/150 ml)in a nitrogen atmosphere at -78°C. the Reaction solution was stirred at the same temperature for one hour. The complex of boron TRIFLUORIDE-diethyl ether (10,7 ml) was added dropwise to the solution containing the compound obtained in the example of a 9-(2) (4.8 g)in toluene (350 ml) in a nitrogen atmosphere at -78°C. the Previously obtained 2-formanilide was added dropwise to the reaction solution at the same temperature. After stirring at the same temperature for one hour to the reaction solution was added an aqueous solution of ammonium chloride and the reaction solution was heated to room temperature. To the reaction solution were added water and ethyl acetate and the separated organic layer. The organic layer was washed with a saturated solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate which has koncentrirebuli under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (5.6 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 3,39 is-3.45 (m, 1H), 3,52-3,62 (USM, 1H), 3,84-3,92 (USM, 2H), 3,98 (USD, J=9,2 Hz, 1H), 4,16 (DDD, J=2,4, 6,4, 11.2 Hz, 1H), 4,50-4,58 (USM, 1H), 5,11 (USS, 1H), 7,06 (DDD, J=1,2, 8,4, and 11.6 Hz, 1H), 7,16 (DDD, J=1,2 and 7.6 and 7.6 Hz, 1H), 7,25-7,31 (m, 1H), 7,84-to 7.95 (m, 1H).

(4)Synthesis of (±)-[(3R*,4S*)-4-amino-4-(2-forfinal)tetrahydrofuran-3-yl]methanol

Zinc (powder: 21 g) was added to the solution containing the compound obtained in the example of a 9-(3) (5.6 g)in acetic acid (140 ml) at room temperature. The reaction solution was stirred at room temperature for 16 hours. The insoluble substance was separated by filtration through celite and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate and sodium bicarbonate solution and separated the organic layer. The organic layer was washed with a saturated aqueous solution of sodium chloride. The organic layers additionally were extracted from the aqueous layer three times with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated under reduced pressure to obtain specified in the connection header (5,46 g).

ESI-MS; m/z 212 [M++H].

1H-NMR (CDCl3) δ (ppm): 2,81-is 2.88 (m, 1H), 3,83 (DD, J6,8, 12.0 Hz, 1H), 3,92 (DD, J=3.2, and an 8.8 Hz, 1H), 3,94-4,00 (m, 2H), 4,07 (DD, J=8,4, and 9.2 Hz, 1H), 4,14 (DD, J=1,2, 8,8 Hz, 1H), to 7.09 (DDD, J=1,2, 8,0, and 12.4 Hz, 1H), 7,16 (DDD, J=1,2, of 7.6, 8.0 Hz, 1H), 7,26-7,32 (m, 1H), 7,53 (dt, J=2,0, 8.0 Hz, 1H).

(5)Synthesis of (±)-1-benzoyl-3-[(3S*,4R*)-3-(2-forfinal)-4-hydroxymethylfurfural-3-yl]thiourea

The compound obtained in the example of a 9-(4) (2.5 g)was added to a solution of benzoylisothiocyanate (2,13 g) in dichloromethane (75 ml) and the mixture was stirred at room temperature for three hours. The reaction solution was concentrated and the residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (4,19 g).

ESI-MS; m/z 307 [M++Na].

1H-NMR (CDCl3) δ (ppm): and 2.83 (DD, J=4,4, 6,8 Hz, 1H), 3,15-up 3.22 (m, 1H), 3,81 (DD, J=2,8, 8,8 Hz, 1H), 3,89-3,95 (m, 1H), 4,01-4,07 (m, 1H), 4,13-4,17 (m, 1H), 4,43 (DD, J=2,8, 9.6 Hz, 1H), 4,69 (d, J=10.0 Hz, 1H),? 7.04 baby mortality (DDD, J=1,2, 8,0, 12.0 Hz, 1H), 7,18 (DDD, J=1,2, of 8.0, 8.0 Hz, 1H), 7.24 to 7,33 (m, 1H), 7,52 (t, J=7,6 Hz, 2H), to 7.64 (TD, J=1,2, 8.0 Hz, 1H), 7,71 (TD, J=1,6, 8.0 Hz, 1H), 7,86 (DD, J=1,6, 6.4 Hz, 1H), 8,90 (USS, 1H), 11.8 in (OSS, 1H).

(6)Synthesis of (±)-N-[(4aS*,7aS*)-7a-(2-forfinal)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]benzamide

Triphenylphosphine (7,08 g) was added to a solution of the compound obtained in the example of a 9-(5) (3,89 g), and tetrabromide carbon (of 8.95 g) in dichloromethane (100 ml) at room temperature. The reaction solution was cooled to 0°C, stirred for 20 minutes and then heated to room temperature. The reaction is ionic solution was stirred at room temperature for 15 hours. Then to the reaction solution were added water and the separated organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (1,93 g).

1H-NMR (CDCl3) δ (ppm): 2,90 (DD, J=4,8, to 13.6 Hz, 1H), 3,23 (DD, J=4,0, to 13.6 Hz, 1H), 3,39-of 3.46 (m, 1H), 4,06 (DD, J=2,8, and 9.2 Hz, 1H), 4,22-of 4.25 (m, 2H), of 4.44 (d, J=9,2 Hz, 1H), 7,13 (DDD, J=1,2, 8,4, and 12.4 Hz, 1H), 7,21 (DDD, J=1,2, and 7.6 and 7.6 Hz, 1H), 7,33-7,52 (m, 5H), 8,15 (d, J=7,6 Hz, 2H).

(7)Synthesis of (±)-(4aS*,7aS*)-7a-(2-forfinal)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-ylamine

A solution of the compound obtained in the example of a 9-(6) (2,08 g)and 1,8-diazabicyclo[5,4,0]undec-7-ene (1.6 ml) in methanol (20 ml) was boiled under reflux for five hours. After cooling the reaction solution to room temperature, evaporated under reduced pressure the solvent. The residue was subjected to chromatography on silica gel. The crude product is suspended in diethyl ether. The obtained solid substance was collected by filtration to obtain specified in the title compound (1.19 g).

ESI-MS; m/z 253 [M++H].

1H-NMR (CDCl3) δ (ppm): and 2.83 (DD, J=5,2, and 12.4 Hz, 1H), 2,99-is 3.08 (m, 2H), 3,82 (DD, J=2.0 a, and 8.4 Hz, 1H), 4,05-to 4.15 (m, 2H), of 4.44 (USS, 2H), 4,49 (d, J=8,8 Hz, 1H), 7,05 (DDD, J=,6, to 8.0, 12.0 Hz, 1H), 7,13 (DDD, J=1,2, 7,2, 8.0 Hz, 1H), 7,22-7,30 (m, 1H), 7,46 (dt, J=1,6, 8.0 Hz, 1H).

(8)Synthesis of tert-butyl (±)-[(4aS*,7aS*)-7a-(2-fluoro-5-nitrophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

Fuming nitric acid (293 ml) was added dropwise to a solution of the compound obtained in the example of a 9-(7) (1.19 g)in concentrated sulfuric acid (20 ml) under cooling with ice. The reaction solution was stirred at the same temperature for 30 minutes and then poured into ice-cold water. The reaction mixture was neutralized 5 N. solution of sodium hydroxide. Was added to a mixture of chloroform and separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated under reduced pressure and the residue was dissolved in tetrahydrofuran (50 ml). The triethylamine (2,62 ml) and di-tert-BUTYLCARBAMATE (2.58 g) was added to the solution and the mixture was stirred at room temperature for 18 hours. To the reaction solution were added water and ethyl acetate and the separated organic layer. The organic layer was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with getting ukazannoj is in the title compound (1.68 g).

ESI-MS; m/z 398 [M++H].

1H-NMR (CDCl3) δ (ppm): is 1.51 (s, 9H), 2,74-2,99 (USM, 2H), 3,15-3,44 (USM, 1H), 3.72 points-of 3.85 (USM, 1H), 4,17-4,19 (m, 2H), 4,37 (DD, J=8,4, and 1.6 Hz, 1H), 7,21-7,29 (m, 1H), 8,19-8,24 (m, 1H), 8,35 (DD, J=7,2, 2.8 Hz, 1H).

(9)Synthesis of tert-butyl (±)-[(4aS*,7aS*)-7a-(5-amino-2-forfinal)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

Iron powder (1.89 g) and a saturated aqueous solution of ammonium chloride (5 ml) was added to a solution of the compound obtained in the example of a 9-(8) (1.68 g)in ethanol (50 ml). The reaction solution was boiled under reflux for 30 minutes and then cooled to room temperature. The reaction solution was diluted with ethyl acetate and the insoluble substance was separated by filtration through celite. The filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate and a saturated aqueous solution of sodium chloride and separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated under reduced pressure to obtain specified in the title compound (1.54 g).

ESI-MS; m/z 368 [M++H].

1H-NMR (CDCl3) δ (ppm): 1.50 in (s, 9H), to 2.75 (DD, J=4,4, 13,2 Hz, 1H), 3,01 (DD, J=3.2, and up to 13.2 Hz, 1H), 3.25 to 3.30 is (m, 1H), 3,62 (USS, 2H), 3,84 (d, J=7,6 Hz, 1H), 4,14-4,17 (m, 2H), to 4.41 (DD, J=0,8, and 9.2 Hz, 1H), 6,55-6,59 (m, 1H), of 6.65 (DD, J=3.2, and 6.4 Hz, 1H), 6.87 in (DD, J=8,4, and 12.4 Hz, 1H).

(10)Synthesis of tert-butyl (-)-[(4aS*,7S*)-7a-(5-amino-2-forfinal)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

The compound obtained in the example of a 9-(9) (50 mg), optically separated using CHIRALPAK™ AD-H production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 7:3, flow rate: 10 ml/min), and the components with retention time from 23.1 up to 26.3 minutes was collected. This operation was repeated to obtain specified in the title compound (220 mg, >99% ee) of 600 mg of the racemate.

ESI-MS; m/z 368 [M++H].

1H-NMR (CDCl3) δ (ppm): 1.50 in (s, 9H), to 2.75 (DD, J=4,4, 13,2 Hz, 1H), 3,01 (DD, J=3.2, and up to 13.2 Hz, 1H), 3.25 to 3.30 is (m, 1H), 3,62 (USS, 2H), 3,84 (d, J=7,6 Hz, 1H), 4,14-4,17 (m, 2H), to 4.41 (DD, J=0,8, and 9.2 Hz, 1H), 6,55-6,59 (m, 1H), of 6.65 (DD, J=3.2, and 6.4 Hz, 1H), 6.87 in (DD, J=8,4, and 12.4 Hz, 1H).

Example 10

Synthesis of (3aR*,5S*,6aS*)-6a-(2-forfinal)-5-methoxycarbonylamino[c]isoxazol and (3aR*,5R*,6aS*)-6a-(2-forfinal)-5-methoxycarbonylamino[c]isoxazol

[Formula 29]

(1)Synthesis of 3-methoxy-5-geksenala

Dimethyl sulfoxide (0,612 ml) was added dropwise to a solution of oxalicacid (0,652 ml) in dichloromethane (15 ml) at -55°C and the mixture was stirred at -70°C for 10 minutes. A solution of 3-methoxy-5-hexenol (Tetrahedron, 61, 3183-3194 (2005)) (660 mg) in dichloromethane (5 ml) was added dropwise to the solution at -60°C and the mixture was stirred at -60°C for 15 minutes. The triethylamine (4,95 ml) was added dropwise to the solution at -60°C and the reaction solution was stirred at a temperature of from -60°C up to on the th temperature for 30 minutes. The reaction solution was poured into water, followed by extraction with dichloromethane. The extract was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain specified in the header compounds containing dichloromethane and triethylamine (3.0 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,24-2,70 (m, 4H), to 3.38 (s, 3H), 3,76-3,86 (m, 1H), 5,00-of 5.40 (m, 2H), 5,70-5,90 (m, 1H), 9,80 (t, J=1.6 Hz, 1H).

(2)Synthesis of 3-methoxy-5-hexanelactam

A mixture of 3-methoxy-5-geksenala (3.0 g, with a mixture of dichloromethane and triethylamine), hydroxylamine sulphate (990 mg) and sodium acetate (624 mg) in ethanol (6.5 ml) and water (0,65 ml) was stirred at room temperature for 12 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on a column of silica gel with obtaining specified in the header of the compound (500 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,22-2,48 (m, 3H), 2,52 of 2.68 (m, 1H), 3,37, and 3.38 (s, summary. 3H), 3,40-of 3.54 (m, 1H), of 5.05-5,20 (m, 2H), 5,72-5,90 (m, 1H), 6,86 and of 7.48 (t, J=5.6 Hz, sums the pH. 1H), 7,80 and by 8.22 (USS, summary. 1H).

(3)Synthesis of 5-methoxy-3a,4,5,6-tetrahydro-3H-cyclopent[c]isoxazol

The sodium hypochlorite solution (5% active chlorine, 9,36 ml) was added dropwise to a solution of 3-methoxy-5-hexanelactam (450 mg) in dichloromethane (20 ml) at 0°C and the mixture was stirred at a temperature from 0°C to room temperature for 1.5 hours. The reaction solution was poured into ice water, followed by extraction with dichloromethane. The extract was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under normal pressure. The crude product was purified by chromatography on a column of silica gel with getting less polar specified in the title compound (230 mg) and the more polar specified in the title compound (150 mg).

Iskopaemoe specified in the header of the connection

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,54 by 1.68 (m, 1H), 2,20-of 2.30 (m, 1H), 2,46-of 2.56 (m, 1H), 2,72-2,84 (m, 1H), 3,30-to 3.34 (m, 3H), 3.72 points-of 3.80 (m, 1H), 3,92-4,06 (m, 1H), 4.26 deaths-4,32 (m, 1H), 4,54-br4.61 (m, 1H).

More polar specified in the header of the connection

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,45-to 1.60 (m, 1H), 2.40 a is 2.55 (m, 2H), and 2.83 (DD, J=8,4, 18,0, 1H), 3,35 (s, 3H), 3,55-3,70 (m, 1H), 3.75 to of 3.85 (m, 1H), 4,20-to 4.33 (m, 1H), 4,50-4,60 (m, 1H).

(4)Synthesis of (3aR*,5S*,6aS*)-6a-(2-forfinal)-5-methoxycarbonylamino[c]isoxazol and (3aR*,5R*,6aS*)-6a-(2-torfin the l)-5-methoxycarbonylamino[c]isoxazol

[Formula 30]

n-Utility (2,77 M to 2.29 ml) was added dropwise to a solution of 2-bromptonville (1.22 g) in a mixture of toluene (20 ml) and tetrahydrofuran (6 ml) at -78°C and the mixture was stirred at the same temperature for one hour. The complex of boron TRIFLUORIDE-diethyl ether (0,797 ml) was added dropwise to a solution of 5-methoxy-3a,4,5,6-tetrahydro-3H-cyclopent[c]isoxazol (427 mg, a mixture of more polar and less polar compounds) in toluene (30 ml) at -78°C. the Previously obtained solution of 2-formanilide was added dropwise to the solution at a temperature of from -78°C to -60°C. the Reaction solution was stirred at -78°C for one hour. To the reaction solution was added a solution of ammonium chloride at -78°C followed by warming to room temperature for one hour. The reaction solution was extracted with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on a column of silica gel with getting less polar specified in the header of the compound (5S, 247 mg) and the more polar specified in the connection header (5R, 275 mg).

Less polar specified in the header of the compound (5S)

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,95-2,17 (m, 2H), 2,17 of-2.32 (m, 2H), 3,20-to 3.35 (m, 1H), 3,30 (s, 3H), of 3.69 (t, J=8.0 Hz, 1H), 4,05-to 4.15 (m, 1H), 4,39 (t, J=8.0 Hz, 1H), 6,03 (s, 1H), 6.90 to-7,32 (m, 3H), 7,94 (t, J=8.0 Hz, 1H).

More polar specified in the title compound (5R)

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,00-of 2.26 (m, 3H), 2,34 is 2.44 (m, 1H), 3,26-to 3.38 (m, 1H), 3,34 (s, 3H), 3,69 (USS, 1H), 4,08-4,22 (m, 2H), 7,06 (DD, J=8,0, 12.0 Hz, 1H), 7,12 (t, J=8.0 Hz, 1H), 7,16-7,32 (m, 1H), 7,58-7,72 (m, 1H).

Example of getting 11

Synthesis of tert-butyl [(4aR*,6S*,7aS*)-7a-(5-amino-2-forfinal)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate ((+)-isomer and (-)-isomer)

[Formula 31]

(1)Synthesis of [(1R*,2S*,4S*)-2-amino-2-(2-forfinal)-4-methoxycyclohexyl]methanol

Zinc (533 mg) was added to a solution of (3aR*,5S*,6aS*)-6a-(2-forfinal)-5-methoxycarbonylamino[c]isoxazol (247 mg) in acetic acid (5 ml) and the mixture was stirred at room temperature for 12 hours. Zinc (500 mg) was added to the reaction solution, followed by stirring at room temperature for three hours. The zinc was removed by filtration and the filtrate was poured into a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain specified in the header link is (245 mg).

ESI-MS; m/z 240 [M++H].

(2)Synthesis of 9H-fluoren-9-ylmethyl ({[(1S*,2R*,4S*)-1-(2-forfinal)-2-(hydroxymethyl)-4-methoxycyclohexyl]amino}carbonothioyl)carbamate

A solution of [(1R*,2S*,4S*)-2-amino-2-(2-forfinal)-4-methoxycyclohexyl]methanol (225 mg) and fluorenylmethoxycarbonyl (316 mg) in dichloromethane (18 ml) was stirred at room temperature for three days. The reaction solution was purified by chromatography on a column of silica gel with obtaining specified in the title compound (330 mg).

ESI-MS; m/z 543[M++Na].

(3)Synthesis of [(4aR*,6S*,7aS*)-7a-(2-forfinal)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]amine

A solution of 9H-fluoren-9-ylmethyl ({[(1S*,2R*,4S*)-1-(2-forfinal)-2-(hydroxymethyl)-4-methoxycyclohexyl]amino}carbonothioyl)carbamate (330 mg) in a mixture of methanol (20 ml) and concentrated chloride-hydrogen acid (1 ml) was boiled under reflux for three hours. The reaction solution was concentrated under reduced pressure. Acetonitrile (10 ml) and piperidine (1 ml) was added to the residue at room temperature and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure. The crude product was purified by chromatography on a column with NH-silica gel with obtaining specified in the title compound (170 mg).

1H-NMR (00 MHz, CDCl3) δ (ppm): 1,98-2,10 (m, 2H), 2,14-of 2.24 (m, 1H), 2,58 of 2.68 (m, 1H), 2,77 (DD, J=4,8, to 12.8 Hz, 1H), only 2.91 (DD, J=3.2, and to 12.8 Hz, 1H), 2,98 (DD, J=8,4, 14.4 Hz, 1H), 3.33 and (s, 3H), 4,10-4,22 (m, 1H), 7,01 (DD, J=8,0, 12,4 Hz, 1H), to 7.09 (t, J=8.0 Hz, 1H), 7,17-7,35 (m, 2H).

(4)Synthesis of tert-butyl [(4aR*,6S*,7aS*)-7a-(2-fluoro-5-nitrophenyl)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

Fuming nitric acid (0,02 ml) was added to a solution of [(4aR*,6S*,7aS*)-7a-(2-forfinal)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]amine (151 mg) in concentrated sulfuric acid (2 ml) at 0°C and the mixture was stirred at 0°C for 30 minutes. The reaction solution was poured into a mixture of 5 n sodium hydroxide solution and ice water followed by extraction with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The triethylamine (0,301 ml) and di-tert-BUTYLCARBAMATE (176 mg) was added to a solution of the crude product in tetrahydrofuran (10 ml) at room temperature and the mixture was stirred at room temperature for 12 hours. The reaction solution was poured into a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. ASU is non agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on a column of silica gel with obtaining specified in the title compound (118 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.52 (s, 9H), 2,00-2,25 (m, 2H), 2,25-to 2.40 (m, 1H), 2,70-2,95 (m, 4H), of 3.32 (s, 3H), 4,10-4,20 (m, 1H), 7,14-7,30 (m, 1H), 8,12 compared to 8.26 (m, H).

(5)Synthesis of tert-butyl [(4aR*,6S*,7aS*)-7a-(5-amino-2-forfinal)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

A solution of tert-butyl [(4aR*,6S*,7aS*)-7a-(2-fluoro-5-nitrophenyl)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate (118 mg) and iron (133 mg) in a mixture of ethanol (8 ml) and a saturated solution of ammonium chloride (0,303 ml) was stirred at 87°C for 30 minutes. The reaction solution was cooled to room temperature and then was poured into a mixture of water-ethyl acetate, followed by extraction with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on a column of silica gel with obtaining specified in the title compound (83 mg).

ESI-MS; m/z 396 [M++H].

(6)Synthesis of tert-butyl [(4aR*,6S*,7aS*)-7a-(5-amino-2-forfinal)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate ((+)-isomer and (-)-isomer)

[Formula 32]

tert-Butyl (±)-[(4aR*,6S*,7aS*)-7a-(5-amino-2-forfinal)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate (83 mg) was optically separated using CHIRALPAK™ ADH production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 8:2, flow rate: 10 ml/min). Components having a retention time of 14 to 17.5 minutes, collected by obtaining specified in the header (+)-isomer (44 mg, >99% ee). Components having a retention time of from 17.5 to 23 minutes, collected by obtaining specified in the header (-)-isomer (45 mg; 95% ee). The characteristic values of (-)-connection is shown below.

Optical rotation (-)

1H-NMR (400 MHz, CDCl3) δ (ppm): is 1.51 (s, 9H), 1,92-of 2.08 (m, 1H), 2,13 (DDD, J=6,4, 6,4, 12.0 Hz, 1H), of 2.25 to 2.35 (m, 1H), 2,69 (DD, J=3,6, 13,2 Hz, 1H), 2,80 was 3.05 (m, 3H), 3,29 (s, 3H), 3,63 (USS, 2H), 4,10-4,20 (m, 1H), 6,54 (DDD, J=3,2, 3,6, and 8.4 Hz, 1H), 6,59 (DD, J=3.2, and 7.2 Hz, 1H), at 6.84 (DD, J=8,4, 12.0 Hz, 1H).

Example 12

Synthesis of tert-butyl [(4aR*,6R*,7aS*)-7a-(5-amino-2-forfinal)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate ((+)-isomer and (-)-isomer)

[Formula 33]

(1)Synthesis of [(1R*,2S*,4R*)-2-amino-2-(2-forfinal)-4-methoxycyclohexyl]methanol

Zinc (533 mg) was added to a solution of (3aR*,5R*,6aS*)-6a-(2-forfinal)-5-methoxycarbonylamino[c]isoxazol (275 mg) in acetic acid (5,57 ml) and the mixture was stirred at room temperature for 12 hours. It is added to the reaction solution zinc (500 mg), followed by stirring at room temperature for three hours. The zinc was removed by filtration and the filtrate was poured into a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain specified in the title compound (270 mg).

ESI-MS; m/z 240 [M++H].

(2)Synthesis of 9H-fluoren-9-ylmethyl ({[(1S*,2R*,4R*)-1-(2-forfinal)-2-(hydroxymethyl)-4-methoxycyclohexyl]amino}carbonothioyl)carbamate

A solution of [(1R*,2S*,4R*)-2-amino-2-(2-forfinal)-4-methoxycyclohexyl]methanol (250 mg) and fluorenylmethoxycarbonyl (351 mg) in dichloromethane (20 ml) was stirred at room temperature for three days. The reaction solution was purified by chromatography on a column of silica gel with obtaining specified in the title compound (340 mg).

ESI-MS; m/z 543 [M++Na].

(3)Synthesis of [(4aR*,6S*,7aS*)-7a-(2-forfinal)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]amine

A solution of 9H-fluoren-9-ylmethyl ({[(1S*,2R*,4R*)-1-(2-forfinal)-2-(hydroxymethyl)-4-methoxycyclohexyl]amino}carbonothioyl)carbamate (340 mg) in a mixture of methanol (20 ml) and concentrated chloride-hydrogen acid (1 ml) was boiled under reflux for three hours. The reaction solution was concentrated under reduced pressure. Acetonitrile (10 ml) and piperidine (2 ml) add the Yali to the residue at room temperature and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure. The crude product was purified by chromatography on a column with NH-silica gel with obtaining specified in the title compound (130 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): to 1.87 (DDD, J=3,6, 9,2, 13,2 Hz, 1H), 2,20-of 2.38 (m, 2H), 2,64 (DD, J=6,8, to 12.8 Hz, 1H), 2,73 (DD, J=3,6, to 12.8 Hz, 1H), 2,95 (DD, J=3,6, to 12.8 Hz, 1H), 3,05 is 3.15 (m, 1H), 3.33 and (s, 3H), a 3.87-4.00 points (m, 1H), 7,02 (DD, J=7,6, 12.0 Hz, 1H), to 7.09 (t, J=7,6 Hz, 1H), 7,17-7,33 (m, 2H).

(4)Synthesis of tert-butyl [(4aR*,6R*,7aS*)-7a-(2-fluoro-5-nitrophenyl)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

Fuming nitric acid (0,0193 ml) was added to a solution of [(4aR*,6R*,7aS*)-7a-(2-forfinal)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]amine (146 mg) in concentrated sulfuric acid (2 ml) at 0°C and the mixture was stirred at 0°C for 30 minutes. The reaction solution was poured into a mixture of 5 n sodium hydroxide solution and ice water followed by extraction with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The triethylamine (0,291 ml) and di-tert-BUTYLCARBAMATE (170 mg) was added to a solution of the crude product in tetrahydrofuran (9,67 ml) at room temperature and the mixture was stirred at room temperature for 12 cha is impressive. The reaction solution was poured into a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on a column of silica gel with obtaining specified in the title compound (198 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.53 (s, 9H), 1,92-to 2.06 (m, 1H), 2,30 at 2.45 (m, 2H), 2,54 (DD, J=6,0, to 12.8 Hz, 1H), 2,68 is 2.80 (m, 1H), 2,80-3,00 (m, 1H), 3,18-to 3.36 (m, 1H), 3,30 (s, 3H), 3,90-4,10 (m, 1H), 7,00-7,40 (m, 1H), 8,05-8,30 (m, 2H).

(5)Synthesis of tert-butyl [(4aR*,6R*,7aS*)-7a-(5-amino-2-forfinal)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate ((+)-isomer and (-)-isomer)

[Formula 34]

A solution of tert-butyl [(4aR*,6R*,7aS*)-7a-(2-fluoro-5-nitrophenyl)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate (198 mg) and iron (223 mg) in a mixture of ethanol (13.4 ml) and saturated solution of ammonium chloride (0,508 ml) was stirred at 87°C for 30 minutes. The reaction solution was poured into a mixture of ethyl acetate-water at room temperature, followed by extraction with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. The drying agent was removed what filtrowanie and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on a column of silica gel with obtaining specified in the header (±)-mixture (118 mg).

The resulting mixture is optically separated using CHIRALPAK™ ADH production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 5:5, flow rate: 10 ml/min). Components having a retention time of from 8 to 11 minutes, collected by obtaining specified in the header (+)-isomer (52 mg, >95% ee). Components having a retention time of from 17.5 to 23 minutes, collected by obtaining specified in the header (-)-isomer (52 mg, >95% ee). The characteristic values of (-)-isomer is specified in the header connections are shown below. Optical rotation (-).

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.52 (s, 9H), 1,90-2,02 (m, 1H), 2.26 and is 2.44 (m, 2H), 2,65 (DD, J=6,0, to 13.6 Hz, 1H), 2,70 (DD, J=3,6, to 13.6 Hz, 1H), 3,03 (DD, J=3,6, to 13.6 Hz, 1H), 3,20-to 3.36 (m, 1H), 3,32 (s, 3H), 3,62 (USS, 2H), 4,00-4,10 (m, 1H), 6,45 of 6.66 (m, 2H), 6,86 (DD, J=8,4, 12.0 Hz, 1H).

Example of getting 13

Synthesis of 5-cyanopyridine-2-carboxylic acid

[Formula 35]

Synthesis of methyl 5-cyano-2-carboxylate

A mixture of methyl 5-bromopyridin-2-carboxylate (2.8 g) and copper cyanide (3.6 g) in NMP (30 ml) was heated with stirring at 170°C for 1.5 hours. To the reaction solution was added water at room temperature and the insoluble substance was removed by filtration. The filtrate was extracted with what acetate. The extract was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on a column of silica gel (system ethyl acetate-heptane) to obtain the specified title compound (920 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 4,06 (s, 3H), 8,16 (DD, J=2,0, 8.0 Hz, 1H), 8,27 (d, J=8.0 Hz, 1H), 9,01 (d, J=2.0 Hz, 1H).

Synthesis of 5-cyanopyridine-2-carboxylic acid

A solution of the compound from example obtain 13-(1) (920 mg) and 5 n sodium hydroxide solution (of 2.26 ml) in ethanol (30 ml) was stirred at room temperature for 10 minutes. To the reaction solution was added 5 N. chloride-hydrogen acid (5.2 ml) at room temperature, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain specified in the title compound (800 mg).

1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8,18 (d, J=8.0 Hz, 1H), 8,51 (DD, J=2,0, 8.0 Hz, 1H), 9,12-9,18 (m, 1H).

Example of getting 14

Synthesis of 5-deformatsiei-2-carboxylic acid

[Formula 36]

(1)Synthesis of methyl 5-deformatsiei-2-carboxylate

p> Potassium carbonate (8,82 g) and chlorodifluoroacetic sodium (6,53 g) was added to a solution of compound (CAS 13924-95-3) (3.3 grams) in DMF (42,8 ml). The reaction solution was stirred at 100°C for 30 minutes and then was added a saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and then dried over magnesium sulfate. The drying agent was removed by filtration and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel with obtaining specified in the header of the compound (928 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): Android 4.04 (s, 3H), 7,49 (t, J=71,2 Hz, 1H), of 8.47 (d, J=0.8 Hz, 1H), of 8.92 (d, J=0.8 Hz, 1H).

(2)Synthesis of 5-deformatsiei-2-carboxylic acid

Water (1,54 ml) and 5 n sodium hydroxide solution (492 ml) was added to a solution of the compound obtained in the example of a 14-(1) (250 mg)in THF (4,60 ml). The reaction solution was stirred at room temperature for five minutes and then was added a 2 n solution of chloride-hydrogen acid, followed by extraction with ethyl acetate. The organic layers were washed with a saturated solution of sodium chloride and then dried over magnesium sulfate. The drying agent was removed by filtration, and then concentrated under reduced pressure and the solvent is obtaining specified in the title compound (200 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 7,51 (t, J=71,2 Hz, 1H), 8,39 (d, J=1.2 Hz, 1H), 9,04 (d, J=1.2 Hz, 1H).

Example get 15

Synthesis of 5-formatexpiry-2-carboxylic acid

[Formula 37]

(1)Synthesis of methyl 5-formatexpiry-2-carboxylate

Formaterror-4-sulfonate (Journal of Labelled Compounds &Radiopharmaceuticals, 46 (6), 555-566; 2003) (344 mg) and cesium carbonate (824 mg) was added to a solution of methyl 5-hydroxypyridine-2-carboxylate (130 mg) in N,N-dimethylformamide (2.0 ml). The reaction solution was stirred at 70°C for five hours and 30 minutes and then cooled to room temperature. To the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column with NH-silica gel with obtaining specified in the connection header (18,0 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): a 4.03 (s, 3H), 6,14 (d, J=51,2 Hz, 2H), 8,42 (d, J=1.2 Hz, 1H), to 8.94 (d, J=1.2 Hz, 1H).

(2)Synthesis of 5-formatexpiry-2-carboxylic acid

Trimethylsilanol potassium (18.6 mg) was added to a solution of methyl 5-formatexpiry-2-carboxylate obtained in example getting 15-(1) in (18.0 mg)in tetrahydrofuran (1.0 ml). The reaction solution was stirred at room temperature for one hour. Was added to the reaction solution, water and et is latitat and separated water layer. The aqueous layer was acidified using 1 M chloride-hydrogen acid, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to get crude product, consisting of the specified in the connection header (10,2 mg). The connection used for the next reaction without further purification.

1H-NMR (400 MHz, CDCl3) δ (ppm): 6,16 (d, J=50,8 Hz, 2H), 8.34 per (d, J=1.4 Hz, 1H), 9,05 (d, J=1.4 Hz, 1H).

Example 16

Synthesis of 5-formatexception-2-carboxylic acid

[Formula 38]

(1)Synthesis of methyl 5-formatexception-2-carboxylate

The solution containing formaterror-4-sulfonate (233 mg)in DMF was added to a solution containing methyl 5-hydroxypyridine-2-carboxylate (100 mg) and cesium carbonate (532 mg)in DMF (5 ml). The reaction solution was stirred at 70°C for three hours. The reaction solution was cooled to room temperature. Was added to the reaction solution, ethyl acetate and a saturated aqueous solution of ammonium chloride and separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated and the residue was purified by chromatography on a column of silica compound is elem obtaining specified in the title compound (51 mg).

1H-NMR (CDCl3) δ (ppm): 4,00 (s, 3H), 5,80 (d, J=45,1 Hz, 2H), 7,51 (DDD, J=0,8, 2,8, 8,8 Hz, 1H), 8,16 (d, J=0,4, 8,8 Hz, 1H), 8,54 (d, J=2,8 Hz, 1H).

(2)Synthesis of 5-formatexception-2-carboxylic acid

To a solution containing methyl 5-formatexception-2-carboxylate (50 mg) in a mixture of tetrahydrofuran/water (2 ml, 3/1)was added 5 n sodium hydroxide (81 μl) and the mixture was stirred at room temperature for 10 minutes. To the reaction solution were added water (1 ml) followed by stirring for 20 minutes. The reaction solution was acidified 5 N. chloride-hydrogen acid. To the reaction solution were added ethyl acetate and a saturated solution of sodium chloride and separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated to obtain specified in the connection header (to 22.6 mg).

1H-NMR (CDCl3) δ (ppm): of 5.81 (d, J=53,2 Hz, 2H), to 7.61 (DDD, J=0,8, 2,8, 8,8 Hz, 1H), 8,25 (d, J=0,8, 8,8 Hz, 1H), 8,42 (d, J=2.4 Hz, 1H).

Example of getting 17

Synthesis of 5-deformalisation-2-carboxylic acid

[Formula 39]

(1)Synthesis of tert-butyl 5-methylpyrazine-2-carboxylate

The complex of boron TRIFLUORIDE-diethyl ether (91,7 ml) was added dropwise to a suspension of 2-methylpyrazine-5-carboxylic acid (1 g) and tert-butyl 2,2,2-trichloroacetimidate (4.7 g) in tetrahydrofuran (20 ml) under cooling with ice. The reaction solution was heated to room temperature, followed by stirring for two hours. To the reaction solution was added a saturated solution of sodium chloride and ethyl acetate and the separated organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated and purified by chromatography on a column of silica gel with obtaining specified in the title compound (1.4 g).

1H-NMR (CDCl3) δ (ppm): 1,65 (s, 9H), to 2.65 (s, 3H), to 8.57 (d, J=1.2 Hz, 1H), 9,10 (d, J =1.6 Hz, 1H).

(2)Synthesis of tert-butyl 5-((E)-2-dimethylaminovinyl)pyrazin-2-carboxylate

A mixture of tert-butyl 5-methylpyrazine-2-carboxylate (1.35 g), N,N-dimethylformamide (25 ml) and dimethylacetal N,N-dimethylformamide (25 ml) was stirred at 130°C for five hours. The reaction solution was cooled to room temperature and was diluted with ethyl acetate. The mixture was washed three times with a saturated solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated and the residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (648 mg).

1H-NMR (CDCl3) δ (ppm): 1,63 (s, 9H), of 3.00 (s, 6H), 5,16 (d, J=12,8 Hz, 1H), 7,72 (d, J=12,8 Hz, 1H), 8,16 (d, J=1.2 Hz, 1H), 8,81 (d, J=1.6 Hz, 1H).

(3)The synthesis required the-butyl 5-formylpyridine-2-carboxylate

Periodate sodium (1,67 g) was added to a solution of tert-butyl 5-((E)-2-dimethylaminovinyl)pyrazin-2-carboxylate (645 mg) in a mixture of 50% tetrahydrofuran-water (26 ml) and the mixture was stirred at room temperature for four hours. To the reaction solution was added saturated sodium bicarbonate solution and ethyl acetate, and separated the organic layer. The organic layer was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (249 mg).

1H-NMR (CDCl3) δ (ppm): 1,68 (s, 9H), 9,25 (d, J=1.2 Hz, 1H), 9,36 (d, J=1.6 Hz, 1H), 10,2 (s, 1H).

(4)Synthesis of tert-butyl 5-deformalisation-2-carboxylate

TRIFLUORIDE [bis(2-methoxyethyl)amino]sulfur (662 μl) was added dropwise to a solution of tert-butyl 5-formylpyridine-2-carboxylate (249 mg) in dichloromethane (12 ml) under nitrogen atmosphere under ice cooling. The reaction solution was stirred for two hours, gradually bringing it to room temperature. To the reaction solution was added saturated sodium bicarbonate solution and ethyl acetate, and separated the organic layer. The organic layer was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. Nerastvorim the second substance was separated by filtration and the filtrate was concentrated. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (175 mg).

1H-NMR (CDCl3) δ (ppm): 1,67 (s, 9H), 6.75 in (t, J=54,4 Hz, 1H), 9,02 (d, J=0.8 Hz, 1H), 9,25 (d, J=0.8 Hz, 1H).

(5)Synthesis of 5-deformalisation-2-carboxylic acid

Triperoxonane acid (1 ml) was added to a solution of tert-butyl 5-deformalisation-2-carboxylate (175 mg) in dichloromethane (1 ml) and the mixture was stirred at room temperature for five hours. Simple ether and 5 n sodium hydroxide was added to the reaction solution. The aqueous layer was separated and acidified 5 N. chloride-hydrogen acid. Added to the water layer in ethyl acetate and the separated organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated to obtain specified in the title compound (100 mg).

1H-NMR (CDCl3) δ (ppm): 6,80 (t, J=54,4 Hz, 1H), of 9.02 (s, 1H), for 9.47 (s, 1H).

Example of getting 18

Synthesis of tert-butyl (±)-{(4aR*,7aS*)-7a-[3-(2-herperidin-3-yl)phenyl]-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-yl}carbamate

[Formula 40]

(1)Synthesis of 2-[allyl(2,4-dimethoxybenzyl)amino]-1-(3-bromophenyl)ethanone

3-Bromophenethylamine (20,9 g) was dissolved in dichloromethane (400 ml). After cooling races the thief ice was dissolved N,N-diisopropylethylamine (14,3 ml) and allyl(2,4-dimethoxybenzyl)Amin (18.7 g) in dichloromethane (50 ml) was added dropwise. The reaction solution was gradually heated to room temperature by immersing in a bath of ice water, and was stirred for about 20 hours. Chloroform, a saturated solution of sodium bicarbonate and a saturated solution of sodium chloride successively added to the reaction solution, and separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate (2 g). The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure to get crude product. The product was subjected to chromatography on a column of silica gel with obtaining specified in the connection header (29,88 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 3,22-of 3.27 (m, 2H), 3,62 (s, 3H), and 3.72 (s, 2H, in), 3.75 (s, 2H), 3,80 (s, 3H), 5,12-of 2.28 (m, 2H), by 5.87-6,00 (m, 1H), to 6.39 (d, J=2.4 Hz, 1H), 6,44 (DD, J=2,4, 8 Hz, 1H), 7,16 (d, J=8 Hz, 1H), 7,22-7,32 (m, 1H), 7,60-to 7.68 (m, 1H), 7,80-7,87 (m, 1H), 8,07 (t, J=1.6 Hz, 1H).

(2)Synthesis of (3aS*,6aR*)-6a-(3-bromophenyl)-5-(2,4-dimethoxybenzyl)hexahydrofuro[3,4-c]isoxazol

The compound obtained in the example of a 18-(1) (29,8 g), was dissolved in ethanol (475 ml). Hydroxylamine hydrochloride (10.3 g) and sodium acetate (12.1 g) was added to the solution and the mixture was heated under stirring at 90°C. After five hours the reaction solution was cooled and then filtered. The filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate and the mixture is successively premillenarianism solution of sodium bicarbonate and a saturated solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate (2 g). The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure to get Aksenovo connection (31,3 g). Oxime connection (31,3 g) was dissolved in toluene (600 ml). The solution was boiled under reflux in nitrogen atmosphere for eight hours. The reaction solution was brought to room temperature and then concentrated under reduced pressure. The residue was subjected to chromatography on a column of silica gel with obtaining specified in the title compound (19 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,44 (USS, 1H), 2,65 (USS, 1H), 2.91 in (USS, 1H), 2,97-3,14 (m, 2H), 3,50-3,62 (m, 1H), 3,66 (s, 2H), 3,79 (s, 3H), 3,81 (s, 3H), 4,47 (USS, 1H), 5,42 (USS, 1H), 6,44-6,50 (m, 2H), 7,15-7,22 (m, 2H), 7,33-7,40 (m, 1H), 7,42-7,49 (m, 1H), 7,69-7,74 (m, 1H).

(3)Synthesis of (±)-[(3S*,4R*)-4-amino-4-(3-bromophenyl)-1-(2,4-dimethoxybenzyl)pyrrolidin-3-yl]methanol

The compound obtained in the example of a 18-(2) (19 g)was dissolved in acetic acid (230 ml). To the solution was added zinc (30 g), followed by stirring at room temperature. After 20 hours the reaction solution was filtered through celite. The filtrate was concentrated under reduced pressure. To the residue was added 5 n sodium hydroxide solution and chloroform, followed by filtration through celite. The filtrate was separated. The organic layer was dried over anhydrous su is hatom magnesium. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was subjected to chromatography on a column of silica gel with obtaining specified in the title compound (19.1 g).

ESI-MS; m/z 421 [M+H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,44 of $ 2.53 (m, 1H), 2,68-2,77 (m, 3H), 2,97 (d, J=9,2 Hz, 1H), 3,62-3,82 (m, 4H), 3,81 (s, 3H), 3,82 (s, 3H) 6,44 (m, 2H), 7.18 in-7,29 (m, 2H), 7,34-7,40 (m, 1H), 7,46-7,53 (m, 1H), 7,71 (t, J=2.0 Hz, 1H).

(4)Synthesis of (±)-1-benzoyl-3-[(3R*,4S*)-3-(3-bromophenyl)-1-(2,4-dimethoxybenzyl)-4-hydroxyethylpyrrolidine-3-yl]thiourea

The compound obtained in the example of a 18-(3) (to 2.29 g)was dissolved in dichloromethane (50 ml). Benzoylisothiocyanate (807 ml) was added to the solution followed by stirring at room temperature. After 11 hours the reaction solution was concentrated under reduced pressure. The residue was subjected to chromatography on a column of silica gel with obtaining specified in the connection header (1,96 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): to 2.55 (t, J=8,4 Hz, 1H), 2,81-2,90 (m, 1H), 2,98-of 3.06 (m, 1H), 3,20 (d, J=10.4 Hz, 1H), 3,63-a 3.83 (m, 3H), 3,81 (s, 3H), 3,83 (s, 3H), a 3.87-to 3.99 (m, 2H), 6,44-of 6.52 (m, 2H), 7,18 (t, J=8.0 Hz, 1H), from 7.24 to 7.32 (m, 1H), 7,33-7,38 (m, 1H), 7,40-7,46 (m, 1H), 7,49-EUR 7.57 (m, 2H), to 7.61-of 7.70 (m, 2H), 7,84-to $ 7.91 (m, 2H), 8,91 (s, 1H), 11,7 (s, 1H).

(5)Synthesis of (±)-N-[(4aR*,7aS*)-7a-(3-bromophenyl)-6-(2,4-dimethoxybenzyl)-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-yl]benzamide

Solution connection polucen the th in the example of a 18-(4) (1,43 g), and pyridine (810 μl) in dichloromethane (55 ml) was cooled to -50°C. Triftormetilfullerenov anhydride (1.1 ml) was added dropwise to the solution and the mixture was gradually heated to 0°C. Over one hour and 30 minutes the reaction solution was cooled to -20°C, was diluted with chloroform and washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was subjected to chromatography on a column of silica gel with obtaining specified in the title compound (1.30 grams).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,73 (DD, J=4,4, to 13.6 Hz, 1H), 2,90 (d, J =10.4 Hz, 1H), 2,92-3,18 (m, 4H), to 3.38 (d, J=10.4 Hz, 1H), 3,70 (s, 2H), of 3.77 (s, 3H), 3,81 (s, 3H), 6,40 (DD, J=2,4, and 8.4 Hz, 1H), 6,44 (d, J=2.4 Hz, 1H), 7,18-7,30 (m, 2H), 7,40-rate of 7.54 (m, 5H), 7.68 per-7,72 (m, 1H), 8.17 and compared to 8.26 (m, 2H).

(6)Synthesis of (±)-(4aR*,7aS*)-7a-(3-bromophenyl)-6-(2,4-dimethoxybenzyl)-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-ylamine

1,8-Diazabicyclo[5,4,0]undec-7-ene (684 μl) was added to a solution of the compound obtained in the example of a 18-(5) (1.3 g)in methanol (22 ml) and the mixture is boiled under reflux. Four hours and 30 minutes the reaction solution was allowed to cool and then concentrated under reduced pressure to obtain a residue. The residue is suspended in tert-butylmethylether ether and collected by filtration to receive the drug specified in the title compound (837 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,52 of 2.68 (m, 3H), 2,72 is 2.80 (m, 1H), 2,92 (DD, J=4,0, to 12.8 Hz, 1H), 3,06-3,14 (m, 1H), 3,39 (d, J=9.6 Hz, 1H), 3,64 (d, J=10 Hz, 2H), 3,81 (s, 3H), 3,83 (s, 3H), 4,48 (USS, 2H), 6,44-6,50 (m, 2H), 7,13-7,19 (m, 1H), 7,27-7,34 (m, 2H), 7,46-7,52 (m, 1H), 7,70-7,74 (m, 1H).

(7)Synthesis of (±)-di-tert-butyl [(4aR*,7aS*)-7a-(3-bromophenyl)-6-(2,4-dimethoxybenzyl)-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-yl]iminodicarboxylate

The compound obtained in the example of a 18-(6) (1,14 g), was dissolved in THF (45 ml) and DMF (20 ml). Di-tert-BUTYLCARBAMATE (3,23 g) and 4-dimethylaminopyridine (2,11 g) was sequentially added to the solution and then the mixture was stirred at room temperature. After about 17 hours, the reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate and saturated sodium bicarbonate solution and separated the organic layer. The organic layer was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was subjected to chromatography on silica gel with obtaining specified in the connection header (1,33 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,56 (s, 18H), of 2.54 (d, J=10 Hz, 1H), 2,60 is 2.80 (m, 3H), 2,92-3,00 (m, 1H), 3,10-3,18 (m, 1H), 3,53-3,70 (m, 3H), 3,81 (s, 3H), 3,82 (s, 3H), 6.42 per-6,54 (m, 2H), 7,16-7,22 (m, 1H), 7,26-7,38 (m, 2H,), 7,46-7,53 (m, 1H), to 7.64 (t, J=2.0 Hz, 1H).

(8)Synthesis of (±)-and tert-butyl {(4aR*,7aS*)-6-(2,4-dimethoxybenzyl)-7a-[3-(2-herperidin-3-yl)phenyl]-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-yl}iminodicarboxylate

The compound obtained in the example of a 18-(7) (1,33 g), was dissolved in THF (25 ml). 2-Herperidin-3-Bronevoy acid (848 mg), potassium fluoride (495 mg), Pd2DBA3 (172 mg) and Pd(t-Bu3P)2 (195 mg) was added to the solution and the mixture was stirred in nitrogen atmosphere at room temperature. After 3.5 hours, the reaction solution was diluted with ethyl acetate and filtered through NH silica gel (80 ml). The resulting product was further washed with a mixture of ethyl acetate:heptane = 1:1 (500 ml). The filtrate was concentrated under reduced pressure to obtain a residue. The residue was subjected to chromatography on silica gel with obtaining specified in the connection header (1,15 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.52 (s, 18H), 2,63 (d, J=10.4 Hz, 1H), 2,68-2,87 (m, 3H), 3.00 and-of 3.07 (m, 1H), 3,13-3,20 (m, 1H), 3,60 at 3.69 (m, 3H), of 3.78 (s, 3H), 3,81 (s, 3H), 6,40-of 6.52 (m, 2H), 7,22-7,29 (m, 1H), 7.29 trend was 7.36 (m, 1H), 7,38-to 7.50 (m, 2H), 7,53-to 7.59 (m, 1H), 7,72 (s, 1H), 7,87-7,94 (m, 1H), 8,16 is 8.22 (m, 1H).

(9)Synthesis of tert-butyl (±)-{(4aR*,7aS*)-7a-[3-(2-herperidin-3-yl)phenyl]-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-yl}carbamate

The triethylamine (387 μl) was added to a solution of the compound obtained in the example of a 18-(8) (411,00 mg), in dichloromethane (20,00 ml). The mixture is sufficiently cooled in an ice bath under nitrogen atmosphere and then slowly added triperoxonane anhydride (344 μl). At the end of the addition the mixture was stirred for three hours and 30 minutes. The solvent is evaporated from a mixture of PR is the reduced pressure and then the residue was dissolved in methanol (30 ml). Was added to a solution of 5 N. aqueous solution of potassium hydroxide (1.6 ml) and the mixture was stirred at room temperature for two hours and 30 minutes. The reaction mixture was diluted with chloroform and then washed with a saturated solution of sodium chloride. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (122 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): was 1.58 (s, 9H), 2,73-2,78 (m, 1H), 2.91 in-2,95 (m, 1H), 3,10-3,15 (m, 1H), 3,24 (d, J=12.0 Hz, 1H), 3,34 is-3.45 (m, 2H), 3,53 (d, J=12.0 Hz, 1H), 7,28-7,32 (m, 1H), 7,42-7,46 (m, 1H), 7,50-rate of 7.54 (m, 3H), the 7.85-7,89 (m, 1H), they were 8.22-8,24 (m, 1H).

Example of getting 19

Synthesis of tert-butyl [(4aS,7R,8aS)-8a-(5-amino-2-forfinal)-7-methoxymethyl-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

[Formula 41]

(1)Synthesis of (R)-1-benzyloxy-3-[1,3]dition-2-improper-2-ol

A solution containing 1,3-dition (11 g) in THF (190 ml), cooled to -70°C. was Added to the reaction solution of n-utility (2,64 M solution in hexane, 35 ml) and then the mixture was heated to -30°C and was stirred for one hour. The reaction solution was cooled to -70°C was added dropwise a solution containing benzyl (R)-(-)-glycidyloxy simple ester (16.5 g) in THF (18 ml). The cooling bath was removed and the mixture is gradually heated is whether to room temperature. After stirring over night to the reaction solution was added a saturated solution of ammonium chloride, a saturated solution of salt and tert-butyl methyl ether, and separated the organic layer. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure to obtain a residue. The residue was subjected to chromatography on a column of silica gel with obtaining specified in the title compound (22.1 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,78-2,00 (m, 3H), 2,08-of 2.16 (m, 1H), 2,42 is 2.46 (m, 1H), 2,79-2,96 (m, 4H), to 3.38 (DD, J=6,8, and 9.6 Hz, 1H), 3,52 (DD, J=3,4, 9.6 Hz, 1H), 4,10-4,18 (m, 1H), 4,24-4,30 (m, 1H), 4,56 (d, J=1.6 Hz, 2H), 7,27-7,39 (m, 5H).

(2)Synthesis of 2-((R)-2-allyloxy-3-benzyloxyphenyl)-[1,3]dithiane

A solution of (R)-1-benzyloxy-3-[1,3]-dition-2-improper-2-ol (22.1 g) in THF (300 ml) was cooled to 0°C. was Added 60% sodium hydride (4.35 g), followed by stirring. After 12 minutes was added allylbromide (10 ml) and then the ice bath was removed. The mixture was additionally stirred at room temperature. After stirring over night the reaction solution was added to a mixture of ice and tert-butyl methyl ether, and separated the organic layer. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The drying agent was removed filter is a W and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was subjected to chromatography on silica gel with obtaining specified in the connection header (24,7 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,80-of 2.16 (m, 4H), was 2.76 of 2.92 (m, 4H), 3,51 (DD, J=2, 4,8 Hz, 2H), 3,78-3,88 (m, 1H), 4.04 the-4,11 (m, 1H), 4,12-4,22 (m, 2H), 4,55 (d, J=5.6 Hz, 2H), 5,12-5,19 (m, 1H), 5,23-5,32 (m, 1H), 5,88-6,00 (m, 1H), 7,27-7,39 (m, 5H).

(3)Synthesis of (R)-3-allyloxy-4-benzyloxybenzaldehyde

Potassium carbonate (5,14 g) and methyliodide (4,90 ml) was added to a mixed solution of 2-((R)-2-allyloxy-3-benzyloxyphenyl)-[1,3]-dithiane (12 g) in acetonitrile (27 ml) and water (4.5 ml) and the mixture is then stirred at 40°C. After four hours, water (3 ml) and methyliodide (2 ml) was added to the reaction solution. After another three hours was added to the reaction solution, methyliodide (1 ml). After stirring for eight hours in total to the reaction solution were added water and tert-butyl methyl ether, and separated the organic layer. The organic layer was washed with a saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to get crude (R)-3-allyloxy-4-benzyloxybenzaldehyde (about 10 g). The crude product was used for next reaction without further purification. Hydroxylamine hydrochloride (4,29 g) and sodium acetate (4.92 in g), was added to the ethanol solution is (60 ml) and water (15 ml). The above aldehyde (10 g) was added to the mixture, followed by stirring for 20 hours. Was added to the reaction solution, a saturated sodium bicarbonate solution and ethyl acetate, and separated the organic layer. The organic layer was sequentially washed with saturated sodium bicarbonate solution and saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure to obtain a residue. The residue was subjected to chromatography on a column of silica gel with obtaining specified in the connection header (5,74 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,41-to 2.55 (m, 1H), 2,59-to 2.74 (m, 1H), 3,47-of 3.60 (m, 2H), 3,68-3,82 (m, 1H), was 4.02-4,19 (m, 2H), to 4.52-4,58 (m, 2H), 5,14-5,20 (m, 1H), 5,23-5,32 (m, 1H), of 5.84 is 5.98 (m, 1H), 6.87 in (t, J=5.4 Hz, 0,5H) 7,24-7,40 (m, 5H), of 7.48 (t, J=6.2 Hz, 0,5H).

(4)Synthesis of (3aS,6R)-6-benzoyloxymethyl-3a,4,6,7 there-tetrahydro-3H-pyrano[4,3-c]isoxazol

Sodium hypochlorite (5% aqueous solution of 42 ml) was added dropwise to the solution containing the oxime synthesized at the previous stage (grade of 5.74 g)in dichloromethane (120 ml) at room temperature, followed by stirring for one hour. To the reaction solution was added sodium thiosulfate solution, and separated the organic layer. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. Ossaudiodev was removed by filtration and then the filtrate was concentrated under reduced pressure to obtain a residue. The residue was subjected to chromatography on a column of silica gel with obtaining specified in the connection header (4,49 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,27-2,39 (m, 1H), 2,70-2,78 (m, 1H), 3,30-to 3.52 (m, 2H), 3,53-3,62 (m, 3H), 3,74 (DD, J=8,4, 10.4 Hz, 1H), and 4.40 (DD, J=6,0, 10,0 Hz, 1H), 4,48 (DD, J=8,4, 10,0 Hz, 1H), br4.61 (s, 2H), 7,27-7,39 (m, 5H).

(5)Synthesis of (3aS,6R,7aS)-6-benzoyloxymethyl-7a-(2-forfinal)hexahydropyrazino[4,3-c]isoxazol

THF (10 ml) and toluene (90 ml) was added to 2-bromptonville (4,14 ml) under nitrogen atmosphere and the mixture was cooled to -78°C. To the solution was slowly added n-utility (2,64 M solution in hexane, to 13.8 ml). After stirring at the same temperature for 10 minutes was sequentially added dropwise a complex of boron TRIFLUORIDE-diethyl ether (4,57 ml) and the solution containing isoxazol synthesized at the previous stage (of 4.49 g)in toluene (10 ml). The mixture was further stirred at the same temperature for four hours. To the reaction solution was added a saturated solution of ammonium chloride followed by heating to room temperature. Then added ethyl acetate and water and separated the organic layer. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on a column with silicagel is eat and chromatography on a column with NH-silica gel with obtaining specified in the header of the compound (5.73 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): is 1.81 (DD, J=3.2, and 15.2 Hz, 1H), 2,28 (DD, J=12,4, 15.2 Hz, 1H), 3,07-and 3.16 (m, 1H), 3,40-of 3.85 (m, 6H), 4,08-4,19 (m, 1H), 4,58 (d, J=5,2 Hz, 2H), 5,94 (s, 1H), 7,00-was 7.08 (m, 1H), 7,10-7,17 (m, 1H), 7,22-7,39 (m, 6H), 7,83-a 7.92 (m, 1H).

(6)Synthesis of [(3R,4S,6R)-4-amino-6-benzoyloxymethyl-4-(2-forfinal)tetrahydropyran-3-yl]methanol

Isoxazol synthesized at the previous stage (5.73 g)was dissolved in acetic acid (70 ml). To the solution was added zinc (11 g), followed by stirring at room temperature. After 15 hours the reaction solution was filtered through celite and washed with methanol. The filtrate was concentrated under reduced pressure. To the residue was added 2 n sodium hydroxide solution and chloroform, and separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain specified in the connection header (between 6.08 g). The connection used for the next reaction without further purification.

ESI-MS; m/z 346 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,44 (DD, J=2,4, of 13.6 Hz, 1H), 2,37 (DD, J=11,6, to 13.6 Hz, 1H), 2,49-of 2.58 (m, 1H), 3,41-3,59 (m, 4H), 3,99-4,16 (m, 3H), 4,59 (d, J=10.0 Hz, 2H), 7,01-to 7.09 (m, 1H), 7,14-7,20 (m, 1H), 7,24 and 7.36 (m, 6H), EUR 7.57-7,63 (m, 1H).

(7)Synthesis of 1-benzoyl-3-[(2R,4S,5R)-2-benzoyloxymethyl-4-(2-forfinal)-5-hydroxyethylacrylate-4-yl]thiourea

Amin, synthesized pre is striding the stage (between 6.08 g), was dissolved in dichloromethane (60 ml). Benzoylisothiocyanate (2,58 ml) was added to the solution followed by stirring at room temperature. After 15 hours the reaction solution was concentrated under reduced pressure. The residue was subjected to chromatography on a column of silica gel with obtaining specified in the connection header (7,83 g).

ESI-MS; m/z 509 [M++H], 531 [M++Na].

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,25-2,50 (m, 1H), 3,50-3,90 (m, 5H), 3,90-of 4.05 (m, 1H), 4,10-4,30 (m, 2H), br4.61 (d, J=2.4 Hz, 2H), 7,02-7,10 (m, 1H), 7,13-7,20 (m, 1H), 7.24 to 7,44 (m, 7H), 7,50-EUR 7.57 (m, 2H), to 7.61-to 7.68 (m, 1H), 7,85-to $ 7.91 (m, 2H), of 8.90 (s, 1H), 11,7 (s, 1H).

(8)Synthesis of N-[(4aS,7R,8aS)-7-benzoyloxymethyl-8a-(2-forfinal)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]benzamide

The thiourea, synthesized at the previous stage (7,83 g), was dissolved in methanol (100 ml) and concentrated chloride-hydrogen acid (3 ml). The solution was boiled under reflux at 95°C. After four hours the reaction solution was allowed to cool and then concentrated under reduced pressure. Chloroform, 5 n sodium hydroxide solution and a saturated salt solution was added to the residue and the separated organic layer. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain specified in the title compound (10 g). Connection and is used for the next reaction without further purification.

ESI-MS; m/z 491 [M++H].

(9)Synthesis of (4aS,7R,8aS)-7-benzoyloxymethyl-8a-(2-forfinal)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-ylamine

The compound obtained in the example of a 19-(8) (10 g)was dissolved in methanol (60 ml). Was added to a solution of DBU (5 ml) and the mixture is boiled under reflux at 95°C. After five hours, the reaction solution was allowed to cool and was concentrated its under reduced pressure. The ethyl acetate, a saturated solution of sodium bicarbonate and a saturated salt solution was added to the residue and the separated organic layer. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on silica gel with obtaining specified in the connection header (6.42 per g).

ESI-MS; m/z 387 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,67 (DD, J=2,0, to 12.8 Hz, 1H), 2,36 is 2.46 (m, 1H), 2,52-2,60 (m, 1H), 2,87 (DD, J=4,4, and 12.4 Hz, 1H), 2,94-to 3.02 (m, 1H), 3,42-to 3.58 (m, 2H), 3,79-3,99 (m, 3H), 4,40-4,70 (m, 4H), 6,99-7,07 (m, 1H), 7,07-7,13 (m, 1H), 7,20 was 7.36 (m, 7H).

(10)Synthesis of [(4aS,7R,8aS)-2-amino-8a-(2-forfinal)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-7-yl]methanol

Concentrated chloride-hydrogen acid (35 ml) was added to the compound obtained in the example of a 19-(9) (6.42 per g), and the mixture is boiled under reflux at 125°C. After two hours the reaction solution Dawa and cool. Added tert-butyl methyl ether, and separated the organic layer. Chloroform and 5 n sodium hydroxide solution was added to the water layer, and separated the organic layer. The organic layers were dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain specified in the connection header (4,16 g).

ESI-MS; m/z 297 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,64 (DD, J=2,0, to 12.8 Hz, 1H), 2,34 is 2.44 (m, 1H), 2,53-2,62 (m, 1H), 2,85-of 2.93 (m, 1H), 2,93-3,03 (m, 1H), 3,54 at 3.69 (m, 2H), 3,78-3,91 (m, 3H), 4,55 (USS, 2H), 6,99-7,07 (m, 1H), 7,08-to 7.15 (m, 1H), 7,20-to 7.32 (m, 2H).

(11)Synthesis of tert-butyl [(4aS,7R,8aS)-8a-(2-forfinal)-7-hydroxymethyl-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

THF (100 ml), methanol (50 ml) and triethylamine (2,80 ml) was added to the compound obtained in the example of a 19-(10) (3.8 g). To the reaction mixture was added di-tert-BUTYLCARBAMATE (3.7 g), followed by stirring. After stirring over night the reaction solution was concentrated under reduced pressure to obtain a residue. The residue was subjected to column chromatography and precipitated using a simple broadcast receiving specified in the title compound (5.35 g).

ESI-MS; m/z 397 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.53 (s, 9H), and 1.63 (DD, J=2,0, of 14.0 Hz, 1H), 1,98 (USS, 1H), 2,46-of 2.58 (m, 2H), 2,86 (DD, J=4,4, 13,2 Hz, 1H), 3.04 from-and 3.16 (m, 1H), 3,54-3,74 (m, 2H), 3,76 to 3.8 (m, 1H), 3.96 points (d, J=7,6 Hz, 2H),? 7.04 baby mortality for 7.12 (m, 1H), 7,14-7,21 (m, 1H), 7,21 and 7.36 (m, 2H).

(12)Synthesis of tert-butyl [(4aS,7R,8aS)-8a-(2-forfinal)-7-methoxymethyl-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

A solution of the compound obtained in the example of a 19-(11) (613 mg), in dichloromethane (15 ml) was cooled with ice. To the solution was added triethylamine (432 μl) and methanesulfonamide (144 μl). The reaction solution was stirred at the same temperature for one hour. Then dichloromethane and saturated sodium bicarbonate solution was added to the reaction solution, and separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure to obtain mesila. Mesyl was dissolved in methanol (10 ml) and then cooled with ice. The sodium methoxide (28% solution in methanol, 1.7 ml) was added to the solution and the mixture was stirred at room temperature. After one hour the reaction solution was heated to 70°C. After about three hours added additional sodium methoxide (28% solution in methanol, 5 ml) and the mixture was stirred for another four hours. The reaction solution was allowed to cool. Then was added chloroform and saturated sodium bicarbonate solution and separated the organic layer. The organic layer was washed with a saturated solution of salt. The organization is practical layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure to obtain a residue. The residue was subjected to chromatography on silica gel with obtaining specified in the title compound (262 mg).

ESI-MS; m/z 41 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.53 (s, 9H), 1,67 (DD, J=2,0, to 13.6 Hz, 1H), 1,98 (USS, 1H), 2,46-of 2.56 (m, 2H), 2,81-2,90 (m, 1H), 3,07-and 3.16 (m, 1H), 3,40 (s, 3H), 3,40-to 3.52 (m, 2H), 3,86-4,01 (m, 3H),? 7.04 baby mortality for 7.12 (m, 1H), 7,14-7,21 (m, 1H), 7,25 was 7.36 (m, 2H).

(13)Synthesis of tert-butyl [(4aS,7R,8aS)-8a-(2-fluoro-5-nitrophenyl)-7-methoxymethyl-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

The compound obtained in the example of a 19-(12) (262 mg)was dissolved in dichloromethane (3 ml) and then cooled with ice. To the solution was added TFOC (1 ml) followed by stirring at room temperature. After four hours the reaction solution was concentrated under reduced pressure to obtain a residue. To the residue was added TFOC (1 ml) and then cooled with ice. To the solution was added concentrated sulfuric acid (0.5 ml). Then was added fuming nitric acid (37 μl) and the mixture was stirred for one hour. The reaction solution was poured into water. Caution was added chloroform and 5 n sodium hydroxide solution and the separated organic layer. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtering and the filtrate was concentrated under reduced pressure to obtain a residue. The residue (239 mg) was dissolved in THF (3 ml) and methanol (1 ml)and then was added triethylamine (200 μl). Di-tert-BUTYLCARBAMATE (215 mg) was dissolved in THF (2 ml) and the solution was added to the above solution. After 18 hours the reaction solution was concentrated under reduced pressure to obtain a residue. The residue was subjected to column chromatography to obtain specified in the title compound (256 mg).

ESI-MS; m/z 456 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): and 1.54 (s, 9H), 1,66-of 1.73 (m, 1H), 2.26 and-to 2.42 (m, 1H), 2,56 (DD, J=2,8, 13,2 Hz, 1H), 2,74-2,84 (m, 1H), 3.00 and-of 3.12 (m, 1H), 3,39 (s, 3H), 3,36-to 3.50 (m, 2H), 3.72 points-was 4.02 (m, 3H), 7.18 in-7,32 (m, 1H), 8,12-8,24 (m, 2H).

(14)Synthesis of tert-butyl [(4aS,7R,8aS)-8a-(5-amino-2-forfinal)-7-methoxymethyl-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

The compound obtained in the example of a 19-(13) (255 mg), was dissolved in ethanol (9 ml). To the solution was added a saturated solution of ammonium chloride (0.9 ml) and iron powder (440 mg) and the mixture was heated at 90°C for 40 minutes. The reaction solution was allowed to cool and filtered through celite. To the filtrate was added ethyl acetate and sodium bicarbonate solution and separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was subjected to chromatography on a column of the silica gel and then besieged, using tert-butyl methyl ether and hexane, obtaining specified in the title compound (151 mg).

ESI-MS; m/z 426 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.53 (s, 9H), and 1.63 (DD, J=2,0, of 14.0 Hz, 1H), 2,44 is 2.55 (m, 2H), 2,92 (DD, J=4,0, 13,2 Hz, 1H), 3.04 from-3,13 (m, 1H), 3,39 (s, 3H), 3,38-to 3.49 (m, 2H), 3,64 (USS, 2H), 3,86-4,00 (m, 3H), 6,50-6,60 (m, 2H), 6,87 (DD, J=8,4, 12.0 Hz, 1H).

Example of getting 20

Synthesis of tert-butyl [(4aS,7R,8aS)-8a-(5-amino-2-forfinal)-7-vermeil-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

[Formula 42]

(1)Synthesis of tert-butyl [(4aS,7R,8aS)-7-vermeil-8a-(2-forfinal)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

Performancemonitoring (990 μl), trihydrochloride of triethylamine (842 μl) and triethylamine (2.2 ml) was sequentially added to the mixture of the compound obtained in the example of a 19-(11) (1 g)in acetonitrile (15 ml) and THF (4 ml), followed by stirring at room temperature. After about 22 hours was added to the reaction solution, a saturated sodium bicarbonate solution. The organic layer was extracted with chloroform and washed with a saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure to obtain a residue. The residue was subjected to chromatography on a silica compound is barely obtaining specified in the title compound (307 mg).

ESI-MS; m/z 399 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.53 (s, 9H), 1.69 in (DD, J=2,0, to 13.6 Hz, 1H), 2,48-2,60 (m, 2H), 2,85 (DD, J=4,4, 13,2 Hz, 1H), 3.04 from-3,18 (m, 1H), 3,85-4,08 (m, 3H), 4,32-of 4.44 (m, 1H), 4,45-4,56 (m, 1H), 7,05-7,14 (m, 1H), 7,14-7,21 (m, 1H), 7.24 to 7,37 (m, 2H).

(2)Synthesis of tert-butyl [(4aS,7R,8aS)-7-vermeil-8a-(2-fluoro-5-nitrophenyl)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

The compound obtained in the example of a 20-(1) (307 mg)was dissolved in dichloromethane (3 ml) and then cooled with ice. To the solution was added TFOC (1 ml) followed by stirring at room temperature. After four hours the reaction solution was concentrated under reduced pressure to obtain a residue. To the obtained residue was added TFOC (1 ml) and then cooled with ice. To the solution was added concentrated sulfuric acid (0.5 ml). Then was added fuming nitric acid (42 μl) and the mixture was stirred for one hour. The reaction solution was poured into water. Caution was added chloroform and 5 n sodium hydroxide solution and the separated organic layer. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue (260 mg). The residue (260 mg) was dissolved in THF (3 ml) and methanol (1 ml)and then was added triethylamine (200 μl). Di-tert-BUTYLCARBAMATE (285 mg) was dissolved wtgf (2 ml) and the solution was added to the solution, obtained above. After 18 hours was added to the reaction solution, ethyl acetate and saturated sodium bicarbonate solution and separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was subjected to column chromatography to obtain specified in the title compound (292 mg).

ESI-MS; m/z 444 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): and 1.54 (s, 9H), 1,66-of 1.74 (m, 1H), 2,27-2,48 (m, 1H), 2.57 m (DD, J=2,8, to 13.6 Hz, 1H), 2,72-is 2.88 (m, 1H), 2,98-and 3.16 (m, 1H), 3,76-Android 4.04 (m, 3H), 4,30-4,56 (m, 2H), 4,45-4,56 (m, 1H), 7.18 in-7,29 (m, 1H), 8,12 is 8.25 (m, 2H).

(3)Synthesis of tert-butyl [(4aS,7R,8aS)-8a-(5-amino-2-forfinal)-7-vermeil-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

The compound obtained in the example of a 20-(2) (290 mg)was dissolved in ethanol (10 ml). To the solution was added a saturated solution of ammonium chloride (1 ml) and iron powder (490 mg) and the mixture was heated at 90°C for 40 minutes. The reaction solution was allowed to cool and filtered through celite. To the filtrate was added ethyl acetate and sodium bicarbonate solution and separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was subjected to the Lee column chromatography to obtain specified in the title compound (186 mg).

ESI-MS; m/z 414 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.53 (s, 9H), 1,58-1,72 (m, 1H), 2,47-2,60 (m, 2H), 2,93 (DD, J=4,0, 13,2 Hz, 1H), 3,03-of 3.12 (m, 1H), 3,65 (USS, 2H), a 3.87-a 4.03 (m, 3H), 4,33-4,43 (m, 1H), of 4.44-of 4.54 (m, 1H), 6.48 in-6,60 (m, 2H), 6,83-6,92 (m, 1H).

Example of getting 21

Synthesis of tert-butyl (-)-[(4aS*,5R*,7aS*)-7a-(5-amino-2-forfinal)-5-ethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

[Formula 43]

(1)Synthesis of (1-ethylethylene)acetyldigitoxin

A solution of 1-penten-3-ol (15.0 ml) in N-methyl-2-pyrrolidone (292 ml) was cooled to 0°C in nitrogen atmosphere. Sodium hydride (60%, 6.42 per g) and diethylacetal of bromoacetaldehyde (31.6) was added to the reaction solution at the same temperature and the mixture was stirred at 80°C for 30 minutes. To the reaction solution at 0°C was added a saturated solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in heptane. The solution was filtered through silica gel, using a mixture of 30% ethyl acetate/heptane, and concentrated under reduced pressure. To the residue was added formic acid (100 ml), hydroxylamine hydrochloride (15.2 g)and sodium acetate (24,0 g) and the mixture was stirred at room temperature for two days. To the reaction solution were added ethyl acetate and a saturated solution of sodium chloride and separated the organic layer. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (4.30 m).

1H-NMR (400 MHz, CDCl3) δ (ppm): 0,88-0,92 (m, 3H), 1,55-to 1.63 (m, 2H) 3,59 is 4.36 (m, 3H), 5,19-5,24 (m, 2H), 5,61-of 5.68 (m, 1H), 6.90 to-6,92 (m, 0,5H), of 7.48-to 7.50 (m, 0,5H).

(2)Synthesis of (3aR*,4R*)-4-ethyl-3a,4-dihydro-3H,6H-furo[3,4-c]isoxazol

5% Solution of sodium hypochlorite (53,6 g) was added to the solution containing the compound obtained in the example of obtaining 21-(1) (4,30 g), in dichloromethane (95,7 ml) at 0°C and the mixture was stirred at 0°C for 30 minutes. A solution of sodium bisulfite was added to the reaction solution at the same temperature. The organic layer was separated and dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (2,02 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): to 0.92 (t, J=7.2 Hz, 3H), 1.56 to to 1.83 (m, 2H), 3,74-of 3.78 (m, 2H), 3,97-was 4.02 (m, 1H), of 4.44-of 4.57 (m, 3H).

(3)Synthesis of (3aR*,4R*,6aS*)-4-ethyl-6a-(2-FPO is phenyl)tetrahydrofuro[3,4-c]isoxazol

A solution of n-utility in hexane (2,60 M; and 12.2 ml) was added dropwise to a solution containing 2-bramptonbest (3,62 ml) in a mixture of tetrahydrofuran/toluene (5,80 ml/58,0 ml)in nitrogen atmosphere at -78°C. the Reaction solution was stirred at the same temperature for 10 minutes. To the reaction solution was sequentially added dropwise a complex of boron TRIFLUORIDE-diethyl ether (3,92 ml) and the solution containing the compound obtained in the example of obtaining 21-(2) (2,02 g)in toluene (20 ml) at the same temperature. After stirring at the same temperature for 40 minutes to the reaction solution was added an aqueous solution of ammonium chloride followed by heating to room temperature. To the reaction solution were added water and ethyl acetate and the separated organic layer. The organic layer was washed with a saturated solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated and the residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (3,39 g).

ESI-MS; m/z 238 [M++H].

(4)Synthesis of 1-benzoyl-3-[(3S*,4R*,5R*)-5-ethyl-3-(2-forfinal)-4-hydroxymethylfurfural-3-yl]thiourea

Zinc powder (a 9.35 g) was added to the solution containing the compound obtained in the example of obtaining 21-(3) (3,39 g), in the UKS the red acid (59,8 ml) at room temperature. The reaction solution was stirred at room temperature for 18 hours. The insoluble substance was separated by filtration through celite and the filtrate was concentrated. To the residue was added ethyl acetate and sodium bicarbonate solution and separated the organic layer. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated under reduced pressure. Benzoylisothiocyanate (2,12 ml) was added to the solution containing the residue in dichloromethane (43,2 ml) and the mixture was stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (3,83 g).

ESI-MS; m/z 402 [M++H].

(5)Synthesis of N-[(4aS*,5R*,7aS*)-5-ethyl-7a-(2-forfinal)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]benzamide

Pyridine (2,15 ml) and triftormetilfullerenov anhydride (3,20 ml) was added to a solution of the compound obtained in the example of obtaining 21-(4) (4.11 g)in dichloromethane (18,0 ml) at 0°C and the mixture was stirred at the same temperature for 10 minutes. A saturated solution of sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over what svodnyy magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (3,53 g).

1H-NMR(400MHz, CDC13) δ (ppm): 1,02(t, J=8.0 Hz, 3H), 1,57-to 1.61(m, 2H), 2,72-to 2.74(m, 1H), 2.95 and-of 2.97(m, 1H), 3,83-to 3.99(m, 2H), 4,40-4,43(m, 1H), 4,60-4,63(m, 1H), 7,02? 7.04 baby mortality(m, 1H), 7,16-7,19(m, 1H), 7,26-7,28 (m, 1H), 7,50-rate of 7.54(m, 2H), 7,62-to 7.64(m, 1H), 7,73-7,74(m, 1H), 7,85-7,88(m, 2H), 8,87(ush., 1H).

(6)Synthesis of (4aS*,5R*,7aS*)-5-ethyl-7a-(2-forfinal)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-ylamine

A solution of the compound obtained in the example of obtaining 21-(5) (3,53 g), and sodium methoxide (28% solution in methanol; 3,67 ml) in methanol (23,4 ml) was boiled under reflux for 2.5 hours. After cooling the reaction solution to room temperature, the solvent evaporated under reduced pressure. The residue was purified by chromatography on silica gel with obtaining specified in the connection header (1,21 g).

ESI-MS; m/z 281 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,06(t, J=7,6 Hz, 3H), 1,62-of 1.73(m, 2H), 2,62 is 2.75(m, 2H), 3,05-to 3.09(m, 1H), 3,79-3,81(m, 1H), 4,10-4,19(m, 1H), 4,57-4,59(m, 1H), 7,01-7,24(m, 3H), 7,40-7,44(m, 1H).

(7)Synthesis of (4aS*,5R*,7aS*)-5-ethyl-7a-(2-fluoro-5-nitrophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-ylamine

Fuming nitric acid (215 ml) was added dropwise to a solution of the compound obtained in the example of obtaining 21-(6) (1,21 g), concentrated sulfuric acid (to 21.6 ml) under cooling with ice. P is a promotional solution was stirred at the same temperature for 30 minutes and then poured into ice-cold water. The reaction mixture was neutralized 5 N. solution of sodium hydroxide. The mixture was twice extracted with ethyl acetate. The organic layers were dried over anhydrous magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated under reduced pressure to obtain specified in the connection header (1,41 g).

ESI-MS; m/z 326 [M++H].

(8)Synthesis of tert-butyl [(4aS*,5R*,7aS*)-5-ethyl-7a-(2-fluoro-5-nitrophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

The compound obtained in the example of obtaining 21-(7) (1,34 g), was dissolved in dichloromethane (20.4 ml). The triethylamine (2,41 ml) and di-tert-BUTYLCARBAMATE (1.88 g) was added to the solution and the mixture was stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (1,41 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,06 (t, J=7,6 Hz, 3H), of 1.52 (s, 9H), 1,52-of 1.65 (m, 2H), 2,66-2,70 (m, 2H), 2.91 in-of 2.93 (m, 1H), 3,78-with 3.79 (m, 1H), 4,25-4.26 deaths (m, 1H), 4,46-4,48 (m, 1H), 7,20-7,22 (m, 1H), 8,21-8,29 (m, 2H).

(9)Synthesis of tert-butyl [(4aS*,5R*,7aS*)-7a-(5-amino-2-forfinal)-5-ethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

A saturated solution of ammonium chloride (3.1 ml) and iron powder (1.48 g) was added to a solution of the compound obtained in the example of obtaining 21-(8) (1,41 g), in ethanol (33,1 ml). The reaction is first solution was boiled under reflux for 30 minutes and then cooled to room temperature. The reaction solution was diluted with ethyl acetate and the insoluble substance was separated by filtration through celite. To the filtrate was added ethyl acetate and water and separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated under reduced pressure to obtain specified in the title compound (920 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,06 (t, J=7,6 Hz, 3H), 1,46-1,71 (m, 2H), 1,49 (s, 9H), 2,63-to 2.67 (m, 1H), 2,84-to 2.85 (m, 1H), 3,07-to 3.09 (m, 1H), 3,62 (ush., 2H), 3,81-a 3.83 (m, 1H), 4,27-to 4.28 (m, 1H), 4,49-4,51 (m, 1H), 6,55-6,63 (m, 2H), at 6.84-6.89 in (m, 1H).

(10)Synthesis of tert-butyl (-)-[(4aS*,5R*,7aS*)-7a-(5-amino-2-forfinal)-5-ethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

The compound obtained in the example of obtaining 21-(9) (50 mg), optically separated using CHIRALPAK™ OJ-H production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 1:1, flow rate: 10 ml/min), and components having a retention time of 19 to 25 minutes, was collected. This operation was repeated to obtain specified in the title compound (365 mg, >99% ee) of 920 mg of the racemate.

Example of getting 22

Synthesis of tert-butyl (-)-[(4aS*,5R*,7aS*)-7a-(5-amino-2-forfinal)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

[Formula 44]

(1)Synthesis of (1-methylacrylate)acetyldigitoxin

the Solution of 3-butene-2-ol (of 5.00 g) in N-methyl-2-pyrrolidone (70,0 ml) was cooled to 0°C in nitrogen atmosphere. Sodium hydride (60%, 3.33 g) and diethylacetal of bromoacetaldehyde (15.0 g) was added to the reaction solution at the same temperature and the mixture was stirred at 60°C for 30 minutes. To the reaction solution was added a saturated solution of ammonium chloride at 0°C followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in heptane. The solution was filtered through silica gel and concentrated under reduced pressure. To the residue was added formic acid (30,0 ml) and water (10.0 ml) and the mixture was stirred at room temperature for 30 minutes. Hydroxylamine hydrochloride (5,78 g) and sodium acetate (11.4 g) was added to the reaction solution at the same temperature and the mixture was stirred at room temperature for five days. To the reaction solution were added ethyl acetate and a saturated solution of sodium chloride and separated the organic layer. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated under reduced pressure. the STATCOM was purified by chromatography on a column of silica gel with obtaining specified in the connection header (to 2.29 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,26-of 1.29 (m, 3H), 3,85 is 4.36 (m, 3H), 5,17-5,24 (m, 2H), 5,68 is 5.77 (m, 1H), 6.90 to (t, J=3,6 Hz, 0,5H), 7,49 (t, J=6.0 Hz, 0,5H).

(2)Synthesis of (3aR*,4R*)-4-methyl-3a,4-dihydro-3H,6H-furo[3,4-c]isoxazol

5% Solution of sodium hypochlorite (87,1 g) was added dropwise to the solution containing the compound obtained in the example of a 22-(1) (of 7.55 g), in dichloromethane (168 ml) at 0°C and the mixture was stirred at 0°C for 30 minutes. A solution of sodium bisulfite was added to the reaction solution at the same temperature. The organic layer was separated and dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (3,95 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): to 1.37 (d, J=5.6 Hz, 3H), 3.75 to of 3.80 (m, 2H), 3,90-4,00 (m, 1H), 4,40-of 4.57 (m, 3H).

(3)Synthesis of (3aR*,4R*,6aS*)-6a-(2-forfinal)-4-methyltetrahydrofuran[3,4-c]isoxazol

A solution of n-utility in hexane (2,60 M; 6,05 ml) was added dropwise to a solution containing 2-bramptonbest (1,79 ml) in a mixture of tetrahydrofuran/toluene (2,88 ml/28,8 ml)in nitrogen atmosphere at -78°C. the Reaction solution was stirred at the same temperature for 10 minutes. The complex of boron TRIFLUORIDE-diethyl ether (1,94 ml) and the solution containing the compound obtained in the example of a 22-(2) (1,00 g)in toluene (10 ml) sequence is correctly added dropwise to the reaction solution at the same temperature. After stirring at the same temperature for one hour to the reaction solution was added an aqueous solution of ammonium chloride and the reaction solution was heated to room temperature. To the reaction solution were added water and ethyl acetate and the separated organic layer. The organic layer was washed with a saturated solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated and the residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (1.60 g).

ESI-MS; m/z 224 [M++H].

(4)Synthesis of [(2R*,3R*,4S*)-4-amino-4-(2-forfinal)-2-methyltetrahydrofuran-3-yl]methanol

Zinc powder (4,69 g) was added to the solution containing the compound obtained in the example of a 22-(3) (1.60 g)in acetic acid (30,0 ml) at room temperature. The reaction solution was stirred at room temperature for 17 hours. The insoluble substance was separated by filtration through celite and the filtrate was concentrated. To the residue was added ethyl acetate and sodium bicarbonate solution and separated the organic layer. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate koncentrirane and under reduced pressure to obtain specified in the connection header (1,57 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,32 (d, J=6,4 Hz, 1H), 2,20-2,22 (m, 1H), 3,76-3,86 (m, 2H), 4.04 the-4,10 (m, 1H), or 4.31-to 4.38 (m, 2H), 7,06-7,26 (m, 3H), 7,45-7,49 (m, 1H).

(5)Synthesis of 1-benzoyl-3-[(3S*,4R*,5R*)-3-(2-forfinal)-4-hydroxymethyl)-5-methyltetrahydrofuran-3-yl]thiourea

Benzoylisothiocyanate (1.25 g) was added to the solution containing the compound obtained in the example of a 22-(4) (1,57 g), in dichloromethane (21,0 ml) and the mixture was stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (1,43 g).

ESI-MS; m/z 389 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): to 1.37 (d, J=6.0 Hz, 1H), 2,61-2,62 (m, 2H), 2,85-of 2.86 (m, 1H), 3.95 to 4,07 (m, 2H), to 4.41-of 4.44 (m, 1H), and 4.68 (d, J=10 Hz, 1H), 7,00-7,30 (m, 3H), 7,52 (t, J=8.0 Hz, 2H), 7,62-7,72 (m, 2H), a 7.85-7,87 (m, 2H), 8,88 (ush., 1H).

(6)Synthesis of N-[(4aS*,5R*,7aS*)-7a-(2-forfinal)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]benzamide

Triftormetilfullerenov anhydride (1,55 ml) was added to a solution of the compound obtained in the example of a 22-(5) (1,43 g)in pyridine (7.0 ml) at 0°C and the mixture was stirred at the same temperature for 10 minutes. To the reaction solution was added a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and insoluble substances which has been separated by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (780 mg).

ESI-MS; m/z 371 [M++H].

(7)Synthesis of (4aS*,5R*,7aS*)-7a-(2-forfinal)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-ylamine

A solution of the compound obtained in the example of a 22-(6) (3,02 g), and sodium methoxide (28% solution in methanol; 3,14 ml) in methanol (20 ml) was boiled under reflux for 2.5 hours. After cooling the reaction solution to room temperature, evaporated under reduced pressure the solvent. The residue was purified by chromatography on silica gel with obtaining specified in the title compound (980 mg).

ESI-MS; m/z 267 [M++H].

(8)Synthesis of (4aS*,5R*,7aS*)-7a-(2-fluoro-5-nitrophenyl)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-ylamine

Fuming nitric acid (199 ml) was added dropwise to a solution of the compound obtained in the example of a 22-(7) (980 mg)in concentrated sulfuric acid (36,6 ml) under cooling with ice. The reaction solution was stirred at the same temperature for 30 minutes and then poured into ice-cold water. The reaction mixture was neutralized 5 N. solution of sodium hydroxide. The mixture was twice extracted with ethyl acetate. The organic layers were dried over anhydrous magnesium sulfate, and the insoluble substance was separated fil the management. The filtrate was concentrated under reduced pressure to obtain specified in the connection header (1,02 g).

ESI-MS; m/z 312 [M++H].

(9)Synthesis of tert-butyl [(4aS*,5R*,7aS*)-7a-(2-fluoro-5-nitrophenyl)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

The compound obtained in the example of a 22-(8) (1,02 g), was dissolved in dichloromethane (15,5 ml). The triethylamine (1,83 ml) and di-tert-BUTYLCARBAMATE (1,43 g) was added to the solution and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (1.68 g).

ESI-MS; m/z 412 [M++H].

(10)Synthesis of tert-butyl [(4aS*,5R*,7aS*)-7a-(5-amino-2-forfinal)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

A saturated solution of ammonium chloride (2.7 ml) and iron powder (1.25 g) was added to a solution of the compound obtained in the example of a 22-(9) (1,15 g), in ethanol (27 ml). The reaction solution was boiled under reflux for 30 minutes and then cooled to room temperature. The reaction solution was diluted with ethyl acetate and the insoluble substance was separated by filtration through celite. To the filtrate was added ethyl acetate and water and separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate is insoluble substance was separated by filtration. The filtrate was concentrated under reduced pressure to obtain specified in the title compound (1.01 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,39-1,50 (m, 3H), of 1.50 (s, 9H), 2,64-to 2.74 (m, 2H), is 3.08-of 3.12 (m, 1H), 3,61 (ush., 2H), 3,82-a-3.84 (m, 1H), 4,43-4,56 (m, 2H), 6,58-6,60 (m, 2H), at 6.84-6.89 in (m, 1H).

(11)Synthesis of tert-butyl (-)-[(4aS*,5R*,7aS*)-7a-(5-amino-2-forfinal)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

The compound obtained in the example of a 22-(10) (50 mg), optically separated using CHIRALPAK™ OJ-H production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 9:1, flow rate: 10 ml/min), and components having a retention time of 19 minutes to 30 minutes, collected. This operation was repeated to obtain specified in the title compound (363 mg, >99% ee) of 1.01 g of the racemate.

1H-NMR (400 MHz, CDCl3) δ (ppm): to 1.38 (d, J=6.0 Hz, 3H), 2,64 of 2.68 (m, 1H), 2,73 is 2.75 (m, 1H), is 3.08-of 3.12 (m, 1H), 3,62 (ush., 2H), 3,82-of 3.85 (m, 1H), 4,42 is 4.45 (m, 1H), 4,54-4,56 (m, 1H), 6,55-6,62 (m, 2H), at 6.84-6.89 in (m, 1H).

An example of retrieving 23

[Formula 45]

(1)Synthesis of 4-(tert-butyldimethylsilyloxy)butane-1-ol

The imidazole (6,77 g) was added to the solution containing 1,4-butanediol (58,8 ml)in DMF (60,0 ml) at room temperature. Was added dropwise a solution of tert-butyldimethylsilyloxy (10.0 g) in dichloromethane (5.0 ml) and the mixture was stirred at the same temperature for three hours. To the reaction RA is Toru was added diethyl ether and water. The organic layer was separated, washed with water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated to obtain specified in the connection header (13,4 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 0,07 (s, 6H), of 0.90 (s, 9H), 1,62 by 1.68 (m, 4H), 3,64 at 3.69 (m, 4H).

(2)Synthesis of 4-(tert-butyldimethylsilyloxy)Butyraldehyde

Dimethyl sulfoxide (23.1 ml), N,N-diisopropylethylamine (45,4 ml) and a complex of a sulfur trioxide-pyridine (36,3 g) was added to the solution containing the compound obtained in the example of a 23-(1) (13.3 g)in dichloromethane (162 ml) at 0°C and the mixture was stirred at the same temperature for 20 minutes. A saturated solution of sodium bicarbonate was added to the reaction solution at the same temperature. The organic layer was separated and dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated. To the residue was added diethyl ether and 2 n solution of chloride-hydrogen acid. The organic layer was separated, washed with saturated sodium bicarbonate solution and then dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration through silica gel and the filtrate was concentrated to obtain specified in the title compound (12.0 g).

1H-NMR (400 MHz, CDCl ) δ (ppm): of 0.05 (s, 6H), to 0.89 (s, 9H), 1,83-1,89 (m, 2H), 2,49-2,62 (m, 2H), 3,64-to 3.67 (m, 2H), 9,79 (t, J=1.6 Hz, 1H).

(3)Synthesis of 6-(tert-butyldimethylsilyloxy)Gex-1-EN-3-ol

A solution of magnesium chloride in THF (1,38 M, 51,6 ml) was added dropwise to the solution containing the compound obtained in the example of a 23-(2) (12.0 g)in THF (138 ml) at -78°C and the mixture was stirred at 0°C for 10 minutes. To the reaction solution was added a saturated solution of ammonium chloride at the same temperature followed by the addition of ethyl acetate and 2 n solution of chloride-hydrogen acid. The organic layer was separated, washed with saturated sodium bicarbonate solution and then dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration through silica gel and the filtrate was concentrated to obtain specified in the title compound (13.5 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 0,07 (s, 6H), of 0.90 (s, 9H), 1,63-of 1.66 (m, 4H), 3,65-3,68 (m, 2H), 4,15-4,17 (m, 1H), 5,09-5,11 (m, 1H), 5,22 at 5.27 (m, 1H), 5,85-by 5.87 (m, 1H).

(4)Synthesis of 4-matochik-5-EN-1-ol

Methyliodide (10.9 ml) and sodium hydride (60%, of 2.34 g) was added to the solution containing the compound obtained in the example of a 23-(3) (13.5 g)in N-methyl-2-pyrrolidone (146 ml) at 0°C and the mixture was stirred at 60°C for 30 minutes. A saturated aqueous solution of ammonium chloride and diethyl ether was added to the reaction solution at 0°C. the Organic layer separated was washed with a saturated solution of sodium bicarbonate and a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration through silica gel and the filtrate was concentrated to obtain a residue. Acetylchloride (15 ml) was added dropwise to methanol (135 ml) at 0°C and the mixture was added to the residue obtained above. The reaction solution was concentrated and the obtained residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (5,52 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,64 by 1.68 (m, 4H), 3,29 (s, 3H), 3,55-the 3.65 (m, 3H), 5,18-5,23 (m, 2H), 5,63-5,72 (m, 1H).

(5)Synthesis of 4-matochik-5-anale

Dimethyl sulfoxide (12.0 ml), N,N-diisopropylethylamine (29.5 ml) and a complex of a sulfur trioxide-pyridine (20.2 g) was added to the solution containing the compound obtained in the example of a 23-(4) (5,52 g), in dichloromethane (84,8 ml) at 0°C and the mixture was stirred at the same temperature for 20 minutes. A saturated solution of sodium bicarbonate was added to the reaction solution at the same temperature. The organic layer was separated and dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated. To the residue was added diethyl ether and 2 n solution of chloride-hydrogen acid. The organic layer was separated, washed with saturated sodium bicarbonate solution and then dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate is the end of what was tarawali obtaining specified in the connection header (3,85 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,84 is 1.91 (m, 2H), 2,50 of $ 2.53 (m, 2H), 3,26 (s, 3H), 3,54 is 3.57 (m, 1H), 5,20-a 5.25 (m, 2H), 5,61-5,70 (m, 1H), 9,76 (t, J=1.6 Hz, 1H).

(6)Synthesis of 4-matochik-5-naloxone

Sodium acetate (4.92 in g) and hydroxylamine hydrochloride (3.13 g) was added to the solution containing the compound obtained in the example of a 23-(5) (3,85 g)in methanol (60,0 ml) at room temperature and the mixture was stirred at the same temperature for three hours. The ethyl acetate and saturated sodium bicarbonate solution was added to the reaction solution. The organic layer was separated, washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated to obtain specified in the connection header (3,40 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,75-to 1.82 (m, 2H), 2.26 and-2,31 (m, 1H), 2,42-2,48 (m, 1H), 3.27 to be 3.29 (m, 3H), 3,52-to 3.58 (m, 1H), 5,20-a 5.25 (m, 2H), 5,61-5,71 (m, 1H), 6.75 in (t, J=5.6 Hz, 0,5N), the 7.43 (t, J=5,2 Hz, 0,5H).

(7)Synthesis of 4-methoxy-3a,4,5,6-tetrahydro-3H-cyclopent[c]isoxazol

Specified in the title compound (1.30 grams) was obtained from the compound obtained in the example of a 23-(6) (3,40 g), in accordance with the example of getting 22-(2).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,18-2,70 (m, 5H), 3,26 of 3.28 (m, 3H), 3,42-with 3.79 (m, 1H), 3.96 points-4,20 (m, 1H), 4,35-and 4.68 (m, 1H).

(8)Synthesis of [2-amino-2-(2-forfinal)-5-methoxycyclohexyl]methanol

Dissolve the n-utility in hexane (2,60 M; 7,07 ml) was added dropwise to a solution containing 2-bramptonbest (2,09 ml) in a mixture of tetrahydrofuran/toluene (3,36 ml/33,6 ml)in nitrogen atmosphere at -78°C. the Reaction solution was stirred at the same temperature for 10 minutes. The complex of boron TRIFLUORIDE-diethyl ether (2,27 ml) and the solution containing the compound obtained in the example of a 23-(7) (1.30 grams)in toluene (10 ml) was added dropwise to the reaction solution at the same temperature. After stirring at the same temperature for 40 minutes to the reaction solution was added an aqueous solution of ammonium chloride followed by heating to room temperature. To the reaction solution were added water and ethyl acetate and the separated organic layer. The organic layer was washed with a saturated solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated and the residue was dissolved in a mixture of ethyl acetate-heptane. The solution was filtered through silica gel and concentrated. Acetic acid (31,0 ml) and zinc powder (5,02 g) was added at room temperature. The reaction solution was stirred at room temperature for four hours. The insoluble substance was separated by filtration through celite and the filtrate was concentrated. To the residue was added ethyl acetate and a solution of bicarbonate is the atrium, and separated the organic layer. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated under reduced pressure to obtain specified in the connection header (1,41 g).

ESI-MS; m/z 240 [M++H].

(9)Synthesis of N-[7a-(2-forfinal)-5-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]benzamide

Benzoylisothiocyanate (0,871 ml) was added to the solution containing the compound obtained in the example of a 23-(8) (1,41 g), in dichloromethane (19.6 ml) and the mixture was stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure and the residue was dissolved in a mixture of ethyl acetate-heptane. The solution was filtered through silica gel and concentrated. Dichloromethane (24,0 ml), pyridine (1,16 ml) and triftormetilfullerenov anhydride (2.20 ml) was added at -78°C and the mixture was stirred at the same temperature for 30 minutes. A saturated solution of sodium bicarbonate was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel with obtaining specified in the header is connected to the I (1,71 g).

ESI-MS; m/z 385 [M++H].

(10)Synthesis of 7a-(2-forfinal)-5-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine

Specified in the header connection (681 mg) was obtained from the compound obtained in the example of a 23-(9) (1,71 g), in accordance with the method of example getting 22-(7).

ESI-MS; m/z 281 [M++H].

(11)Synthesis of 7a-(2-fluoro-5-nitrophenyl)-5-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine

Specified in the title compound (506 mg) was obtained from the compound obtained in the example of a 23-(10) (681 mg), in accordance with the method of example getting 22-(8).

ESI-MS; m/z 326 [M++H].

(12)Synthesis of tert-butyl [(4aS*,5S*,7aS*)-7a-(2-fluoro-5-nitrophenyl)-5-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate and tert-butyl [(4aS*,5R*,7aS*)-7a-(2-fluoro-5-nitrophenyl)-5-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

More polar specified in the title compound (283 mg) and less polar specified in the title compound (135 mg) was obtained from the compound obtained in the example of a 23-(11) (506 mg), in accordance with the method of example getting 22-(9).

More polar specified in the header of the connection (tert-butyl [(4aS*,5S*,7aS*)-7a-(2-fluoro-5-nitrophenyl)-5-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate)

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.53 (s, 9H), 1,87 is 2.10 (m, 5H), 2,66-2,90 (m, 2H), 3,41 (s, 3H), 4,10-to 4.15 (m, 1H), 7,2-7,26 (m, 1H), 8,18-8,21 (m, 2H).

Less polar specified in the header of the connection (tert-butyl [(4aS*,5R*,7aS*)-7a-(2-fluoro-5-nitrophenyl)-5-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate)

1H-NMR (400 MHz, CDCl3) δ (ppm): 1.50 in (s, 9H), 1,81 at 2.45 (m, 5H), 2,88-a 3.01 (m, 2H), 3,41 (s, 3H), 4,11-4,13 (m, 1H), 7,20-7,26 (m, 1H), 8,19-of 8.28 (m, 2H).

(13)Synthesis of tert-butyl [(4aS*,5S*,7aS*)-7a-(5-amino-2-forfinal)-5-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

Specified in the title compound (244 mg) was obtained from the more polar compound obtained in the example of a 23-(12) (283 mg), in accordance with the method of example getting 22-(10).

1H-NMR (400 MHz, CDCl3) δ (ppm): is 1.51 (s, 9H), 1,52-of 2.15 (m, 5H), 2,75-3,00 (m, 2H), 3,40 (s, 3H), 4,10-to 4.15 (m, 1H), 6,54-to 6.57 (m, 2H), 6,83-6,86 (m, 1H).

(14)Synthesis of tert-butyl [(4aS*,5R*,7aS*)-7a-(5-amino-2-forfinal)-5-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

Specified in the header connection (79,0 mg) was obtained from the less polar compound obtained in the example of a 23-(12) (100 mg), in accordance with the method of example getting 22-(10).

1H-NMR (400 MHz, CDCl3) δ (ppm): for 1.49 (s, 9H), 1,57-of 2.20 (m, 4H), of 2.45-2.49 USD (m, 1H), 2,86-3,03 (m, 3H), of 3.32 (s, 3H), 3,98-4,00 (m, 1H), 6,54-6,55 (m, 2H), 6,83-to 6.88 (m, 1H).

(15)Synthesis of tert-butyl [(4aS*,5S*,7aS*)-7a-(5-amino-2-forfinal)-5-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

The compound obtained in the example of a 23-(3) (50 mg), optically separated using CHIRALPAK™ OJ-H production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 1:1 - 0:1 (gradient, 30 min), flow rate: 10 ml/min), and components having a retention time of 14 to 20 minutes, was collected. This operation was repeated to obtain specified in the title compound (89 mg, >99% ee) of 244 mg of the racemate.

Example of getting 24

tert-Butyl [(4aS,5S,7aS)-7a-(5-amino-2-forfinal)-5-methoxymethyl-4,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

[Formula 46]

(1)Synthesis of (S)-1-methoxybutyl-3-EN-2-ol

The solution of iodide trimethylsilane (50.0 g) in toluene (200 ml) was boiled under reflux, using a trap Dean-stark for one hour and concentrated. The residue was dissolved in THF (444 ml) and a solution of n-BuLi in hexane (2,6 M; 94,0 ml) was added dropwise at -15°C. After stirring at the same temperature for 30 minutes was added dropwise (S)-goldilicious simple ether (7,31 ml) and the mixture was stirred at room temperature for 14 hours. To the reaction solution was added water at 0°C followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a Sealy is agile obtaining specified in the connection header (3,30 g).

(2)Synthesis of (S)-3-(2,2-diethoxyethane)-4-methoxybutyl-1-ene

A solution of the compound obtained in the example of a 24-(1) (5,00 g), N-methyl-2-pyrrolidone (98,0 ml) was cooled to 0°C. sodium Hydride (60%, 2.16 g) and diethylacetal of bromoacetaldehyde (8,86 g) was added to the reaction solution at the same temperature and the mixture was stirred at 100°C for two hours. To the reaction solution was added a saturated solution of ammonium chloride at 0°C followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel with obtaining specified in the connection header (of 5.82 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,91-of 1.26 (m, 6H), 3,37 (s, 3H), 3,38-4,00 (m, 5H), 4,63-of 4.67 (m, 1H), 5.25 to 5.35 (m, 2H), 5,70-5,74 (m, 1H).

(3)Synthesis of ((S)-1-methoxymethylethoxy)acetyldigitoxin

Formic acid (35.1 ml), hydroxylamine hydrochloride (2.83 g) and sodium acetate (4,46 g) was added to the compound obtained in the example of a 24-(2) (of 5.82 g)and the mixture was stirred at room temperature for 30 minutes. To the reaction solution were added ethyl acetate and a saturated solution of sodium chloride and separated the organic layer. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the header of the compound (2.00 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 3,34-3,51 (m, 4H), 3,93-to 4.23 (m, 3H), 4,33-to 4.46 (m, 1H), 5,31 is 5.38 (m, 2H), 5,69-5,78 (m, 1H), 6,98 (t, J=3,6 Hz, 0,5H), 7,53 (t, J=4,8 Hz, 0,5H).

(4)Synthesis of (3aR,4S)-4-methoxymethyl-3a,4-dihydro-3H,6H-furo[3,4-c]isoxazol

Specified in the title compound (870 mg) was obtained from the compound obtained in the example of a 24-(3) (2.00 g), in accordance with the example of getting 22-(2).

1H-NMR (400 MHz, CDCl3) δ (ppm): 3,38-3,55 (m, 4H), to 3.41 (s, 3H), 3,97 is 4.13 (m, 2H), 4,48-4,58 (m, 2H).

(5)Synthesis of (3aR,4S,6aS)-6a-(2-forfinal)-4-ethoxymethyleneamino[3,4-c]isoxazol

Specified in the title compound (940 mg) was obtained from the compound obtained in the example of a 24-(4) (870 mg), in accordance with the example of getting 22-(3).

ESI-MS; m/z 254 [M++H].

(6)Synthesis of [(2S,3R,4S)-4-amino-4-(2-forfinal)-2-methoxyethylmercury-3-yl]methanol

Specified in the title compound (850 mg) was obtained from the compound obtained in the example of a 24-(5) (940 mg), in accordance with the example of getting 22-(4).

ESI-MS; m/z 256 [M++H].

(7)Synthesis benzoyl-3-[(3S,4R,5S)-3-(2-forfinal)-4-hydroxymethyl-5-methoxyethylmercury-3-yl]thiourea

Specified in the title compound (1.22 g) was obtained from the compound obtained in the example of a 24-(6) (850 mg), in accordance with the example of getting 22-(5).

ESI-MS; m/z 441 [M++Na].

(8)Synthesis of (4aS,5S,7aS)-7a-(2-forfinal)-5-methoxymethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-ylamine

Pyridine (0,66 ml) and triftormetilfullerenov anhydride (0,983 ml) was added to a solution of the compound obtained in the example of a 24-(7) (1.22 g)in dichloromethane (5,80 ml) at -78°C and the mixture was stirred at 0°C for 10 minutes. A saturated solution of sodium bicarbonate was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated under reduced pressure. The residue was filtered through silica gel, using ethyl acetate and heptane, and concentrated under reduced pressure. A solution of sodium methoxide (28% solution in methanol; 1.08 ml) in methanol (7,00 ml) was added to the residue, followed by boiling under reflux for 2.5 hours. After cooling the reaction solution to room temperature, evaporated under reduced pressure the solvent. The residue was purified by chromatography on silica gel with obtaining specified in the title compound (231 mg).

ESI-MS; m/z 297 [M++H].

(9)Synthesis of (4aS,5S,7aS-7a-(2-fluoro-5-nitrophenyl)-5-methoxymethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-ylamine

Specified in the title compound (211 mg) was obtained from the compound obtained in the example of a 24-(8) (231 mg), in accordance with the example of getting 22-(8).

ESI-MS; m/z 342 [M++H].

(10)Synthesis of tert-butyl [(4aS,5S,7aS)-7a-(2-fluoro-5-nitrophenyl)-5-methoxymethyl-4,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

Specified in the title compound (144 mg) was obtained from the compound obtained in the example of a 24-(9) (211 mg), in accordance with the example of getting 22-(9).

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.52 (s, 9H), 2,68-2,77 (m, 1H), 2,88-of 2.93 (m, 2H), 3,39 (s, 3H), 3,44-3,62 (m, 2H), 3,97-to 3.99 (m, 1H), 4,46-to 4.52 (m, 2H), 7,14-7,17 (m, 1H), 8,21-8,30 (m, 2H).

(11)tert-Butyl [(4aS,5S,7aS)-7a-(5-amino-2-forfinal)-5-methoxymethyl-4,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

Specified in the title compound (86 mg) was obtained from the compound obtained in the example of a 24-(10) (114 mg), in accordance with the example of getting 22-(10).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1.50 in (s, 9H), 2,72 was 2.76 (m, 1H), 3,12-3,13 (m, 2H), of 3.56 (s, 3H), to 3.58-the 3.65 (m, 2H), 3,81-3,82 (m, 1H), 4,49-4,51 (m, 2H), 6,56-6,63 (m, 2H), at 6.84-6.89 in (m, 1H).

Example get 25

Synthesis of tert-butyl [(4aS,5S,7aS)-7a-(5-amino-2-forfinal)-5-vermeil-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

[Formula 47]

(1)Synthesis of (S)-1-trityloxy-3-EN-2-ol

A solution of n-BuLi in hexane (2,6 M; 182 ml) was added dropwise to a solution of iodide trim tilsley (96.8 g) in THF (800 ml) at -30°C. After stirring at -20°C for 20 minutes was added (S)-tricyglycerol simple ether (50.0 g) at the same temperature and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added water, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (52,0 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 3,09-3,13 (m, 1H), 3,20 is 3.23 (m, 1H), 4.26 deaths-the 4.29 (m, 1H), 5,14-5,32 (m, 2H), 5,76 of 5.84 (m, 1H), 7.23 percent was 7.45 (m, 15H).

(2)Synthesis of ethyl ((S)-1-trielaxhillshire)acetate

Sodium hydride (60%, 6,18 g) and Bromeliaceae (17,1 ml) was added to the solution containing the compound obtained in the example of a 25-(1) (25,5 g), N-methyl-2-pyrrolidone (210 ml) at 0°C. the Mixture was stirred at 50°C for 18 hours and was stirred at 100°C for one hour. To the reaction solution was added a saturated solution of ammonium chloride at 0°C followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated. The residue was purified by chromatography on a column of silica gel with receiving the receiving specified in the title compound (15.5 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,32 (t, J=7.2 Hz, 3H), 3,13-3,17 (m, 1H), 3,31-to 3.35 (m, 1H), 3,98-4,27 (m, 5H), 5,28-5,33 (m, 2H), 5,74-USD 5.76 (m, 1H), 7,20-7,47 (m, 15H).

(3)Synthesis of ((S)-1-trielaxhillshire)acetyldigitoxin

The solution diisobutylaluminium in toluene (1,0 M; 55,2 ml) was added dropwise to the solution containing the compound obtained in the example of a 25-(2) (15.5 g)in dichloromethane (74,0 ml) at -78°C. the Mixture was stirred at the same temperature for 30 minutes. To the reaction solution was added a 2 n solution of chloride-hydrogen acid, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated. Methanol (70,0 ml), sodium acetate (6,04 g) and hydroxylamine hydrochloride (3,84 g) was added to the residue at room temperature and the mixture was stirred at the same temperature for 15 minutes. The ethyl acetate and water were added to the reaction solution and the organic layer was separated and dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (11.3 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): is 3.08-of 3.12 (m, 1H), 3,24-3,26 (m, 1H), 3,81 was 4.42 (who, 4H), 5,23-and 5.30 (m, 2H), 5,70-5,72 (m, 1H), 6,95-of 6.96 (m, 0,5H), 7,21-7,47 (m, 15H), 7,52-7,53 (m, 0,5H).

(4)Synthesis of (3aR,4S)-4-trisiloxane-3a,4-dihydro-3H,6H-furo[3,4-c]isoxazol

5% Solution of sodium hypochlorite (52,2 ml) was added dropwise to the solution containing the compound obtained in the example of a 25-(3) (11.3 g)in dichloromethane (100 ml) at 0°C and the mixture was stirred at 0°C for 30 minutes. A solution of sodium bisulfite was added to the reaction solution at the same temperature. The organic layer was separated and dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration and the filtrate was concentrated. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (5.20 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 3,21-to 3.35 (m, 1H), 3,37 is 3.40 (m, 1H), 3,93-4,07 (m, 3H), 4,47-of 4.57 (m, 3H), 7.23 percent-7,42 (m, 15H).

(5)Synthesis of (3aR,4S,6aS)-6a-(2-forfinal)-4-trailorspercentage[3,4-c]isoxazol

A solution of n-utility in hexane (2,60 M; 10.4 ml) was added dropwise to a solution containing 2-bramptonbest (2,93 ml) in a mixture of tetrahydrofuran/toluene (10,8 ml/108 ml)in nitrogen atmosphere at -78°C. the Reaction solution was stirred at the same temperature for 10 minutes. The complex of boron TRIFLUORIDE-diethyl ether of 3.33 ml) and the solution containing the compound obtained in the example of a 25-(4) (5.20 g)in toluene (50 ml) was sequentially added dropwise to actionname solution at the same temperature. After stirring at the same temperature for 40 minutes to the reaction solution was added an aqueous solution of ammonium chloride followed by heating to room temperature. To the reaction solution were added water and ethyl acetate and the separated organic layer. The organic layer was washed with a saturated solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated and the residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (6,23 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 3.24 in (m, 3H), 3,91-3,98 (m, 2H), 4,07 is 4.35 (m, 3H), 7,00 to 7.62 (m, 19H).

(6)Synthesis of [(2S,3R,4S)-4-amino-4-(2-forfinal)-2-trialxinhuatehran-3-yl]methanol

Zinc powder (8.44 grams) was added to the solution containing the compound obtained in the example of a 25-(5) (6,22 g)in acetic acid (50,0 ml) at room temperature. The reaction solution was stirred at room temperature for 18 hours. The insoluble substance was separated by filtration through celite and the filtrate was concentrated. To the residue was added ethyl acetate and sodium bicarbonate solution and separated the organic layer. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Insoluble in the society was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was purified column chromatography on silica gel with obtaining specified in the connection header (4,10 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,63-to 2.65 (m, 1H), 3,24-of 3.31 (m, 2H), 3,61-the 3.65 (m, 1H), 3,92-of 3.97 (m, 2H), 4,15-4.26 deaths (m, 1H), 4,37-to 4.41 (m, 1H), 7,00-7,52 (m, 19H).

(7)Synthesis of 1-benzoyl-3-[(3S,4R,5S)-3-(2-forfinal)-4-hydroxymethyl-5-trialxinhuatehran-3-yl]thiourea

Benzoylisothiocyanate (1,37 ml) was added to the solution containing the compound obtained in the example of a 25-(6) (4,10 g), in dichloromethane (16.0 ml) and the mixture was stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (4,32 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 3,19-to 3.36 (m, 3H), 3,79-of 4.05 (m, 3H), 4,57-4,58 (m, 2H), 7.03 is-7,89 (m, 24H), 8,89 (ush., 1H).

(8)Synthesis of N-[(4aS,5S,7aS)-7a-(2-forfinal)-5-trityloxy-4,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]benzamide

Pyridine (2,01 ml) and triftormetilfullerenov anhydride (2.25 ml) was added to a solution of the compound obtained in the example of a 25-(7) (4,32 g), in dichloromethane (27.7 ml) at 0°C and the mixture was stirred at the same temperature for 20 minutes. A saturated solution of sodium bicarbonate was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was dried over be the aqueous magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (3,52 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,65-2,69 (m, 1H), 3,15-3,19 (m, 1H), 3,32-3,47 (m, 3H), 4,08-4,10 (m, 1H), 4,55-4,58 (m, 2H), 7,11-7,52 (m, 22H), 8,15-8,17 (m, 2H).

(9)Synthesis of N-[(4aS,5S,7aS)-7a-(2-forfinal)-5-hydroxymethyl-4,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]benzamide

Formic acid (15.0 ml) and diethyl ether (15.0 ml) was added to the compound obtained in the example of a 25-(8) (3,52 g)at room temperature and the mixture was stirred at the same temperature for eight hours. The reaction solution was concentrated under reduced pressure. Formic acid (20 ml) was added at room temperature and the mixture was stirred at the same temperature for 15 hours. The reaction solution was concentrated under reduced pressure. A solution of triethylamine in methanol (10%; 20,0 ml) was added at room temperature, followed by boiling under reflux for 30 minutes. The reaction solution was concentrated. Added ethyl acetate and a saturated salt solution and the organic layer was separated and dried over anhydrous magnesium sulfate. The insoluble substance was separated by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on a column of forces is by Kagel obtaining specified in the connection header (1,72 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,80-2,84 (m, 1H), 3.25 to be 3.29 (m, 1H), 3,40-3,44 (m, 1H), of 3.73-of 3.77 (m, 1H), 3,94-3,98 (m, 1H), 4,08-4,11 (m, 1H), 4,13-of 4.57 (m, 2H), 7,12-7,53 (m, 7H), 8,14-8,16 (m, 2H).

(10)Synthesis of N-[(4aS,5S,7aS)-5-vermeil-7a-(2-forfinal)-4,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]benzamide

The triethylamine (3,52 ml), trihydrochloride of triethylamine (1,37 ml) and performancemonitoring (1,45 ml) was added to a solution of the compound obtained in the example of a 25-(9) (1,62 g)in acetonitrile (16.2 ml) at 0°C and the mixture was stirred at room temperature for 20 minutes. The reaction solution was purified by chromatography on a column of silica gel with obtaining specified in the title compound (920 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,81-to 2.85 (m, 1H), 3,28-of 3.31 (m, 1H), 3,41-of 3.43 (m, 1H), 4,05-4,07 (m, 1H), 4,55-4,74 (m, 4H), 7,12-rate of 7.54 (m, 7H), 8,12-to 8.14 (m, 2H).

(11)Synthesis of (4aS,5S,7aS)-5-vermeil-7a-(2-forfinal)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-ylamine

A solution of the compound obtained in the example of a 25-(10) (970 mg), and sodium methoxide (28% solution in methanol; 0,965 ml) in methanol (to 6.43 ml) was boiled under reflux for 14 hours. After cooling the reaction solution to room temperature, evaporated under reduced pressure the solvent. The residue was purified by chromatography on silica gel with obtaining specified in the title compound (310 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): was 2.76 is 2.80 (m, 1H), 3.00 and-3,4 (m, 1H), 3,09-3,13 (m, 1H), 3,85-3,88 (m, 1H), 4,47-4,63 (m, 4H), 7,00-7,16 (m, 2H), 7,27-7,44 (m, 2H).

(12)Synthesis of tert-butyl [(4aS,5S,7aS)-5-vermeil-7a-(2-fluoro-5-nitrophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

Fuming nitric acid (55 ml) was added dropwise to a solution of the compound obtained in the example of a 25-(11) (310 mg)in concentrated sulfuric acid (of 5.53 ml) under cooling with ice. The reaction solution was stirred at the same temperature for 10 minutes and then poured into ice-cold water. The reaction mixture was neutralized 5 N. solution of sodium hydroxide. The mixture was twice extracted with ethyl acetate. The organic layers were dried over anhydrous magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated under reduced pressure and the residue was dissolved in dichloromethane (5.40 ml). The triethylamine (0,602 ml) and di-tert-BUTYLCARBAMATE (471 mg) was added to the solution. The reaction solution was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (419 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): and 1.56 (s, 9H), 2,70-to 2.74 (m, 1H), 2,96-to 2.99 (m, 1H), 3,18-3,19 (m, 1H), 3,84-of 3.85 (m, 1H), 4,47-4,70 (m, 4H), 7,22-7,24 (m, 1H), 8,20-8,31 (m, 2H).

(13)Synthesis of tert-butyl [(4aS,5S,7aS)-7a-(5-amino-2-forfinal)-5-vermeil-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

A saturated solution of chloride is ammonium (1.0 ml) and iron powder (436 mg) was added to a solution of compounds received in the sample receiving 25-(12) (419 mg)in ethanol (10 ml). The reaction solution was boiled under reflux for 30 minutes and then cooled to room temperature. The reaction solution was diluted with ethyl acetate and the insoluble substance was separated by filtration through celite. To the filtrate was added ethyl acetate and water and separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble substance was separated by filtration. The filtrate was concentrated under reduced pressure to obtain specified in the title compound (291 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): is 1.51 (s, 9H), 3,10-is 3.21 (m, 2H), 3,62 (ush., 1H), 3,85-3,86 (m, 1H), 4,15-of 4.66 (m, 4H), 6,56-6,62 (m, 2H), 6,85-6,92 (m, 1H).

Example of getting 26

Synthesis of 3-ethoxy-5-HEXEN-1-ol

[Formula 48]

(1)Synthesis of tert-butyl(3-ethoxy-5-hexenoate)diphenylsilane

A solution of 1-(tert-butyl-diphenylsilane)-5-HEXEN-3-ol (Tetrahedron, 57, 4023-4034 (2001)) (5.0 g) and ethyliodide (2,03 ml) in THF (10 ml) was added dropwise to a suspension of sodium hydride (60%, 1.85 g) in THF (40 ml) at 50°C for 10 minutes. The reaction solution was stirred at 50°C for one hour. Ethyliodide (6.0 ml) was added to the solution at 50°C and the mixture was stirred at 60°C for 1.5 hours. The reaction solution was brought to room temperature and poured into ice-cold water for the next extraction with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on a column of silica gel with obtaining specified in the title compound (4.1 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.05 (s, 9H), 1.14 in (t, J=7.2 Hz, 3H) 1,66 and 1.80 (m, 2H), 2,22-of 2.30 (m, 2H), 3,36-3,86 (m, 5H), 5,00-5,10 (m, 2H), 5,74-5,88 (m, 1H), 7,30-7,46 (m, 6H), 7,60-7,74 (m, 4H).

(2)Synthesis of 3-ethoxy-5-HEXEN-1-ol

Tetrabutylammonium (1 M solution in THF, 13 ml) was added to a solution of tert-butyl(3-ethoxy-5-hexenoate)diphenylsilane (4.1 g)in THF (40 ml) at room temperature, followed by stirring for one hour. The reaction solution was concentrated. The crude product was purified by chromatography on a column of silica gel with obtaining specified in the title compound (1.1 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,20 (t, J=7.2 Hz, 3H) 1,68-to 1.82 (m, 2H), 2,22 is 2.44 (m, 2H), 2,70 (s, 1H), 3,36-3,88 (m, 5H), 5,00-5,16 (m, 2H), 5,70-5,90 (m, 1H).

Example of getting 27

Synthesis of (3aR*,5S*,6aS*)-5-ethoxy-6a-(2-forfinal)hexahydrotriazine[c]isoxazol and (3aR*,5R*,6aS*)-5-ethoxy-6a-(2-forfinal)hexahydrotriazine[c]isoxazol

[Formula 49]

Less polar specified in the header connection and more on the Yarnykh specified in the title compound was obtained by treatment of 3-ethoxy-5-HEXEN-1-ol according to the method of example 10-(1)-(4).

Less polar specified in the header of the connection ((3aR*,5S*,6aS*)-5-ethoxy-6a-(2-forfinal)hexahydrotriazine[c]isoxazol)

ESI-MS; m/z 252 [M++H].

More polar specified in the header of the connection ((3aR*,5R*,6aS*)-5-ethoxy-6a-(2-forfinal)hexahydrotriazine[c]isoxazol)

ESI-MS; m/z 252 [M++H].

Example of getting 28

Synthesis of tert-butyl [(4aR*,6R*,7aS*)-7a-(5-amino-2-forfinal)-6-ethoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate ((+)-isomer and (-)-isomer)

[Formula 50]

(1)Synthesis of [(1R*,2S*,4R*)-2-amino-4-ethoxy-2-(2-forfinal)cyclopentyl]methanol

Zinc (3,68 g) was added to a solution of (3aR*,5R*,6aS*)-5-ethoxy-6a-(2-forfinal)hexahydrotriazine[c]isoxazol (540 mg) in acetic acid (15 ml) and the mixture was stirred at room temperature for two hours. Was added to the reaction solution, a saturated sodium bicarbonate solution and ethyl acetate, and zinc was removed by filtration. The filtrate was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain specified in the title compound (540 mg).

ESI-MS; m/z 254 [M++H].

(2)Synthesis of N-({[(1S*,2R*,4R*)-4-ethoxy-1-(2-forfinal)-2-(hydroxymethyl)cyclopentyl]amino}carbonothioyl)benzamide

Benzoylisothiocyanate (0,345 ml) we use the and to the amine solution, synthesized at the previous stage (540 mg)in dichloromethane (9 ml) and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (180 mg).

ESI-MS; m/z 439 [M++Na].

(3)Synthesis of (4aR*,6S*,7aS*)-6-ethoxy-7a-(2-forfinal)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]amine

The solution of the thiourea obtained at the previous stage (180 mg)in a mixture of methanol (20 ml) and concentrated chloride-hydrogen acid (0.7 ml) was boiled under reflux for three hours. The reaction solution was brought to room temperature and then poured into a chilled solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on a column of silica gel with getting cyklinowanie compound (94 mg). DBU (0.2 ml) was added to a solution of cyklinowanie compounds in methanol (10 ml), followed by boiling under reflux for four hours. The reaction solution was concentrated under reduced pressure. The crude product was purified x is matography on a column of silica gel with obtaining specified in the title compound (69 mg).

ESI-MS; m/z 295 [M++H].

(4)to(6)Synthesis of tert-butyl [(4aR*,6R*,7aS*)-7a-(5-amino-2-forfinal)-6-ethoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate ((+)-isomer and (-)-isomer)

Specified in the header (-)-compound was obtained by processing cyklinowanie compound obtained in the preceding stage, in accordance with the method of stages (4)-(5) of example 12. Optical separation was performed using a CHIRALPAK™ ADH production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 8:2, flow rate: 10 ml/min). Components having a retention time of 7 to 10 minutes, collected by obtaining specified in the header (+)-isomer. Components having a retention time of 16 to 19 minutes, collected by obtaining specified in the header (-)-isomer. (-)-Isomer was used for the synthesis of chiral compounds in this example.

The characteristic values of (-)-isomer are given below.

optical rotation (-)

ESI-MS; m/z 410 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): to 1.21 (t, J=7.2 Hz, 3H), of 1.52 (s, 9H), 1,90-2,05 (m, 1H), 2,25-of 2.45 (m, 2H), 2,60-of 2.75 (m, 2H), 3,03 (DD, J=3,6, to 13.6 Hz, 1H), of 3.25 to 3.35 (m, 1H), 3.46 in (kV, J=7.2 Hz, 2H), 3,62 (USS, 2H), 4,10-4,20 (m, 1H), 6,51 return of 6.58 (m, 2H), 6,86 (DD, J=8,0, 12.0 Hz, 1H).

An example of obtaining 29

Synthesis of tert-butyl (±)-[(4aR*,6S*,7aS*)-7a-(5-amino-2-forfinal)-6-ethoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

[Formula 51]

Specified in the title compound was obtained by treatment of (3aR*,5S*,6aS*)-5-ethoxy-6a-(2-forfinal)hexahydrotriazine[c]isoxazol received in the sample receiving 27, in accordance with the method of example obtaining a 28-(1)-(3) and the sample receiving 11-(4)-(5).

ESI-MS; m/z 410 [M++H].

Example 30

Synthesis of tert-butyl (-)-[(4aR*,6R*,7aS*)-7a-(5-amino-2-forfinal)-6-butoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

[Formula 52]

Specified in the title compound was obtained by treatment of 1-(tert-butyl-diphenylsilane)-5-HEXEN-3-ol and idbutton in accordance with the method of examples obtain 26-29.

1H-NMR (400 MHz, CDCl3) δ (ppm): to 0.92 (t, J=7.2 Hz, 3H), 1.32 to to 1.42 (m, 2H), of 1.52 (s, 9H), 1,48 is 1.60 (m, 2H), 1.85 to 2.05 is (m, 1H), 2,20-of 2.45 (m, 2H), 2,55 is 2.75 (m, 2H), 3,03 (d, J=13,2 Hz, 1H), 3,20 is-3.45 (m, 3H), 3,62 (s, 2H), 4,05-4,20 (m, 1H), 6,50-6,60 (m, 2H), 6,80-to 6.95 (m, 1H).

ESI-MS m/z 438 [M++H]

An example of retrieving 31

Synthesis of tert-butyl (±)-[(4aR*,6S*,7aS*)-7a-(5-amino-2-forfinal)-6-butoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

[Formula 53]

Specified in the title compound was obtained by treatment of 1-(tert-butyl-diphenylsilane)-5-HEXEN-3-ol and idbutton in accordance with the method of examples obtain 26-29.

ESI-MS m/z 438 [M++H]

Example of getting 32

Synthesis of (3aR*,5S*,6aS*)-6a-(2-forfinal)-5-(3,4-ditto is benzyl)oxygencarrying[c]isoxazol and (3aR*,5R*,6aS*)-6a-(2-forfinal)-5-(3,4-diferensial)oxygencarrying[c]isoxazol

[Formula 54]

Specified in the title compound was obtained by treatment of 1-(tert-butyldiphenylsilyl)-5-HEXEN-3-ol and 3,4-diferenciada in accordance with the method of example obtaining 26-(1)-(2) and example 10-(1)-(4).

Less polar specified in the header of the connection ((3aR*,5S*,6aS*)-6a-(2-forfinal)-5-(3,4-diferensial)oxygencarrying[c]isoxazol);

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,00-of 2.20 (m, 2H), 2,20-2,40 (m, 2H), 3,02 (USS, 1H), and 3.31 (q, J=7,6 Hz, 1H), of 3.73 (t, J=7,6 Hz, 1H), 4,30 (s, 1H), 4,30-4,55 (m, 2H), 4,39 (t, J=8.0 Hz, 1H), 6,03 (s, 1H), 6.90 to-8,00 (m, 7H).

More polar specified in the header of the connection ((3aR*,5R*,6aS*)-6a-(2-forfinal)-5-(3,4-diferensial)oxygencarrying[c]isoxazol);

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,00-of 2.28 (m, 2H), 2,32 (DD, J=8,8, to 13.6 Hz, 1H), 2,41 (DD, J=5,6, or 13.6 Hz, 1H), 3,30 is-3.45 (m, 1H), of 3.73 (USS, 1H), 4,13 (USS, 1H), 4,25-and 4.40 (m, 1H), of 4.44 (s, 2H), 6,94-to 7.32 (m, 6H), 7,56-7,66 (m, 1H).

An example of obtaining 33

Synthesis of tert-butyl [(4aR*,6S*,7aS*)-7a-(2-forfinal)-6-hydroxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

[Formula 55]

(1)Synthesis of [(1R*,2S*,4S*)-2-amino-2-(2-forfinal)-4-(3,4-deferasirox)cyclopentyl]methanol

Zinc (3.0 g) was added to a solution of (3aR*,5S*,6aS*)-6a-(2-forfinal)-5-(3,4-deferasirox)hexahydrotriazine[c]isoxazol (620 mg) in acetic acid (25 ml) and the mixture was stirred at on the th temperature for two hours. To the reaction solution was added saturated sodium bicarbonate solution and ethyl acetate, and zinc was removed by filtration. The filtrate was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain specified in the title compound (630 mg).

ESI-MS; m/z 352 [M++H].

(2)Synthesis of N-({[(1S*,2R*,4S*)-1-(2-forfinal)-2-(hydroxymethyl)-4-(3,4-deferasirox)cyclopentyl]amino}carbonothioyl)benzamide

Benzoylisothiocyanate (0,362 ml) was added to a solution of amine synthesized at the previous stage (630 mg)in dichloromethane (20 ml) and the mixture was stirred at room temperature for 12 hours. The reaction solution was purified by chromatography on a column of silica gel with obtaining specified in the title compound (550 mg).

ESI-MS; m/z 537 [M++Na].

(3)Synthesis of N-((4aR*,6S*,7aS*)-7a-(2-forfinal)-6-(3,4-deferasirox)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl)benzamide

Concentrated chloride-hydrogen acid (1.7 ml) was added to a solution of thiourea, synthesized at the previous stage (550 mg)in methanol (50 ml) and the mixture is boiled under reflux for three hours. The reaction solution was allowed to cool and then it was poured into ice solution of sodium bicarbonate followed the m by extraction with ethyl acetate. The extract was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (480 mg).

ESI-MS; m/z 497 [M++H].

(4)Synthesis of tert-butyl [(4aR*,6S*,7aS*)-7a-(2-forfinal)-6-hydroxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

A solution of the amide compound obtained in the preceding stage (135 mg)in concentrated chloride-hydrogen acid (20 ml) was boiled under reflux for four hours. The reaction solution was brought to room temperature and was poured into ice solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extract was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in THF (3.3 ml). Was added triethylamine (0,0525 ml) and di-tert-BUTYLCARBAMATE (49,3 mg) and the reaction solution was stirred at room temperature for two hours. The reaction solution was poured into a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extract was washed with a saturated solution of salt and who left the house taking over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (64 mg).

ESI-MS; m/z 367 [M++H].

An example of retrieving 34

Synthesis of tert-butyl [(4aR*,6R*,7aS*)-7a-(5-amino-2-forfinal)-6-fluoro-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate ((+)-isomer and (-)-isomer)

[Formula 56]

(1)Synthesis of tert-butyl [(4aR*,6R*,7aS*)-7a-(2-forfinal)-6-fluoro-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

TRIFLUORIDE [bis(2-methoxyethyl)amino]sulfur (0,0564 ml) was added to a solution of tert-butyl [(4aR*,6S*,7aS*)-7a-(2-forfinal)-6-hydroxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate (51 mg) in dichloromethane (2 ml) at 0°C and the mixture was stirred at 0°C for 1.5 hours. To the reaction solution was added water, followed by extraction with ethyl acetate. The extract was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. Specified in the title compound (51 mg) was obtained by removal of the drying agent and concentrated under reduced pressure.

ESI-MS; m/z 369 [M++H].

(2)Synthesis of tert-butyl [(4aR*,6R*,7aS*)-7a-(2-fluoro-5-nitrophenyl)-6-fluoro-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

TFOC (1.0 ml) was added to a solution of tert-butyl is about the complex ester, obtained at the previous stage (51 mg)in dichloromethane (2.0 ml) at room temperature and the reaction solution was stirred at room temperature for one hour. The reaction solution was poured into cold sodium bicarbonate solution, followed by extraction with ethyl acetate. The extract was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The drying agent was removed, followed by concentration under reduced pressure. The residue was purified by chromatography on a column of silica gel to obtain the amino compounds (34 mg). Fuming nitric acid (4,48 ml) was added to a solution of the amino compounds (34 mg) in concentrated sulfuric acid (1.5 ml) at 0°C and the mixture was stirred at 0°C for 30 minutes. The reaction solution was poured into a mixture of 5 n sodium hydroxide solution and ice water followed by extraction with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The triethylamine (44,2 μl) and di-tert-BUTYLCARBAMATE (to 41.6 mg) was added to a solution of the crude product in THF (5 ml) at room temperature and the mixture was stirred at room temperature for 12 hours. The reaction solution was poured into the feast upon the hydrated sodium bicarbonate solution, followed by extraction with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on a column of silica gel with obtaining specified in the title compound (27 mg).

ESI-MS; m/z 414 [M++H].

(3)Synthesis of tert-butyl [(4aR*,6R*,7aS*)-7a-(5-amino-2-forfinal)-6-fluoro-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

A solution of the nitro compounds obtained at the previous stage (27 mg), and iron (60 mg) in ethanol (1.25 ml) and a saturated solution of ammonium chloride (0.1 ml) was stirred at 87°C for 30 minutes. After adjusting the reaction solution to room temperature, the iron was removed by filtration. The filtrate was poured into a mixture of water-ethyl acetate, followed by extraction with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure to obtain specified in the title compound (23 mg).

ESI-MS; m/z 384 [M++H].

(4)Synthesis of tert-butyl [(4aR*,6R*,7aS*)-7a-(5-amino-2-forfinal)-6-fluoro-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate ((+)-isomer and (-)-isomer)

tert-Butyl (±)-[(4aR*,6R*,7aS*)-7a-(5-amino-2-f is arvanil)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate (46 mg) was optically separated, using CHIRALPAK™ ADH production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 8:2, flow rate: 10 ml/min). Received 15 mg of the components having a retention time of 15 to 20 minutes. Received 11 mg components having a retention time of from 28 to 33 minutes.

Connection received from components having a retention time of from 28 to 33 minutes, was used for the synthesis of chiral compounds in this example.

1H-NMR (400 MHz, CDCl3) δ (ppm): is 1.51 (s, 9H), 2,10-of 2.30 (m, 1H), 2,30-to 2.55 (m, 2H), 2,73 (d, J=13,2 Hz, 1H), 2,92 (DD, J=14,4, 32,4 Hz, 1H), 3,05 (d, J=13,2 Hz, 1H), 3.33 and (USS, 1H), 3,63 (USS, 2H), 5,02-of 5.45 (m, 1H), 6,45-6,60 (m, 2H), 6,80-to 6.95 (m, 1H).

Example of getting 35

Synthesis of tert-butyl [(4aR*,6R*,7aS*)-7a-(2-forfinal)-6-hydroxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

[Formula 57]

Specified in the title compound was obtained by treatment of (3aR*,5R*,6aS*)-6a-(2-forfinal)-5-(3,4-deferasirox)hexahydrotriazine[c]isoxazol in accordance with the method of example obtaining 33.

ESI-MS; m/z 367 [M++H].

Example of getting 36

Synthesis of tert-butyl (-)-[(4aR*,6S*,7aS*)-7a-(5-amino-2-forfinal)-6-fluoro-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

[Formula 58]

Specified in the title compound was obtained by treatment of tert-butyl [(4aR*,6R*,7aS*)-7a-(2-forfinal)-6-hydroxy-4,4a,5,6,7,7a-GE is algeriennement[d][1,3]thiazin-2-yl]carbamate in accordance with the method of example obtaining 34. Optical separation was performed using a CHIRALPAK™ ADH production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 7:3, flow rate: 10 ml/min). Components having a retention time of 18 to 23 minutes, collected by obtaining specified in the header (-)-isomer.

The characteristic values of (-)-isomer are given below.

optical rotation (-)

1H-NMR (400 MHz, CDCl3) δ (ppm): is 1.51 (s, 9H), 2,10-2,60 (m, 3H), 2,70 (d, J=12.0 Hz, 1H), 2,75-3,10 (m, 3H), 3,64 (USS, 2H), 5,20-of 5.50 (m, 1H), 6,45-of 6.65 (m, 2H), 6.75 in-6,90 (m, 1H).

An example of retrieving 37

Synthesis of tert-butyl [(4aR*,7aS*)-7a-(5-amino-2-forfinal)-6,6-debtor-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

[Formula 59]

(1)Synthesis of tert-butyl [(4aR*,7aS*)-7a-(2-forfinal)-4a,5,7,7a-tetrahydro-4H-cyclopent[d][1,3]thiazin-6-it-2-yl]carbamate

Dimethyl sulfoxide (0,014 ml) was added dropwise to a solution of oxalicacid (0,0169 ml) in dichloromethane (5 ml) at -55°C and the mixture was stirred at -70°C for 10 minutes. A solution of the alcohol obtained in example obtain 33 (48 mg), in dichloromethane (5 ml) was added dropwise to the solution at -60°C and the mixture was stirred at -60°C for 15 minutes. To the solution at -60°C was added drop wise addition of triethylamine (0,128 ml) and the reaction solution was stirred at a temperature of from -60°C to room temperature for 30 minutes. The reaction solution was poured into water with p the following extraction with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (28 mg).

ESI-MS; m/z 365 [M++H].

(2)Synthesis of tert-butyl [(4aR*,7aS*)-7a-(2-forfinal)-6,6-debtor-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

TRIFLUORIDE [bis(2-methoxyethyl)amino]sulfur (1,42 ml) was added to a solution of the derivative of the ketone obtained at the previous stage (281 mg), in dichloromethane (3 ml) at room temperature and the mixture was stirred at room temperature for 12 hours. To the reaction solution was added ice water, followed by extraction with ethyl acetate. The extract was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The drying agent was removed, followed by concentration under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (50 mg).

ESI-MS; m/z 387 [M++H].

(3)to(5)Synthesis of tert-butyl [(4aR*,7aS*)-7a-(5-amino-2-forfinal)-6,6-debtor-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

Specified in the title compound was obtained by processing diversecity, the floor is built in the example of a 37-(2), in accordance with the method of example obtaining a 34-(2)-(4). Optical separation was performed using a CHIRALPAK™ ADH production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 7:3, flow rate: 10 ml/min).

Connection received from components having a retention time of 18.5 to 21 minutes, was used for the synthesis of chiral compounds in this example.

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.52 (s, 9H), 2,30 was 2.76 (m, 4H), 2,98 (d, J=13,2 Hz, 1H), 3,10-3,30 (m, 2H), 3,63 (USS, 2H), 6,50 (DD, J=2,8, 7.2 Hz, 1H), 6,53-6,63 (m, 1H), 6.87 in (DD, J=8,4, 12.0 Hz, 1H).

An example of retrieving 38

Synthesis of di-tert-butyl [(4aR*,7aS*)-7a-(5-amino-2-forfinal)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]iminodicarboxylate

[Formula 60]

(1)Synthesis of di-tert-butyl [(4aR*,7aS*)-7a-(2-fluoro-5-nitrophenyl)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]iminodicarboxylate

N,N-Dimethylaminopyridine (721 mg) and di-tert-BUTYLCARBAMATE (1,03 g) was added to a solution of [(4aR*,7aS*)-7a-(2-fluoro-5-nitrophenyl)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]amine obtained in example of preparation of 3-(6) (350 mg)in dichloromethane (10 ml) and the mixture was stirred at room temperature for 12 hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The extract was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. Azusa is a first agent was removed, followed by concentration under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (580 mg).

ESI-MS; m/z 496 [M++H].

(2)Synthesis of di-tert-butyl [(4aR*,7aS*)-7a-(5-amino-2-forfinal)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]iminodicarboxylate

The solution diimides compound obtained in the preceding stage (630 mg), and iron (945 mg) in ethanol (10 ml) and a saturated solution of ammonium chloride (1 ml) was stirred at 87°C for 30 minutes. After cooling the reaction solution to room temperature, the reaction solution was poured into ethyl acetate and the insoluble substance was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (380 mg).

ESI-MS; m/z 466 [M++H].

An example of retrieving 39

Synthesis of 5-cyclopropylacetylene-2-carboxylic acid

[Formula 61]

(1)Synthesis of ethyl 5-cyclopropylacetylene-2-carboxylate

Cyclopropylacetylene (73,7 ml), copper iodide (3,16 mg) and tetrakis(triphenylphosphine)palladium (9,59 mg) was added to a solution of ethyl 5-bromopyridin-2-carboxylate (95,5 mg) in Diisopropylamine (2 ml) at room temperature and the mixture was stirred at room temperature for 17 hours and five minutes. The reaction solution to which has centriole under reduced pressure. The residue was purified by chromatography on a column with NH-silica gel with obtaining specified in the connection header (to 19.4 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 0,86-of 0.90 (m, 2H), 0,91-0,97 (m, 2H), 1,44 (t, J=7.2 Hz, 3H), 1,47-and 1.54 (m, 1H), 4,47 (kV, J=7.2 Hz, 2H), to 7.77 (DD, J=8,0, 2.0 Hz, 1H), 8,04 (DD, J=8,0, 0.8 Hz, 1H), 8,70 (DD, J=2.0 a, and 0.8 Hz, 1H).

(2)Synthesis of 5-cyclopropylacetylene-2-carboxylic acid

5 M sodium hydroxide solution (36,6 ml) was added to a solution of the compound obtained in the preceding stage (to 19.4 mg)in ethanol (500 μl) and the mixture was stirred at room temperature for 40 minutes. 5 M chloride-hydrogen acid (36,6 ml) was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the drying agent was filtered. The filtrate was concentrated under reduced pressure to obtain specified in the connection header (18.7 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): of 0.87 to 0.92 (m, 2H), 0,94-1,00 (m, 2H), 1,48-of 1.55 (m, 1H), 7,86 (DD, J=8,0, 2.0 Hz, 1H), 8,13 (DD, J=8.0 a, 1,1 Hz, 1H), 8,56 (DD, J=2.0 a, 1,1 Hz, 1H).

Example of getting 40

Synthesis of 5-thiazol-2-espiridion-2-carboxylic acid

[Formula 62]

(1)Synthesis of ethyl 5-thiazol-2-espiridion-2-carboxylate

2-Tributylstannyl (325 mg) and bis(tri-tert-butylphosphine)palladium(0) (25 mg) was added to a solution of ethyl 5-bromopyridin-2-carbox elata (100 mg) in 1,4-dioxane (2 ml). After replacement with nitrogen, the mixture was stirred at 100°C for eight hours. The reaction solution was brought to room temperature and evaporated under reduced pressure, the solvent is obtaining specified in the title compound (10 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,47 (t, J=7.2 Hz, 3H), to 4.52 (q, J=7,2, 2H), 7,50 (d, J=3.2 Hz, 1H), to 7.99 (d, J=3.2 Hz, 1H), they were 8.22 (DD, J=0,8, and 8.4 Hz, 1H), 8,39 (DD, J=2,2, and 8.4 Hz, 1H), 9,31 (DD, J=0,8 and 2.2 Hz, 1H).

(2)Synthesis of 5-thiazol-2-espiridion-2-carboxylic acid

5 M sodium hydroxide solution (17,1 ml) was added to a solution of the compound obtained in the preceding stage (10 mg)in ethanol (250 μl) at room temperature, followed by stirring for 35 minutes. 5 M chloride-hydrogen acid (17,1 ml) was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the drying agent was filtered. The filtrate was concentrated under reduced pressure to obtain specified in the title compound (8.6 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): rate of 7.54 (d, J=3.2 Hz, 1H), 8,02 (d, J=3.2 Hz, 1H), 8.30 to-a 8.34 (m, 1H), 8,46-8,51 (m, 1H), which 9.22-9,24 (m, 1H).

An example of retrieving 41

Synthesis of 5-cyclopropylmethyl-2-carboxylic acid

[Formula 63]

(1)Synthesis of tert-butyl 5-cyclopropylmethyl-2-carboxylate

Cyclopropylboronic sour is (to 43.2 mg), tricyclohexylphosphine (10,9 mg), palladium acetate (4,34 mg) and potassium phosphate (288 mg) was added to a mixed solution of tert-butyl 5-bromopyridin-2-carboxylate (100 mg) in toluene (2 ml) and water (100 μl) and the mixture was stirred at 100°C for nine hours and 30 minutes. After bringing to room temperature, to the reaction solution were added water. After extraction with ethyl acetate the organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (11.6 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 0,76-of 0.82 (m, 2H), 1,08-to 1.14 (m, 2H), and 1.63 (s, 9H), 1.91 a is 2.00 (m, 1H), was 7.36 (DD, J=8,4, 2.4 Hz, 1H), to 7.93 (d, J=8,4 Hz, 1H), 8,51 (d, J=2.4 Hz, 1H).

(2)Synthesis of 5-cyclopropylmethyl-2-carboxylic acid

A mixed solution of the compound obtained in the preceding stage (11.6 mg), triperoxonane acid (333 μl) and dichloromethane (666 μl) was allowed to stand at room temperature for two hours and 20 minutes. The reaction solution was concentrated under reduced pressure to obtain specified in the title compound (16.6 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 0,95-of 1.03 (m, 2H), 1,31-of 1.41 (m, 2H), 2,08-of 2.20 (m, 1H), 7,94 (USD, J=8.0 Hz, 1H), 8,33 (USD, J=8.0 Hz, 1H), 8,65 (USS, 1H).

An example of retrieving 42

Synthesis of 5-methylsulfinylphenyl-2-carboxylic acid

[Formula 64]

(1)Synthesis of methyl 5-methylsulfinylphenyl-2-carboxylate

Meantioned sodium (44,6 mg) was added to a solution of methyl 5-chloropyrazine-2-carboxylate (87 mg) in hexamethylphosphorotriamide (1 ml) at room temperature, followed by stirring for 13 hours and 30 minutes. To the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column with NH-silica gel with obtaining specified in the title compound (6.8 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2.63 in (s, 3H), was 4.02 (s, 3H), 8,53 (d, J=1.4 Hz, 1H), 9,07 (d, J=1.4 Hz, 1H).

(2)Synthesis of 5-methylsulfinylphenyl-2-carboxylic acid

Trimethylsilanol potassium (6,15 mg) was added to a solution of the compound obtained in the preceding stage (6,8 mg)in tetrahydrofuran (500 μl) at room temperature, followed by stirring for one hour. To the reaction solution were added water and ethyl acetate and the separated aqueous layer. To the aqueous layer was added 1 M chloride-hydrogen acid, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the drying agent was filtered. The filtrate was concentrated under reduced pressure to obtain specified in the title compound (6.6 mg).

1H-NMR (400 MHz, CDCl ) δ (ppm): to 2.67 (s, 3H), 8,49 (USS, 1H), 9,17 (USS, 1H).

An example of retrieving 43

Synthesis of 5-(3-methoxypropan-1-yl)pyridine-2-carboxylic acid

[Formula 65]

(1)Synthesis of methyl 5-(3-methoxypropan-1-yl)pyridine-2-carboxylate

Chloride bis(triphenylphosphine)palladium(II) (82,4 mg), copper iodide (22,3 mg), methylpropyloxy simple ether (828 ml) and triethylamine (1.9 ml) was added to a solution of methyl 5-bromo-pyridine-2-carboxylate (423 mg) in tetrahydrofuran (10,6 ml) and the mixture was stirred at room temperature for 19 hours and 50 minutes. The reaction solution was concentrated under reduced pressure and to the residue was added water. After extraction with ethyl acetate the organic layer was washed with saturated salt solution and evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (88,1 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 3,47 (s, 3H), was 4.02 (s, 3H), 4,36 (s, 2H), 7,88 (DD, J=8,0, 2.0 Hz, 1H), 8,10 (DD, J=8,0, 0.8 Hz, 1H), 8,78 (DD, J=2.0 a, and 0.8 Hz, 1H).

(2)Synthesis of 5-(3-methoxypropan-1-yl)pyridine-2-carboxylic acid

Trimethylsilylcyanation potassium (26.9 mg) was added to a solution of the compound obtained in the preceding stage (33 mg)in tetrahydrofuran (1 ml) and the mixture was stirred at room temperature for one hour and 20 minutes. The reaction is first solution was concentrated under reduced pressure. To the residue was added water and diethyl ether and the separated aqueous layer. To the aqueous layer was added 1 M chloride-hydrogen acid, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the drying agent was filtered. The filtrate was concentrated under reduced pressure to obtain specified in the connection header (to 25.4 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 3,48 (s, 3H), 4,37 (s, 2H), of 7.97 (DD, J=8,0, 1.8 Hz, 1H), 8,19 (DD, J=8,0, 0.8 Hz, 1H), 8,66 (DD, J=1,8, 0.8 Hz, 1H).

An example of retrieving 44

Synthesis of tert-butyl (-)-[(4aS*,5S*,8aS*)-8a-(5-amino-2-forfinal)-5-vermeil-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

[Formula 66]

(1)Synthesis of 1-benzyloxy-3-butene-2-ol

2,64 M solution of n-utility in hexane (35,7 ml) was added to a solution of iodide trimethylsilane (19.9 g) in tetrahydrofuran (300 ml) at -25°C. the Mixture was stirred at the same temperature for 30 minutes. Benzylpenicilloyl ether (5,00 ml) was added to the reaction solution at the same temperature and then the mixture was heated to room temperature over two hours and 50 minutes. To the reaction solution was added water, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered and the filtrate was concentrated p and reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (6,98 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,44 (d, J=3.6 Hz, 1H), 3,38 (DD, J=9,6, 8.0 Hz, 1H), 3,55 (DD, J=9,6, 3.0 Hz, 1H), 4,32-and 4.40 (m, 1H), 4,58 (s, 2H), 5,18-5,23 (m, 1H), 5,33-of 5.40 (m, 1H), 5,79-of 5.89 (m, 1H), 7,28-7,40 (m, 5H).

In this example, receiving 44-(2)-(8) the synthesis was carried out in accordance with the example of getting 22-(1)-(5). But instead of diethylacetal of bromoacetaldehyde used dimethylacetal 3-bromopropionaldehyde.

In this example, receiving 44-(9)-(11) the synthesis was carried out in accordance with the example of getting 19-(8)-(10).

(12)Synthesis of [(4aS*,5S*,8aS*)-2-amino-8a-(2-fluoro-5-nitrophenyl)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-5-yl]methanol

Fuming nitric acid (121 μl) was added to a mixed solution of the compound obtained in the preceding stage (720 mg), triperoxonane acid (12 ml) and sulfuric acid (6 ml) at 0°C, followed by stirring for one hour. The reaction solution was poured into ice and 2 M sodium hydroxide solution was added at 0°C. After extraction with ethyl acetate the organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered and the filtrate was concentrated under reduced pressure to obtain specified in the connection header (908 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,68-to 1.77 (m, 1H), 2,56-to 2.67 (m, 1H), 2,73-and 2.79(m, 2H), 2,90-3,00 (m, 1H), 3,67 of 3.75 (m, 1H), of 3.77-to 3.92 (m, 3H), 3,93-4,00 (m, 1H), 7,19-7,26 (m, 1H), 8,16 is 8.22 (m, 1H), 8,24-of 8.28 (m, 1H).

(13)Synthesis of tert-butyl [(4aS*,5S*,8aS*)-8a-(2-fluoro-5-nitrophenyl)-5-hydroxymethyl-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

Di-tert-BUTYLCARBAMATE (1,16 g) and triethylamine (1,48 ml) was added to a solution of the compound obtained in the preceding stage (908 mg)in tetrahydrofuran (30 ml) and the mixture was stirred at room temperature for five hours and 30 minutes. The reaction solution was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (454 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): and 1.54 (s, 9H), 1,63-1,71 (m, 1H), 2,55-2,77 (m, 3H), 2,97-is 3.08 (m, 1H), 3,67-was 4.02 (m, 5H), 7,21-7,27 (m, 1H), 8,14-8,24 (m, 2H).

(14)Synthesis of tert-butyl [(4aS*,5S*,8aS*)-5-vermeil-8a-(2-fluoro-5-nitrophenyl)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

TRIFLUORIDE [bis(2-methoxyethyl)amino]sulfur (500 μl) was added to a solution of the compound obtained in the preceding stage (398 mg), in dichloromethane (20 ml) at -78°C and the mixture was stirred at the same temperature for 30 minutes. After that, the reaction solution was stirred at 0°C for 30 minutes and at room temperature for four hours. To the reaction solution was added a saturated solution of sodium bicarbonate, followed extra is the key chloroform. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (414 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1.55V (s, 9H), 1,62-1,71 (m, 1H), 2,56 is 2.80 (m, 3H), 3,05-and 3.16 (m, 1H), 3,64-a 4.03 (m, 3H), 4,55-of 4.75 (m, 2H), 7,22-7,28 (m, 1H), 8,15-8,24 (m, 2H).

In this example, receiving 44-(15) the synthesis was carried out in accordance with the example of getting 20-(3).

(16)Synthesis of tert-butyl (-)-[(4aS*,5S*,8aS*)-8a-(5-amino-2-forfinal)-5-vermeil-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

The compound obtained in the preceding stage (33 mg), optically separated using CHIRALPAK™ AD-H production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 7:3, flow rate: 8 ml/min), and the component having a retention time of 20 to 27 minutes, was collected. This operation was repeated to obtain specified in the title compound (174 mg, >99% ee) of 364 mg of the racemate.

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.53 (s, 9H), 1,58-of 1.66 (m, 1H), 2,62-2,69 (m, 1H), 2,75-of 2.86 (m, 1H), 2,89-2,96 (m, 1H), is 3.08-3.15 in (m, 1H), 3,66 (USS, 2H), 3,78-Android 4.04 (m, 3H)and 4.65 (DD, J=47,6, 2,8 Hz, 2H), 6,52-of 6.61 (m, 2H), 6,85-6,93 (m, 1H).

An example of retrieving 45

Synthesis of tert-butyl [(4aS*,8aS*)-8a-(5-amino-2-trifloromethyl)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

[Formula 67]

In this example, receiving 45 in image quality is as educt used connection received in the sample receiving 8-(2).

In this example, receiving 45-(1)-(3) the synthesis was carried out in accordance with the example of getting 22-(3)-(5). But instead of 2-bromptonville used 1-bromo-2-cryptomaterial.

(4)Synthesis of N-[(4aS*,8aS*)-8a-(2-trifloromethyl)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]benzamide

Tetrabromide carbon (542 mg) and triphenylphosphine (429 mg) was added to a solution of the compound obtained in the preceding stage (286 mg), in dichloromethane (6,41 ml) at room temperature, followed by stirring for four hours. The reaction solution was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (52,4 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,65-of 1.75 (m, 1H), 2,55-of 2.64 (m, 1H), 2.77-to 2,95 (m, 2H), of 3.25 to 3.35 (m, 1H), 3,80-a 4.03 (m, 4H), 7,27-of 7.55 (m, 7H), by 8.22-of 8.27 (m, 2H).

(5)to(8)Synthesis of tert-butyl [(4aS*,8aS*)-8a-(5-amino-2-trifloromethyl)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

Specified in the title compound was obtained by synthesis in this example, receiving 45-(5) in accordance with the example of a 19-(9) and synthesis in this example, receiving 45-(6), (7) and (8) in accordance with the example of getting 22-(8), (9) and (10).

1H-NMR (400 MHz, CDCl3) δ (ppm): and 1.54 (s, 9H), 1,54-of 1.62 (m, 1H), 2,45 of $ 2.53 (m, 1H), 2,67 is 2.80 (m, 1H), 2,83 of 2.92 (m, 1H), 3,09-3,18 (m, 1H), 3,6-of 3.96 (m, 6H), 6,58-only 6.64 (m, 2H), 7,09-7,14(m, 1H).

An example of retrieving 46

Synthesis of tert-butyl (-)-[(6S*,7S*,7aS*)-7a-(5-amino-2-forfinal)-7-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

[Formula 68]

(1)Synthesis of 1,1-dimethoxypropane-2-ol

Sodium borohydride was added to a mixed solution of dimethylacetal pyruvic aldehyde (10 ml) in methanol (50 ml) and tetrahydrofuran (50 ml) at 0°C, followed by stirring for 10 minutes. The reaction solution was heated to room temperature and was stirred for one hour and 20 minutes. To the reaction solution was added a saturated solution of ammonium chloride. After extraction with diethyl ether, the organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered and the filtrate was concentrated under reduced pressure to obtain specified in the connection header (9,86 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,20 (d, J=6.4 Hz, 3H), 2,17 (USD, J=3.2 Hz, 1H), 3,44 (s, 3H), 3.46 in (s, 3H), 3.72 points-of 3.80 (m, 1H), 4,08 (d, J=6,4 Hz, 1H).

(2)Synthesis of 3-(2,2-dimethoxy-1-methylethoxy)propene

60% sodium Hydride (992 mg) was added to a solution of 1,1-dimethoxypropane-2-ol (2,49 g) in dimethylformamide (50 ml) at 0°C, followed by stirring for 15 minutes. Allylbromide (1,96 ml) was added at the same temperature, followed by stirring for 15 minutes. To react the traditional solution was added ice, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (of 3.46 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): to 1.16 (d, J=6.5 Hz, 3H), 3.43 points (s, 3H), of 3.45 (s, 3H), 3,48-of 3.54 (m, 1H), 4,03-to 4.14 (m, 2H), 4,18 (d, J=5,2 Hz, 1H), 5,14-5,19 (m, 1H), 5.25-in, 5,32 (m, 1H), by 5.87 is 5.98 (m, 1H).

In this example, receiving 46-(3) and (4) the synthesis was carried out in accordance with the example of obtaining 24-(3).

In this example, receiving 46-(5)-(9) the synthesis was carried out in accordance with example 22 receiving-(2)-(6).

In this example, receiving 46-(10) the synthesis was carried out in accordance with the example of a 19-(9).

In this example, receiving 46-(11), (12) and (13) the synthesis was carried out in accordance with the example of getting 22-(8), (9) and (10).

(14)Synthesis of tert-butyl (-)-[(6S*,7S*,7aS*)-7a-(5-amino-2-forfinal)-7-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

The compound obtained in the preceding stage (12 mg), optically separated using CHIRALPAK™ AD-H production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 8:2, flow rate: 10 ml/min), and the component having a retention time of 16 to 21 minutes, was collected. This operation was repeated to obtain specified in the title compound (112 mg, >99% ee) of 240 mg of the racemate.

1H-NMR (400 MHz, CDCl3) δ (ppm): 0,96 (d, J=6.0 Hz, 3H), 1,49 (s, 9H), 2,81-2,90 (m, 1H), 3,30 is 3.40 (m, 1H), 3,43-3,2 (m, 1H), 3,61 (USS, 2H), 4,10-4,19 (m, 1H), 4,20-to 4.38 (m, 2H), 6,56-only 6.64 (m, 2H), 6.87 in-6,94 (m, 1H).

An example of retrieving 47

Synthesis of tert-butyl (-)-[(6R*,7S*,7aS*)-7a-(5-amino-2-forfinal)-7-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

[Formula 69]

(1)to(8)Synthesis of tert-butyl (-)-[(6R*,7S*,7aS*)-7a-(5-amino-2-forfinal)-7-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

In this example, getting in as the starting material used (3S*,3aS*,5R*)-6a-(2-forfinal)-6-methyltetrahydrofuran[3,4-c]isoxazol obtained in the example of a 46-(6).

Specified in the title compound was obtained by synthesis in this example, receiving 47-(1)-(8) in accordance with the example of obtaining 46-(7)-(14).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1.14 in (USD, J=6,4 Hz, 3H), of 1.52 (s, 9H), 2,62-2,70 (m, 1H), 3,03 is 3.15 (m, 1H), 3.46 in-of 3.60 (m, 1H), 3,64 (USS, 2H), 4,10-to 4.23 (m, 2H), 4,56 with 4.65 (m, 1H), 6,55-6,62 (m, 1H), 6,63 is 6.67 (m, 1H), 6,83-6,90 (m, 1H).

Example obtain 48

Synthesis of tert-butyl (-)-[(4aS*,5R*,8aS*)-8a-(5-amino-2-forfinal)-5-methyl-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

[Formula 70]

In this example, receiving 48-(1)-(7) the synthesis was carried out in accordance with the example of getting 22-(1)-(5). But instead of diethylacetal of bromoacetaldehyde used dimethylacetal 3-bromopropionaldehyde.

In this example, receiving 48-(8) and (9) the synthesis was carried out with the availa able scientific C sample receiving 19-(8) and (9). In this example, receiving 48-(10), (11) and (12) the synthesis was carried out in accordance with the example of getting 22-(8), (9) and (10).

(13)Synthesis of tert-butyl (-)-[(4aS*,5R*,8aS*)-8a-(5-amino-2-forfinal)-5-methyl-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

The compound obtained in the preceding stage (44 mg), optically separated using CHIRALPAK™ OJ-H production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 2:8, flow rate: 10 ml/min), and the component having a retention time of 14 to 28 minutes, was collected. This operation was repeated to obtain specified in the title compound (223 mg, >99% ee) of 700 mg of the racemate.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,32 (d, J=5,2 Hz, 3H), of 1.53 (s, 9H), 1.56 to of 1.65 (m, 1H), 2,56-2,70 (m, 2H), 2,73-only 2.91 (m, 2H), 3,66 (USS, 2H), 3.75 to of 3.97 (m, 3H), 6,53-6,59 (m, 2H), 6,84-6,91 (m, 1H).

An example of retrieving 49

Synthesis of 5-deformationen-2-carboxylic acid

[Formula 71]

(1) Synthesis of methyl 5-deformationen-2-carboxylate

The cesium carbonate (7,45 g) and 2-chloro-2,2-defloration (5.75 g) was added to a solution of methyl 5-hydroxypyridine-2-carboxylate (2.5 g) in DMF and the mixture was stirred at 100°C for three hours. The reaction solution was brought to room temperature. Was added aqueous ammonium chloride and ethyl acetate and the separated organic layer. The organic layer was washed with saturated aqueous what astora of sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (760 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): was 4.02 (s, 3H), only 6.64 (t, J=72,0 Hz, 1H), 7.62mm (DD, J=2,8, 8,8 Hz, 1H), 8,18 (d, J=9,2 Hz, 1H), 8,58 (d, J=2,8 Hz, 1H).

(2) Synthesis of 5-deformationen-2-carboxylic acid

To a solution of methyl 5-deformationen-2-carboxylate, obtained in the example of a 49-(1) (760 mg)in methanol (15 ml) was added 2 n sodium hydroxide solution (3,74 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction solution was acidified chloride-hydrogen acid. To the reaction solution was added saturated aqueous solution of sodium chloride and ethyl acetate and the separated organic layer. The organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain specified in the title compound (482 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 6,67 (t, J=71,6 Hz, 1H), 7,72 (DD, J=2.0 a, and 8.4 Hz, 1H), 8,28 (d, J=8,8 Hz, 1H), and 8.50 (d, J=2.0 Hz, 1H).

Example of getting 50

Synthesis of 5-(2,2,2-triptoreline)pyrazin-2-carboxylic acid

[Formula 72]

(1)Synthesis of methyl 5-(2,2,2-triptoreline)pyrazin-2-carboxylate

The cesium carbonate (2,96 g) and 2,2,2-triftoratsetilatsetonom (1,57 g)was added to a solution of methyl 5-hydroxypyridine-2-carboxylate (700 mg) in DMF (20 ml) and the mixture was stirred at room temperature for 20 hours. To the reaction solution was added aqueous ammonium chloride and ethyl acetate and the separated organic layer. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on silica gel with obtaining specified in the title compound (197 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): was 4.02 (s, 3H), 4,85 (kV, J=8.0 Hz, 2H), 8,44 (d, J=1.2 Hz, 1H), 8,88 (d, J=1.2 Hz, 1H).

(2)Synthesis of 5-(2,2,2-triptoreline)pyrazin-2-carboxylic acid

To a solution of methyl 5-(2,2,2-triptoreline)pyrazin-2-carboxylate obtained in example getting 50-(1) (197 mg)in THF (5 ml) was added 5 n sodium hydroxide solution (3 ml) and ethanol (3 ml) and the mixture is boiled under reflux for 15 minutes. After bringing to room temperature, added water and ethyl acetate and the aqueous layer was separated. The aqueous layer was brought to pH 1 chloride-hydrogen acid was added to the water layer in ethyl acetate. The organic layer was separated and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to obtain specified in the title compound (87 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 4,88 (kV, J=8,4 Hz, 2H), of 8.37 (d, J=1.2 Hz, 1H), 8,99 (d, J=1.2 Hz, 1H).

An example of retrieving 51

Synthesis of 5-(2,2-diflorasone)pyrazin-2-Carbo the OIC acid

[Formula 73]

(1)Synthesis of methyl 5-(2,2-diflorasone)pyrazin-2-carboxylate

The cesium carbonate (2,12 g) and 2-bromo-1,1-differetn (939 mg) was added to a solution of methyl 5-hydroxypyridine-2-carboxylate (500 mg) in DMF (20 ml) and the mixture was stirred at 80°C for four hours. The reaction solution was brought to room temperature. Was added a saturated aqueous solution of sodium chloride and ethyl acetate and the separated organic layer. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (145 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): was 4.02 (s, 3H), with 4.64 (dt, J=4,0, 13,2 Hz, 2H), 6,15 (TT, J=4,0, of 54.8 Hz, 1H), 8,39 (d, J=1.2 Hz, 1H), 8,88 (d, J=1.2 Hz, 1H).

(2)Synthesis of 5-(2,2-diflorasone)pyrazin-2-carboxylic acid

To a solution of methyl 5-(2,2-diflorasone)pyrazin-2-carboxylate obtained in example obtaining a 51-(1) (145 mg)in ethanol (4 ml) was added 5 n sodium hydroxide solution (266 μl) and the mixture was stirred at room temperature for one hour. To the reaction solution was added 5 N. chloride-hydrogen acid for acidification of the solution. To the reaction solution were added ethyl acetate and a saturated salt solution, and separated the organic layer. Organic with the Oh was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to obtain specified in the title compound (92 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): and 4.68 (dt, J=4,0, 13,2 Hz, 2H), 6,16 (TT, J=4,0, of 54.8 Hz, 1H), 8.34 per (s, 1H), 8,99 (d, J=0.8 Hz, 1H).

An example of retrieving 52

Synthesis of 5-(2,2-diflorasone)pyridine-2-carboxylic acid

[Formula 74]

The cesium carbonate (423 mg) and 2-bromo-1,1-differetn (189 mg) was added to a solution of methyl 5-hydroxypyridine-2-carboxylate (100 mg) in DMF (4 ml) and the mixture was stirred at room temperature for 20 hours. To the reaction solution was added saturated aqueous solution of sodium chloride and ethyl acetate and the separated organic layer. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the header of the intermediate compounds. To a solution of the obtained intermediate compound in ethanol (5 ml) was added 5 n sodium hydroxide solution (262 μl). The reaction solution was stirred at room temperature for 30 minutes. The reaction solution was acidified 5 N. chloride-hydrogen acid (1 ml). To the reaction solution was added saturated aqueous solution of sodium chloride and ethyl acetate and the separated organic layer. Organicheskikh was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to obtain specified in the connection header (22,4 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 4,33 (dt, J=4,0, to 12.8 Hz, 2H), 6,15 (TT, J=4,0, of 54.8 Hz, 1H), 7,42 (DD, J=2,8, and 8.4 Hz, 1H), they were 8.22 (d, J=8,8 Hz, 1H), 8.34 per (s, 1H).

Example of getting 53

Synthesis of 5-(2-floratone)pyrazin-2-carboxylic acid

[Formula 75]

(1)Synthesis of methyl 5-(2-floratone)pyrazin-2-carboxylate

The cesium carbonate (6,34 g) and 1-iodine-2-foraten (of 2.26 g) was added to a solution of methyl 5-hydroxypyridine-2-carboxylate (1 g) in DMF (30 ml) and the mixture was stirred at room temperature for 20 hours. To the reaction solution was added aqueous ammonium chloride and ethyl acetate and the separated organic layer. The organic layer was washed saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (200 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 4,00 (s, 3H), 4.63 to-a 4.86 (m, 4H), at 8.36 (d, J=1.2 Hz, 1H), 8,87 (d, J=1.6 Hz, 1H).

(2)Synthesis of 5-(2-floratone)pyrazin-2-carboxylic acid

To a solution of methyl 5-(2-floratone)pyrazin-2-carboxylate, obtained in the example of a 53-(1) (200 mg)in ethanol (4 ml) was added 5 n solution guide is sodium oxide (400 µl). Added water up until the reaction solution became complete solution, followed by stirring at room temperature for 10 minutes. The reaction solution was acidified 5 N. chloride-hydrogen acid. To the reaction solution was added saturated aqueous solution of sodium chloride and ethyl acetate and the separated organic layer. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to obtain specified in the title compound (150 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 4,67-to 4.87 (m, 4H), of 8.27 (d, J=1.2 Hz, 1H), 8,97 (d, J=1.2 Hz, 1H).

An example of retrieving 54

Synthesis of (±)-(4aR*,7aS*)-7a-(5-bromo-2-forfinal)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine

[Formula 76]

(1)to(4)Synthesis of (±)-(4aR*,7aS*)-7a-(5-bromo-2-forfinal)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine

Specified in the header of the compound (a 4.03 g) was obtained from the compound obtained in example of preparation of 3-(1) (10 g), in accordance with the example of getting 3 using 5-bromo-2-ftorhinolonovy acid in the above stage (2) and using lithium borohydride while boiling under reflux instead of lithium aluminum hydride in stage (3).

ESI-MS; m/z 331 [M++H].

Example of getting 55

Synthesis of (±)-di-tert-butyl[(4aR*,7aS*)-7a-(3-amino-5-terphenyl)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]iminodicarboxylate

[Formula 77]

(1)-(2)Synthesis of ethyl 2-(3-bromo-5-forfinal)cyclopent-1-enecarboxylate

Specified in the title compound (12.9 g) was obtained from ethyl 2-oxocyclopentanecarboxylate (6.8 g) in accordance with the example of getting 3.

ESI-MS; m/z 313 [M++H].

(3)Synthesis of 2-(3-bromo-5-forfinal)cyclopent-1-inkarbaeva acid

To a solution of the compound obtained in the example of a 55-(2) (12.9 g)in ethanol (130 ml) was added 5 n sodium hydroxide solution (16.5 ml) and the mixture was stirred at room temperature for 16 hours. The ethanol is evaporated under reduced pressure. To the residue was added water (100 ml) and ether (150 ml) and the separated aqueous layer. The aqueous layer was acidified 5 N. chloride-hydrogen acid was added to the water layer in ethyl acetate. The organic layer was separated and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The obtained solid was washed with heptane (150 ml) to obtain specified in the connection header (of 10.58 g).

1H-NMR (CDCl3) δ (ppm): 1,96-2,05 (m, 2H), 2,80-to 2.85 (m, 4H), of 6.96-7,00 (m, 1H), 7,15-to 7.18 (m, 1H), 7,22-7,24 (m, 1H).

(4)Synthesis of [2-(3-bromo-5-forfinal)cyclopent-1-enyl]methanol

Isobutylparaben (5,08 ml) was added dropwise to a solution of the compound obtained in the example of a 55-(3) (10.6 g), and triethylamine (5,41 ml) in tetrahydrofuran (230 is l) under nitrogen atmosphere at -20°C. The reaction solution was stirred at the same temperature for 30 minutes and then the insoluble substance was separated by filtration through celite. The filtrate was added dropwise to a solution of sodium borohydride in water (2,81 g/162 ml) at a temperature of from 0 to -10°C. the Mixture was stirred at the same temperature for two hours and then was heated to room temperature. The reaction solution was stirred at room temperature for 3 hours. To the reaction solution were added ethyl acetate and a saturated aqueous solution of sodium chloride and separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (9.3 g).

1H-NMR (CDCl3) δ (ppm): 1,93-2,05 (m, 2H), 2,66 was 2.76 (m, 4H), 4,30 (d, J=2,8 Hz, 2H), 6.89 in-6,92 (m, 1H), 7,11-7,19 (m, 2H).

(5)-(6)Synthesis of (±)-(4aR*,7aS*)-7a-(3-bromo-5-forfinal)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine

Specified in the title compound (12.2 g) was obtained from the compound obtained in the example of a 55-(4) (9.3 g), in accordance with the example of getting 3.

ESI-MS; m/z 331 [M++H].

(7)Synthesis of tert-butyl (±)-[(4aR*,7aS*)-7a-(3-bromo-5-forfinal)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

The triethylamine (1,11 ml) and di-tert-bout dicarbonate (1,16 g) was added to a solution of compounds obtained in the example of a 55-(6) (1 g)in tetrahydrofuran (30 ml) and the mixture was stirred at room temperature for 14 hours. To the reaction solution were added water and ethyl acetate and the separated organic layer. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (1,03 g).

ESI-MS; m/z 431 [M++H].

(8)Synthesis of (±)-di-tert-butyl [(4aR*,7aS*)-7a-(3-bromo-5-forfinal)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]iminodicarboxylate

4-Dimethylaminopyridine (880 mg) and di-tert-BUTYLCARBAMATE (1,05 g) was added to a solution of the compound obtained in the example of a 55-(7) (1,03 g)in acetonitrile (20 ml). The reaction solution was stirred at room temperature for two hours. To the reaction solution were added ethyl acetate and a saturated aqueous solution of sodium chloride and separated the organic layer. The organic layer was again washed with saturated salt solution and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (1.12 g).

ESI-MS; m/z 531 [M++H].

(9)Synthesis of (±)-di-tert-butyl {(4aR*,7aS*)-7a-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl}iminodicarboxylate

A solution of the compound obtained in the example of a 55-(8) (635 mg), bis(pinacolato)DIBORANE (totaling 3.04 g), potassium acetate (471 mg) and 1,1'-bis(diphenylphosphino)periodically(II) (87,5 mg) in DMF (12 ml) was stirred under nitrogen atmosphere at 80°C for five hours. The reaction solution was brought to room temperature. To the reaction solution were added ethyl acetate and a saturated aqueous solution of sodium chloride and separated the organic layer. The organic layer was again washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (692 mg).

ESI-MS; m/z 577 [M++H].

(10)Synthesis of (±)-di-tert-butyl [(4aR*,7aS*)-7a-(3-azido-5-forfinal)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]iminodicarboxylate

A solution of the compound obtained in the example of a 55-(9) (695 mg), sodium azide (118 mg) and copper acetate(II) (44 mg) in methanol (15 ml) was stirred at room temperature for 72 hours. To the reaction solution were added water and ethyl acetate and the separated organic layer. Org the organic layer was twice washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (370 mg).

ESI-MS; m/z 492 [M++H].

(11)Synthesis of (±)-di-tert-butyl [(4aR*,7aS*)-7a-(3-amino-5-forfinal)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]iminodicarboxylate

Water (2 ml) and triphenylphosphine (257 mg) was added to a solution of the compound obtained in the example of a 55-(10) (370 mg)in tetrahydrofuran (8 ml) and the mixture was stirred at 60°C for three hours. The reaction solution was further heated under reflux for 40 hours. The reaction solution was brought to room temperature. To the reaction solution were added ethyl acetate and a saturated aqueous solution of sodium chloride and separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (103 mg).

ESI-MS; m/z 466 [M++H].

An example of receiving 56

Synthesis of tert-butyl (-)-[(4aS*,8aR*)-8a-(5-amino-2-forfinal)-4,4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

[Formula 78]

(1)Synthesis of 4-allyloxy-2-(2-fluoro who enyl)butyronitrile

tert-Piperonyl potassium Ltd (9.93 g) was added to a solution of 2-perforaciones (10 g), 2-alliloxietanol ester toluene-4-sulfonic acid (19 g) and 18-crown-6 (3,91 g) in tetrahydrofuran (400 ml) under cooling with ice. The reaction solution was stirred at the same temperature for 10 minutes. The reaction solution was heated to room temperature and was further stirred for four hours. To the reaction solution was added aqueous ammonium chloride and ethyl acetate and the separated organic layer. The organic layer was washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (10,9 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,18 (kV, J=6,4 Hz, 2H), 3.46 in-to 3.52 (m, 1H), 3,60-3,66 (m, 1H), 3,99 (d, J=6,4 Hz, 2H), 4,35 (t, J=7.2 Hz, 1H), to 5.21-by 5.87 (m, 2H), 5,86-5,96 (m, 1H), 7,07 for 7.12 (m, 1H), 7,16-7,20 (m, 1H), 7,30-7,35 (m, 1H), 7,42-7,47 (m, 1H).

(2)Synthesis of 4-(2,3-dihydroxypropane)-2-(2-forfinal)butyronitrile

The osmium tetroxide (2.5 wt.% a solution of tert-butyl alcohol, and 15.6 ml) was added to a solution of the compound obtained in the example of a 56-(1) (10,9 g), and 4-methylmorpholine-4-oxide (8,75 g) in a mixture of acetone/water (2/1, 390 ml) under cooling with ice. The reaction solution was heated to CONTROLTEMPLATES and was stirred for 15 hours. Sodium bisulfite (5,18 g) was added to the reaction solution and the mixture was stirred at the same temperature for 20 minutes. To the reaction solution were added ethyl acetate and a saturated aqueous solution of sodium chloride and separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (10.5 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,99-2,02 (m, 1H), 2,17-2,22 (m, 2H), 2,53-to 2.57 (m, 1H), 3,50-3,59 (m, 3H), 3,61 is 3.76 (m, 3H), a 3.87-3,91 (m, 1H), 4,32 (t, J=6,4 Hz, 1H), 7,08-7,13 (m, 1H), 7.18 in-of 7.23 (m, 1H), 7,32-7,38 (m, 1H), 7,45 is 7.50 (m, 1H).

(3)Synthesis of 4-[3-(tert-butyldiphenylsilyl)-2-hydroxypropoxy]-2-(2-forfinal)butyronitrile

The imidazole (7,05 g) and tert-butyldiphenylchlorosilane (12.3 ml) was added to a solution of the compound obtained in the example of a 56-(2) (10.5 g)in DMF (125 ml) under cooling with ice. The reaction solution was heated to room temperature and was stirred at room temperature for 18 hours. To the reaction solution was added saturated aqueous solution of sodium chloride and ethyl acetate and the separated organic layer. The organic layer was again washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and the organic layer koncentrirane and under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (16.4 g).

1H-NMR (400 MHz, CDCl3) δ (ppm)with 1.07 (s, 9H), 2,11-to 2.18 (m, 2H), 2,47-2,49 (m, 1H), 3,45-3,55 (m, 3H), 3,59-to 3.64 (m, 1H), 3,69-3,71 (m, 2H), 3,88-3,91 (m, 1H), 4,21-4.26 deaths (m, 1H), 7,05-7,10 (m, 1H), 7,14-7,19 (m, 1H), 7,29-7,35 (m, 1H), of 7.36 was 7.45 (m, 7H), to 7.64-to 7.68 (m, 4H).

(4)Synthesis of 1-(tert-butyldiphenylchlorosilane)-2-[3-cyano-3-(2-forfinal)propoxy]ethyltrichlorosilane

A solution of the compound obtained in the example of a 56-(3) (16.4 g)and N,N-diisocyanatobutane a (17.4 ml) in dichloromethane (330 ml) was cooled to -78°C under nitrogen atmosphere. Triftormetilfullerenov anhydride (8,28 ml) was added dropwise to the reaction solution at the same temperature. The reaction solution was stirred for six hours, gradually warming to room temperature. To the reaction solution was added aqueous ammonium chloride and separated the organic layer. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was concentrated and the residue was purified column chromatography to obtain specified in the title compound (15.1 g).

1H-NMR (400 MHz, CDCl3) δ (ppm)with 1.07 (s, 9H), 2,12-2,17 (m, 2H), 3,48-of 3.53 (m, 1H), 3,62-of 3.80 (m, 3H), 3,85-a 3.87 (m, 2H), 4,23-to 4.28 (m, 1H), 5,01-5,04 (m, 1H), 7,06-7,11 (m, 1H), 7,15-7,19 (m, 1H), 7,29-7,34 (m, 1H), 7,37-of 7.48 (m, 6H), 7,52-to 7.67 (m, 4H), to 7.67-7,73 (m, 1H).

(5)inches 3-(tert-butyldiphenylchlorosilane)-4-(2-forfinal)tetrahydropyran-4-carbonitrile

Tert-piperonyl potassium (2,98 g) was added to a solution of the compound obtained in the example of a 56-(4) (15.1 g)and 18-crown-6 (1.28 g) in tetrahydrofuran (250 ml) under cooling with ice. The reaction solution was stirred at the same temperature for one hour. To the reaction solution was added aqueous ammonium chloride and ethyl acetate and the separated organic layer. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (11.1 g).

ESI-MS; m/z 496 [M++Na].

(6)Synthesis of 4-(2-forfinal)-3-hydroxyethylacrylate-4-carbonitrile

Tetrabutylammonium (1 M solution in tetrahydrofuran, 46,9 ml) was added dropwise to a solution of the compound obtained in the example of a 56-(5) (11.1 g)in tetrahydrofuran (240 ml). The reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated and to the residue was added ethyl acetate and a saturated aqueous solution of sodium chloride. The organic layer was separated and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel with receiving the receiving specified in the title compound (4.0 g).

ESI-MS; m/z 236 [M++H].

(7)Synthesis of (±)-(3R*,4S*)-4-(2-forfinal)-3-methoxysalicylaldehyde-4-carbonitrile

N,N-Diisopropylethylamine (14,8 ml) and chloromethylation ether (a 3.87 ml) was added to the compound obtained in the example of a 56-(6) (4 g)in dichloromethane (100 ml). The reaction solution was stirred at room temperature for 16 hours. To the reaction solution were added water and chloroform, and separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated and the residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (1.65 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,00 (d, J=11,6 Hz, 1H), 2,38 is 2.46 (m, 1H), 2,72 (d, J=8,8 Hz, 1H), 2,93 (DD, J=4,0, 9.6 Hz, 1H), 3,19 (s, 3H), 3,62 (t, J=9.6 Hz, 1H), 3,99-4,06 (m, 2H), 4,17 (d, J=12.0 Hz, 2H), 4,37-4,43 (m, 2H,), 7,14-7,21 (m, 3H), of 7.36-7,41 (m, 1H).

(8)Synthesis of (±)-(3R*,4S*)-4-(2-forfinal)-3-methoxysalicylaldehyde-4-carboxamide

Potassium hydroxide (1,33 g) was added to a solution of the compound obtained in the example of a 56-(7) (1.65 g)in tert-butyl alcohol (35 ml). The reaction solution was boiled under reflux for six hours. The reaction solution was cooled to room temperature. Ethyl acetate and a saturated aqueous solution of sodium chloride was added to the reaction solution, and separated the organic layer. Organic the ski layer was again washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (1,37 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,18 of-2.32 (m, 2H), 2,86-2,90 (m, 1H), to 3.02 (DD, J=3.2, and 9.6 Hz, 1H), 3,23 (s, 3H), to 3.58-and 3.72 (m, 2H), 3,99-to 4.15 (m, 3H), of 4.44-4,48 (m, 2H), and 5.30-of 5.55 (m, 2H),? 7.04 baby mortality-7,10 (m, 1H), 7,16-7,20 (m, 1H), 7.29 trend-7,35 (m, 2H).

(9)Synthesis of (±)-(3R*,4S*)-4-(2-forfinal)-3-methoxysalicylaldehyde-4-ylamine

[Bis(triptoreline)iodine]benzene (2,36 g) was added to a solution of the compound obtained in the example of a 56-(8) (1,37 g)in a mixture of acetonitrile/water (35 ml/15 ml). The reaction solution was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure. To the residue was added 5 n sodium hydroxide and chloroform, and separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (619 mg).

ESI-MS; m/z 270 [M++H].

(10)Synthesis of (±)-1-benzoyl-3-[(3R*,4S*)-4-(2-forfinal)-3-methoxysalicylaldehyde-4-yl]thiourea

Benzoylisothiocyanate (412 mg) was added to a solution of the compound obtained in the example of a 56-(9) (619 mg, in dichloromethane (15 ml). The reaction solution was stirred at room temperature for 15 hours. The reaction solution was concentrated and the residue was purified by chromatography on a column with NH-silica gel with obtaining specified in the connection header (956 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,24 is 2.33 (m, 1H), 2,58 (d, J=9,2 Hz, 1H), 2,99-3,03 (m, 1H), 3,21 (s, 3H), 3,55 (DD, J=1,6, of 14.0 Hz, 1H), 3,71-a-3.84 (m, 2H), 3,98-4,08 (m, 2H), 4,19 (d, J=12,4 Hz, 1H), to 4.41 is 4.45 (m, 2H), 6,99-7,06 (m, 1H), 7,14-to 7.18 (m, 1H), 7,26-7,38 (m, 2H), 7,52 (t, J=7.2 Hz, 2H), 7,63 (TT, J=2,0, 7.2 Hz, 1H), 7,84-7,87 (m, 2H), 8,76 (s, 1H), 11,7 (s, 1H).

(11)Synthesis of (±)-1-benzoyl-3-[(3S*,4S*)-4-(2-forfinal)-3-hydroxyethylacrylate-4-yl]thiourea

Concentrated chloride-hydrogen acid (1 ml) was added to a solution of the compound obtained in the example of a 56-(10) (956 mg), in methanol (20 ml). The reaction solution was boiled under reflux for four hours. The reaction solution was concentrated under reduced pressure. To the residue was added ethyl acetate and aqueous sodium bicarbonate and separated the organic layer. The organic layer was washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (465 mg).

ESI-MS; m/z 411 [M++a].

(12)-(15)Synthesis of tert-butyl (±)-[(4aR*,8aS*)-8a-(5-amino-2-forfinal)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

Specified in the title compound (58 mg) was obtained from the compound obtained in the example of a 56-(11) (465 mg), in accordance with the example of obtaining 9.

ESI-MS; m/z 382 [M++H].

(16)Synthesis of tert-butyl (-)-[(4aR*,8aS*)-8a-(5-amino-2-forfinal)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

The compound obtained in the example of a 56-(15) (19 mg), optically separated using CHIRALPAK™ AD-H production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 7:3, flow rate: 10 ml/min), and the component having a retention time ranging from 15.3 to 18.3 minutes was collected. This operation was repeated to obtain specified in the title compound (23 mg, >99% ee) of 58 mg of the racemate.

ESI-MS; m/z 382 [M++H].

An example of retrieving 57

Synthesis of tert-butyl (-)-[(4aR*,7S*,8aS*)-8a-(5-amino-2-forfinal)-7-methoxy-4a,5,6,7,8,8a-hydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

[Formula 79]

(1)Synthesis of 1,1-diethoxylate-6-EN-3-ol

The solution oxalicacid (4,07 ml, specific gravity: 1,455 g/cm3) in dichloromethane (200 ml) was cooled to -78°C under nitrogen atmosphere. Then slowly added a solution of DMSO (6,62 ml, specific gravity: 1,101 g/cm3) in dichloromethane (50 ml), so that the internal temperature did not exceed 60°C. After stirring for 15 minutes was slowly added a solution of 3,3-diethoxy-1-propanol in dichloromethane (50 ml), so that the internal temperature did not exceed -65°C. After stirring for one hour and 45 minutes was slowly added TEA (25,9 ml). The mixture was stirred after the specified add more within 30 minutes. After heating to room temperature was added a saturated solution of ammonium chloride, followed by stirring. The aqueous layer was separated and then the organic layer was washed with a saturated solution of ammonium chloride. The obtained organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue is suspended in diethyl ether and the solid was removed by filtration. The obtained filtrate was concentrated under reduced pressure. To the obtained residue were added THF (60 ml) and the mixture is sufficiently cooled in an ice bath under nitrogen atmosphere. A solution of 3-butylmagnesium in THF (0.5 M, 100 ml) was added to the mixture, so that the internal temperature did not exceed 10°C. after the addition the mixture was stirred for 13 hours and 30 minutes, gradually warming to room temperature. Was slowly added to the reaction system with water, followed by stirring for some time. the ATEM was added ethyl acetate and a saturated solution of ammonium chloride, followed by stirring. The aqueous layer was separated, after which the resulting organic layer was sequentially washed with a saturated solution of ammonium chloride, water and a saturated salt solution. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Then the residue was purified by chromatography on a column with NH-silica gel with obtaining specified in the connection header (3,71 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,19-1,25 (m, 6H), 1,50-of 1.64 (m, 2H), 1.77 in-between 1.79 (m, 2H), 2,10-of 2.24 (m, 2H), 3,18 (s, 1H), 3,49-to 3.58 (m, 2H), 3,62-of 3.78 (m, 2H), 3,83 (USS, 1H), 4,69-4,71 (m, 1H), 4.95 points-of 5.06 (m, 2H), 5,79-of 5.89 (m, 1H).

(2)Synthesis of 7,7-diethoxy-5-meloxicam-1-ene

DMF (30 ml) was added to 1,1-diethoxylate-6-EN-3-Olu obtained in the example of a 57-(1) (3,07 g), and the mixture was cooled in an ice bath under nitrogen atmosphere. Then was added sodium hydride (60%, 699 mg), followed by stirring for 10 minutes. Added methyliodide (1.8 ml, specific gravity: 2.28 g/cm3), followed by stirring for one hour and 50 minutes. Then the mixture was heated to room temperature and was further stirred for one hour and 30 minutes. Addition was added sodium hydride (60%, 300 mg) and methyliodide (0.9 ml, specific gravity: 2.28 g/cm3), followed by stirring for two hours and 30 minutes. Then slowly added water and a saturated solution of ammonium chloride and subsequent AC is sevanam for some time. After extraction with ethyl acetate the organic layer was sequentially washed with a saturated solution of ammonium chloride, water and a saturated salt solution. The obtained organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (2,98 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,19 is 1.23 (m, 6H), 1.56 to to 1.63 (m, 2H), 1.70 to of 1.84 (m, 2H), 2,08 with 2.14 (m, 2H), 3,31-3,37 (m, 4H), 3.46 in of 3.56 (m, 2H), 3,62-3,71 (m, 2H), of 4.66 (DD, J=4,4, 8.0 Hz, 1H), 4,94-of 5.06 (m, 2H), 5,76-5,88 (m, 1H).

(3)Synthesis of 3-meloxicam-6-naloxone

80% formic acid (30 ml) was added to 7.7-diethoxy-5-meloxicam-1-ENU obtained in the example of a 57-(2) (2,98 g)and the mixture was stirred at room temperature for 10 minutes. Adding further 75% solution of ethanol (64 ml)was added sodium acetate (3.75 g) and hydroxylamine hydrochloride (1.92 g), followed by additional stirring for one hour and 20 minutes. The solvent was concentrated to about 40 ml under reduced pressure, followed by extraction with ethyl acetate. The resulting organic layer was sequentially washed with a saturated solution of sodium bicarbonate (three times), water and saturated salt solution. Received organicheskikh was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (1,95 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,51-of 1.74 (m, 2H), 2,08-of 2.16 (m, 2H), 2,35 of 2.68 (m, 2H), on 3.36 (s, 3H), 3,38-of 3.46 (m, 1H), 4,96-5,08 (m, 2H), 5,76 and 5.86 (m, 1H), 6,84-6,86 and 7,47-7,49 (m, summary. 1H), 7,56 and 7,97 (ush., summary. 1H).

(4)Synthesis of (±)-(3aR*,6S*)-6-methoxy-3,3a,4,5,6,7-hexahydrobenzo[c]isoxazol

The sodium hypochlorite solution (5%, 18.5 ml) was added to a solution of 3-meloxicam-6-naloxone obtained in the example of a 57-(3) (1,95 g), in dichloromethane and the mixture was stirred at room temperature for one hour and 10 minutes. An excess of sodium hypochlorite was dissolved in sodium thiosulfate, followed by extraction three times with chloroform. The obtained organic layers were dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (796 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,54 (DDT, J=2,0, 3,6, 14,0, 1H), 1,68-to 1.79 (m, 1H), 1,90-of 1.97 (m, 1H), is 2.05 and 2.13 (m, 1H), measuring 2.20 (DDD, J=1,6, 7,6, 11.2 Hz, 1H), 3.04 from (TD, J=2,4, of 14.8 Hz, 1H), 3,13-is 3.21 (m, 1H), 3,32 (s, 3H), of 3.78 (t, J=the 2.4 Hz, 1H), 3,79 (DD, J=8,0, 11.2 Hz, 1H), 4.53-in (DD, J=7,6, 10,0 Hz, 1H).

(5)Sin is ez (±)-(3aR*,6S*,7aS*)-7a-(2-forfinal)-6-methoxyacetophenone[c]isoxazol

THF (3 ml) and toluene (20 ml) was added to 2-bromptonville (1.23 ml, specific gravity: 1,614 g/cm3in nitrogen atmosphere and the mixture was cooled to -78°C. a Solution of n-utility in hexane (3.9 ml, 2,63 M) was slowly added so that the internal temperature was as low as -60°C or below. At the end of the addition the mixture was stirred for 10 minutes. After slow addition of a complex of boron TRIFLUORIDE-diethyl ether (1,29 ml) was added a solution of (±)-(3aR*,6S*)-6-methoxy-3,3a,4,5,6,7-hexahydrobenzo[c]isoxazol obtained in the example of a 57-(4) (796 mg)in toluene (10 ml) slowly so that the internal temperature was as low as -60°C or below. At the end of the addition the mixture was stirred for one hour and 50 minutes. Was added a saturated solution of ammonium chloride followed by heating to room temperature. Added ethyl acetate and water, followed by additional stirring. Separated water layer, after which the organic layer was sequentially washed with a saturated solution of ammonium chloride, water and a saturated salt solution. The obtained organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel with obtaining specified in the header of the compound (711 mg).

ESI-MS; m/z 252 [M+H]

(6)Synthesis of (±)-1-benzoyl-3-[(1S*,2R*,5S*)-1-(2-forfinal)-2-hydroxymethyl-5-methoxycyclohexyl]thiourea

(±)-(3aR*,6S*,7aS*)-7a-(2-forfinal)-6-methoxyacetophenone[c]isoxazol obtained in the example of a 57-(5) (872 mg)was dissolved in acetic acid (20 ml). Then was added zinc powder (2,27 g) and the mixture was stirred at room temperature for 14 hours and 10 minutes. The solid was removed by filtration through celite and then celite was washed with ethyl acetate. The obtained filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate. Then was added a saturated solution of sodium bicarbonate, followed by intensive mixing. The organic layer was separated and then the aqueous layer was again extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (7 ml). Then added benzoylisothiocyanate (524 μl, specific gravity: 1,21 g/cm3) and the mixture was stirred at room temperature for 16 hours and 30 minutes. The reaction solution was concentrated under reduced pressure and then purified by chromatography on a column of silica gel with obtaining specified in the title compound (453 mg).

1H-NMR (400 is Hz, CDCl3) δ (ppm): 1,67 to 1.76 (m, 2H), 2.05 is (ush., 3H), 2.26 and (ush., 2H), 2.63 in (ush., 1H), 3,39 (s, 3H); 3,57 (ush., 1H), 3,67 (ush., 1H), 3,78 (ush., 1H), 6,99? 7.04 baby mortality (m, 1H), 7,13 (s, 1H), 7,51 to 7.62 (m, 4H), 7,87-7,88 (m, 2H), 8,83 (s, 1H), 11,60 (s, 1H).

(7)Synthesis of (±)-N-[(4aR*,7S*,8aS*)-8a-(2-forfinal)-7-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide

Dichloromethane (20 ml) and pyridine (264 μl, specific gravity: 0,978 g/cm3) was added to (±)-1-benzoyl-3-[(1S*,2R*,5S*)-1-(2-forfinal)-2-hydroxymethyl-5-methoxycyclohexyl]the thiourea obtained in the example of a 57-(6) (453 mg), in accordance with the method of example getting 18-(5). The mixture was cooled to -78°C under nitrogen atmosphere and was stirred for 15 minutes. Triftormetilfullerenov anhydride (358 μl, specific gravity: 1,72 g/cm3) was slowly added to the reaction solution. At the end of the addition the mixture was stirred for 15 minutes and then stirred for one hour, heating to 0°C. After adding ethyl acetate was added a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The solid was removed by filtration. After concentration under reduced pressure the residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (268 mg).

ESI-MS; m/z 399 [M+H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,50-of 1.52 (m, 1H), 1,72 (TT, J=3.2, and to 13.6 Hz, 1H), 2,18-of 2.30 (m, 3H), 2,43 (DD, J=3,6, and 15.2 Hz, 1H), 2,61 (DD, J=2,8, to 12.8 Hz, 1H), 2,90 (DD, J=4,0, to 12.8 Hz, 1H), 2.95 and-a 3.01 (m, 1H), 3,35 (s, 3H), 3,63 (t, J=2,8 Hz, 1H), 7,07 (DDD, J=1,2, 8,0, to 12.8 Hz, 1H), 7,15 (dt, J=1,2, 8.0 Hz, 1H), 7,28-7,33 (m, 1H), 7,38-the 7.43 (m, 3H), 7,45-7,49 (m, 1H), compared to 8.26 (DD, J=1,6, and 8.4 Hz, 2H).

(8)Synthesis of (±)-(4aR*,7S*,8aS*)-8a-(2-forfinal)-7-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-ylamine

(±)-N-[(4aR*,7S*,8aS*)-8a-(2-Forfinal)-7-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide obtained in the example of a 57-(7) (268 mg), was dissolved in methanol (8 ml). Then added DBU (202 μl, specific gravity: 1,018 g/cm3) and the mixture was stirred at the boil under reflux for four hours and 15 minutes. Then the reaction solution was stirred at 64°C for 13 hours and 30 minutes. After that, the reaction solution was stirred at the boil under reflux for nine hours and 30 minutes. The reaction solution was allowed to cool to room temperature and then concentrated his under reduced pressure. The residue was purified by chromatography on a column with NH-silica gel with obtaining specified in the title compound (150 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,37-of 1.40 (m, 1H), 1,66-of 1.73 (m, 1H), 2,05-2,19 (m, 3H), 2,35-2,39 (m, 1H), 2,58-2,60 (m, 1H), 2,72 is 2.75 (m, 1H), 2,81-2,90 (m, 1H), 3,34 (s, 3H), 3,61 (ush., 1H), 6,98-7,03 (m, 1H), 7,09 for 7.12 (m, 1H), 7,20-of 7.23 (m, 1H), 7,38 (ush., 1H).

(9)Synthesis of tert-butyl (±)-[(4aR*,7S*,8aS*)-8a-(2-fluoro-5-NITR is phenyl)-7-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

TFOC (1 ml) and concentrated sulfuric acid (0.5 ml) was added to (±)-(4aR*,7S*,8aS*)-8a-(2-forfinal)-7-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-ylamine obtained in the example of a 57-(8) (150 mg). The mixture is sufficiently cooled in an ice bath and then slowly added fuming nitric acid (27,3 µl). At the end of the addition the mixture was stirred for 15 minutes. The reaction solution was diluted with dichloromethane and then slowly poured on crushed ice. Added 5 n sodium hydroxide solution until until the reaction solution became alkaline, after which it three times was extracted with dichloromethane. The obtained organic layers were dried over anhydrous magnesium sulfate and the solid was removed by filtration. The filtrate was concentrated under reduced pressure. Then THF (2.5 ml), water (2.5 ml) and di-tert-BUTYLCARBAMATE (170 mg) was added to the residue at room temperature and the mixture was stirred at room temperature for two hours. Added ethyl acetate and water and then separating the aqueous layer. The organic layer was sequentially washed with a saturated solution of ammonium chloride, water and a saturated salt solution. The obtained organic layer was dried over anhydrous magnesium sulfate and the solid was removed by filtration. The filtrate was concentrated under reduced pressure and then cleaned and chromatography on a column of silica gel with obtaining specified in the title compound (138 mg).

ESI-MS; m/z 440 [M+H].

(10)Synthesis of tert-butyl (±)-[(4aR*,7S*,8aS*)-8a-(5-amino-2-forfinal)-7-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

Ethanol (5 ml), a saturated solution of ammonium chloride (0.5 ml) and iron powder (175 mg) was added to tert-butyl (±)-[(4aR*,7S*,8aS*)-8a-(2-fluoro-5-nitrophenyl)-7-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in example receiving 57-(9) (138 mg), and the mixture was stirred when boiling under reflux for 30 minutes. The reaction solution was cooled to room temperature and then the solid was removed by filtration through celite. The filtrate was concentrated under reduced pressure. Then the residue is suspended in dichloromethane and the solid was removed by filtration. The filtrate was concentrated under reduced pressure and then purified by chromatography on a column of silica gel with obtaining specified in the title compound (98 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,42-1,49 (m, 1H), 1,53 (s, 9H), 1,66 is 1.70 (m, 1H), 2.06 to 2,10 (m, 1H), 2,14-2,19 (m, 2H), of 2.38 (DD, J=3,6, and 15.2 Hz, 1H), 2,49-of 2.54 (m, 1H), 2,84-2,90 (m, 2H), and 3.31 (s, 3H), to 3.58-of 3.60 (m, 1H), 3,66 (ush., 2H), 6,52-6,56 (m, 1H), 6,62 (DD, J=2,8, 6,8 Hz, 1H), at 6.84 (DD, J=8,4, and 12.4 Hz, 1H).

(11)Synthesis of tert-butyl (-)-[(4aR*,7S*,8aS*)-8a-(5-amino-2-forfinal)-7-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

tert-Butyl (±)-[(4aR*,7S*,8aS*)-8a-(5-amino-2-forfinal)-7-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-yl]carbamate, obtained in the example of a 57-(10), optically separated using CHIRALPAK™ AD-H production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 85:15, flow rate: 20 ml/min, loaded with a solution of about 10 mg in 0.5 ml of ethanol for one cycle). Component having a retention time from 18.1 to 21.2 minutes, collected by obtaining specified in the title compound (41 mg, >99% ee, optical rotation (-)).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,43 of 1.46 (m, 1H), 1,53 (s, 9H), 1,67 is 1.70 (m, 1H), 2.06 to to 2.18 (m, 3H), 2,36-2,39 (m, 1H), 2,50 of $ 2.53 (m, 1H), 2,86-2,89 (m, 2H), and 3.31 (s, 3H), to 3.58 (ush., 1H), 3,67 (ush., 2H), 6,53-6,55 (m, 1H), 6,60-6,62 (m, 1H), for 6.81-6,86 (m, 1H).

An example of retrieving 58

Synthesis of tert-butyl (-)-[(4aR*,7R*,8aS*)-8a-(5-amino-2-forfinal)-7-methoxy-4a,5,6,7,8,8a-hydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

[Formula 80]

(1)Synthesis of [1-(2,2-diatexite)Penta-4-relaxometer]benzene

DMF (40 ml) and benzylbromide (2.4 ml, specific gravity: 1.44 g/cm3) was added to 1,1-diethoxylate-6-EN-3-Olu obtained in the example of a 57-(1) (3,71 g), and the mixture was cooled in an ice bath under nitrogen atmosphere. Then was added sodium hydride (60%, 883 mg) followed by stirring for 60 minutes. Added additional benzylbromide (1,09 ml) followed by stirring for one hour. Added additional sodium hydride (60%, 116 mg) and the mixture was stirred for one hour and 50 m of the nut, gradually warming to room temperature. Next was added tetrabutylammonium (680 mg), followed by stirring for one hour and 10 minutes. Was slowly added water and a saturated solution of ammonium chloride. After stirring for some time separated water layer. The organic layer was sequentially washed with a saturated solution of ammonium chloride, water and a saturated salt solution. The obtained organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (4,06 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,19 (dt, J=4,4, 7.2 Hz, 6H), 1,63 is 1.70 (m, 2H), 1,76-of 1.93 (m, 2H), 2,11-2,17 (m, 2H), 3,39-of 3.54 (m, 2H), 3,56 at 3.69 (m, 3H), 4,46-4,56 (m, 2H), and 4.68 (DD, J=4,0, 7.2 Hz, 1H), 4.95 points is equal to 4.97 (m, 1H), 4,99-of 5.05 (m, 1H), of 5.82 (TDD, J=6,8, 10,0, is 16.8 Hz, 1H), 7,25-7,32 (m, 1H), 7,32 and 7.36 (m, 4H).

(2)Synthesis of 3-benzyloxy-6-naloxone

Specified in the header of the connection (of 3.53 g) was obtained from [1-(2,2-diatexite)Penta-4-relaxometer]benzene obtained in the example of a 58-(1) (3,71 g), in accordance with the method of example obtaining a 57-(3) without purification by chromatography on a column of silica gel.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,59-of 1.81 (m, 2H), 2,11-of 2.23 (m, 2H), 2,42 is 2.51 (m, 1H), 2,65 of 2.68 (m, 1H), 3,64 (TD, J=6,0, 18,4 G is, 1H), 4,50-4,58 (m, 2H), 4,95-5,04 (m, 2H), 5,73-to 5.85 (m, 1H), 6,86-6,89 and of 7.48-7,51 (m, summary. 1H), 7,17 and 7,53 (ush., summary. 1H), 7,29 (ush., 1H), 7,34 (s, 4H).

(3)Synthesis of 6-benzyloxy-3,3a,4,5,6,7-hexahydrobenzo[c]isoxazol

Specified in the header of the connection (only 2.91 g) was obtained from 3-benzyloxy-6-naloxone obtained in the example of a 58-(2) (3,53 g), in accordance with the method of example obtaining a 57-(4).

ESI-MS; m/z 232 [M+H].

(4)Synthesis of (±)-(3aR*,6R*,7aS*)-6-benzyloxy-7a-(2-forfinal)octahedrons[c]isoxazol

Specified in the header connection (1,69 g) was obtained from 6-benzyloxy-3,3a,4,5,6,7-hexahydrobenzo[c]isoxazol obtained in the example of a 58-(3) (2.91 in g), in accordance with the method of example obtaining a 57-(5).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,38-1,49 (m, 1H), 1,59 was 1.69 (m, 1H), 1,98-2,05 (m, 1H), 2,12-2,17 (m, 1H), 2,22 to 2.35 (m, 2H), 2,90-2,96 (m, 1H), 3,50-to 3.58 (m, 2H), to 3.67 (d, J=6,8 Hz, 1H), to 4.52 (s, 2H), 5,77 (ush., 1H), 7,03 (DDD, J=1,6, 8,0, and 12.4 Hz, 1H), 7,13 (dt, J=1,2, 7,6 Hz, 1H), 7,22-7,35 (m, 6H), 7,82 (dt, J=1,6, 8.0 Hz, 1H).

(5)Synthesis of (±)-1-benzoyl-3-[(1S*,2R*,5R*)-5-benzyloxy-1-(2-forfinal)-2-hydroxymethylcellulose]thiourea

Specified in the header of the connection (of 2.26 g) was obtained from (±)-(3aR*,6R*,7aS*)-6-benzyloxy-7a-(2-forfinal)octahedrons[c]isoxazol obtained in the example of a 58-(4) (1,69 g), in accordance with the method of example obtaining a 57-(6).

1H-NMR (400 MHz, CDCl3) δ (ppm): to 1.70 to 1.76 (m, 1H), 1,83-to 1.87 (m, 1H), 2,14 was 2.25 (m, 3H), 2,42 at 2.45 (m, 2H), 3,66 (ush., 2H), 3,84 (ush., 1H), 4,49 with 4.64 (m, 2H), 6,94-7,14 (who, 5H), 7,22-7,28 (m, 1H), 7,29-to 7.32 (m, 2H), 7,40-7,49 (m, 3H), 7,55-of 7.60 (m, 3H), 8,57 (ush., 1H), 11,57 (ush., 1H).

(6)Synthesis of (±)-N-[(4aR*,7R*,8aS*)-7-benzyloxy-8a-(2-forfinal)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide

Specified in the header connection (1,81 g) was obtained from (±)-1-benzoyl-3-[(1S*,2R*,5R*)-5-benzyloxy-1-(2-forfinal)-2-hydroxymethylcellulose]thiourea obtained in the example of a 58-(5) (of 2.26 g), in accordance with the method of example obtaining a 57-(7).

ESI-MS; m/z 475 [M+H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,59 was 1.69 (m, 1H), 1,78-of 1.85 (m, 1H), 1,97 is 2.10 (m, 1H), 2,27 of-2.32 (m, 2H), 2,41-2,47 (m, 1H), 2,62 (DD, J=2,8, to 12.8 Hz, 1H), 2,90-3,00 (m, 2H), 3,78-3,86 (m, 1H), 4,58 (s, 2H), 7,07-7,13 (m, 1H), 7,14-to 7.18 (m, 1H), 7.24 to 7,28 (m, 1H), 7,30 and 7.36 (m, 6H), 7,42-7,46 (m, 2H), 7,49-rate of 7.54 (m, 1H) 8,24-of 8.27 (m, 2H).

(7)Synthesis of (±)-(4aR*,7R*,8aS*)-7-benzyloxy-8a-(2-forfinal)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-ylamine

(±)-N-[(4aR*,7R*,8aS*)-7-Benzyloxy-8a-(2-forfinal)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide obtained in the example of a 58-(6) (1,81 g), was dissolved in methanol (60 ml). Then added DBU (1,14 ml, specific gravity: 1,018 g/cm3) and the mixture was stirred at the boil under reflux for three hours. Then the reaction solution was stirred at 64°C for 14 hours. The reaction solution was allowed to cool to room temperature and then concentrated his under reduced pressure. The residue was purified by chromatography on a column with NH-silica gel with receipt of the m specified in the title compound (1.20 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,53-to 1.63 (m, 2H), 1,76-of 1.88 (m, 1H), 2,18-2,22 (m, 1H), 2.26 and-of 2.30 (m, 2H), 2,58 (DD, J=2,8, 12.0 Hz, 1H), 2,68-to 2.74 (m, 1H), 2,85 (DD, J=4,0, 12.0 Hz, 1H), 3,63-3,71 (m, 1H), 4,42 (ush., 2H), to 4.52-4,59 (m, 2H), 7,00-7,05 (m, 1H), 7,10 (dt, J=1,2, 7,6 Hz, 1H), 7,20-7,27 (m, 3H), 7,29-7,34 (m, 4H).

(8)Synthesis of tert-butyl (±)-[(4aR*,7R*,8aS*)-8a-(2-forfinal)-7-hydroxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

(±)-(4aR*,7R*,8aS*)-7-Benzyloxy-8a-(2-forfinal)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-ylamine, obtained in the example of a 58-(7) (1.2 g)was stirred in concentrated chloride-hydrogen acid (120 ml) at boiling under reflux for three hours and 10 minutes. The reaction solution was cooled to room temperature and the solvent was concentrated under reduced pressure. Then to the residue was added 1 n sodium hydroxide solution (16.2 ml), THF (16 ml) and di-tert-BUTYLCARBAMATE (1.06 g) and the mixture was stirred at room temperature. After one hour and 30 minutes added additional di-tert-BUTYLCARBAMATE (15 g), followed by stirring for 12 hours and 30 minutes. To the reaction solution were added ethyl acetate and water, followed by additional stirring. Then the separated aqueous layer. The organic layer was sequentially washed with a saturated solution of ammonium chloride, water and a saturated salt solution. The obtained organic layer was dried over anhydrous sulfate is magnesium and the solid was removed by filtration. The filtrate was concentrated under reduced pressure and then purified by chromatography on a column of silica gel with obtaining specified in the title compound (1.31 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.53 (s, 9H), 1,55-1,65 (m, 1H), 1,71 to 1.76 (m, 1H), 1,96-of 2.20 (m, 3H), 2,32-of 2.38 (m, 1H), 2,52-of 2.54 (m, 1H), 2,79-2,87 (m, 2H), 3.95 to 4.00 points (m, 1H), was 7.08 (DDD, J=1,2, 8,0, to 12.8 Hz, 1H), 7,16-7,20 (m, 1H), 7,24-7,27 (m, 1H), 7,28-7,34 (m, 1H).

(9)Synthesis of tert-butyl (±)-[(4aR*,7R*,8aS*)-8a-(2-forfinal)-7-hydroxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]-(4-methoxybenzyl)carbamate

tert-Butyl (±)-[(4aR*,7R*,8aS*)-8a-(2-forfinal)-7-hydroxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in example getting 58-(8) (500 mg)was dissolved in DMF (10 ml) and the mixture was cooled in an ice bath under nitrogen atmosphere. To the mixture was added p-methoxybenzylamine (161 μl, specific gravity: 1,154 g/cm3) and potassium carbonate (247 mg), followed by stirring for one hour. After that, the reaction solution was heated to room temperature and was stirred for 19 hours. To the reaction solution were added ethyl acetate and water, followed by additional stirring. Then the separated aqueous layer. The organic layer was sequentially washed with a saturated solution of ammonium chloride, water and a saturated salt solution. The obtained organic layer was dried over anhydrous magnesium sulfate and the solid was removed by filtering the. The filtrate was concentrated under reduced pressure and then purified by chromatography on a column of silica gel with obtaining specified in the connection header (541 mg).

ESI-MS; m/z 501 [M+H].

(10)Synthesis of tert-butyl (±)-[(4aR*,7R*,8aS*)-8a-(2-forfinal)-7-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]-(4-methoxybenzyl)carbamate

tert-Butyl (±)-[(4aR*,7R*,8aS*)-8a-(2-forfinal)-7-hydroxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]-(4-methoxybenzyl)carbamate obtained in example getting 58-(9) (541 mg), was dissolved in DMF (5 ml). Added methyliodide (113 μl, specific gravity: 2.28 g/cm3) and then the mixture was cooled in an ice bath under nitrogen atmosphere. Was added sodium hydride (60%, 55 mg), followed by stirring for one hour and 45 minutes. Then added methyliodide (113 μl, specific gravity: 2.28 g/cm3) and sodium hydride (60%, 55 mg) and the mixture was heated to room temperature and was stirred for one hour and 45 minutes. Then further added methyliodide (113 μl, specific gravity: 2.28 g/cm3), followed by stirring for 13 hours. To the reaction solution were added ethyl acetate and water, followed by stirring. Then the separated aqueous layer. The organic layer was sequentially washed with a saturated solution of ammonium chloride, water and a saturated salt solution. The obtained organic layer was dried over anhydrous sulfate is m magnesium and the solid was removed by filtration. The filtrate was concentrated under reduced pressure and then purified by chromatography on a column of silica gel with obtaining specified in the title compound (409 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,32-of 1.42 (m, 1H) 1,47-of 1.52 (m, 2H), 1,53 (s, 9H), 1,95 of 1.99 (m, 1H), 2,10-of 2.16 (m, 1H), 2.26 and-2,31 (m, 1H), 2,47 (DD, J=2,8, and 12.4 Hz, 1H), 2,59-of 2.64 (m, 1H), 2,77 (DD, J=4.0 a, and 12.4 Hz, 1H), 2,96 totaling 3.04 (m, 1H), 3,26 (s, 3H), of 3.80 (s, 3H), 4.92 in-5,04 (m, 2H), 6,85-to 6.88 (m, 2H), of 6.96-7,05 (m, 3H), 7.18 in-of 7.23 (m, 1H), 7,31-7,34 (m, 2H).

(11)Synthesis of tert-butyl (±)-[(4aR*,7R*,8aS*)-8a-(2-fluoro-5-nitrophenyl)-7-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

Specified in the title compound (283 mg) was obtained from tert-butyl (±)-[(4aR*,7R*,8aS*)-8a-(2-forfinal)-7-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]-(4-methoxybenzyl)carbamate obtained in example getting 58-(10) (409 mg), in accordance with the method of example obtaining a 57-(9), using 82,1 ál of fuming nitric acid (specific gravity: 1.52 g/cm3, 2.6 equivalent relative to the original substance).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,38-of 1.52 (m, 2H), and 1.54 (s, 9H), 1.70 to around 1.74 (m, 1H), 1,89-of 1.92 (m, 1H), 2,08-of 2.24 (m, 3H), 2,56-2,60 (m, 1H), 2,74-of 2.81 (m, 2H), 3,35-3,39 (m, 4H), 7,20-7,25 (m, 1H), 8,12-8,21 (m, 2H).

(12)Synthesis of tert-butyl (±)-[(4aR*,7R*,8aS*)-8a-(5-amino-2-forfinal)-7-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

Specified in the title compound (221 mg) was obtained from tert-butyl (±)-[(4aR*,7R*,8aS*)-8a-(2-fluoro-5-nitrophenyl)-7-methoxy-4a,5,6,7,8,8a-hexahydro-4H-is Enzo[d][1,3]thiazin-2-yl]carbamate, obtained in the example of a 58-(11) (283 mg), in accordance with the method of example obtaining a 57-(10), where the purification was performed by chromatography on a column with NH-silica gel.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1.30 and for 1.49 (m, 1H), 1,53 (s, 9H), 1.70 to 1.77 in (m, 1H), 1,89 of 1.99 (m, 1H), 2,09-2,12 (m, 1H), 2,23-to 2.29 (m, 2H), 2,52 (DD, J=2,4, of 12.8 Hz, 1H), 2,81-only 2.91 (m, 2H), on 3.36 (s, 3H), 3,42-3,47 (m, 1H), 3,65 (ush., 2H), of 6.49-to 6.57 (m, 2H), 6,83-to 6.88 (m, 1H).

(13)Synthesis of tert-butyl (-)-[(4aR*,7R*,8aS*)-8a-(5-amino-2-forfinal)-7-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

tert-Butyl (±)-[(4aR*,7R*,8aS*)-8a-(5-amino-2-forfinal)-7-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in example getting 58-(12) (221 mg), optically separated using CHIRALPAK™ AD-H production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 70:30, flow rate: 10 ml/min, loaded with a solution of approximately 35 mg in 1 ml ethanol for one cycle). Component having a retention time from 17,8 to 23.7 minutes, collected by obtaining specified in the title compound (93 mg, >99% ee, optical rotation (-)).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,46-1,49 (m, 1H), and 1.54 (s, 9H), 1,71 is 1.75 (m, 1H), 1,89 of 1.99 (m, 1H), 2,09-2,12 (m, 1H), 2,23-to 2.29 (m, 2H), 2,50 of $ 2.53 (m, 1H), 2,81-only 2.91 (m, 2H), on 3.36 (s, 3H), 3,44-to 3.49 (m, 1H), 3,65 (ush., 2H), of 6.49-of 6.52 (m, 1H), 6,53-to 6.57 (m, 1H), 6,83-to 6.88 (m, 1H).

Example retrieve 59

Synthesis of (±)-N-[(4aR*,6S*,8aS*)-8a-(2-forfinal)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide and (±)-N-[4aR*,6R*,8aS*)-8a-(2-forfinal)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide

[Formula 81]

(1)Synthesis of 7,7-dimethoxy-1-EN-4-ol

4,4-Dimethoxybenzaldehyde (Org. Biomol. Chem. 4 (2006) 2158) (vs. 5.47 g) was dissolved in THF (55 ml) and the solution was cooled in an ice bath under nitrogen atmosphere. Then slowly added to the solution of allylanisole in THF (62,1 ml, 1 M). At the end of the addition the mixture was stirred for three hours. After slow addition of water was added ethyl acetate and a saturated solution of ammonium chloride, followed by additional stirring. The aqueous layer was separated and then the organic layer was sequentially washed with a saturated solution of ammonium chloride, water and a saturated salt solution. The obtained organic layer was dried over anhydrous magnesium sulfate and the solid was removed by filtration. The filtrate was concentrated under reduced pressure and then purified by chromatography on a column of silica gel with obtaining specified in the connection header (of 5.55 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,44-of 1.62 (m, 2H), 1,67 is 1.86 (m, 2H), 2,09 (d, J=3,6, 1H), 2,14-of 2.23 (m, 1H), 2,24 of-2.32 (m, 1H), 3,34 (s, 6H), 3,63 at 3.69 (m, 1H), to 4.38-to 4.41 (m, 1H), 5,11 (d, J=1.2 Hz, 1H), 5,13-5,16 (m, 1H), 5,78-of 5.89 (m, 1H).

(2)Synthesis of 4,7,7-trimethoxy-1-ene

7,7-Dimethoxy-1-EN-4-ol obtained in the example of a 59-(1) book (6.16 g), was dissolved in 1-methyl-2-pyrrolidinone (60 ml) and the solution was cooled in an ice bath under nitrogen atmosphere. Then dobavlialsea sodium (60%, 2,12 g), followed by stirring for 10 minutes. Next was added methyliodide (6,61 g, 2.28 g/cm3) and the mixture was additionally stirred for two hours and 10 minutes. After slow addition of water was added ethyl acetate, followed by additional stirring. The aqueous layer was separated and then the organic layer was sequentially washed with a saturated solution of ammonium chloride, water and a saturated salt solution. The obtained organic layer was dried over anhydrous magnesium sulfate and the solid was removed by filtration. The filtrate was concentrated under reduced pressure and then purified by chromatography on a column of silica gel with obtaining specified in the connection header (of 5.83 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,47 to 1.76 (m, 4H), 2,20-of 2.33 (m, 2H), 3,20-3,26 (m, 1H), 3,32 (s, 6H), to 3.34 (s, 3H), 4,36 (t, J=5.6 Hz, 1H), of 5.05-5,10 (m, 2H), 5,76 and 5.86 (m, 1H).

(3)Synthesis of 4-meloxicam-6-naloxone

Specified in the title compound (4.61 in) received from 4,7,7-trimethoxy-1-ene obtained in the example of a 59-(2) (5.83 in), in accordance with the method of example obtaining a 57-(3) without purification by chromatography on a column of silica gel.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,62-of 1.73 (m, 2H), 2.21 are a 2.36 (m, 3H), 2,46 (dt, J=5,6, 8.0 Hz, 1H), 3,21 of 3.28 (m, 1H), 3,36 (d, J=3,6 Hz, 3H), 5,06-5,13 (m, 2H), 5,70 and 5.86 (m, 1H), 6,74-6,77 and 7,43-7,46 (m, summary. 1H), 7,44 and 7,82 (ush., summary. 1H).

(4)Synthesis of 5-methoxy-3,3a,4,5,6,7-hexage Robins[c]isoxazol

Specified in the header connection (3,95 g) was obtained from 4-meloxicam-6-naloxone obtained in the example of a 59-(3) (4.61 in), in accordance with the method of example obtaining a 57-(4).

ESI-MS; m/z 156 [M+H].

(5)Synthesis of (±)-(3aR*,7aS*)-7a-(2-forfinal)-5-methoxyacetophenone[c]isoxazol

Specified in the header of the connection (the ceiling of 5.60 g) was obtained from 5-methoxy-3,3a,4,5,6,7-hexahydrobenzo[c]isoxazol obtained in the example of a 59-(4) (3,95 g), in accordance with the method of example obtaining a 57-(5).

ESI-MS; m/z 252 [M+H].

(6)Synthesis of (±)-[(1R*,2S*)-2-amino-2-(2-forfinal)-5-methoxycyclohexyl]methanol

(±)-(3aR*,7aS*)-7a-(2-Forfinal)-5-methoxyacetophenone[c]isoxazol obtained in the example of a 59-(5) (ceiling of 5.60 g)was dissolved in acetic acid (128 ml). Then was added zinc powder (14.1 g) and the mixture was stirred at room temperature for eight hours. The solid was removed by filtration through celite and then celite was washed with ethyl acetate. The obtained filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate. Then was added a saturated solution of sodium bicarbonate, followed by intensive mixing. The organic layer was separated and then the aqueous layer was again extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate. The solid was removed by filtration and the filter is t concentrated under reduced pressure to obtain specified in the connection header (5.49 g).

ESI-MS; m/z 254 [M+H].

(7)Synthesis of (±)-1-benzoyl-3-[(1S*,2R*)-1-(2-forfinal)-2-hydroxymethyl-4-methoxycyclohexyl]thiourea

(±)-[(1R*,2S*)-2-Amino-2-(2-forfinal)-5-methoxycyclohexyl]methanol obtained in the example of a 59-(6) (5.49 g)was dissolved in dichloromethane (22 ml). Then added benzoylisothiocyanate (3.04 from ml, specific gravity: 1,21 g/cm3) and the mixture was stirred at room temperature for 16 hours and 30 minutes. The reaction solution was concentrated under reduced pressure and then purified by chromatography on a column of silica gel with obtaining specified in the connection header (7,16 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,51 is 1.70 (m, 3H), 1,84-2,19 (m, 2H), 2,27-of 2.30 (m, 1H), 2.57 m (ush., 1H), 3,39-of 3.42 (m, 3H), 3,56 (ush., 2H), 3,67 (ush., 1H),? 7.04 baby mortality-to 7.15 (m, 2H), 7,43-7,63 (m, 5H), 7,88 (s, 2H), 8,90 (ush., 1H), 11,53 (ush., 1H).

(8)Synthesis of (±)-N-[(4aR*,6S*,8aS*)-8a-(2-forfinal)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide and (±)-N-[(4aR*,6R*,8aS*)-8a-(2-forfinal)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide

Listed in the connection header (±)-N-[(4aR*,6S*,8aS*)-8a-(2-forfinal)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide (3.11 g) and (±)-N-[(4aR*,6R*,8aS*)-8a-(2-forfinal)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide (1.65 g) was obtained from (±)-1-benzoyl-3-[(1S*,2R*)-1-(2-forfinal)-2-hydroxymethyl-4-methoxycyclohexyl]thiourea obtained in the example of a 59-(7) (7,16 g), CE is accordance with the method of example obtaining a 57-(7).

(±)-N-[(4aR*,6S*,8aS*)-8a-(2-Forfinal)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide

ESI-MS; m/z 399 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,64 (d, J=14,8 Hz, 1H), 1,77-of 1.85 (m, 1H), 1,89-of 1.94 (m, 1H), 1,99-of 2.08 (m, 2H), 2,54 (DD, J=2,8, to 12.8 Hz, 1H), 2,75 (dt, J=4,0, to 13.6 Hz, 1H), 2,97 (DD, J=4,0, to 12.8 Hz, 1H), 3,30-to 3.38 (m, 1H), 3,40 (s, 3H), 3,68 (t, J=2.4 Hz, 1H), to 7.09 (DDD, J=1,2, 8,0, and 12.4 Hz, 1H), 7,14 (dt, J=1,6 and 7.6 Hz, 1H), 7,28-7,35 (m, 2H), 7,41 was 7.45 (m, 2H), of 7.48-7,52 (m, 1H), 8,24-of 8.27 (m, 2H).

(±)-N-[(4aR*,6R*,8aS*)-8a-(2-Forfinal)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide

ESI-MS; m/z 399 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,63-of 1.74 (m, 1H), 1,89-of 1.95 (m, 2H), is 2.05 and 2.13 (m, 2H), 2,46 (dt, J=3,6, 14.4 Hz, 1H), 2,60 (DD, J=2,8, to 12.8 Hz, 1H), 2,93 (DD, J=4,0, to 12.8 Hz, 1H), 2,98 totaling 3.04 (m, 1H), 3,40 (s, 3H), 3,47-of 3.54 (m, 1H), to 7.09 (DDD, J=1,2, 8,0, to 12.8 Hz, 1H), 7,16 (dt, J=1,6 and 7.6 Hz, 1H), 7,29-7,38 (m, 2H), 7,41 was 7.45 (m, 2H), of 7.48-7,52 (m, 1H), they were 8.22-of 8.25 (m, 2H).

Example of getting 60

Synthesis of tert-butyl (-)-[(4aR*,6S*,8aS*)-8a-(5-amino-2-forfinal)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

[Formula 82]

(1)Synthesis of (±)-(4aR*,6S*,8aS*)-8a-(2-forfinal)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-ylamine

(±)-N-[(4aR*,6S*,8aS*)-8a-(2-Forfinal)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide obtained in the example of a 59-(8) (3.11 g), was dissolved in methanol (100 ml). Then added DBU (2,34 ml, specific gravity: 1,018 g/cm3) and the mixture is stirred at boiling reverse you can see what these lamps for two hours and 15 minutes. Then the reaction solution was stirred at 64°C for 13 hours and 30 minutes. The reaction solution was allowed to cool to room temperature and then concentrated his under reduced pressure. The residue was purified by chromatography on a column with NH-silica gel with obtaining specified in the connection header (1,96 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,53 (TD, J=3,6, 13,2 Hz, 1H), of 1.66 and 1.75 (m, 2H), 1,81 is 1.91 (m, 2H), 2.49 USD (DD, J=2,8, and 12.4 Hz, 1H), 2,61 (dt, J=4,0, 13,2 Hz, 1H), 2,90 (DD, J=4,4, 12.0 Hz, 1H), 3,09 (arcs, J=3,6, and 12.4 Hz, 1H), 3,39 (s, 3H), of 3.60 (t, J=2,8 Hz, 1H), 7,02 (DDD, J=1,6, 8,0, to 12.8 Hz, 1H), 7,06-7,10 (m, 1H), 7.18 in-7,24 (m, 1H), 7,25-7,29 (m, 1H).

(2)Synthesis of tert-butyl (±)-[(4aR*,6S*,8aS*)-8a-(2-fluoro-5-nitrophenyl)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

Specified in the header connection (1,37 g) was obtained from (±)-(4aR*,6S*,8aS*)-8a-(2-forfinal)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-ylamine received in the sample receiving 60-(1) (1 g), in accordance with the method of example obtaining a 57-(9).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,42-of 1.55 (m, 1H), and 1.54 (s, 9H), 1,66-of 1.73 (m, 1H), 1.85 to 2,00 (m, 3H), 2,49-2,61 (m, 2H), 2,83-2,87 (m, 1H), 3,21-of 3.25 (m, 1H), 3,39 (s, 3H), 3,66 (ush., 1H), 7,21-7,25 (m, 1H), 8,19-8,21 (m, 2H).

(3)Synthesis of tert-butyl (±)-[(4aR*,6S*,8aS*)-8a-(5-amino-2-forfinal)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

Specified in the header connection (1,21 g) was obtained from tert-butyl (±)-[(4aR*,6S*,8aS*)-8a-(2-fluoro-5-nitrophenyl)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-b is the site, located between[d][1,3]thiazin-2-yl]carbamate, received in the sample receiving 60-(2) (2,56 g), in accordance with the method of example obtaining a 57-(10).

ESI-MS; m/z 410 [M+H].

(4)Synthesis of tert-butyl (-)-[(4aR*,6S*,8aS*)-8a-(5-amino-2-forfinal)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

tert-Butyl (±)-[(4aR*,6S*,8aS*)-8a-(5-amino-2-forfinal)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in example getting 60-(3), optically separated using CHIRALPAK™ AD-H production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 70:30, flow rate: 10 ml/min, loaded with a solution of about 50 mg in 2 ml ethanol for one cycle). Component having a retention time from 15.7 to 20.5 minutes, collected by obtaining specified in the title compound (502 mg, >99% ee, optical rotation (-)).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,48-and 1.54 (m, 2H), 1,53 (s, 9H), of 1.66 and 1.75 (m, 1H), 1,82-of 1.88 (m, 1H), 1.91 a is 2.00 (m, 2H), 2,41 at 2.45 (m, 1H), 2,66-to 2.74 (m, 1H), equal to 2.94 (DD, J=4,0, 12.0 Hz, 1H), 3,19-of 3.25 (m, 1H), 3,38 (s, 3H), 3,64-3,65 (m, 2H), 6,52-to 6.57 (m, 2H), 6,83-to 6.88 (m, 1H).

An example of retrieving 61

Synthesis of tert-butyl (-)-[(4aR*,6R*,8aS*)-8a-(5-amino-2-forfinal)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

[Formula 83]

(1)Synthesis of (±)-(4aR*,6R*,8aS*)-8a-(2-forfinal)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-ylamine

(±)-N-[(4aR*,6R*,8aS*)-8a-(2-Forfinal)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]Ben who amide, obtained in the example of a 59-(8) (1.65 g)was dissolved in methanol (60 ml). Then added DBU (1,24 ml, specific gravity: 1,018 g/cm3) and the mixture was stirred at the boil under reflux for 13 hours and 30 minutes. The reaction solution was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by chromatography on a column with NH-silica gel with obtaining specified in the connection header (1,16 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,52-of 1.74 (m, 2H), 1,80-1,90 (m, 2H), 1,94 is 2.01 (m, 1H), and 2.27 to 2.35 (m, 1H), 2,56 (DD, J=2,8, 12.0 Hz, 1H), 2.71 to 2,77 (m, 1H), 2,87 (DD, J=4,0, 12.0 Hz, 1H), 3,36-to 3.49 (m, 4H), 4,46 (ush., 2H), 7,01 (DDD, J=1,2, 8,0, to 12.8 Hz, 1H), 7,10 (DDD, J=1,2, of 7.2 and 7.6 Hz, 1H), 7,19-7,25 (m, 1H), 7,26-7,31 (m, 1H).

(2)Synthesis of tert-butyl (±)-[(4aR*,6R*,8aS*)-8a-(2-fluoro-5-nitrophenyl)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

Specified in the title compound (1.27 g) was obtained from (±)-(4aR*,6R*,8aS*)-8a-(2-forfinal)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-ylamine obtained in the example of a 61-(1) (1,16 g), in accordance with the method of example obtaining a 57-(9).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,46-of 1.55 (m, 1H), and 1.54 (s, 9H), 1.77 in-to 1.87 (m, 2H), 1,99-of 2.08 (m, 2H), 2.21 are of 2.27 (m, 1H), 2,54-of 2.58 (m, 1H), was 2.76 is 2.80 (m, 1H), 2,86-2,90 (m, 1H), 3,39-to 3.49 (m, 4H), 7,20-7,28 (m, 1H), 8,18-8,21 (m, 2H).

(3)Synthesis of tert-butyl (±)-[(4aR*,6R*,8aS*)-8a-(5-amino-2-forfinal)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

The decree is Noah in the title compound (838 mg) was obtained from tert-butyl (±)-[(4aR*,6R*,8aS*)-8a-(2-fluoro-5-nitrophenyl)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate, obtained in the example of a 61-(2) (1.27 g), in accordance with the method of example obtaining a 57-(10).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,46-and 1.54 (m, 1H), 1,53 (s, 9H), 1.77 in is 1.86 (m, 2H), 1,98-2,07 (m, 2H), 2,41 (dt, J=4,0, 6.4 Hz, 1H), 2,47-2,52 (m, 1H), 2,87-of 2.93 (m, 2H), 3,38-to 3.49 (m, 4H), 3,65 (ush., 2H), 6,53-to 6.57 (m, 2H), PC 6.82-6.87 in (m, 1H).

HPLC (CHIRALPAK™ AD-H production Daicel Chemical Industries, Ltd., 2 cm × 25 cm, mobile phase: hexane:ethanol = 70:30, flow rate: 1 ml/min): 3.1 minutes (optical rotation (+)), 4.3 minutes (optical rotation (-))

(4)Synthesis of tert-butyl (-)-[(4aR*,6R*,8aS*)-8a-(5-amino-2-forfinal)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

tert-Butyl (±)-[(4aR*,6R*,8aS*)-8a-(5-amino-2-forfinal)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in example getting 58-(12) (838 mg), optically separated using CHIRALPAK™ AD-H production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 50:50, flow rate: 10 ml/min, loaded with a solution of about 16 mg in 2 ml ethanol for one cycle). A component that has two major components over a long retention time, collected with obtaining specified in the title compound (335 mg, >99% ee, optical rotation (-)).

HPLC (CHIRALPAK™ AD-H production Daicel Chemical Industries, Ltd., 2 cm × 25 cm, mobile phase: hexane:ethanol = 70:30, flow rate: 1 ml/min): 4.3 minutes

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,44-and 1.54 (m, 1H), 1,53 (s, 9H), 1,80-1,8 (m, 2H), 1,98-2,07 (m, 2H), 2,37 at 2.45 (m, 1H), 2,48 is 2.51 (m, 1H), 2,87 of 2.92 (m, 2H), 3,41 (s, 3H), 3.45 points-to 3.49 (m, 1H), 3,65 (ush., 2H), 6,53-6,55 (m, 2H), PC 6.82-6.87 in (m, 1H).

An example of retrieving 62

Synthesis of (±)-(3aR*,5S*,7aS*)-5-benzyloxy-7a-(2-forfinal)octahedrons[c]isoxazol-and (±)-(3aR*,5R*,7aS*)-5-benzyloxy-7a-(2-forfinal)octahedrons[c]isoxazol

[Formula 84]

(1)Synthesis of [1-(3,3-dimethoxypropane)-but-3-relaxometer]benzene

7,7-Dimethoxy-1-EN-4-ol obtained in the example of a 59-(1) (5,47 g), was dissolved in 1-methyl-2-pyrrolidinone (35 ml). Added benzylbromide (3.12 ml, specific gravity: 1.44 g/cm3) and the mixture is sufficiently cooled in an ice bath under nitrogen atmosphere. Was added sodium hydride (60%, 2,12 g), followed by stirring for one hour and 30 minutes. Was slowly added water and a saturated ammonium chloride and then added ethyl acetate, followed by additional stirring. The aqueous layer was separated and then the organic layer was sequentially washed with a saturated solution of ammonium chloride, water and a saturated salt solution. The obtained organic layer was dried over anhydrous magnesium sulfate and the solid was removed by filtration. The filtrate was concentrated under reduced pressure and then purified by chromatography on a column of silica gel with obtaining specified in the connection header (4,14 g).

1H-NMR (400 MHz, CDCl3 ) δ (ppm): 1,55 by 1.68 (m, 3H), 1,73-of 1.81 (m, 1H), 2,27-to 2.41 (m, 2H), 3,30 (d, J=2.0 Hz, 6H), 3,44-to 3.50 (m, 1H), 4,33-4,37 (m, 1H), 4,47-4,59 (m, 2H), of 5.05-5,12 (m, 2H), 5,79-5,90 (m, 1H), 7,28-7,34 (m, 5H).

(2)Synthesis of 4-benzyloxy-6-naloxone

Specified in the title compound (6.42 per g) were obtained from [1-(3,3-dimethoxypropane)-but-3-relaxometer]benzene obtained in the example of a 62-(1) (7.78 g), in accordance with the method of example obtaining a 57-(3) without purification by chromatography on a column of silica gel.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,70-1,75 (m, 2H), 2,22 is 2.43 (m, 3H), 2,46 is 2.51 (m, 1H), 3.45 points-to 3.52 (m, 1H), 4,46-4,50 (m, 1H), 4,58-br4.61 (m, 1H), 5,06-5,14 (m, 2H), 5,78-of 5.89 (m, 1H), of 6.71-6,74 and 7,41-7,44 (m, summary. 1H), 7,16 and 7,53 (ush., summary. 1H), 7,26-7,32 (m, 1H), 7,34-7,35 (m, 4H).

(3)Synthesis of 5-benzyloxy-3,3a,4,5,6,7-hexahydrobenzo[c]isoxazol

Specified in the header connection (to 5.66 g) was obtained from 4-benzyloxy-6-naloxone obtained in the example of a 62-(2) (6.42 per g), in accordance with the method of example obtaining a 57-(4).

ESI-MS; m/z 232 [M+H].

(4)Synthesis of (±)-(3aR*,5S*,7aS*)-5-benzyloxy-7a-(2-forfinal)octahedrons[c]isoxazol-and (±)-(3aR*,5R*,7aS*)-5-benzyloxy-7a-(2-forfinal)octahedrons[c]isoxazol

Listed in the connection header (±)-(3aR*,5S*,7aS*)-5-benzyloxy-7a-(2-forfinal)octahedrons[c]isoxazol (5,04 g) and (±)-(3aR*,5R*,7aS*)-5-benzyloxy-7a-(2-forfinal)octahedrons[c]isoxazol (2,49 g) was obtained from 5-benzyloxy-3,3a,4,5,6,7-hexahydrobenzo[c]isoxazol obtained in the example of a 62-(3) to 5.66 g), in accordance with the method of example obtaining a 57-(5).

(±)-(3aR*,5S*,7aS*)-5-Benzyloxy-7a-(2-forfinal)octahedrons[c]isoxazol

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,63 (ush., 2H), of 1.76 and 1.80 (m, 1H), 1,87 (ush., 1H), 2,10-of 2.15 (m, 1H), 2,58-of 2.64 (m, 1H), 3,21 (ush., 1H), 3,66 (ush., 2H), 3,81 (ush., 1H), 4,56-4,63 (m, 2H), 5,95 (ush., 1H), 7,02-7,07 (m, 1H), 7,11-to 7.15 (m, 1H), 7.23 percent-7,31 (m, 2H), 7,35-the 7.43 (m, 4H), 7,82 (ush., 1H).

(±)-(3aR*,5R*,7aS*)-5-Benzyloxy-7a-(2-forfinal)octahedrons[c]isoxazol

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,40-and 1.54 (m, 2H), 1,99-2,05 (m, 1H), 2,07 and 2.13 (m, 1H), 2,18 was 2.25 (m, 1H), 2,28-of 2.36 (m, 1H), 2,99 was 3.05 (m, 1H), 3,53 of 3.56 (m, 1H), 3,64-3,74 (m, 2H), br4.61 (d, J=1.6 Hz, 2H), 6,00 (ush., 1H), 7,01 (DDD, J=1,2, 8,4, and 12.4 Hz, 1H), 7,13 (dt, J=1,2, 7,6 Hz, 1H), 7,21-7,27 (m, 1H), 7,28-7,33 (m, 1H), was 7.36-7,37 (m, 4H), 7,87 (dt, J=1,6, 8.0 Hz, 1H).

An example of retrieving 63

Synthesis of tert-butyl (-)-[(4aR*,6R*,8aS*)-8a-(5-amino-2-forfinal)-6-fluoro-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

[Formula 85]

(1)Synthesis of (±)-1-benzoyl-3-[(1S*,2R*,4S*)-4-benzyloxy-1-(2-forfinal)-2-hydroxymethylcellulose]thiourea

Specified in the header connection (6,24 g) was obtained from (±)-(3aR*,5S*,7aS*)-5-benzyloxy-7a-(2-forfinal)octahedrons[c]isoxazol obtained in the example of a 62-(4) (5,04 g), in accordance with the method of example obtaining a 57-(6).

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.40 and 1.80 (m, 3H), 1,99-2,02 (m, 1H), 2,13-2,19 (m, 3H), 3,54-to 3.73 (m, 3H), 3,90 (s, 1H), 4,54 with 4.65 (m, 2H), 7,00-was 7.08 (m, 1H), 7,16 (ush., 1H), 7,26-7,30 (m, 2H), 7,35-7,41 (m, 4H), 7,44-7,47 (m, 1H), 7,50-7,54 (who, 2H), to 7.61-to 7.64 (m, 1H), 7,88 (d, J=3,6 Hz, 2H), 8,88 (ush., 1H), to 11.52 (ush., 1H).

(2)Synthesis of (±)-N-[(4aR*,6S*,8aS*)-6-benzyloxy-8a-(2-forfinal)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide

Specified in the header of the connection (of 4.57 g) was obtained from (±)-1-benzoyl-3-[(1S*,2R*,4S*)-4-benzyloxy-1-(2-forfinal)-2-hydroxymethylcellulose]thiourea obtained in the example of a 63-(1) (6,24 g), in accordance with the method of example obtaining a 57-(7).

ESI-MS; m/z 475 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,68 (d, J=14.4 Hz, 1H), 1,81-1,89 (m, 1H), 1.93 and-of 1.97 (m, 1H), 2,03 is 2.10 (m, 2H), 2,52 (DD, J=3.2, and to 12.8 Hz, 1H), 2,85-of 2.93 (m, 1H), 2,97 (DD, J=4,0, to 12.8 Hz, 1H), 3.43 points-to 3.49 (m, 1H), 3,92 (s, 1H), 4,54-of 4.66 (m, 2H), 7,09-7,17 (m, 2H), 7,28 was 7.45 (m, 9H), of 7.48-7,52 (m, 1H), 8,24-of 8.27 (m, 2H), 12,32 (ush., 1H).

(3)Synthesis of (±)-(4aR*,6S*,8aS*)-6-benzyloxy-8a-(2-forfinal)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-ylamine

Specified in the header connection (3,96 g, purity according to1H-NMR: about 90%) was obtained from (±)-N-[(4aR*,6S*,8aS*)-6-benzyloxy-8a-(2-forfinal)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide are obtained in the example of a 63-(2) (4,58 g), in accordance with the method of example obtaining a 61-(1).

ESI-MS; m/z 371 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,54-1,72 (m, 1H), 1,74 of-1.83 (m, 2H), 1,84-of 1.88 (m, 1H), 1,90-of 1.97 (m, 1H), 2,48 (DD, J=2,8, 12.0 Hz, 1H), was 2.76 (dt, J=3,6, 13,2 Hz, 1H), 2,87-only 2.91 (m, 1H), 3,18-3,24 (m, 1H), 3,84 (t, J=2,8 Hz, 1H), 4,54 (ush., 2H), 4,51-of 4.66 (m, 2H),? 7.04 baby mortality (DDD, J=1,2, 8,0, and 12.4 Hz, 1H), to 7.09 (dt, J=1,6 and 7.6 Hz, 1H), 7,19-7,25 (m, 1H), 7,26-7,31 (m, 2H), 7,35-7,39 (m, 2H), 7,437,45 (m, 2H).

(4)Synthesis of tert-butyl (±)-[(4aR*,6S*,8aS*)-8a-(2-forfinal)-6-hydroxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

Specified in the title compound (3.58 g) was obtained from (±)-(4aR*,6S*,8aS*)-6-benzyloxy-8a-(2-forfinal)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-ylamine obtained in the example of a 63-(3) (3,96 g, purity according to1H-NMR: about 90%), in accordance with the method of example obtaining a 58-(8).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,54 by 1.68 (m, 1H), 1,71-to 1.79 (m, 2H), 1,87 is 1.96 (m, 1H), 2,07-of 2.15 (m, 1H), 2,45 (DD, J=2,8, 10,0 Hz, 1H), 2,82-only 2.91 (m, 2H), 3,31 is-3.45 (m, 2H), 4,29-to 4.33 (m, 1H), 7,06-7,11 (m, 1H), 7,15-7,19 (m, 1H), 7,29-7,34 (m, 2H).

(5)Synthesis of tert-butyl (±)-[(4aR*,6R*,8aS*)-6-fluoro-8a-(2-forfinal)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

tert-Butyl (±)-[(4aR*,6S*,8aS*)-8a-(2-forfinal)-6-hydroxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in example obtaining 63-(4) (1.5 g)was dissolved in THF. Then performancemonitoring (1,36 ml, specific gravity: 1,682 g/cm3), triethylamine complex-trifluromethane acid (1.23 ml, specific gravity: 0,989 g/cm3) and triethylamine (3.15 ml, specific gravity: 0.73 g/cm3) was sequentially added at room temperature. At the end of the addition the mixture was stirred for 16 hours. The mixture was heated to 50°C and stirred for another 24 hours. Performancemonitoring (0.68 ml), triethylamine complex-trifluromethane acid is that of 0.62 ml) and triethylamine (1,58 ml) has consistently added to the mixture, followed by additional stirring at boiling under reflux for eight hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Then the residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (106 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.53 (s, 9H), 1,84-1,89 (m, 2H), 2.06 to a 2.13 (m, 3H), 2,39-2,47 (m, 1H), 2,52 (DD, J=3.2, and to 12.8 Hz, 1H), 2,80-to 2.85 (m, 1H), 2,89-of 2.97 (m, 1H), 4,69-of 4.90 (m, 1H),? 7.04 baby mortality-7,11 (m, 1H), 7,15-7,20 (m, 1H), 7,27-7,34 (m, 2H).

(6)Synthesis of tert-butyl (±)-[(4aR*,6R*,8aS*)-6-fluoro-8a-(2-fluoro-5-nitrophenyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

Specified in the title compound (406 mg) was obtained from tert-butyl (±)-[(4aR*,6R*,8aS*)-6-fluoro-8a-(2-forfinal)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in example obtaining 63-(5) (402 mg), in accordance with the method of example obtaining a 57-(9), using fuming nitric acid (87,1 μl, two equivalent relative to the original substance).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1.55V (s, 9H), 1,80-of 1.88 (m, 2H), 2.06 to (ush., 3H), 2,18-of 2.27 (m, 1H), 2,56 (DD, J=2,8, to 12.8 Hz, 1H), 2,75 is 2.80 (m, 1H), 2,87 (ush., 1H), 4,66-a 4.86 (m, 1H), 7,19-7,25 (m, 1H), 8,14 is 8.22 (m, 2H).

(7)Synthesis of tert-butyl (±)-[(4aR*,6R*,8aS*)-8a-(5-amino-2-forfinal)-6-fluoro-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

Specified in the title compound (330 mg) was obtained from tert-butyl (±)-[(4aR*,6R*,8aS*)-6-fluoro-8a-(2-fluoro-5-nitrophenyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in example polucheniya-(6) (406 mg), in accordance with the method of example obtaining a 57-(10).

1H-NMR (400 MHz, CDCl3) δ (ppm): and 1.54 (s, 9H), 1,80-of 1.88 (m, 2H), 2,04-2,11 (m, 3H), 2,38-2,47 (m, 1H), 2,48 of $ 2.53 (m, 1H), 2,89-2,95 (m, 2H), the 3.65 (s, 2H), 4,68-4,88 (m, 1H), 6,51-to 6.57 (m, 2H), 6,83-to 6.88 (m, 1H).

HPLC (CHIRALPAK™ AD-H production Daicel Chemical Industries, Ltd., 2 cm × 25 cm, mobile phase: hexane:ethanol = 80:20, flow rate: 1 ml/min): 4.4 minutes (optical rotation (+)), 6.8 minutes (optical rotation (-))

(8)Synthesis of tert-butyl (-)-[(4aR*,6R*,8aS*)-8a-(5-amino-2-forfinal)-6-fluoro-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

tert-Butyl (±)-[(4aR*,6R*,8aS*)-8a-(5-amino-2-forfinal)-6-fluoro-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in example getting 58-(12) (330 mg), optically separated using CHIRALPAK™ AD-H production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 50:50, flow rate: 10 ml/min, loaded with a solution of about 40 mg in 1 ml ethanol for one cycle). Two major components component having a retention time of from 12.2 to 15.5 minutes, collected by obtaining specified in the title compound (155 mg, >99% ee, optical rotation (-)).

HPLC (CHIRALPAK™ AD-H production Daicel Chemical Industries, Ltd., 2 cm × 25 cm, mobile phase: hexane:ethanol = 80:20, flow rate: 1 ml/min): 7.0 minutes.

1H-NMR (400 MHz, CDCl3) δ (ppm): and 1.54 (s, 9H), 1,80-of 1.88 (m, 2H), 2,04-2,12 (m, 3H), 2,38 is 2.46 (m, 1H), 2,48 of $ 2.53 (m, 1H), 2,89-to 2.94 (m, 2H), 3,66 (ush., 2H), 4,68-4,88 (m, 1H), 6,51-to 6.57 (m, H), 6,83-to 6.88 (m, 1H).

Example of getting 64

Synthesis of tert-butyl (-)-[(4aR*,6S*,8aS*)-8a-(5-amino-2-forfinal)-6-fluoro-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

[Formula 86]

(1)Synthesis of (±)-1-benzoyl-3-[(1S*,2R*,4R*)-4-benzyloxy-1-(2-forfinal)-2-hydroxymethylcellulose]thiourea

Specified in the title compound (3.13 g) was obtained from (±)-(3aR*,5R*,7aS*)-5-benzyloxy-7a-(2-forfinal)octahedrons[c]isoxazol obtained in the example of a 62-(4) (2,48 g), in accordance with the method of example obtaining a 57-(6).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,59 was 1.69 (m, 2H), 1,95-2,10 (m, 2H), 2,31-of 2.34 (m, 2H), to 3.58-and 3.72 (m, 3H), 3,85 (ush., 1H), with 4.64 (s, 2H), 7,02-was 7.08 (m, 1H), 7,12-7,16 (m, 1H), 7,27-7,30 (m, 2H), 7,35-7,46 (m, 5H), 7,51-of 7.55 (m, 2H), to 7.61-the 7.65 (m, 1H), 7,86-7,89 (m, 2H), 8,89 (ush., 1H), to 11.56 (ush., 1H).

(2)Synthesis of (±)-N-[(4aR*,6R*,8aS*)-6-benzyloxy-8a-(2-forfinal)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide

Specified in the header connection (2,03 g) was obtained from (±)-1-benzoyl-3-[(1S*,2R*,4R*)-4-benzyloxy-1-(2-forfinal)-2-hydroxymethylcellulose]thiourea obtained in the example of a 64-(1) (3.13 g), in accordance with the method of example obtaining a 57-(7).

ESI-MS; m/z 475 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,80 (kV, J=12,8 Hz, 1H), 1,93 (d, J=14,8 Hz, 1H), 2,01-2,17 (m, 3H), 2,42-2,49 (m, 1H), 2,59 (d, J=12,4 Hz, 1H), 2,93 (d, J=12,8 Hz, 1H), 3,00 (d, J=10,8, 1H), 3,68-to 3.73 (m, 1H), to 4.62 (s, 2H), 7,05-7,11 (m, 1H), 7,14-to 7.18 (m, 1H), 7.29 trend was 7.36 (m, 7H), 7,41 was 7.45 (m, 2H), of 7.48-7,52 (m, 1H), 8,24(d, J=7.2 Hz, 2H), 12,30 (ush., 1H).

(3)Synthesis of (±)-(4aR*,6S*,8aS*)-6-benzyloxy-8a-(2-forfinal)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-ylamine

Specified in the title compound (1.50 g) was obtained from (±)-N-[(4aR*,6R*,8aS*)-6-benzyloxy-8a-(2-forfinal)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide are obtained in the example of a 64-(2) (2,03 g), in accordance with the method of example obtaining a 58-(7).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,64-to 1.77 (m, 1H), 1,80 is 1.86 (m, 2H), 1,88-of 1.94 (m, 1H), 2.00 in to 2.06 (m, 1H), 2.26 and is 2.33 (m, 1H), 2,53-to 2.57 (m, 1H), 2,71 was 2.76 (m, 1H), 2,84-is 2.88 (m, 1H), 3,61 at 3.69 (m, 1H), 4,43 (ush., 2H), to 4.62 (d, J=4.4 Hz, 2H), 7,00 (DDD, J=1,2, 8,0, to 12.8 Hz, 1H), 7,07-7,11 (m, 1H), 7,19-7,24 (m, 1H), 7,28-7,31 (m, 2H), 7,33-7,39 (m, 4H).

(4)Synthesis of tert-butyl (±)-[(4aR*,6R*,8aS*)-8a-(2-forfinal)-6-hydroxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

Specified in the header connection (1,59 g) was obtained from (±)-(4aR*,6R*,8aS*)-6-benzyloxy-8a-(2-forfinal)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-ylamine obtained in the example of a 64-(3) (1.50 g), in accordance with the method of example obtaining a 58-(8).

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.53 (s, 9H), 1,62-of 1.73 (m, 1H), 1,80-2,02 (m, 4H), 2,42-of 2.54 (m, 2H), 2,80-2,84 (m, 1H), 2,93-2,99 (m, 1H), 3,90-3,98 (m, 1H),? 7.04 baby mortality-to 7.09 (m, 1H), 7,15-7,20 (m, 1H), 7,28-7,34 (m, 2H).

(5)Synthesis of tert-butyl (±)-[(4aR*,6S*,8aS*)-6-fluoro-8a-(2-forfinal)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

tert-Butyl (±)-[(4aR*,6R*,8aS*)-8a-(2-forfinal)-6-hydroxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in example obtain the 64-(4) (500 mg), was dissolved in THF. Then performancemonitoring (of 0.43 ml, specific gravity: 1,682 g/cm3), triethylamine complex-trifluromethane acid (0,39 ml, specific gravity: 0,989 g/cm3) and triethylamine (0,99 ml, specific gravity: 0.73 g/cm3) was sequentially added at room temperature. At the end of the addition the mixture was stirred for 15 hours. The reaction solution was concentrated under reduced pressure and then the residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (351 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.53 (s, 9H), 1,63-to 1.67 (m, 1H), 1,76-2,19 (m, 4H), 2,46-2,49 (m, 1H), was 2.76-and 2.83 (m, 1H), 2,88 of 2.92 (m, 1H), 3,29-of 3.32 (m, 1H), 5,04 (d, J=48,0 Hz, 1H), 7,07 for 7.12 (m, 1H), 7,16-7,20 (m, 1H), 7,30-7,32 (m, 2H).

(6)Synthesis of tert-butyl (±)-[(4aR*,6S*,8aS*)-6-fluoro-8a-(2-fluoro-5-nitrophenyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

Specified in the title compound (266 mg) was obtained from tert-butyl (±)-[(4aR*,6S*,8aS*)-6-fluoro-8a-(2-forfinal)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in example obtain the 64-(5) (351 mg), in accordance with the method of example obtaining a 57-(9) by adding di-tert-BUTYLCARBAMATE (401 mg), stirring at room temperature for 14 hours and then adding di-tert-BUTYLCARBAMATE (200 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): and 1.54 (s, 9H), 1,65 by 1.68 (m, 1H), 1,77 is 1.91 (m, 1H), 1,98 with 2.14 (m, 3H), of 2.54 (DD, J=2,8, 1.8 Hz, 1H), 2,61-to 2.67 (m, 1H), 2,86 (DD, J=3,6, to 12.8 Hz, 1H), 3.27 to (ush., 1H), to 5.03 (d, J=48,4 Hz, 1H), 7.23 percent-7,28 (m, 1H), 8,18-8,23 (m, 2H).

(7)Synthesis of tert-butyl (±)-[(4aR*,6S*,8aS*)-8a-(5-amino-2-forfinal)-6-fluoro-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

Specified in the title compound (191 mg) was obtained from tert-butyl (±)-[(4aR*,6S*,8aS*)-6-fluoro-8a-(2-fluoro-5-nitrophenyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in example obtain the 64-(6) (266 mg), in accordance with the method of example obtaining a 57-(10).

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.53 (s, 9H), 1.56 to its 1.68 (m, 1H), 1,75-of 1.93 (m, 1H), 1,99-of 2.16 (m, 3H), 2,47 (d, J=13,2 Hz, 1H), 2,78 (t, J=13,2 Hz, 1H), 2,98 (d, J=12.0 Hz, 1H), 3,26 of 3.28 (m, 1H), 3,65 (ush., 2H), to 5.03 (d, J=48,0 Hz, 1H), 6,53 return of 6.58 (m, 2H), 6,85-of 6.90 (m, 1H).

HPLC (CHIRALPAK™ AD-H production Daicel Chemical Industries, Ltd., 2 cm × 25 cm, mobile phase: hexane:ethanol = 80:20, flow rate: 1 ml/min): 3.3 minutes (optical rotation (+)), 5.9 minutes (optical rotation (-))

(8)Synthesis of tert-butyl (-)-[(4aR*,6S*,8aS*)-8a-(5-amino-2-forfinal)-6-fluoro-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

tert-Butyl (±)-[(4aR*,6S*,8aS*)-8a-(5-amino-2-forfinal)-6-fluoro-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in example getting 58-(12) (191 mg), optically separated using CHIRALPAK™ AD-H production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 50:50, flow rate: 10 ml/min, loaded with a solution of about 6 mg in 2 ml ethanol for one cycle). And the two main components component having a retention time from 10.9 to 12.6 minutes, collected by obtaining specified in the title compound (72 mg, >99% ee, optical rotation (-)).

HPLC (CHIRALPAK™ AD-H production Daicel Chemical Industries, Ltd., 2 cm × 25 cm, mobile phase: hexane:ethanol = 80:20, flow rate: 1 ml/min): 5.9 minutes.

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.52 (s, 9H), 1,60 by 1.68 (m, 1H), 1,74-of 1.93 (m, 1H), 1,98-of 2.15 (m, 3H), 2,47 (d, J=12,8 Hz, 1H), 2,77 (t, J=13,2 Hz, 1H), 2,97 (d, J=12,4 Hz, 1H), 3,26 (d, J=10.0 Hz, 1H), 3.72 points ush., 2H), 5,02 (d, J=48,0 Hz, 1H), 6,53 return of 6.58 (m, 2H), 6,85-of 6.90 (m, 1H).

Example getting 65

Synthesis of (±)-N,N-bis(tert-butoxycarbonyl)[(4aR*,7aS*)-7a-(3-bromophenyl)-6-pyrazin-2-yl-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-yl]amine

[Formula 87]

(1)Synthesis of (±)-N-[(4aR*,7aS*)-7a-(3-bromophenyl)-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-yl]benzamide

Specified in the header connection (7,52 g) was obtained from (±)-N-[(4aR*,7aS*)-7a-(3-bromophenyl)-6-(2,4-dimethoxybenzyl)-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-yl]benzamide obtained in example getting 18-(5) (14.5 g), in accordance with the method of example getting 18-(9).

ESI-MS; m/z 416 [M+H].

(2)Synthesis of (±)-N-(4aR*,7aS*)-7a-(3-bromophenyl)-6-pyrazin-2-yl-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-ylamine

2-Chloropyrazine (2,14 ml, specific gravity: 1,284 g/cm3) was added to (±)-N-[(4aR*,7aS*)-7a-(3-bromophenyl)-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-yl]benzamide obtained in example recip is of 65-(1) (2 g), and the mixture was heated to 90°C and stirred in a nitrogen atmosphere. After 13 hours, the reaction solution was cooled to room temperature. Added chloroform and saturated sodium bicarbonate solution, followed by extraction three times with chloroform. The obtained organic layers were dried over anhydrous magnesium sulfate and the solid was removed by filtration. The obtained filtrate was concentrated under reduced pressure and then purified by chromatography on a column with NH-silica gel. To the mixture containing the N-aryl compound, was added methanol (9.6 ml). Then was added a solution of sodium methoxide in methanol (373 μl, 25%, specific gravity: 0,945 g/cm3) and the mixture was stirred at the boil under reflux. After three hours and 50 minutes the reaction solution was cooled to room temperature. Added chloroform, a saturated solution of sodium bicarbonate and a saturated salt solution, followed by extraction three times with chloroform. The obtained organic layers were dried over anhydrous magnesium sulfate and the solid was removed by filtration. The obtained filtrate was concentrated under reduced pressure and then purified by chromatography on a column with NH-silica gel with obtaining specified in the title compound (138 mg).

ESI-MS; m/z 390 [M+H].

(3)Synthesis of (±)-N,N-bis(tert-butoxycarbonyl)[(4aR*,7aS*)-7a-(3-bromophenyl)-6-pyrazin-yl-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-yl]amine

(±)-N-(4aR*,7aS*)-7a-(3-Bromophenyl)-6-pyrazin-2-yl-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-ylamine, obtained in the example of a 65-(2) (138 mg), was dissolved in THF (10 ml). Then was added di-tert-BUTYLCARBAMATE (232 mg) and 4-dimethylaminopyridine (151 mg) and the mixture was stirred at room temperature. After 11 hours and 30 minutes the reaction solution was diluted with ethyl acetate. Then was added a saturated solution of ammonium chloride followed by extraction with ethyl acetate. The resulting organic layer was sequentially washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The solid was removed by filtration. The filtrate was concentrated under reduced pressure and then the residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (154 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,41 (m, 18H), 2,88-of 3.12 (m, 3H), 3,17-is 3.21 (m, 1H), 3,80-of 3.96 (m, 3H), 7,40-7,47 (m, 3H), 7,65-7,66 (m, 1H), a 7.85 (d, J=2.0 Hz, 1H), 7,88 (d, J=1.6 Hz, 1H), 8,04-with 8.05 (m, 1H).

The following compound was synthesized from ethyl 2-triftoratsetilatsetonom-1 enecarboxylate and relevant Baranovich acids in accordance with the example of obtaining 1.

An example of retrieving 66

Synthesis of tert-butyl (±)-[(4aR*,8aS*)-8a-(5-amino-2,4-differenl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

[Formula 88]

<> 1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.53 (s, 9H), 1,46-of 1.73 (m, 6H), 1,83-1,89 (m, 1H), 2,28-of 2.34 (m, 1H), 2,48 (DD, J=3,2, and 12.4 Hz, 1H), 2.77-to of 2.81 (m, 1H), 2,87 (DD, J=4.0 a, and 12.4 Hz, 1H), 3,68 (s, 2H), 6,66 (DD, J=8,0, 9.6 Hz, 1H), 6,78 (DD, J=10,4, and 11.6 Hz, 1H).

An example of retrieving 67

Synthesis of tert-butyl (±)-[(4aR*,8aS*)-8a-(5-amino-2,6-differenl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

[Formula 89]

1H-NMR (400 MHz, CDCl3) δ (ppm): is 1.51 (s, 9H), 1,43-2,05 (m, 7H), 2,16-of 2.24 (m, 1H), 2,54-of 2.58 (m, 1H), 2,97-a 3.01 (m, 1H), 3,18 (DD, J=4,4, to 12.8 Hz, 1H), 3,63 (s, 2H), 6,64-of 6.73 (m, 2H).

Example of getting 68

Synthesis of 5-(1-ethoxyphenyl)pyridine-2-carboxylic acid

[Formula 90]

(1)Synthesis of ethyl 5-(1-ethoxyphenyl)pyridine-2-carboxylate

1-Ethoxyphenyl-n-botillo (880 μl) and tetrakis(triphenylphosphine)palladium (125 mg) was added to a solution of 5-bromopyridin-2-carboxylic acid (500 mg) in DMF (10 ml). After replacement with nitrogen, the mixture was heated to 85°C and was stirred overnight. After cooling to room temperature, to the reaction mixture were added ethyl acetate. The organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (342 mg).

1H-NMR (400 MHz, CDCl3 ) δ (ppm): of 1.42 to 1.47 (m, 6H), 3.96 points (kV, J=6,4 Hz, 2H), and 4.40 (d, J=3,4 Hz, 1H), 4,49 (kV, J=6,8 Hz, 2H), to 4.81 (d, J=3,4 Hz, 1H), 8,03 (DD, J=2,2, and 8.4 Hz, 1H), 8,10 (DD, J=0,8, and 8.4 Hz, 1H), 8,98 (DD, J=0.8, the 2,2 Hz, 1H).

(2)Synthesis of 5-(1-ethoxyphenyl)pyridine-2-carboxylic acid

To a solution of ethyl 5-(1-ethoxyphenyl)pyridine-2-carboxylate (100 mg) in ethanol (5 ml) was added 5 n sodium hydroxide solution (2 ml). The mixture was stirred at room temperature for two hours. After confirming completion of the reaction, the reaction solution was neutralized 1 N. chloride-hydrogen acid. The aqueous layer was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain specified in the title compound (92 mg).

1H-NMR (400 MHz, CD3OD) δ (ppm): the 1.44 (t, J=6.8 Hz, 3H), 3,99 (kV, J=6,8 Hz, 2H), to 4.52 (d, J=3,4 Hz, 1H), 4,96 (d, J=3,4 Hz, 1H), 8,13 (DD, J=0,8, and 8.4 Hz, 1H), 8,21 (DD, J=2,4, and 8.4 Hz, 1H), 8,90 (DD, J=0,8, 2.4 Hz, 1H).

Example of getting 69

Synthesis of 3-methoxypyridine-2-carboxylic acid

[Formula 91]

(1)Synthesis of methyl 3-methoxypyridine-2-carboxylate

Sodium hydride (60%, 253 mg) was added to a solution of 3-hydroxypyridones acid (440 mg) in DMF (4 ml) in an ice bath. After stirring at room temperature for 30 minutes was added logmean (393 μl) and the mixture was stirred at room temperature during the night. To the reaction mixture were added ice to stop the reaction. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with water and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (112 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 3,85 (s, 3H), 3,90 (s, 3H), 7,30 (DD, J=1,2, 8.6 Hz, 1H), 7,35 (DD, J=4,4, 8.6 Hz, 1H), to 8.20 (DD, J=1,2, 4,4 Hz, 1H).

(2)Synthesis of 3-methoxypyridine-2-carboxylic acid

To a solution of methyl 3-methoxypyridine-2-carboxylate (112 mg) in methanol (2 ml) was added 5 n sodium hydroxide solution (147 μl) and the mixture was stirred at room temperature overnight. The excess methanol is evaporated under reduced pressure and the residue was diluted with water. The aqueous layer was washed with ether and then slightly acidified 5 N. chloride-hydrogen acid. The aqueous layer was extracted with a mixed solvent of THF-ethyl acetate and then the organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain specified in the title compound (19 mg).

1H-NMR (400 MHz, CD3OD) δ (ppm): 3,95 (s, 3H), of 7.96 (DD, J=4,4, 8,2 Hz, 1H), 7,71 (d, J=8,2 Hz, 1H), 8,18 (d, J=4.4 Hz, 1H).

Example of getting 70

Synthesis of 5-(1-methyl-1H-p is razol-4-yl)pyridine-2-carboxylic acid

[Formula 92]

(1)Synthesis of tert-butyl 5-(1-methyl-1H-pyrazole-4-yl)pyridine-2-carboxylate

1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (80,7 mg), bis(tri-tert-butylphosphine)palladium(0) (to 9.91 mg) and a 1 n solution of potassium phosphate (388 μl) was added to a solution of tert-butyl 5-bromopyridin-2-carboxylate (50 mg) in 1,4-dioxane (2 ml). After replacement with nitrogen, the mixture was heated to 100°C and was stirred for eight hours. The reaction solution was cooled to room temperature and evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compounds as a mixture (81 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,65 (s, 9H), to 3.99 (s, 3H), 7,74 (s, 1H), 7,82-a 7.85 (m, 2H), 8,04 (DD, J=1,2, and 8.4 Hz, 1H), cent to 8.85 (DD, J=0,8, 2.4 Hz, 1H).

ESI-MS; m/z 260 [M++H].

(2)Synthesis of 5-(1-methyl-1H-pyrazole-4-yl)pyridine-2-carboxylic acid

TFOC (1 ml) was added to a solution of tert-butyl 5-(1-methyl-1H-pyrazole-4-yl)pyridine-2-carboxylate (81 mg) in dichloromethane (4 ml) and the mixture was stirred at room temperature overnight. The solvent is evaporated under reduced pressure to get crude product, consisting of the specified in the title compound (170 mg).

1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3,90 (s, 3H), 8,03 (DD, J=0,8, 8,2 Hz, 1H), of 8.09 (d, J=0.8 Hz, 1H), 8,14 (DD, J=2.0 a, 8,2 Hz, 1H), to 8.41 (s, 1H, of 8.95 (DD, J=0,8, 2.0 Hz, 1H).

Example of getting 71

Synthesis of (±)-N,N-bis(tert-butoxycarbonyl)[(4aR*,7aS*)-7a-(3-amino-5-chlorophenyl)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]amine

[Formula 93]

(1)Synthesis of (±)-(4aR*,7aS*)-7a-(3-bromo-5-chlorophenyl)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine

Specified in the title compound was synthesized from Gex-5-naloxone (JOC, 41(5), 863-9; 1976) in accordance with the method of example obtaining 8, using 1,3-dibromo-5-chlorobenzene instead of 2-ferramenta.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,66-2,00 (m, 5H), 2,17-of 2.24 (m, 1H), 2,33-2,39 (m, 1H), 2,73 (DD, J=4,0, of 12.6 Hz, 1H), 2,97 (DD, J=3.2, and of 12.6 Hz, 1H), 4,36 (ush., 2H), 7,27 (t, J=2.0 Hz, 1H), was 7.36 (t, J=2.0 Hz, 1H), 7,37 (t, J=1.6 Hz, 1H).

(2)Synthesis of (±)-N,N-bis(tert-butoxycarbonyl)[(4aR*,7aS*)-7a-(3-bromo-5-chlorophenyl)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]amine

Di-tert-BUTYLCARBAMATE (1,05 g) and 4-dimethylaminopyridine (393 mg) was added to a solution of (±)-(4aR*,7aS*)-7a-(3-bromo-5-chlorophenyl)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine (555 mg) in dichloromethane (30 ml). The mixture was stirred at room temperature overnight and then evaporated under reduced pressure the solvent at room temperature or below. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (140 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,53, N), 1,77 with 2.14 (m, 5H), 2,22-of 2.30 (m, 1H), 2,48-of 2.54 (m, 1H), 2,82 (DD, J=3.2, and by 13.0 Hz, 1H), 3,06 (DD, J=3,6, at 13.0 Hz, 1H), 7,34 (t, J=2.0 Hz, 1H), 7,38 (t, J=1.6 Hz, 1H), 7,44 (t, J=1.6 Hz, 1H).

ESI-MS; m/z 547 [M++H].

(±)-N-(tert-Butoxycarbonyl)-N-(methoxycarbonyl)[(4aR*,7aS*)-7a-(3-bromo-5-chlorophenyl)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]amine formed during cleanup (575 mg)was obtained as a side product.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1.55V (s, 9H), 1,78-2,04 (m, 4H), 2,12 (DDD, J=3,2, 7,2, 13,2 Hz, 1H), 2.26 and is 2.33 (m, 1H), of 2.44-2.50 (m, 1H), and 2.83 (DD, J=3,6, to 12.8 Hz, 1H), 3,06 (DD, J=3.2, and to 12.8 Hz, 1H), 3,92 (s, 3H), 7,32 (t, J=2.0 Hz, 1H), 7,40 (t, J=2.0 Hz, 1H), 7,42 (t, J=1.6 Hz, 1H).

ESI-MS; m/z 505 [M++H].

(3)Synthesis of (±)-N,N-bis(tert-butoxycarbonyl){(4aR*,7aS*)-7a-[3-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl}amine

1,1'-Bis(diphenylphosphino)periodically(II) (40,2 mg), bis(pinacolato)LIBOR (1.40 g) and potassium acetate (216 mg) was added to a solution of (±)-N,N-bis(tert-butoxycarbonyl)[(4aR*,7aS*)-7a-(3-bromo-5-chlorophenyl)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]amine (300 mg) in DMF (6 ml). After replacement with nitrogen, the mixture was stirred at 80°C for six hours. The reaction mixture was cooled to room temperature and was diluted with ethyl acetate. The organic layer was washed twice with water and once with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure ostatok was purified by chromatography on a column of silica gel with obtaining specified in the connection header (1,16 g) in the form of a mixture.

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.34 (s, 12H), of 1.52 (s, 18H), 1,76 with 2.14 (m, 5H), 2,22-of 2.30 (m, 1H), 2,48-of 2.54 (m, 1H), 2,80 (DD, J=3,6, 13,2 Hz, 1H), is 3.08 (DD, J=3,6, 13,2 Hz, 1H), 7,50 (t, J=2.0 Hz, 1H), 7,65 (m, 2H).

ESI-MS; m/z 593 [M++H].

(4)Synthesis of (±)-N,N-bis(tert-butoxycarbonyl)[(4aR*,7aS*)-7a-(3-azido-5-chlorophenyl)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]amine

Sodium azide (53 mg) and copper acetate(II) (19.9 mg) was added to a solution of (±)-N,N-bis(tert-butoxycarbonyl){(4aR*,7aS*)-7a-[3-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl}amine (1,16 g) in methanol (20 ml). The mixture was stirred at room temperature for six days. To the reaction mixture were added a saturated salt solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (58,0 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,53 (s, 18H), 1,78-of 2.15 (m, 5H), 2,25 of-2.32 (m, 1H), 2,46 is 2.51 (m, 1H), 2,81 (DD, J=3.2, and to 12.8 Hz, 1H), 3,05 (DD, J=3.2, and to 12.8 Hz, 1H), 6.89 in (t, J=2.0 Hz, 1H), 7.03 is Hz (t, J=2.0 Hz, 1H), 7,16 (t, J=1,6 Hz, 1H).

ESI-MS; m/z 508 [M++H].

(5)Synthesis of (±)-N,N-bis(tert-butoxycarbonyl)[(4aR*,7aS*)-7a-(3-amino-5-chlorophenyl)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]amine

The ammonium formate (12,4 mg) and zinc (3,86 mg) was added to a solution of (is)-N,N-bis(tert-butoxycarbonyl)[(4aR*,7aS*)-7a-(3-azido-5-chlorophenyl)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]amine (20.0 mg) in methanol (2 ml). The mixture was stirred at room temperature overnight and then the excess methanol is evaporated under reduced pressure. The residue was diluted with ethyl acetate and the organic layer was washed with a solution of ammonium chloride. The solvent is evaporated under reduced pressure and the residue was purified ptsh obtaining specified in the connection header (13,0 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.52 (s, 18H), a 1.75-2,11 (m, 5H), 2,25 is 2.33 (m, 1H), of 2.44-2.50 (m, 1H), 2,81 (DD, J=3,6, to 12.8 Hz, 1H), 3,12 (DD, J=3,6, to 12.8 Hz, 1H), 3.72 points OSS, 2H), 6,53 (t, J=2.0 Hz, 1H), 6,65 Hz (t, J=1.6 Hz, 1H), 6,74 (t, J=1.6 Hz, 1H).

ESI-MS; m/z 482 [M++H].

Example of getting 72

Synthesis of (±)-N,N-bis(tert-butoxycarbonyl)[(4aR*,7aS*)-7a-(5-bromo-2-forfinal)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]amine

[Formula 94]

4-Dimethylaminopyridine (1,62 g) and di-tert-BUTYLCARBAMATE (2,31 g) was added to a solution of the compound obtained in the example of a 54-(4) (1,00 g), in dichloromethane (25 ml). After stirring at room temperature for 14 hours was added to the reaction mixture water to stop the reaction. The aqueous layer was extracted with dichloromethane and the organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (1.13 g).

ESI-MS; m/z531 [M ++H].

Example of getting 73

Synthesis of (±)-N,N-bis(tert-butyloxycarbonyl)[(4aR*,6R*,7aS*)-7a-(5-bromo-2-forfinal)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]amine and (±)-N,N-bis(tert-butyloxycarbonyl)[(4aR*,6R*,7aS*)-7a-(5-bromo-2-forfinal)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]amine

[Formula 95]

(1)Synthesis of (±)-(3aR*,5S*,6aS*)-6a-(5-bromo-2-forfinal)-5-methoxycarbonylamino[c]isoxazol-and (±)-(3aR*,5R*,6aS*)-6a-(5-bromo-2-forfinal)-5-methoxycarbonylamino[c]isoxazol

Less polar specified in the header of the compound (5S; 62 mg) and the more polar specified in the title compound (5R; 170 mg) was obtained from the compound of example 10-(3) (a mixture of more polar and less polar compounds; 450 mg) and 2,4-dibromo-1-fervently (1.78 g) in accordance with the example of obtaining 21-(3).

Less polar specified in the header of the connection

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,08-of 2.26 (m, 3H), 3,21-3,29 (m, 2H), 3,30 (s, 3H),3,68 (t, J=8.0 Hz, 1H), 4,08 (t, J=5,2 Hz, 1H), and 4.40 (t, J=8,4 Hz, 1H), to 6.88 (DD, J=8,4, 11.2 Hz, 1H), 7,31 (DDD, J=2,8, to 4.4, and 8.4 Hz, 1H), 8,09 (DD, J=2,8, 7.2 Hz, 1H).

More polar specified in the header of the connection

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,03-of 2.20 (m, 3H), 2,33 (DD, J=5,8, a 13.4 Hz, 1H), 3,23-3,29 (m, 1H), 3,35 (s, 3H), 3,59 (USS, 1H), 4,10-4,16 (m, 1H), 4,25-to 4.28 (m, 1H), 6,94 (DD, J=9,0, to 10.8 Hz, 1H), 7,35 (DDD, J=2,8, 4,8, 8,8 Hz, 1H), the 7.85-7,87 (m, 1H).

(2)Synthesis of (±)-(4aR*,6S*,7aS*)-7a-(5-bromo-2-FPO is phenyl)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine

Specified in the title compound was obtained from (±)-(3aR*,5S*,6aS*)-6a-(5-bromo-2-forfinal)-5-methoxycarbonylamino[c]isoxazol in accordance with the method of example obtaining 28.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,98-2,10 (m, 2H), 2,16-2,22 (m, 1H), 2.57 m-of 2.64 (m, 1H), was 2.76 (DD, J=4,4, 13,2 Hz, 1H), 2,87-of 2.93 (m, 2H), 3.33 and (s, 3H), 4,10-4,17 (m, 1H), 6.90 to (DD, J=4,4, to 11.6 Hz, 1H), 7,32 (DDD, J=2,4, 4,0, an 8.4 Hz, 1H), the 7.43 (DD, J=2,4, and 7.6 Hz, 1H).

ESI-MS; m/z 359 [M++H].

(3)Synthesis of (±)-N,N-bis(tert-butyloxycarbonyl)[(4aR*,6S*,7aS*)-7a-(5-bromo-2-forfinal)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]amine

Specified in the title compound (22 mg) was obtained from (±)-(4aR*,6S*,7aS*)-7a-(5-bromo-2-forfinal)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine (15 mg) according to example getting 72.

ESI-MS; m/z 559 [M++H].

(4)Synthesis of (±)-(4aR*,6R*,7aS*)-7a-(5-bromo-2-forfinal)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine

Specified in the title compound was obtained from (±)-(3aR*,5R*,6aS*)-6a-(5-bromo-2-forfinal)-5-methoxycarbonylamino[c]isoxazol in accordance with the method of example obtaining 19.

1H-NMR (400 MHz, CDCl3) δ (ppm): to 1.87 (DDD, J=4,0, 9,6, to 13.6 Hz, 1H), 2,25-of 2.30 (m, 2H), 2,56 (DD, J=7,0, at 13.0 Hz, 1H), 2,72 (DD, 3,6, to 12.8 Hz, 1H), equal to 2.94 (DD, J=3.2, and to 12.8 Hz, 1H), 3,06-of 3.12 (m, 1H), 3,32 (s, 3H), a 3.87-of 3.94 (m, 1H), to 4.41 (ush., 2H), 6,91 (DD, J=8,8, 12.0 Hz, 1H), 7,33 (DDD, J=2,4, 4,4, 8,8 Hz, 1H), 7,40 (DD, J=2,4, 7.2 Hz, 1H).

ESI-MS; m/z 361 [M++H].

(5)Synthesis of (±)-N,N-bis(tert-bout oxycarbonyl)[(4aR*,6R*,7aS*)-7a-(5-bromo-2-forfinal)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]amine

Specified in the title compound (92 mg) was obtained from (±)-(4aR*,6R*,7aS*)-7a-(5-bromo-2-forfinal)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine (65 mg) according to example getting 72.

ESI-MS; m/z 559 [M++H].

Example of getting 74

Synthesis of benzyl (±)-[(4aR*,8aS*)-8a-(5-bromo-2,4-differenl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

[Formula 96]

(1)Synthesis of (±)-(4aR*,8aS*)-8a-(2,4-differenl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-ylamine

Specified in the title compound was synthesized from ethyl 2-triftoratsetilatsetonom-1 enecarboxylate and 2.4-diftorhinolonom acid in accordance with example get 1.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,43-of 1.80 (m, 7H), 2,16-of 2.24 (m, 1H), 2,48 (DD, J=3.2, and 12.0 Hz, 1H), 2,60-of 2.66 (m, 1H), 2,85 (DD, J=4,0, 12.0 Hz, 1H), 4,47 (s, 2H), 6,74-6,84 (m, 1H), 7,21-7,28 (m, 1H).

(2)Synthesis of (±)-(4aR*,8aS*)-8a-(5-bromo-2,4-differenl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-ylamine

(±)-(4aR*,8aS*)-8a-(2,4-Differenl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-ylamine (270 mg) was dissolved in concentrated sulfuric acid (3 ml). N-Bromosuccinimide (170 mg) was added in an ice bath and the mixture was stirred at the same temperature for two hours. Added ice to stop the reaction, followed by dilution with ether. The reaction solution was neutralized with aqueous bicarbonate n the sodium and the water layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (330 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,43-of 1.80 (m, 7H), 2,09-of 2.16 (m, 1H), 2,56 (DD, J=2,8, 12.0 Hz, 1H), 2,59-2,63 (m, 1H), 2,85 (DD, J=4,0, 12.0 Hz, 1H), 6,86 (DD, J=8.0 a, and 11.6 Hz, 1H), 7,45 (t, J=8,4, 1H).

ESI-MS; m/z 361 [M++H].

(3)Synthesis of benzyl (±)-[(4aR*,8aS*)-8a-(5-bromo-2,4-differenl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate

(±)-(4aR*,8aS*)-8a-(5-Bromo-2,4-differenl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-ylamine (330 mg) suspended in 1,4-dioxane (10 ml) and a saturated solution of sodium carbonate (10 ml).

Added benzylchloride (156 μl) and the mixture was stirred at room temperature overnight. The aqueous layer was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (501 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,47-1,90 (m, 7H), 2,25-of 2.30 (m, 1H), 2,55 (DD, J=2,4, of 12.8 Hz, 1H), 2,81-2,87 (m, 2H), 4,71 (s, 1H), 5,18 (s, 2H), 6,93 (DD, J=8,0, 12.0 Hz, 1H), 7,26 was 7.45 (m, 6H).

Example of getting 75

Synthesis of tert-butyl (±)-[(3aS*,7aR*)-7a-(3-AMINOPHENYL)-3a,6,7,7a-tetrahydro-4H-pyrano[4,3-d]thiazol-2-yl]carbamate

[Formula 97]

(1)Synthesis of 4-(3-bromophenyl)-3,6-dihydro-2H-Piran

n-Utility (2,64 M, of 37.9 ml) was added dropwise to a solution of 1,3-dibromobenzene with (23,5 g) in tetrahydrofuran (469 ml) at -78°C. the Mixture was stirred at the same temperature for 30 minutes and then was added dropwise tetrahydro-4H-Piran-4-one (10.0 g). The mixture was stirred at the same temperature for 30 minutes and then heated to room temperature. After stirring at room temperature for four hours to the reaction mixture solution was added ammonium chloride to stop the reaction. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with water and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was dissolved in toluene (400 ml). Added monohydrate p-toluensulfonate acid (2 g) and the mixture was stirred at the boil under reflux for two hours. The reaction mixture was cooled to room temperature and was purified by chromatography on a column with NH-silica gel with obtaining specified in the connection header (21,4 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,46-of 2.50 (m, 2H), 3,94 (t, J=5.6 Hz, 2H), 4,32 (DD, J=2,4, 5,6 Hz, 2H), 6,13-x 6.15 (m, 1H), 7,20 (t, J=8.0 Hz, 1H), 7,30-7,32 (m, 1H), 7,38 (DDD, J=1,2, of 1.6, 8.0 Hz, 1H), 7,52 (t, J=1.6 Hz, 1H).

(2 Synthesis of (±)-6-(3-bromophenyl)was 3.7-dioxabicyclo[4,1,0]heptane

3-Chloroperbenzoic acid (purity: 80%, 25.1 g) was added to a solution of 4-(3-bromophenyl)-3,6-dihydro-2H-Piran (21,4 g) in dichloromethane (400 ml) in an ice bath. The mixture was stirred at the same temperature for three hours and then was heated to room temperature and was stirred for five hours. To the reaction mixture were added ice and saturated sodium bicarbonate solution and separated the organic layer. The organic layer was sequentially washed with a saturated solution of sodium bicarbonate, sodium thiosulfate solution and saturated salt solution. The aqueous layers were combined, extracted with ethyl acetate and the organic layer was sequentially washed with sodium bicarbonate solution, sodium thiosulfate solution and saturated salt solution. The organic layers were combined, dried over anhydrous magnesium sulfate and evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (17.5 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,09 (dt, J=3,6, of 14.8 Hz, 1H), of 2.51 (DDD, 6,0, 8,0, of 14.8 Hz, 1H), 3,17 (d, J=3.2 Hz, 1H), 3,65-3,68 (m, 2H), 4,01 (d, J=13,6 Hz, 1H), 4,13 (DD, J=3.2, and up to 13.2 Hz, 1H), 7,24 (t, J=8.0 Hz, 1H), 7,33 (DDD, J=1,2 at 1.6, 8.0 Hz, 1H), 7,44 (DDD, 1,2, a 2.0, 8.0 Hz, 1H), 7,55 (t, J=2.0 Hz, 1H).

(3)Synthesis of (±)-(3R*,4R*)-4-azido-4-(3-bromophenyl)tetrahydropyran-3-ol

In the (88 ml) and ammonium chloride (11.7 g) was added to a solution of (±)-6-(3-bromophenyl)was 3.7-dioxabicyclo[4,1,0]heptane (17.5 g) in methanol (700 ml), followed by stirring at room temperature. Then was added sodium azide (32.1 g), followed by stirring at 80°C for eight hours. After bringing to room temperature, the excess methanol is evaporated under reduced pressure. The residual aqueous layer three times were extracted with chloroform and the organic layers were dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (22.1 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,94 (DDD, J=1,6, 3,6, 14.4 Hz, 1H), 2,09 (d, J=7.2 Hz, 1H), 2,61 (DDD, J=5,2, 12,4, 14.4 Hz, 1H), 3,71 (DD, J=1,6, 7.2 Hz, 1H), 3,84 (d, J=1.6 Hz, 1H), 3,88 (t, J=1.6 Hz, 1H), 3,97-4,00 (m, 1H), 4,03 (DD, J=1,2, and 12.4 Hz, 1H), 7,34 (t, J=8.0 Hz, 1H), 7,42 (DDD, J=1,2, of 2.0, 8.0 Hz, 1H), 7,52 (DDD, J=1,2, of 2.0, 8.0 Hz, 1H), 7.62mm (t, J=2.0 Hz, 1H).

(4)Synthesis of (±)-(3R*,4R*)-4-amino-4-(3-bromophenyl)tetrahydropyran-3-ol

The ammonium formate (16,9 g) and zinc (the 5.25 g) was added to a solution of (±)-(3R*,4R*)-4-azido-4-(3-bromophenyl)tetrahydropyran-3-ol (16.0 g) in methanol (250 ml). The mixture was stirred at room temperature overnight and then the excess methanol is evaporated under reduced pressure. The residue was diluted with a solution of ammonium chloride and the aqueous layer was extracted with chloroform. The organic layer was washed with a solution of ammonium chloride and a saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced giving the situation and the residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (10,9 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.62 (DD, J=2,0, of 14.0 Hz, 1H), 2,58 (dt, 8,8, of 14.0 Hz, 1H), 3,68 (d, 1.6 Hz, 1H), 3,85 (DD, J=2,0, 12.0 Hz, 1H), 3,92 (d, J=2.0 Hz, 1H), 3,95 (d, J=2.0 Hz, 1H), 4,14 (DD, J=1,6, 12.0 Hz, 1H), 7,27 (DD, J=8.0 Hz, 10.0 Hz, 1H), 7,40-the 7.43 (m, 2H), 7,63 (t, J=2.0 Hz, 1H).

(5)Synthesis of (±)-[(3R*,4R*)-4-(3-bromophenyl)-3-hydroxyethylamino-4-yl]thiourea

Benzoylisothiocyanate (7.20 g) was added to a suspension of (±)-(3R*,4R*)-4-amino-4-(3-bromophenyl)tetrahydropyran-3-ol (10,9 g) in toluene (200 ml). The mixture was stirred at room temperature overnight and then was diluted with tetrahydrofuran followed by the addition of silica gel. The solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel with obtaining an intermediate compound in the form of a crude product. The obtained intermediate compound suspended in methanol (300 ml) was added potassium carbonate (20,0 g). The mixture was stirred at room temperature overnight. Then the insoluble substance was removed by filtration through celite and evaporated under reduced pressure the solvent. The residue was diluted with ethyl acetate and the resulting solid was removed by filtration through celite. The solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (8,63 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,12 (d, J=13,6 Hz, 1H), 2,34 (d, J=6,4 Hz, 1H), 2,58 (DDD, J=4,4, 10,8, of 14.0 Hz, 1H), of 3.77-a 3.83 (m, 2H), 3,88 (dt, J=4,0, 12.0 Hz, 1H), 3,95 (DD, J=2,8, to 12.8 Hz, 1H), a 4.03 (DD, J=2,0, to 12.8 Hz, 1H), 6,60 (s, 1H), 7,35 (t, J=8.0 Hz, 1H), 7,50 (DDD, J=1,2, of 2.0, 8.0 Hz, 1H), 7,54 (DDD, J=1,2, of 2.0, 8.0 Hz, 1H), 7,71 (t, J=2.0 Hz, 1H).

ESI-MS; m/z 333 [M++H].

(6)Synthesis of (±)-(3aS*,7aR*)-7a-(3-bromophenyl)-3a,6,7,7a-tetrahydro-4H-pyrano[4,3-d]thiazole-2-ylamine

Diethylazodicarboxylate (13,0 ml) was added dropwise to a solution of triphenylphosphine (7.51 g) in tetrahydrofuran (200 ml) in an ice bath. The mixture was heated to room temperature and was stirred for 30 minutes. The reaction solution was cooled to 0°C was added dropwise a solution of (±)-[(3R*,4R*)-4-(3-bromophenyl)-3-hydroxyethylamino-4-yl]thiourea (6,33 g) in tetrahydrofuran (44 ml). The mixture was stirred overnight, gradually warming to room temperature. To the reaction mixture were added water and the aqueous layer was extracted with ethyl acetate. The solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel to obtain the crude product. The crude product was again purified by chromatography on a column of silica gel with obtaining specified in the title compound (3.55 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,13-of 2.23 (m, 2H), 3,36 (DD, J=10,8, and 11.6 Hz, 1H), 3,71 (dt, J=3,4 Hz, 1H), 3,89-of 3.96 (m, 2H), 4,08 (DD, J=6,4, 12.0 Hz, 1H), 7,21 (t, J=8.0 Hz, 1H), 7,37-7,40 (m, 2H), 7,60 (t, J=2.0 Hz, 1H).

(7)Synthesis of (±)-N,N-bis(Trets the-butoxycarbonyl)[(3aS*,7aR*)-7a-(3-bromophenyl)-3a,6,7,7a-tetrahydro-4H-pyrano[4,3-d]thiazol-2-yl]amine

4-Dimethylaminopyridine (2,77 g) and di-tert-n-BUTYLCARBAMATE (12.3 g) was added to a solution of (±)-(3aS*,7aR*)-7a-(3-bromophenyl)-3a,6,7,7a-tetrahydro-4H-pyrano[4,3-d]thiazole-2-ylamine (3.55 g) in tetrahydrofuran (500 ml). The mixture was stirred at room temperature for four hours and then evaporated under reduced pressure the solvent at room temperature or below. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (4,49 g).

1H-NMR (400 MHz, CDCl3) δ (ppm): and 1.54 (s, 18H), 2,11 (DDD, J=5,2, 12,4, 14.4 Hz, 1H), 2,31 (dt, J=2,0, 14.4 Hz, 1H), 3,41 (DD, J=10,4, 12.0 Hz, 1H), 3,60-to 3.67 (m, 1H), 3,83-of 3.94 (m, 2H), 4,10 (DD, J=6,2, 11.8 Hz, 1H), 7,20 (t, J=8.0 Hz, 1H), 7,37-7,40 (m, 2H), to 7.59 (d, J=2.0 Hz, 1H).

(8)Synthesis of tert-butyl (±)-{(3aS*,7aR*)-7a-[3-(benzhydrylidene)phenyl]-3a,6,7,7a-tetrahydro-4H-pyrano[4,3-d]thiazol-2-yl}carbamate

Benzophenone (244 μl), BINAP (to 60.6 mg), Tris(dibenzylideneacetone)dipalladium(0) (44,6 mg) and tert-piperonyl sodium (233 mg) was added to a solution of (±)-N,N-bis(tert-butoxycarbonyl)[(3aS*,7aR*)-7a-(3-bromophenyl)-3a,6,7,7a-tetrahydro-4H-pyrano[4,3-d]thiazol-2-yl]amine (250 mg) in toluene (20 ml). After replacement with nitrogen, the mixture was stirred at 85°C for four hours. The reaction solution was brought to room temperature and was added to the reaction mixture water. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with a saturated solution of salt. Organic with the Oh was dried over anhydrous magnesium sulfate and evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (165 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): to 1.38 (s, 9H), to 1.98-2.06 to (ush., 2H), 3,24 (DD, J=6,0, to 10.8 Hz, 1H), 3,35 (t, J=10,8 Hz, 1H), 3,61 (t, J=12,6 Hz, 1H), 3,80-a 3.87 (m, 1H), 3.96 points (DD, J=6,0, the 11.6 Hz, 1H), 6,57 (USS, 1H), PC 6.82 (d, J=7,6 Hz, 1H), 6,95-6,97 (m, 1H), 7,06-was 7.08 (m, 2H), 7,17 (t, J=8.0 Hz, 1H), 7,25-7,28 (m, 4H), 7,39-7,44 (m, 2H), 7,47-7,51 (m, 1H), 7,75-to 7.77 (m, 2H).

ESI-MS; m/z 536 [M++Na].

(9)Synthesis of tert-butyl (±)-[(3aS*,7aR*)-7a-(3-AMINOPHENYL)-3a,6,7,7a-tetrahydro-4H-pyrano[4,3-d]thiazol-2-yl]carbamate

To a solution of tert-butyl (±)-{(3aS*,7aR*)-7a-[3-(benzhydrylidene)phenyl]-3a,6,7,7a-tetrahydro-4H-pyrano[4,3-d]thiazol-2-yl}carbamate (165 mg) in a simple ether (1 ml) was added 1 N. chloride-hydrogen acid (1 ml) and the mixture was stirred at room temperature for one hour. The reaction solution was neutralized with sodium bicarbonate solution, the organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column with NH-silica gel with obtaining specified in the title compound (77 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.41 (s, 9H), 2,04-of 2.28 (m, 2H), 3,38 (t, J=11.2 Hz, 1H), 3,65-4,12 (m, 4H), 6,56-6,60 (m, 1H), 6,69-6,85 (m, 2H), 7,10-to 7.15 (m, 1H).

ESI-MS; m/z 350 [M++H].

Example of getting 76

Synthesis of (±)-N-tert-butoxycarbonyl-N-[(4aS*,8aS*)-8a-(4-bromothiophene-2-yl)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-t is a-1-azonaphthalene-2-yl]benzamide

[Formula 98]

(1)Synthesis of (±)-(3aS*,7aS*)-7a-(4-bromothiophene-2-yl)hexahydropyrazino[4,3-c]isoxazol

Specified in the title compound (166 mg) was obtained from the compound obtained in example obtain 8-(2) (100 mg)and 2,4-dibromothiophene (400 mg) in accordance with the method of example obtaining 21-(3).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,05 (ush., 1H), 2.26 and (ush., 1H), 2,80 (ush., 1H), 3,44-to 4.23 (m, 6H), 7,03 (s, 1H), 7,21 (s, 1H).

(2)Synthesis of (±)-[(3R*,4S*)-4-amino-4-(4-bromothiophene-2-yl)-tetrahydropyran-3-yl]methanol

Zinc (374 mg) was added to a solution of (±)-(3aS*,7aS*)-7a-(4-bromothiophene-2-yl)hexahydropyrazino[4,3-c]isoxazol (166 mg) in acetic acid (5 ml) and the mixture was stirred at room temperature overnight. The insoluble substance was removed by filtration through celite and evaporated under reduced pressure the solvent. To the residue was added ice, followed by neutralization 2 N. a solution of sodium hydroxide. The aqueous layer was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (147 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,65 (dt, J=2,8, of 14.0 Hz, 1H), 2.00 in to 2.06 (m, 1H), 2,25 (DDD, J=5,2, 10,8, of 14.0 Hz, 1H), 3,62 (DD, J=4.0 a, and 11.6 Hz, 1H), 3,70 (DD, J=4,4, to 11.6 Hz, 1H), 3,81-3,95 (m, 4H), 6,94 (d, J=1.4 Hz, 1H), 7,14 (d, J=1,4 Hz, 1H).

(3)Synthesis of (±)-1-benzoyl-3-[(3R*,4S*)-4-(4-bromothiophene-2-yl)-3-hydroxyethylacrylate-4-yl]thiourea

Benzoylisothiocyanate to 66.5 μl) was added to a solution of (±)-[(3R*,4S*)-4-amino-4-(4-bromothiophene-2-yl)tetrahydropyran-3-yl]methanol (144 mg) in dichloromethane (5 ml). The mixture was stirred at room temperature overnight and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (233 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,65 (DD, 4,4, 6.0 Hz, 1H), 2,19 (DDD, J=3,6, to 10.8, 14.4 Hz, 1H), 2,27 (USS, 1H), 3,74-4,06 (m, 6H), 6,94 (d, J=1.6 Hz, 1H), 7,18 (d, J=1.6 Hz, 1H), 7,52-7,56 (m, 2H), 7,63-to 7.67 (m, 1H), 7,86-7,88 (m, 2H), 8,88 (s, 1H), 11,64 (s, 1H).

(4)Synthesis of (±)-N-[(4aS*,8aS*)-8a-(4-bromothiophene-2-yl)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]benzamide

(±)-1-Benzoyl-3-[(3R*,4S*)-4-(4-bromothiophene-2-yl)-3-hydroxyethylacrylate-4-yl]thiourea (233 mg) was dissolved in methanol (5 ml). Added a few drops of concentrated chloride-hydrogen acid, followed by stirring for two hours. The reaction solution was brought to room temperature and evaporated under reduced pressure, the solvent is obtaining specified in the connection header.

ESI-MS; m/z 439 [M++H].

(5)Synthesis of (±)-N-tert-butoxycarbonyl-N-[(4aS*,8aS*)-8a-(4-bromothiophene-2-yl)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-Aza is aftalen-2-yl]benzamide

4-Dimethylaminopyridine (of 40.3 mg) and di-tert-BUTYLCARBAMATE (48 mg) was added to a solution of (±)-N-[(4aS*,8aS*)-8a-(4-bromothiophene-2-yl)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]benzamide (48 mg) in tetrahydrofuran (2 ml). The mixture was stirred at room temperature for two hours and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (60,0 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.36 (s, 9H), to 2.06 (d, J=12,8 Hz, 1H), and 2.26 (dt, J=4,4, to 12.8 Hz, 1H), 2,37 is 2.43 (m, 1H), 2,65 (DD, J=2,8, 13,2 Hz, 1H), 3,25 (DD, J=4,0, 13,2 Hz, 1H), 3,36 (dt, J=2.0 Hz, and 12.4 Hz, 1H), 3,78-a 3.83 (m, 3H), 7,01 (d, J=1.8 Hz, 1H), 7,15 (d, J=1.8 Hz, 1H), 7,44-of 7.48 (m, 2H), 7,54-7,58 (m, 1H), 7,74-7,76 (m, 2H).

Example of getting 77

Synthesis of (±)-6-{(E)-2-[3-((4aR*,7aS*)-2-amino-4a,5,6,7,-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]vinyl}nicotinanilide

[Formula 99]

Synthesis of (±)-N,N-bis(tert-butoxycarbonyl)-6-{(E)-2-[3-((4aR*,7aS*)-2-amino-4a,5,6,7,7a-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]vinyl}nicotinanilide

The compound obtained in example getting 72 (100 mg)was mixed with TRANS-1,2-bis(tri-n-butylstannyl) (114 mg), 2-bromo-5-cyanopyridine (35 mg), three(o-tolyl)phosphine (9,2 mg) and bis(acetonitrile)dichloropalladium(II) (2.8 mg) in toluene (3 ml) and the mixture was stirred in nitrogen atmosphere at 80°C during the night. Reactio the bacterial suspension was concentrated and then the residue was purified preparative HPLC. The resulting product was again purified ptsh obtaining specified in the title compound (17 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1.57 in (s, 18H), 1,80-2,20 (m, 5H), 2,68-is 2.88 (m, 3H), of 3.07 (DD, J=3,4, 13.3 Hz, 1H), 7,07 (DD, J=8,5, and 12.2 Hz, 1H), 7,32 (d, J=15,8 Hz, 1H), 7,41 (m, 2H), 7,81 (d, J=and 12.2 Hz, 1H), 7,87 (DD (DD, J=2.1 and and 8.2 Hz, 2H), 8,81 (d, J=2.1 Hz, 1H).

An example of retrieving 78

Synthesis of (±)-(4aR*,7aS*)-7a-(5-ethinyl-2-forfinal)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-amine

[Formula 100]

(1)Synthesis of (±)-(4aR*,7aS*)-7a-{2-fluoro-5-[(trimethylsilyl)ethinyl]phenyl}-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-amine

The compound obtained in the example of a 54-(4) (100 mg)was mixed with dichloride bis(triphenylphosphine)palladium(II) (60 mg), copper iodide(I) (2.3 mg) and amenitiesalarm (60 mg) in triethylamine (1.75 ml) and tetrahydrofuran (0.25 ml) and the mixture was stirred in nitrogen atmosphere at 90°C during the night. The reaction suspension was filtered and concentrated. Then the obtained residue was purified preparative HPLC to obtain specified in the title compound (31 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 0,26 (s, 9H), from 2.00 (m, 4H), 2,30 (m, 1H), to 2.55 (m, 1H), 2,88 (DD, J=3,5, 12,5 Hz, 1H), 3.00 and-3,14 (m, 2H), 7,00 (DD, J=8,4, 12.3 Hz, 1H), 7,34 (DD, J=2,0, 7.9 Hz, 1H), 7,40 (m, 1H), 9,31 (USS, NH2).

(2)Synthesis of (±)-(4aR*,7aS*)-7a-(5-ethinyl-2-forfinal)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-amine

Tetrabutylammonium (2.9 m is) was added to a solution of compounds obtained in the example of a 78-(1) (500 mg)in tetrahydrofuran (30 ml) and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture were added a saturated salt solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by chromatography on a column of silica gel with obtaining specified in the title compound (59 mg).

ESI-MS; m/z 275 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,74-2,00 (m, 5H), 2,58 (m, 1H), 2,81 (m, 2H), 2,97 (DD, J=3,1, 12,5 Hz, 1 H), 3,05 (s, 1H), 6,99 (DD, J=8,3, and 12.2 Hz, 1H), 7,37 (m, 1H), of 7.48 (DD, J=2,2, of 8.00 Hz, 1H).

Example 1

Synthesis of tert-butyl (±)-((4aR*,8aS*)-8a-{5-[(5-chloropyridin-2-carbonyl)amino]-2-forfinal}-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl)carbamate

[Formula 101]

5-Chloropyridin-2-carboxylic acid (30,4 mg) and triethylamine (89,0 ml) was added to a solution of compound of example, obtain 1-(8) (58,0 mg) in DMF (5,63 ml). 1-Hydroxybenzotriazole (26,0 mg) and EDC·HCl (61,4 mg) was added to the reaction solution in an ice bath. The reaction solution was heated to room temperature, followed by stirring overnight. To the reaction mixture were added ice with subsequent extraction atilas what tatom. The organic layer was washed with water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on a column of silica gel with obtaining specified in the connection header (23,0 mg).

ESI-MS; m/z 519 [M+H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1.57 in (s, 9H), 1,64-1,89 (m, 7H), is 2.37 (m, 1H), 2,53 (m, 1H), 2,88 (USS, 1H), only 2.91 (d, J=2.4 Hz, 1H), 7,12 (DD, J=8,8, 12.0 Hz, 1H), 7,18 (m, 1H), 7,88 (DD, J=2,8, and 8.4 Hz, 1H), they were 8.22 (d, J=8,4 Hz, 1H), 8,23 (m, 1H), 8,59 (d, J=2.0 Hz, 1H), 9,84 (s, 1H).

Example 2

Synthesis of (±)-N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-chloropyridin-2-carboxamide

[Formula 102]

Triperoxonane acid (200 μl) was added to a solution of compound from example 1 (23,0 mg) in dichloromethane (1,00 ml) and the mixture was stirred at room temperature for four hours. The reaction solution was diluted with diethyl ether and neutralized with sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with a saturated solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to get osteoto was purified by chromatography on a column with NH-silica gel with obtaining specified in the connection header (18,0 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,37-1,90 (m, 7H), of 2.20 (m, 1H), 2,56 (DD, J=2,8, and 12.2 Hz, 1H), 2,74 (m, 1H), equal to 2.94 (DD, J=4.0 a, and 12.2 Hz, 1H), 7,06 (DD, J=8,8, 12.0 Hz, 1H), 7,27 (m, 1H), 7,87 (DD, J=2,8, and 8.4 Hz, 1H), 7,98 (m, 1H), 8,24 (DD, J=0,8, and 8.4 Hz, 1H), 8,56 (DD, J=0,8, 2.4 Hz, 1H), made up 9.77 (s, 1H).

Example 3

Synthesis of (+)-N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-chloropyridin-2-carboxamide

[Formula 103]

(±)-2-[(4aR*,8aS*)-2-Amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl]-4-(5-chloropyridin-2-carbylamine)torbenson obtained in example 2 (10 mg), optically separated using CHIRALPAK™ OD-H production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 8:2, flow rate: 20 ml/min). Component having a retention time of six minutes, collected and again purified sequentially NH-ptsh, LC-MS and chromatography on a column with NH-silica gel with obtaining specified in the header (+)-isomer (2.0 mg; >99% ee).

ESI-MS; m/z 419 [M+H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,37-1,90 (m, 7H), of 2.20 (m, 1H), 2,56 (DD, J=2,8, and 12.2 Hz, 1H), 2,74 (m, 1H), equal to 2.94 (DD, J=4.0 a, and 12.2 Hz, 1H), 7,06 (DD, J=8,8, 12.0 Hz, 1H), 7,27 (m, 1H), 7,87 (DD, J=2,8, and 8.4 Hz, 1H), 7,98 (m, 1H), 8,24 (DD, J=0,8, and 8.4 Hz, 1H), 8,56 (DD, J=0,8, 2.4 Hz, 1H), made up 9.77 (s, 1H).

Example 4 (method, alternative to example 3)

Synthesis of (+)-N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-chloropyridin-2-carboxamide

[Formula 104]

N,N-Dimethylformamide (one drop) and thionyl chloride (1 ml) was added to a suspension of 5-khlorpirimidinov acid (55,2 mg) in toluene (5 ml). The mixture was boiled under reflux for one hour. The reaction solution was cooled to room temperature and then evaporated under reduced pressure, the solvent is getting chloride 5-khlorpirimidinov acid. The solution of chloride of 5-khlorpirimidinov acid in THF (5 ml) and pyridine (115 ml) was sequentially added to a solution of compound of example obtaining 2-(2) (111 mg) in THF (10 ml) under cooling with ice. The mixture was heated to room temperature and was stirred for 30 minutes. After confirming the completion of reaction, to the mixture was added a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain amide synthetic intermediate compounds. The obtained amide was dissolved in dichloromethane (10 ml). Added triperoxonane acid (2 ml) and the mixture was stirred at room temperature for three hours. The reaction solution was diluted with diethyl ether. Then the reaction mixture was neutralized with aqueous bicarbonate NAT the Oia with subsequent extraction with ethyl acetate. The organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on a column with NH-silica gel with obtaining specified in the title compound (115 mg, >99% ee).

Example 5

Synthesis of (+)-N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-chloropyridin-2-carboxamide

[Formula 105]

Specified in the header connection (to 39.5 mg, >99% ee) was obtained from the compound obtained in example of preparation of 3-(8) (45.0 mg)and 5-chloropyridin-2-carboxylic acid (23,3 mg) according to example 4.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,73-2,00 (m, 5H), 2,61 (m, 1H), 2,75 (DD, J=4,0, of 12.6 Hz, 1H), and 2.83 (m, 1H), 2,99 (DD, J=3.2, and of 12.6 Hz, 1H), 7,05 (DD, J=8,8, 12.0 Hz, 1H), 7,40 (DD, J=2,8, 7.2 Hz, 1H), 7,87 (DD, J=2,4, and 8.4 Hz, 1H), 7,94 (m, 1H), 8,23 (d, J=8,4 Hz, 1H), 8,55 (DD, J=0,8, 2.4 Hz, 1H), 9,79 (s, 1H).

Example 6

Synthesis of N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]pyridine-2-carboxamide

[Formula 106]

Specified in the header connection (4,20 mg) was obtained from the compound obtained in example of preparation of 3-(8) (15,0 mg), and hydrochloride of ptolemaida (8,76 mg) according to the method of example 5.

1H-I Is R (400 MHz, CDCl3) δ (ppm): 1,76-2,02 (m, 5H), 2,62 (m, 1H), was 2.76 (DD, J=4,0, to 12.8 Hz, 1H), 2,84 (m, 1H), 3,01 (DD, J=3.2, and to 12.8 Hz, 1H), 7,06 (DD, J=8,8, 12.0 Hz, 1H), 7,39 (DD, 2,4, 6,8 Hz, 1H), 7,49 (DD, J=4,4, 7,6 Hz, 1H), to $ 7.91 (m, 1H), 8,00 (m, 1H), 8,29 (DD, J=1,2, 7,6 Hz, 1H), 8,62 (DDD, J=0,8, 1,2, 4,8 Hz, 1H), 9,99 (s, 1H).

Example 7

Synthesis of N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]nicotinamide

[Formula 107]

The triethylamine (30,4 μl), 1-hydroxybenzotriazole (12,2 mg) and EDC·HCl (21,0 mg) was added to a solution of the compound obtained in example of preparation of 3-(8) (10.0 mg)and nicotinic acid (10.1 mg) in DMF (2.00 ml). The reaction solution was stirred at room temperature for four days. Then to the reaction mixture was added ice water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then evaporated under reduced pressure the solvent. The crude product was purified ptsh to obtain the corresponding amide. TFOC (2.00 ml) was added to a solution of the obtained amide in dichloromethane (5,00 ml) and the mixture was stirred at room temperature for three hours. After confirming completion of the reaction, the reaction solution was diluted with toluene and evaporated under reduced pressure, R is storytell at room temperature or below. The residue was purified by NH-ptsh obtaining specified in the connection header (3,80 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,75-of 1.94 (m, 5H), 2,36 (ush., 2H), 2,60 (m, 1H), was 2.76 (DD, J=4,0, to 12.8 Hz, 1H), 2,85 (m, 1H), 2,97 (DD, 3,6, to 12.8 Hz, 1H), 7,06 (DD, J=8,8, 12.0 Hz, 1H), 7,26 (m, 1H), 7,43 (DD, J=4,8, 7.2 Hz, 1H), 7,89 (m, 1H), to 8.20 (d, J=8.0 Hz, 1H), 8,77 (DD, J=1,6, 4.8 Hz, 1H), which is 9.09 (d, J=1.6 Hz, 1H).

Example 8

Synthesis of N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]isonicotinamide

[Formula 108]

Specified in the header connection (3,20 mg) was obtained from the compound obtained in example of preparation of 3-(8) (10.0 mg), and isonicotinic acid (10.1 mg) according to the method of example 7.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,75-of 1.97 (m, 5H), at 2.59 (m, 1H), was 2.76 (DD, J=4,0, to 12.8 Hz, 1H), 2,84 (m, 1H), 2,96 (DD, J=3.2, and to 12.8 Hz, 1H), 7,07 (DD, J=8,8, and 12.4 Hz, 1H), 7,27 (m, 1H), 7,69 (DD, J=1,6, 4,4 Hz, 2H), 7,88 (m, 1H), 8,79 (DD, J=1,2, 4,4 Hz, 2H).

Example 9

Synthesis of N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-herperidin-2-carboxamide

[Formula 109]

Specified in the header connection (7,20 mg) was obtained from the compound obtained in example of preparation of 3-(8) (12.0 mg), and 5-herperidin-2-carboxylic acid (10.5 mg) in accordance with the method of example 4.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,63-2,00 (m, 5H), 2,61 (m, 1H), was 2.76 (DD, J=4,0, to 12.8 Hz, 1H), 2,82 (m, 1H), 3,00 (DD, J=3.2, and to 12.8 Hz, 1H), 4,43 (ush., 2H), 7,05 (DD, J=8,8, and 12.4 Hz, 1H), 7,38 (DD, J=2,8, 7.2 Hz, 1H), to 7.59 (m, 1H), 7,95 (m, 1H), with 8.33 (DD, J=4,8, 8,8 Hz, 1H), 8,45 (d, J=2,8 Hz, 1H), made up 9.77 (s, 1H).

Example 10

Synthesis of N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-6-chloropyridin-2-carboxamide

[Formula 110]

Specified in the header connection (10,8 mg) was obtained from the compound obtained in example of preparation of 3-(8) (10.0 mg), and 6-chloropyridin-2-carboxylic acid (7,75 mg) according to the method of example 4.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1.70 to 2,07 (m, 5H), 2,60 (m, 1H), was 2.76 (DD, J=4,0, to 12.8 Hz, 1H), 2,85 (m, 1H), 3,01 (DD, J=3.2, and to 12.8 Hz, 1H), 7,05 (DD, J=8,8, 12.0 Hz, 1H), 7,41 (DD, J=2,8, 7.2 Hz, 1H), 7,51 (DD, J=1,2, 8.0 Hz, 1H), 7,87 (t, J=8.0 Hz, 1H), 7,95 (m, 1H), they were 8.22 (DD, J=0,8 and 7.6 Hz, 1H), to 9.66 (s, 1H).

Example 11

Synthesis of N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-4-chloropyridin-2-carboxamide

[Formula 111]

Specified in the header connection (9,60 mg) was obtained from the compound obtained in example of preparation of 3-(8) (10.0 mg), and 4-chloropyridin-2-carboxylic acid (7,75 mg) according to the method of example 4.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,69-to 1.98 (m, 5H), 2,61 (m, 1H), was 2.76 (DD, J=4,0, to 12.8 Hz, 1H), and 2.83 (m, 1H), 2,99 (DD, 3,2, to 12.8 Hz, 1H), 7,06 (DD, J=8,8, 12.0 Hz, 1H), 7,39 (DD, J=2,8, 7.2 Hz, 1H), of 7.48 (DD, J=2.0 a, 5,2 Hz, 1H), of 7.96 (m, 1H), 8,29 (DD, J=0,4, 2.0 Hz, 1H), 8,51 (DD, J=0,4, and 5.2 Hz, 1H), 9,87 (s, 1H).

Example 12

Synthesis of N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-3-chloropyridin-2-carboxamide

[Formula 112]

Specified in the header connection (4,20 mg) was obtained from the compound obtained in example of preparation of 3-(8) (11.0 mg)and 3-chloropyridin-2-carboxylic acid (7,11 mg) according to the method of example 4.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,69-of 1.97 (m, 5H), 2,60 (m, 1H), was 2.76 (DD, J=4,0, of 12.6 Hz, 1H), 2,84 (m, 1H), 9,40 (DD, J=3.2, and of 12.6, 1H), 7,05 (DD, J=8,8, 12.0 Hz, 1H), 7,25 (m, 1H), 7,43 (DD, J=4,4, 8.0 Hz, 1H), 7,88 (DD, 1,2, 8.0 Hz, 1H), 8,08 (m, 1H), 8,53 (DD, J=1,2, 4,8 Hz, 1H), 9,86 (s, 1H).

Example 13

Synthesis of (+)-N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)phenyl]5-chloropyridin-2-carboxamide

[Formula 113]

Specified in the header connection (66,1 mg, >99% ee) was obtained from tert-butyl [(4aR*,8aS*)-8a-(3-AMINOPHENYL)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in example 4-(8) (110 mg), and 5-chloropyridin-2-carboxylic acid (62.3 mg) according to the method of example 4.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,49-1,89 (m, 8H), and 2.26 (m, 1H), 2,47 (DD, J=2,8, 12.0 Hz, 1H), 2,93 (DD, J=4,4, 12.0 Hz, 1H), 7,12 (dt, J=1,6, 8.0 Hz, 1H), 7,35 (t, J=8.0 Hz, 1H), to 7.67 (m, 2H), 7,88 (DD, J=2,4, and 8.4 Hz, 1H), 8,25 (d, J=8,4 Hz, 1H), 8,58 (d, J=0.8 Hz, 1H), 9,83 (s, 1H).

Example 14

Synthesis of (+)-N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4,5-differenl]-5-chloro what iridin-2-carboxamide

[Formula 114]

5-Khlorpirimidinov acid (4.16 mg), N,N-diisopropylethylamine (8,98 ml) and PyBOP (22.9 mg) was added to a solution of the compound obtained in example obtain 5-(8) (7,00 mg), in dichloromethane (4,00 ml). The reaction solution was stirred at room temperature for three days. Then the reaction mixture was purified by chromatography on a column with NH-silica gel to obtain the amide. The obtained amide was dissolved in dichloromethane (4,00 ml) and added triperoxonane acid (1,00 ml). The reaction solution was stirred at room temperature for three hours. Then was added a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column of silica gel with obtaining specified in the connection header (5,80 mg, >99% ee).

ESI-MS; m/z 437 [M+H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,51-of 1.95 (m, 7H), of 2.20 (m, 1H), 2,62 (DD, J=2,8, and 12.2 Hz, 1H), and 2.79 (m, 1H), 2,98 (DD, J=4.0 a, and 12.2 Hz, 1H), 6,95 (m, 1H), 7,89 (DD, J=2,4, and 8.4 Hz, 1H), 8,12 (m, 1H), they were 8.22 (d, J=8,4 Hz, 1H), 8,58 (d, J=2.0 Hz, 1H), 9,84 (s, 1H).

Example 15

Synthesis of N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4,5-differenl]-pyridine-2-carboxamide

[Formula 115]

Specified in the header connection (6,30 mg) was obtained from the compound obtained in example obtain 5-(8) (7,00 mg), and pikolinos acid (4.16 mg) according to the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,52-of 1.84 (m, 7H), of 2.21 (m, 1H), 2,59 (DD, J=2,8, 12.0 Hz, 1H), 2,73 (m, 1H), 2,96 (DD, J=4,0, 12.0 Hz, 1H), of 6.96 (m, 1H), 7,50 (DDD, J=1,2, 4,8, 8.0 Hz, 1H), to $ 7.91 (dt, J=1,6, 8.0 Hz, 1H), 8,12 (DDD, J=2,8, 6,8, and 11.6 Hz, 1H), 8,27 (DD, J=1,2, 8.0 Hz, 1H), 8,61 (DDD, J=0,8, of 1.6, 4.8 Hz, 1H), 9,99 (s, 1H).

Example 16

Synthesis of N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4,5-differenl]-5-herperidin-2-carboxamide

[Formula 116]

Specified in the title compound (2.30 mg) was obtained from the compound obtained in example obtain 5-(8) (7,00 mg), and 5-herperidin-2-carboxylic acid (7,45 mg) according to the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,53 of-1.83 (m, 7H), of 2.21 (m, 1H), 2,60 (d, J=12.0 Hz, 1H), 2,73 (m, 1H), 2,96 (DD, J=3.2, and 12.0 Hz, 1H), 6,95 (m, 1H), 7,60 (dt, J=2,8, and 8.4 Hz, 1H), 8,08 (DDD, J=2.0 a, 6,8, and 11.6 Hz, 1H), 8,31 (DD, J=4,8, 8,8 Hz, 1H), 8,45 (d, J=2,8 Hz, 1H), 9,78 (s, 1H).

Example 17

Synthesis of N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4,5-differenl]-3-chloropyridin-2-carboxamide

[Formula 117]

Specified in the header connection (6,20 mg) was obtained from the compound obtained in example obtain 5-(8) (7,00 mg)and 3-chloropicolinic acid (4.16 mg) in the accordance with the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,52-to 1.82 (m, 7H), 2,19 (m, 1H), 2,59 (DD, J=2,8, and 12.4 Hz, 1H), 2,72 (m, 1H), 2,96 (DD, J=4.0 a, and 12.4 Hz, 1H), PC 6.82 (m, 1H), 7,44 (DD, J=4,8, 8.0 Hz, 1H), 7,89 (DD, J=1,2, 8.0 Hz, 1H), 8,21 (DDD, J=2,8, 6,8, and 11.6 Hz, 1H), charged 8.52 (DD, J=1,2, 4,8 Hz, 1H), of 9.89 (s, 1H).

Example 18

Synthesis of N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4,5-differenl]for 3,5-differencein-2-carboxamide

[Formula 118]

Specified in the header connection (5,20 mg) was obtained from the compound obtained in example obtain 5-(8) (7,00 mg)and 3,5-diftorhinolonom acid (4.16 mg) according to the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,49-to 1.82 (m, 7H), 2,19 (m, 1H), 2,59 (DD, J=2,8, and 12.2 Hz, 1H), 2,72 (m, 1H), 2,96 (DD, J=4.0 a, and 12.2 Hz, 1H), 6.87 in (m, 1H), 7,39 (DDD, J=2,4, 8,0, 10.4 Hz, 1H), 8,12 (DDD, J=2,8, 6,8, and 11.6 Hz, 1H), 8,35 (d, J=2.4 Hz, 1H), to 9.57 (s, 1H).

Example 19

Synthesis of N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 119]

(1)Synthesis of tert-butyl ((4aR*,8aS*)-8a-{5-[(5-cyano-2-carbonyl)amino]-2-forfinal}-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl)carbamate

PyBOP (219 mg) was added to a solution of compound of example, obtain 13-(2) (46 mg), N,N-diisopropylethylamine (0,11 ml) and the compound of example obtaining 2-(2) (40 mg) in dichloromethane (4 ml). The mixture was stirred at room temperature for 1.5 hours. Re clanny solution was poured into a sodium bicarbonate solution, followed by extraction with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on a column of silica gel (system ethyl acetate-heptane) to obtain the specified title compound (47 mg).

ESI-MS; m/z 510 [M+H].

(2)Synthesis of N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

Triperoxonane acid (1.0 ml) was added to a solution of the compound obtained in example 19-(1) (47 mg), in dichloromethane (2 ml), and the reaction solution was stirred at room temperature for 1.5 hours. The reaction solution was poured into an aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on a column with NH-silica gel system (ethyl acetate-heptane) to obtain the specified title compound (28 mg).

ESI-MS; m/z 410 [M+H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,40-to 1.86 (m, 7H), 2,16-of 2.30 (m, 1H), 2,50-2,60 (m, 1H), 2,66-2,78 (m, 1H), 2,92 (DD, J=4,0, 12.0 Hz, 1H), 7,01 (DD, J=8,8, 12.0 Hz, 1H), 7,24 and 7.36 (m, 1H), 7,86-7,98 (m, 1H), 8,18 (d, J=8.0 Hz, 1H),8,39 (d, J=8.0 Hz, 1H), 8,84 (s, 1H), 9,73 (s, 1H).

Example 20

Synthesis of N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl-4-forfinal]-5-deformatsiei-2-carboxamide

[Formula 120]

Specified in the title compound (275 mg) was obtained from the compound obtained in example of preparation of 3-(8) (230 mg), and 5-deformatsiei-2-carboxylic acid, obtained in the example of a 14-(2) (180 mg), in accordance with the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,78 of 1.99 (m, 6H), 2,60-3,00 (m, 3H), 7,00-7,10 (m, 1H), 7,28-7,35 (m, 1H), 7,51 (t, J=71,6 Hz, 1H), 7,94-of 7.97 (m, 1H), 8.34 per (s, 1H), remaining 9.08 (s, 1H), to 9.45 (s, 1H).

Example 21

Synthesis of N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-formatexpiry-2-carboxamide

[Formula 121]

5-Formatexpiry-2-carboxylic acid obtained in example getting 15-(2) (10,2 mg), N,N-diisopropylethylamine (24,7 ml) and PyBOP (61,5 mg) was added to a solution of the compound obtained in example of preparation of 3-(8) (17.3 mg), in dichloromethane (1.0 ml). The reaction solution was stirred at room temperature for one hour. Then the reaction mixture was purified by chromatography on a column of silica gel to obtain the amide. The obtained amide was dissolved in dichloromethane (750 μl) was added triperoxonane acid (250 μl). The reaction solution is allowed to stand at room temperature for 55 minutes and then evaporated under reduced pressure the solvent. To the residue was added a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column with NH-silica gel with obtaining specified in the title compound (12.1 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,69-2,02 (m, 5H), 2,55-of 2.66 (m, 1H), was 2.76 (DD, J=12,6, a 4.9 Hz, 1H), 2,79-is 2.88 (m, 1H), 3,00 (DD, J=12,6, 4.0 Hz, 1H), 6,07-6,11 (m, 1H), to 6.19-6,23 (m, 1H), 7,06 (DD, J=12,0, 8.6 Hz, 1H), was 7.36 (DD, J=7,2, 3.0 Hz, 1H), 7,92-7,98 (m, 1H), 8,29 (d, J=1.2 Hz, 1H), remaining 9.08 (d, J=1.2 Hz, 1H), for 9.47 (USS, 1H).

Example 22

Synthesis of N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 122]

5 n sodium hydroxide Solution (50,1 ml) was added to a solution of the compound obtained in the example of a 13-(1), methyl 5-cyano-2-carboxylate (30 mg) in ethanol and the mixture was stirred at room temperature for 15 minutes. The reaction solution was acidified 5 N. chloride-hydrogen acid. To the reaction solution were added ethyl acetate and a saturated salt solution, and separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure the solvent. Specified in the title compound (28 mg) was obtained from the obtained 5-cyano-2-carboxylic acid and compounds, is received in the sample preparation of 3-(8) (35 mg), in accordance with the method of example 14.

ESI-MS; m/z 396 [M++H].

1H-NMR (CDCl3) δ (ppm): 1,74-2,00 (m, 5H), 2.57 m-of 2.64 (m, 1H), 2,78 (DD, J=4,0, to 12.8 Hz, 1H), 2,85-only 2.91 (m, 1H), 3,00 (DD, J=3.2, and to 12.8 Hz, 1H), was 7.08 (DD, J=8,8, and 12.4 Hz, 1H), 7,40 (DD, J=2,8, 7.2 Hz, 1H), 7.95 is-to 7.99 (m, 1H), 8,20 (DD, J=2,0, 8.0 Hz, 1H), 8,42 (DD, J=0,8, 8.0 Hz, 1H), 8,90 (DD, J=0,8, 2.0 Hz, 1H), 9,84 (USS, 1H).

Example 23

Synthesis of N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-formatexception-2-carboxamide

[Formula 123]

Specified in the title compound (31 mg) was obtained from 5-formatexception-2-carboxylic acid, obtained in example 16-(2) (22,4 mg)and the compound obtained in example of preparation of 3-(8) (35 mg), in accordance with the method of example 14.

ESI-MS; m/z 419 [M++H].

1H-NMR (CDCl3) δ (ppm): 1,60-2,00 (m, 5H), 2.57 m-of 2.64 (m, 1H), was 2.76 (DD, J=4.0 a, and 12.4 Hz, 1H), 2,80-to 2.85 (m, 1H), 2,99 (DD, J=3,2, and 12.4 Hz, 1H), 5,80 (d, J=53,2 Hz, 2H), 7,05 (DD, J=8,8, and 12.4 Hz, 1H), 7,37 (DD, J=2,8, 7.2 Hz, 1H), EUR 7.57 (DD, J=2,8, 8,8 Hz, 1H), 7,94-7,98 (m, 1H), 8,29 (d, J=8,8 Hz, 1H), to 8.41 (d, J=2,8 Hz, 1H), 9,80 (USS, 1H).

Example 24

Synthesis of N-[3-((4aS*,7aS*)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 124]

Specified in the title compound (30 mg) was obtained from 5-cyano-2-carboxylic acid obtained in example obtain 13-(2) (21.2 mg)and the compound obtained in the example is receiving 9-(10) (35 mg), in accordance with the method of example 14.

ESI-MS; m/z 398 [M++H].

1H-NMR (CDCl3) δ (ppm): 2,82-is 2.88 (m, 1H), 3,07-3,10 (m, 2H), 3,84 (DD, J=2,4, 8,8 Hz, 1H), 4,08-4,19 (m, 2H), 4,46 (DD, J=2,4, 8,8 Hz, 1H), 7,11 (DD, J=8,4, 12.0 Hz, 1H), 7.62mm (DD, J=2,8, 7.2 Hz, 1H), 7,94-7,98 (m, 1H), 8,21 (DD, J=1,6, 8.0 Hz, 1H), 8,43 (d, J=8.0 Hz, 1H), 8,90 (d, J=1.6 Hz, 1H), 9,86 (s, 1H).

Example 25

Synthesis of N-[3-((4aS*,7aS*)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformatsiei-2-carboxamide

[Formula 125]

Specified in the title compound (27 mg) was obtained from 5-deformatsiei-2-carboxylic acid, obtained in the example of a 14-(2) (21,7 mg)and the compound obtained in the example of a 9-(10) (35 mg), in accordance with the method of example 14.

ESI-MS; m/z 440 [M++H].

1H-NMR (CDCl3) δ (ppm): 2,82-2,87 (m, 1H), 3,06-3,13 (m, 2H), 3,83 (DD, J=2,4, and 9.2 Hz, 1H), 4,07-4,18 (m, 2H), 4,46 (DD, J=1,2, and 8.4 Hz, 1H), to 7.09 (DD, J=8,8, and 11.6 Hz, 1H), 7,51 (t, J=71,6 Hz, 1H), to 7.59 (DD, J=2,8, 7.2 Hz, 1H), to $ 7.91-to 7.95 (m, 1H), 8.34 per (d, J=0.8 Hz, 1H), 9,07 (d, J=1.2 Hz, 1H), to 9.45 (s, 1H).

Example 26

Synthesis of N-[3-((4aS*,7aS*)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-chloropyridin-2-carboxamide

[Formula 126]

Specified in the title compound (30 mg) was obtained from 5-chloropyridin-2-carboxylic acid (21,7 mg) and the compound obtained in the example of a 9-(10) (35 mg), in accordance with the method of example 14.

ESI-MS; m/z 407 [M+ +H].

1H-NMR (CDCl3) δ (ppm): 2,81-of 2.86 (m, 1H), 3,07-3,13 (m, 2H), 3,83 (DD, J=2,4, 8,8 Hz, 1H), 4,08-4,18 (m, 2H), 4,46 (DD, J=1,6, and 8.4 Hz, 1H), to 7.09 (DD, J=8,8, and 11.6 Hz, 1H), to 7.61 (DD, J=2,4, 7.2 Hz, 1H), 7,88 (DD, J=2,4, and 8.4 Hz, 1H), to $ 7.91-to 7.95 (m, 1H), 8,24 (d, J=8,4 Hz, 1H), 8,56 (DD, J=0,8, 2.4 Hz, 1H), 9,83 (s, 1H).

Example 27

Synthesis of N-[3-((7S*,7aS*)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-formatexpiry-2-carboxamide

[Formula 127]

The compound obtained in the example of a 15-(2) (18,4 mg), N,N-diisopropylethylamine (39,8 ml) and PyBOP (99,1 mg) was added to a solution of the compound obtained in the example of a 9-(10) (28,0 mg), in dichloromethane (800 ml). The reaction solution was stirred at room temperature for 16 hours and 30 minutes. Then the reaction mixture was purified by chromatography on a column of silica gel to obtain the amide. The obtained amide was dissolved in dichloromethane (600 ml) and was added triperoxonane acid (200 μl). The reaction solution was allowed to stand at room temperature for one hour and then evaporated under reduced pressure the solvent. To the residue was added a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column with NH-silica gel with obtaining specified in the connection header (14,5 mg).

sup> 1H-NMR (400 MHz, CDCl3) δ (ppm): 2,80-is 2.88 (m, 1H), 3,05-3,14 (m, 2H), 3,81-of 3.85 (m, 1H), 4,06-4,19 (m, 2H), of 4.44 figure-4.49 (m, 1H), between 6.08-6,10 (m, 1H), 6,21-6,23 (m, 1H), 7,10 (DD, J=11,6, 8,8 Hz, 1H), 7,58 (DD, J=7,0, 3.0 Hz, 1H), 7,93-7,97 (m, 1H), 8,29 (d, J=1.2 Hz, 1H), remaining 9.08 (d, J=1.2 Hz, 1H), 9,50 (USS, 1H).

Example 28

Synthesis of N-[3-((4aS*,8aS*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 128]

Specified in the title compound (135 mg) was obtained from 5-cyano-2-carboxylic acid obtained in example obtain 13-(2) (113 mg)and the compound obtained in example obtain 8-(9) (195 mg), in accordance with the method of example 14.

ESI-MS; m/z 412 [M++H].

1H-NMR (CDCl3) δ (ppm): 1,68 (d, J=13,6 Hz, 1H), 2,58 (DD, J=2,4, 13,2 Hz, 1H), 2,63-a 2.71 (m, 1H), 2,95 (DD, J=4,4, and 12.4 Hz, 1H), 3,03-of 3.06 (m, 1H), 3,69-3,82 (m, 3H), 3,90 (DD, J=4,0, 11.2 Hz, 1H), 7,10 (DD, J=9,2, 12.0 Hz, 1H), 7,42 (DD, J=2,8, 6,8 Hz, 1H), to $ 7.91-to 7.95 (m, 1H), to 8.20 (DD, J=2.0 a, and 8.4 Hz, 1H), 8,42 (d, J=8.0 Hz, 1H), 8,89 (d, J=2.4 Hz, 1H), 9,82 (s, 1H).

Example 29

Synthesis of N-[3-((4aS*,8aS*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-deformatsiei-2-carboxamide

[Formula 129]

Specified in the title compound (24 mg) was obtained from 5-deformatsiei-2-carboxylic acid, obtained in the example of a 14-(2) (26.1 mg)and the compound obtained in example obtain 8-(9) (35 mg), in accordance with the method of the example 14.

ESI-MS; m/z 454 [M++H].

1H-NMR (CDCl3) δ (ppm): 1,68 (d, J=12,8 Hz, 1H), 2,58 (DD, J=2,4, of 12.8 Hz, 1H), 2,63-a 2.71 (m, 1H), 2,95 (DD, J=4,4, and 12.4 Hz, 1H), 3,03-of 3.07 (m, 1H), 3,69-3,82 (m, 3H), with 3.89 (DD, J=4,4, to 11.6 Hz, 1H), 7,10 (DD, J=9,2, and 12.4 Hz, 1H)that was 7.36 (DD, J=2,8, 6,8 Hz, 1H), of 7.90-7,94 (m, 1H), 8.34 per (d, J=1.2 Hz, 1H), 9,07 (d, J=1.2 Hz, 1H), 9,44 (s, 1H).

Example 30

Synthesis of N-[3-((4aS*,8aS*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-chloropyridin-2-carboxamide

[Formula 130]

Specified in the title compound (21 mg) was obtained from 5-chloropyridin-2-carboxylic acid (21,7 mg) and the compound obtained in example obtain 8-(9) (35 mg), in accordance with the method of example 14.

ESI-MS; m/z 421 [M++H].

1H-NMR (CDCl3) δ (ppm): 1,70 of-1.83 (m, 1H), 2,62 (DD, J=3.2, and to 12.8 Hz, 1H), 2,68 (DD, J=4,4, to 12.8 Hz, 1H), 2,99 (DD, J=4.0 a, and 12.4 Hz, 1H), is 3.08-3.15 in (m, 1H), 3,70-of 3.77 (m, 2H), 3,83 (DD, J=4,4, to 11.6 Hz, 1H), 3,92 (DD, J=4,0, 11.2 Hz, 1H), 7,10 (DD, J=8,8, 12.0 Hz, 1H), 7,41 (DD, J=2,4, 7.2 Hz, 1H), 7,88 (DD, J=2,4, and 8.4 Hz, 1H), 7,92-of 7.96 (m, 1H), 8,24 (d, J=8,4 Hz, 1H), 8,58 (d, J=2.4 Hz, 1H), 9,82 (s, 1H).

Example 31

Synthesis of (+)-N-[3-((4aR*,6S*,7aS*)-2-amino-6-methoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 131]

(1)Synthesis of tert-butyl ((4aR*,6S*,7aS*)-7a-{5-[(5-cyano-2-carbonyl)amino]-2-forfinal}-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl)carbamate

PyBOP (86,9 mg) was added to a solution of tre the-butyl (-)-[(4aR*,6S*,7aS*)-7a-(5-amino-2-forfinal)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate (22 mg), connection example of a 26-(2) (11.6 mg) and N,N-diisopropylethylamine (of 0.11 ml) in dichloromethane (2.2 ml). The mixture was stirred at room temperature for one hour. The reaction solution was poured into a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on a column of silica gel with obtaining specified in the title compound (29 mg).

ESI-MS; m/z 526 [M++H].

(2)Synthesis of (+)-N-[3-((4aR*,6S*,7aS*)-2-amino-6-methoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

Triperoxonane acid (1.0 ml) was added to a solution of tert-butyl (4aR*,6S*,7aS*)-7a-{5-[(5-cyano-2-carbonyl)amino]-2-forfinal}-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate (29 mg) in dichloromethane (2 ml), and the reaction solution was stirred at room temperature for one hour. The reaction solution was poured into a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and f is ltrate concentrated under reduced pressure. The crude product was purified by chromatography on a column with NH-silica gel with obtaining specified in the title compound (12 mg).

Optical rotation (+)

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,98-and 2.14 (m, 2H), 2,22 (DDD, J=6,8, 6,8, 13,2 Hz, 1H), 2,64-to 2.74 (m, 1H), 2,78 (DD, J=4,4, 13,2 Hz, 1H), 2,88-to 3.02 (m, 2H), 3,34 (s, MN), 4,08-4,24 (m, 1H), 7,07 (DD, J=8,8, 12.0 Hz, 1H), 7,38 (DD, J=2,8, 7.2 Hz, 1H), of 7.90-8,02 (m, 1H), to 8.20 (DD, J=2,0, 8.0 Hz, 1H), 8,42 (d, J=8.0 Hz, 1H), of 8.90 (s, 1H), 9,82 (s, 1H).

Example 32

Synthesis of (+)-N-[3-((4aR*,6R*,7aS*)-2-amino-6-methoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 132]

(1)Synthesis of tert-butyl ((4aR*,6R*,7aS*)-7a-{5-[(5-cyano-2-carbonyl)amino]-2-forfinal}-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl)carbamate

PyBOP (86,9 mg) was added to a solution of tert-butyl (-)-[(4aR*,6R*,7aS*)-7a-(5-amino-2-forfinal)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate (22 mg), compound of example, receiving 26-(2) (11.6 mg) and N,N-diisopropylethylamine (of 0.11 ml) in dichloromethane (2.2 ml). The mixture was stirred at room temperature for one hour. The reaction solution was poured into a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and Phi is Trat concentrated under reduced pressure. The crude product was purified by chromatography on a column of silica gel with obtaining specified in the title compound (29 mg).

ESI-MS; m/z 526 [M++H].

(2)Synthesis of (+)-N-[3-((4aR*,6R*,7aS*)-2-amino-6-methoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

Triperoxonane acid (1.0 ml) was added to a solution of tert-butyl ((4aR*,6R*,7aS*)-7a-{5-[(5-cyano-2-carbonyl)amino]-2-forfinal}-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl)carbamate (29 mg) in dichloromethane (2 ml), and the reaction solution was stirred at room temperature for one hour. The reaction solution was poured into a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on a column with NH-silica gel with obtaining specified in the title compound (12 mg).

Optical rotation (+)

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,91 (DDD, J=3,6, 9,6, 13,2 Hz, 1H), 2,22-to 2.40 (m, 2H), 2,62 (DD, J=6,8, to 12.8 Hz, 1H), was 2.76 (DD, J=3.2, and to 12.8 Hz, 1H), 2,99 (DD, J=3.2, and to 12.8 Hz, 1H), 3,10-up 3.22 (m, 1H), 3,34 (s, 3H), 3,88-4,00 (m, 1H), 7,08 (DD, J=8,8, 12.0 Hz, 1H), 7,34-7,46 (m, 1H), 7,86-7,98 (m, 1H), to 8.20 (DD, J=1,2, 8.0 Hz, 1H), 8,42 (d, J=8.0 Hz, 1H), 8,89 (s, 1H), 9,82 (s, 1H).

The use of the 33

Synthesis of (+)-N-[3-((4aR*,9aS*)-2-amino-4a,5,6,7,8,9-hexahydro-4H-cyclohepta[d][1,3]thiazin-9a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 133]

Specified in the title compound (41 mg) was obtained from tert-butyl (-)-[(4aR*,9aS*)-9a-(5-amino-2-forfinal)-4,4a,5,6,7,8,9,9a-octahydrocyclopenta[d][1,3]thiazin-2-yl]carbamate obtained in example obtain 7-(8) (60,0 mg), and 5-cyanopyridine-2-carboxylic acid obtained in example obtain 13-(2) (of 97.8 mg), in accordance with the method of example 14.

ESI-MS; m/z 424 [M+H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,50 is 1.91 (m, 9H), 2,39 (m, 1H), 2,56 (DD, J=3.2, and 12.0 Hz, 1H), 2,71 (m, 1H), 2,86 (DD, J=3.2, and 12.0 Hz, 1H), 7,07 (DD, J=8,8, 12.0 Hz, 1H), 7,27 (m, 1H), 7,97 (DDD, J=2,4, 4,8, 8,8 Hz, 1H), 8,19 (DD, J=of 2.0, 8.0 Hz, 1H), 8,42 (DD, J=1,2, 8.0 Hz, 1H), 8,88 (DD, J=1,2, 2,4 Hz, 1H), 9,79 (s, 1H).

Example 34

Synthesis of (±)-N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-methoxyphenyl]-5-chloropyridin-2-carboxamide

[Formula 134]

5-Chloropyridin-2-carboxylic acid (6,26 mg), N,N-diisopropylethylamine (13,8 ml) and PyBOP (34,5 mg) was added to a solution of the compound obtained in example obtain 6-(2) (10.0 mg), in dichloromethane (1.0 ml). The reaction solution was stirred at room temperature for one hour and 50 minutes and then added triperoxonane acid (250 μl). The reaction solution was allowed to stand at room te is the temperature for 40 minutes and then evaporated under reduced pressure the solvent. To the residue was added a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column with NH-silica gel with obtaining specified in the title compound (1.0 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,72-to 1.98 (m, 5H) of 2.72 (DD, J=12,8, a 4.7 Hz, 1H), 2,74-2,82 (m, 1H), 2,97 (DD, J=of 12.8, 4.0 Hz, 1H), 3,05-of 3.12 (m, 1H), 3,86 (s, 3H), 6,93 (d, J=8,8 Hz, 1H), 7,31 (USD, J=3.5 Hz, 1H), 7,86 (DD, J=8,4, 3,5 Hz, 1H), to 7.99 (DD, J=8,8, 3.5 Hz, 1H), 8,24 (d, J=8,4 Hz, 1H), 8,56 (d, J=3.5 Hz, 1H), 9,73 (USS, 1H).

Example 35

Synthesis of N-[3-((4aS*,7aS*)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamide

[Formula 135]

Specified in the title compound (27 mg) was obtained from 5-deformalisation-2-carboxylic acid, obtained in the example of a 17-(5) in (17.0 mg)and the compound obtained in the example of a 9-(10) (30 mg), in accordance with the method of example 14.

ESI-MS; m/z 424 [M++H].

1H-NMR (CDCl3) δ (ppm): 2,82-2,87 (m, 1H), 3,07-3,13 (m, 2H), 3,83 (DD, J=2,4, 8,8 Hz, 1H), 4,08-4,18 (m, 2H), 4,47 (DD, J=1,6, and 8.4 Hz, 1H), 6,80 (t, J=54,8 Hz, 1H), 7,13 (DD, J=8,8, 12.0 Hz, 1H), 7.62mm (DD, J=2,8, 6,8 Hz, 1H), 7,94-7,98 (m, 1H), 8,93 (s, 1H), at 9.53 (s, 1H), 9,65 (s, 1H).

Example 36

Synthesis of (±)-(4aR,7aS)-7a-[3-(2-herperidin-3-yl)phenyl]-6-phenyl-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-ylamine

[Formula 136]

(1)Synthesis of tert-butyl (±)-{(4aR*,7aS*)-7a-[3-(2-herperidin-3-yl)phenyl]-6-phenyl-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiadiazin-2-yl}carbamate

The compound obtained in the example of a 18-(9) (50,00 mg)was mixed with phenylboronic acid (23.9 mg), copper acetate(II) (3,56 mg), triethylamine (54,3 ml) and molecular sieves 4A (powder) (40,00 mg) in THF, and the mixture was stirred in nitrogen atmosphere at room temperature for 23 hours. The reaction suspension was purified by chromatography on a column with NH-silica gel. The resulting product was again purified by NH-ptsh obtaining specified in the title compound (8 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): for 1.49 (s, 9H), only 2.91 (DD, J=4,8, 13,2 Hz, 1H), 3,01-is 3.08 (m, 2H), 3,60-to 3.64 (m, 1H), 3,69 (d, J=10.4 Hz, 1H), 3.75 to with 3.79 (m, 1H), 4.00 points (d, J=10.0 Hz, 1H), return of 6.58 (d, J=8.0 Hz, 2H), 6.75 in (t, J=7.2 Hz, 1H) 7,21-to 7.32 (m, 3H), 7,41-7,44 (m, 1H), 7,46-of 7.55 (m, 3H), a 7.85 (DDD, J=2.0, the 3,6, and 9.6 Hz, 1H), 8,21-8,23 (m, 1H).

(2)Synthesis of (±)-(4aR*,7aS*)-7a-[3-(2-herperidin-3-yl)phenyl]-6-phenyl-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-ylamine

TFOC (0,50 ml) was added to a solution of the compound obtained in example 36-(1) (8,00 mg)in chloroform (0,50 ml). After stirring at room temperature for 2.5 hours the reaction solution was diluted with chloroform and poured into a mixture of saturated sodium bicarbonate solution and saturated sodium chloride solution, followed by an intense shaking. The aqueous layer was separated and ZAT the organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then evaporated under reduced pressure the solvent. To a solution of the residue in chloroform (0,50 ml) was added TFOC (0,50 ml). After stirring at room temperature for 23 hours, the reaction solution was diluted with chloroform and poured into a mixture of saturated sodium bicarbonate solution and saturated sodium chloride solution, followed by an intense shaking. The aqueous layer was separated and then the organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column with NH-silica gel. The obtained product was dissolved in chloroform and methanol and the solvent evaporated in a stream of nitrogen. To the residue was added diethyl ether and sufficient besieged solid. The solvent is then evaporated in a stream of nitrogen. The residue was dried under reduced pressure to obtain specified in the connection header (6,50 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,75-2,78 (m, 1H), 2,96-is 3.08 (m, 2H), 3,60 (d, J=7,6 Hz, 2H), to 3.67 (d, J=9.6 Hz, 1H), was 4.02 (d, J=10.0 Hz, 1H), 6,59 (d, J=8,4 Hz, 2H), 6,72 (t, J=7.2 Hz, 1H), 7.24 to 7,28 (m, 3H), 7,41-7,46 (m, 3H), 7,54 (s, 1H), 7,82-7,86 (m, 1H), 8,19 (d, J=4.4 Hz, 1H).

Example 37

Synthesis of (±)-(4aR*,7aS*)-7a-[3-(2-herperidin-3-yl)phenyl]-6-pyrimidine-2-yl-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-ylamine

[ormula 137]

2-Bromopyrimidine (93,00 mg), Tris(dibenzylideneacetone)dipalladium(0) (10,70 mg),rat-2,2-bis(diphenylphosphino)-1,1-binaphthyl (10,90 mg) and tert-piperonyl sodium (45,00 mg) was added to a solution of the compound obtained in the example of a 18-(9) (50,00 mg)in toluene (1,00 ml). The mixture was heated with stirring in a nitrogen atmosphere at 70°C for five hours and 45 minutes. The reaction mixture was cooled to room temperature and was diluted with ethyl acetate. Then the reaction solution was filtered through NH-silica gel under reduced pressure and washed with ethyl acetate. The obtained filtrate was concentrated under reduced pressure and then purified by chromatography on a column with NH-silica gel to obtain Boc-protected compound as a synthetic intermediate compounds. TFOC (0,50 ml) was added to a solution of the obtained product in chloroform (0,50 ml). After stirring at room temperature for six hours the reaction solution was diluted with chloroform and poured into a mixture of saturated sodium bicarbonate solution and saturated sodium chloride solution, followed by an intense shaking. The aqueous layer was separated and then the organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then evaporated under reduced pressure the solvent. The residue was purified chromate what graphy on a column with NH-silica gel. The obtained product was dissolved in ethyl acetate and the solvent evaporated in a stream of nitrogen. To the residue was added diethyl ether and sufficient besieged solid. Then evaporated in a stream of nitrogen the solvent. The residue was dried under reduced pressure to obtain specified in the connection header (1,60 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,82-is 2.88 (m, 1H), 2,98 (DD, J=5,2, 13,2 Hz, 1H), 3,13 (DD, J=4,0, 5,2 Hz, 1H), a 3.87 (DD, J=2,8, 4.0 Hz, 2H), 4,07 (d, J=11,6 Hz, 1H), 4,23 (d, J=11,6 Hz, 1H), 6,53 (t, J=4,8 Hz, 1H), 7.24 to 7,29 (m, 1H), 7,44-of 7.48 (m, 3H), 7,56-EUR 7.57 (m, 1H), 7,86 (DDD, J=2,0, to 7.6 and 9.6 Hz, 1H), 8,19-8,21 (m, 1H), 8.34 per (d, J=4,8 Hz, 2H).

Example 38

Synthesis of N-[3-((4aS,7R,8aS)-2-amino-7-methoxymethyl-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-formatexpiry-2-carboxamide

[Formula 138]

The compound obtained in the example of a 19-(14) (45 mg)was dissolved in dichloromethane (2 ml). To the solution was added 5-formatexpiry-2-carboxylic acid (28 mg), N,N-diisopropylethylamine (48 ml) and PyBOP (113 mg), followed by stirring at room temperature. After three hours, the reaction solution was concentrated and the residue was subjected to chromatography on a column of silica gel to obtain the amide (66 mg). Amide (66 mg) was dissolved in dichloromethane (2 ml). Added TFOC (1 ml) and the mixture was stirred at room temperature for 1.5 hours. The reaction solution conc is listed. To the residue was added chloroform, a saturated solution of sodium bicarbonate and 1 n sodium hydroxide solution and the separated organic layer. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was besieged by using tert-butyl methyl ether, ethyl acetate and hexane. The solid substance was collected by filtration to obtain specified in the title compound (36 mg).

ESI-MS; m/z 480 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1.69 in (DD, J=1,6, or 12.8 Hz, 1H), of 2.38 (t, J=12.0 Hz, 1H), 2,56-of 2.64 (m, 1H), 2,96 (DD, J=4,4, to 12.8 Hz, 1H), 2,98-of 3.06 (m, 1H), 3,40 (s, 3H), 3,37-3,51 (m, 2H), 3,79-3,95 (m, 3H), 6,09 (DD, J=2,0, 3.6 Hz, 1H), from 6.22 (DD, J=2,0, 3.6 Hz, 1H), was 7.08 (DD, J=8,8, 12.0 Hz, 1H), 7,30-7,40 (m, 1H), 7,85-to 7.95 (m, 1H), 8,29 (d, J=1.6 Hz, 1H), remaining 9.08 (d, J=1.2 Hz, 1H) 9,45 (USS, 1H).

Examples 39-40

Compounds of examples 39-40, shown below in table 1, was synthesized according to example 38, using the appropriate carboxylic acid.

[Table 1]

Table 1
Example 39Chemical structure
Connection name: N-[3-((4aS,7R,8aS)-2-amino-7-methoxymethyl-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-ftoh the Nile]-5-cyanopyridine-2-carboxamide
ESI-MS m/z 456 [M++H]
Example 40Chemical structure
Connection name: N-[3-((4aS,7R,8aS)-2-amino-7-methoxymethyl-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-deformalisation-2-carboxamide
ESI-MS m/z 482 [M++H]

Example 41

Synthesis of N-[3-((4aS,7R,8aS)-2-amino-7-vermeil-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-formatexpiry-2-carboxamide

[Formula 139]

The compound obtained in the example of a 20-(3) (45 mg)was dissolved in dichloromethane (2 ml). To the solution was added 5-formatexpiry-2-carboxylic acid (28 mg), N,N-diisopropylethylamine (48 ml) and PyBOP (113 mg), followed by stirring at room temperature. After three hours, the reaction solution was concentrated and the residue was subjected to chromatography on a column of silica gel to obtain the amide (67 mg). Amide (67 mg) was dissolved in dichloromethane (2 ml). Then add TFOC (1 ml) and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure. Then to the residue was added chloroform, a saturated solution of sodium bicarbonate and 1 N. Rast is the PR of sodium hydroxide and separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was utverjdali adding tert-butyl methyl ether and hexane. The solid substance was collected by filtration to obtain specified in the title compound (41 mg).

ESI-MS; m/z 468 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,50-1,90 (m, 1H), 2,36-2,48 (m, 1H), 2,58-of 2.66 (m, 1H), 2,92-3,10 (m, 2H), 3,80-Android 4.04 (m, 3H), 4,32-4,43 (m, 1H), of 4.44-of 4.54 (m, 1H), 6,09 (DD, J=2.0 a, 4.0 Hz, 1H), from 6.22 (DD, J=2.0 a, 4.0 Hz, 1H), 7,10 (DD, J=8,8, 12.0 Hz, 1H), 7,35-7,45 (m, 1H), 7,85-to 7.95 (m, 1H), 8,29 (d, J=1.6 Hz, 1H), remaining 9.08 (d, J=1.6 Hz, 1H) 9,46 (USS, 1H).

Examples 42-45

Connection examples 42-45, shown below in table 2, was synthesized according to example 41, using the appropriate carboxylic acid.

[Table 2]

Table 2
Example 42Chemical structure
Connection name: N-[3-((4aS,7R,8aS)-2-amino-7-vermeil-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide
ESI-MS m/z 444 [M++H]
Example 43Himicheskaya structure
Connection name: N-[3-((4aS,7R,8aS)-2-amino-7-vermeil-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-deformalisation-2-carboxamide
ESI-MS m/z 470 [M++H]
Example 44Chemical structure
Connection name: N-[3-((4aS,7R,8aS)-2-amino-7-vermeil-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-deformationen-2-carboxamide
ESI-MS m/z 485 [M++H]
Example 45Chemical structure
Connection name: N-[3-((4aS,7R,8aS)-2-amino-7-vermeil-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-chloropyridin-2-carboxamide
ESI-MS m/z 453 [M++H]

Example 46

Synthesis of (±)-(4aR*,7aS*)-7a-[3-(2-herperidin-3-yl)phenyl]-6-(2,2,2-triptorelin)-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-ylamine

[Formula 140]

The compound obtained in the example of a 18-(9) (50 mg), and N,N-diisopropylethylamine (45 μl) was dissolved in acetonitrile (1 ml). Then was added 2,2,2-triffterer streptomycinresistant (24 μl), followed by stirring at room temperature. After 14 hours was added to the reaction solution, water and ethyl acetate and the separated organic layer. The organic layer was sequentially washed with a saturated solution of salt and saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on a column with NH-silica gel to obtain N-alkyl compound (38 mg) as a crude product. N-alkyl compound (38 mg) was dissolved in dichloromethane (2 ml). Then add TFOC (0.5 ml) followed by stirring for two hours. The reaction solution was concentrated under reduced pressure. To the residue was added chloroform and 2 n sodium hydroxide and the separated organic layer. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was subjected to chromatography on a column with NH-silica gel with obtaining specified in the title compound (18 mg).

ESI-MS; m/z 411 [M++H].

Example 47

Synthesis of (±)-1-{(4aR*,7aS*)-2-amino-7a-[3-(2-herperidin-3-yl)phenyl]-4a,5,7,7a-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-6-yl}-3,3,3-cryptochrome-1-it

[Formula 141]

The connection is obtained when the ore receiving 18-(9) (45 mg), 3,3,3-triptocaine acid (10 μl), N,N-diisopropylethylamine (17 μl) was dissolved in tetrahydrofuran (1 ml). Then was added PyBOP (51 mg), followed by stirring at room temperature. After 14 hours was added to the reaction solution, a saturated sodium bicarbonate solution and ethyl acetate, and separated the organic layer. The organic layer was sequentially washed with saturated salt solution and a saturated solution of ammonium chloride. The organic layer was dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was subjected to NH-ptsh obtaining amide (26 mg) as a crude product. Amide (26 mg) was dissolved in dichloromethane (2 ml). Then add TFOC (0.5 ml) followed by stirring for two hours. The reaction solution was concentrated under reduced pressure. To the residue was added chloroform and 2 n sodium hydroxide and the separated organic layer. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was subjected to chromatography on a column of silica gel with obtaining specified in the title compound (15 mg).

ESI-MS; m/z 439 [M++H].

Example 48

The compound of example 48, shown below in table 3, Sintesi the Wali in accordance with example 47, using the appropriate carboxylic acid.

[Table 3]

Table 3
Example 48Chemical structure
ESI-MS; m/z 411 [M++H].

Example 49

Synthesis of N-[3-((4aS*,5R*,7aS*)-2-amino-5-ethyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 142]

Specified in the header of the connection (of 28.0 mg) was obtained from the compound obtained in the example of obtaining 21-(10) (30.0 mg)and 5-cyanopyridine-2-carboxylic acid obtained in example obtain 13-(2) (22,5 mg), in accordance with the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,04-of 1.07 (m, 3H), 1,65-1,72 (m, 2H), 2,68-2,77 (m, 2H), is 3.08-of 3.12 (m, 1H), 3,80-3,82 (m, 1H), 4,17-4,22 (m, 1H), 4,54-of 4.57 (m, 1H), 7,07-7,13 (m, 1H), 7,52-rate of 7.54 (m, 1H), of 7.96-of 8.00 (m, 1H), 8,19-8,21 (m, 1H), 8,42-8,44 (m, 1H), of 8.90 (s, 1H), 9,85 (ush., 1H).

Example 50

Synthesis of N-[3-((4aS*,5R*,7aS*)-2-amino-5-ethyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformatsiei-2-carboxamide

[Formula 143]

Specified in the header connection (22,0 mg) was obtained from the compound obtained in the example of obtaining 21-(10) (28,0 mg), and 5-deformatsiei-2-carboxylic acid, obtained in PR is a 14-(2) (20.2 mg), in accordance with the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,04-of 1.07 (m, 3H), 1,67 is 1.70 (m, 2H), 2,70 was 2.76 (m, 2H), is 3.08-3,11 (m, 1H), 3,80-a 3.83 (m, 1H), 4,17-4,20 (m, 1H), 4,54-4,56 (m, 1H), 7,06-7,11 (m, 1H), 7,51 (t, J=72 Hz, 1H), 7,93-to 7.95 (m, 1H), 8,33 (s, 1H), 9,06 (s, 1H), 9,48 (ush., 1H).

Example 51

Synthesis of N-[3-((4aS*,5R*,7aS*)-2-amino-5-ethyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-chloropyridin-2-carboxamide

[Formula 144]

Specified in the header connection (26,0 mg) was obtained from the compound obtained in the example of obtaining 21-(10) (28,0 mg), and 5-chloropyridin-2-carboxylic acid (23,2 mg) according to the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.05 (t, J=7.2 Hz, 3H), 1,65-1,72 (m, 2H), 2,68 was 2.76 (m, 2H), is 3.08-3,13 (m, 1H), 3,81-a 3.83 (m, 1H), 4,17-4,22 (m, 1H), 4,54-4,56 (m, 1H), 7,05-7,10 (m, 1H), 7,51-7,53 (m, 1H), 7,87-7,98 (m, 2H), 8,23 is 8.25 (m, 1H), 8,56-8,56 (m, 1H), 9,83 (ush., 1H).

Example 52

Synthesis of N-[3-((4aS*,5R*,7aS*)-2-amino-5-ethyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-formatexpiry-2-carboxamide

[Formula 145]

Specified in the header connection (23,0 mg) was obtained from the compound obtained in the example of obtaining 21-(10) (30.0 mg)and 5-formatexpiry-2-carboxylic acid obtained in example getting 15-(2) (18,8 mg), in accordance with the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,04-of 1.07 (m, 3H), 1,65-1,70 (m, 2H), 2,71 was 2.76 (m, 2H), 3,09-3,13 (m, 1H), 3,80-a 3.83 (m, 1H), 4,15-420 (m, 1H), 4,54-4,56 (m, 1H), x 6.15 (d, J=51 Hz, 1H), 7,06-7,11 (m, 1H), of 7.48-7,49 (m, 1H), of 7.96-of 7.97 (m, 1H), 8,29 (s, 1H), remaining 9.08 (s, 1H), 9,50 (ush., 1H).

Example 53

Synthesis of N-[3-((4aS*,5R*,7aS*)-2-amino-5-ethyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamide

[Formula 146]

Specified in the title compound (30.0 mg) was obtained from the compound obtained in the example of obtaining 21-(10) (28,0 mg), and 5-deformalisation-2-carboxylic acid, obtained in the example of a 17-(5) (18.5 mg), in accordance with the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,04-1,08 (m, 3H), 1,66-of 1.73 (m, 2H), 2,69-2,78 (m, 2H), 3,09-3,13 (m, 1H), 3,81-a 3.83 (m, 1H), 4,18-to 4.23 (m, 1H), 4,55-of 4.57 (m, 1H), 6,80 (t, J= 55 Hz, 1H), 7,09 for 7.12 (m, 1H), 7,53-7,56 (m, 1H), 7.95 is-to 7.99 (m, 1H), 8,93 (s, 1H), at 9.53 (s, 1H), 9,65 (ush., 1H).

Example 54

Synthesis of N-[3-((4aS*,5R*,7aS*)-2-amino-5-methyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 147]

Specified in the header of the connection in (18.0 mg) was obtained from the compound obtained in the example of a 22-(11) (30.0 mg)and 5-cyanopyridine-2-carboxylic acid obtained in example obtain 13-(2) (23,3 mg), in accordance with the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,37-of 1.39 (m, 3H), 2.57 m-of 2.58 (m, 1H), 2,73 was 2.76 (m, 1H), 3,10-3,13 (m, 1H), 3,81-a 3.83 (m, 1H), 4,35-to 4.38 (m, 1H), 4,59-br4.61 (m, 1H), 7,08-7,13 (m, 1H), 7,52-7,53 (m, 1H), of 7.96-7,98 (m, 1H), to 8.20 (d, J=8.0 Hz, 1H), 8,43 (d, J=8.0 Hz, 1H), 8,90 (s, H), 9,85 (ush., 1H).

Example 55

Synthesis of N-[3-((4aS*,5R*,7aS*)-2-amino-5-methyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformatsiei-2-carboxamide

[Formula 148]

Specified in the header connection (22,0 mg) was obtained from the compound obtained in the example of a 22-(11) (30.0 mg)and 5-deformatsiei-2-carboxylic acid, obtained in the example of a 14-(2) (22,5 mg), in accordance with the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,37-of 1.39 (m, 3H), 2,56-2,60 (m, 1H), 2,72 was 2.76 (m, 1H), 3,10-3,14 (m, 1H), 3,81-a-3.84 (m, 1H), 4,35-to 4.38 (m, 1H), 4,59-br4.61 (m, 1H), 7,07 for 7.12 (m, 1H), 7,49-7,51 (m, 1H), 7,51 (t, J=71,6 Hz, 1H), 7,93-of 7.96 (m, 1H), 8.34 per (d, J=1.6 Hz, 1H), 9,07 (d, J=1.6 Hz, 1H), for 9.47 (ush., 1H).

Example 56

Synthesis of N-[3-((4aS*,5R*,7aS*)-2-amino-5-methyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-chloropyridin-2-carboxamide

[Formula 149]

Specified in the header connection (17,0 mg) was obtained from the compound obtained in the example of a 22-(11) (28,0 mg), and 5-chloropyridin-2-carboxylic acid (23,2 mg) according to the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,37-of 1.39 (m, 3H), 2.57 m-2,61 (m, 1H), 2,72 was 2.76 (m, 1H), 3,11-3,15 (m, 1H), 3,82-of 3.85 (m, 1H), 4,35-to 4.38 (m, 1H), 4,59-to 4.62 (m, 1H), 7,06-7,11 (m, 1H), 7,50-7,52 (m, 1H), 7,88-7,98 (m, 2H), 8,24 (d, J=8,4 Hz, 1H), to 8.57 (s, 1H), 9,82 (ush., 1H).

Example 57

Synthesis of N-[3-((4aS*,5R*,7aS*)-2-amino-5-methyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluoro who enyl]-5-formatexpiry-2-carboxamide

[Formula 150]

Specified in the header connection (22,0 mg) was obtained from the compound obtained in the example of a 22-(11) (28,0 mg), and 5-formatexpiry-2-carboxylic acid obtained in example getting 15-(2) (19,0 mg), in accordance with the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,37-of 1.39 (m, 3H), 2,59-2,61 (m, 1H), 2,73-2,77 (m, 1H), 3,10-3,15 (m, 1H), 3,82-of 3.85 (m, 1H), 4,35-4,37 (m, 1H), 4,59-br4.61 (m, 1H), between 6.08 and to 6.22 (m, 1H), 7,07 for 7.12 (m, 1H), 7,49-7,51 (m, 1H), 7,93-7,97 (m, 1H), 8,29 (s, 1H), remaining 9.08 (s, 1H), 9,50 (ush., 1H).

Example 58

Synthesis of N-[3-((4aS*,5R*,7aS*)-2-amino-5-methyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamide

[Formula 151]

Specified in the header connection (21,0 mg) was obtained from the compound obtained in the example of a 22-(11) (25.0 mg), and 5-deformalisation-2-carboxylic acid, obtained in the example of a 17-(5) in (17.0 mg), in accordance with the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,37-of 1.39 (m, 3H), 2.57 m-2,61 (m, 1H), 2,73-2,77 (m, 1H), 3,10-3,14 (m, 1H), 3,81-a-3.84 (m, 1H), 4,35-4,39 (m, 1H), 4,60-to 4.62 (m, 1H), 6,66-6,93 (m, 1H), 7,09-7,14 (m, 1H), 7,53-of 7.55 (m, 1H), 7,93-7,97 (m, 1H), of 8.92 (d, J=8.0 Hz, 1H), at 9.53 (s, 1H), for 9.64 (ush., 1H).

Example 59

Synthesis of N-[3-((4aS*,5R*,7aS*)-2-amino-5-methyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformationen-2-carboxamide

[Formula 152]

Specified in the agolove connection (28,0 mg) was obtained from the compound, received in the sample receiving 22-(11) (30.0 mg)and 5-deformationen-2-carboxylic acid (22,3 mg) according to the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,37-of 1.39 (m, 3H), 2,58-2,61 (m, 1H), 2,72 was 2.76 (m, 1H), 3,11-3,15 (m, 1H), 3,82-a-3.84 (m, 1H), 4,34-and 4.40 (m, 1H), 4,60-to 4.62 (m, 1H), 6,65 (t, J=72 Hz, 1H), 7,08-7,11 (m, 1H), 7,51-7,53 (m, 1H), 7,65-to 7.67 (m, 1H), 7,93-of 7.97 (m, 1H), 8,31-of 8.33 (m, 1H), 8,46 (s, 1H), 9,83 (ush., 1H).

Example 60

Synthesis of N-[3-((4aS*,5R*,7aS*)-2-amino-5-methyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]pyrimidine-4-carboxamide

[Formula 153]

Specified in the title compound (16.0 mg) was obtained from the compound obtained in the example of a 22-(11) (20.0 mg), and the pyrimidine-4-carboxylic acid (15,0 mg) according to the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,37-of 1.39 (m, 3H), 2,59-2,61 (m, 1H), 2,73-2,77 (m, 1H), 3,10-3,14 (m, 1H), 3,83-3,86 (m, 1H), 4,35-4,39 (m, 1H), 4,59-to 4.62 (m, 1H), 7,08-7,14 (m, 1H), 7,53-7,56 (m, 1H), 7,94-of 7.96 (m, 1H), 8,21-8,23 (m, 1H), 9,04-9,05 (m, 1H), to 9.32-to 9.32 (m, 1H), 9,87 (ush., 1H).

Example 61

Synthesis of N-[3-((4aS*,5R*,7aS*)-2-amino-5-methyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]pyridine-2-carboxamide

[Formula 154]

Specified in the header of the connection in (18.0 mg) was obtained from the compound obtained in the example of a 22-(11) (20.0 mg), and pikolinos acid (12.9 mg) according to the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,37-1,39 (who, 3H), 2,58-2,62 (m, 1H), 2,72-2,77 (m, 1H), 3,12-and 3.16 (m, 1H), 3,84-a 3.87 (m, 1H), 4,35-4,39 (m, 1H), 4,60-to 4.62 (m, 1H), 7,06-7,11 (m, 1H), of 7.48-rate of 7.54 (m, 2H), 7,89 shed 8.01 (m, 2H), 8,28-8,30 (m, 1H), 8,62-8,63 (m, 1H).

Example 62

Synthesis of N-[3-((4aS*,5R*,7aS*)-2-amino-5-methyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-herperidin-2-carboxamide

[Formula 155]

Specified in the header connection (13,0 mg) was obtained from the compound obtained in the example of a 22-(11) (20.0 mg)and 5-herperidin-2-carboxylic acid (15,0 mg) according to the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,37-of 1.39 (m, 3H), 2,59-2,61 (m, 1H), 2,72-2,77 (m, 1H), 3,11-3,15 (m, 1H), 3,83-3,86 (m, 1H), 4,35-4,39 (m, 1H), 4,59-to 4.62 (m, 1H), 7,06 for 7.12 (m, 1H), 7,49 to 7.62 (m, 2H), 7,95-of 7.97 (m, 1H), 8,31-of 8.47 (m, 2H), 9,80 (ush., 1H).

Example 63

Synthesis of N-[3-((4aS*,5S*,7aS*)-2-amino-5-methoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 156]

Specified in the title compound (7.0 mg) was obtained from the compound obtained in the example of a 23-(15) (20.0 mg)and 5-cyanopyridine-2-carboxylic acid obtained in example obtain 13-(2) (15,0 mg), in accordance with the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,84-of 2.09 (m, 3H), 2,73-to 2.85 (m, 2H), 2,96-of 2.97 (m, 2H), 3,41 (s, 3H), 4,01-4,06 (m, 1H), 7,06-7,11 (m, 1H), 7,39-7,40 (m, 1H), 7,93-of 7.97 (m, 1H), 8,19-to 8.20 (m, 1H), 8,42-8,44 (m, 1H), of 8.90 (s, 1H), 9,82 (ush., 1H).

Example 64

Synthesis of N-[3-((4aS*,5S*,7aS*)2-amino-5-methoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformatsiei-2-carboxamide

[Formula 157]

Specified in the title compound (10.0 mg) was obtained from the compound obtained in the example of a 23-(15) in (18.0 mg)and 5-deformatsiei-2-carboxylic acid, obtained in the example of a 14-(2) (13,0 mg), in accordance with the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,85-to 2.06 (m, 3H), 2,75-2,84 (m, 2H), 2,96-of 2.97 (m, 2H), 3,41 (s, 3H), was 4.02-Android 4.04 (m, 1H), 7,05-7,10 (m, 1H), 7,35-7,38 (m, 1H), 7,51 (t, J=72 Hz, 1H), of 7.90-7,94 (m, 1H), with 8.33 (s, 1H), 9,07 (s, 1H), 9,45 (ush., 1H).

Example 65

Synthesis of N-[3-((4aS*,5R*,7aS*)-2-amino-5-methoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 158]

Specified in the title compound (11.0 mg) was obtained from the compound obtained in the example of a 23-(14) (20.0 mg)and 5-cyanopyridine-2-carboxylic acid obtained in example obtain 13-(2) (15,0 mg), in accordance with the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,77-of 2.26 (m, 3H), 2,53-of 2.58 (m, 1H), 2,83-of 3.06 (m, 3H), of 3.32 (s, 3H), 3,94-of 3.96 (m, 1H), 7,05-7,10 (m, 1H), to 7.67-to 7.68 (m, 1H), 7,76 for 7.78 (m, 1H), 8,20 is 8.22 (m, 1H), 8,42-8,44 (m, 1H), 8,91 (s, 1H), 9,84 (ush., 1H).

Example 66

Synthesis of N-[3-((4aS,5S,7aS)-2-amino-5-methoxymethyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 159]

The following compound was synthesized in accordance with example 14 using the connection, received in the sample receiving 24-(11), and the corresponding carboxylic acid.

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,83-of 2.86 (m, 1H), 2,96-3,00 (m, 1H), 3,09-3,13 (m, 1H), 3,44 (s, 3H), 3,53 is 3.57 (m, 1H), 3,63-to 3.67 (m, 1H), 3,86-3,88 (m, 1H), of 4.44-4,48 (m, 1H), 4,55-of 4.57 (m, 1H), 7,08-7,13 (m, 1H), 7,53-rate of 7.54 (m, 1H), 7,97-of 8.00 (m, 1H), 8,20 is 8.22 (m, 1H), 8,42-8,44 (m, 1H), of 8.90 (s, 1H), 9,86 (ush., 1H).

Example 67

Synthesis of N-[3-((4aS,5S,7aS)-2-amino-5-methoxymethyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformatsiei-2-carboxamide

[Formula 160]

The following compound was synthesized in accordance with example 14, using the compound obtained in the example of a 24-(11), and the corresponding carboxylic acid.

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,82-to 2.85 (m, 1H), 2,96 are 2.98 (m, 1H), 3,10-3,13 (m, 1H), 3.43 points (s, 3H), 3,53 of 3.56 (m, 1H), 3,64-3,66 (m, 1H), 3,85-a 3.87 (m, 1H), 4,45-to 4.46 (m, 1H), 4,54-of 4.57 (m, 1H), 7,07 for 7.12 (m, 1H), 7,49-7,51 (m, 1H), 7,51 (t, J=72 Hz, 1H), 7.95 is-of 7.97 (m, 1H), 8.34 per (s, 1H), 9,07 (s, 1H), 9,49 (ush., 1H).

Example 68

Synthesis of N-[3-((4aS,5S,7aS)-2-amino-5-methoxymethyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamide

[Formula 161]

The following compound was synthesized in accordance with example 14, using the compound obtained in the example of a 24-(11), and the corresponding carboxylic acid.

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,82-of 2.86 (m, 1H), 2.95 and-2,99 (m, 1H), 3,09-3,14 (m, 1H), 3,44 (s, 3H, 3,54 is 3.57 (m, 1H), 3,65-to 3.67 (m, 1H), 3,85-a 3.87 (m, 1H), of 4.44-4,48 (m, 1H), 4,55-of 4.57 (m, 1H), 6,80 (t, J=55 Hz, 1H), 7,08-7,14 (m, 1H), 7,55-7,56 (m, 1H), 7.95 is-to 7.99 (m, 1H), of 8.92 (s, 1H), 9,52 (s, 1H), 9,65 (ush., 1H).

Example 69

Synthesis of N-[3-((4aS,5S,7aS)-2-amino-5-methoxymethyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-formatexpiry-2-carboxamide

[Formula 162]

The following compound was synthesized in accordance with example 14, using the compound obtained in the example of a 24-(11), and the corresponding carboxylic acid.

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,83-of 2.86 (m, 1H), 2,97-2,99 (m, 1H), 3,10-of 3.43 (m, 1H), 3,44 (s, 3H), 3,54 of 3.56 (m, 1H), 3,64-to 3.67 (m, 1H), 3,86-to 3.89 (m, 1H), 4,45-4,47 (m, 1H), 4,54-of 4.57 (m, 1H), 6,09-to 6.22 (m, 1H), 7,07 for 7.12 (m, 1H), 7,47-7,49 (m, 1H), 7,97-to 7.99 (m, 1H), 8.30 to (s, 1H), remaining 9.08 (s, 1H), 9,52 (ush., 1H).

Example 70

Synthesis of N-[3-((4aS,5S,7aS)-2-amino-5-vermeil-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-triptorelin-2-carboxamide

[Formula 163]

Specified in the title compound (29.0 mg) was obtained from the compound obtained in the example of a 25-(13) (25.0 mg), and 5-triptorelin-2-carboxylic acid (17.9 mg) according to the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,79-and 2.83 (m, 1H), is 3.08-3,19 (m, 2H), 3,88-3,91 (m, 1H), 4,51-of 4.66 (m, 4H), 7,09-7,14 (m, 1H), 7,58-to 7.61 (m, 1H), of 7.96-of 8.00 (m, 1H), 8,16-8,18 (m, 1H), 8,42-8,44 (m, 1H), of 8.90 (s, 1H).

Example 71

Synthesis of N-[3-((4aS,5S,7aS)-2-amino-5-vermeil-4a,5-is hydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-chloropyridin-2-carboxamide

[Formula 164]

Specified in the title compound (16.0 mg) was obtained from the compound obtained in the example of a 25-(13) (25.0 mg), and 5-chloropyridin-2-carboxylic acid (14,8 mg) according to the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,79-and 2.83 (m, 1H), is 3.08-3,19 (m, 2H), 3,88-3,91 (m, 1H), 4,51-of 4.66 (m, 4H), 7,07 for 7.12 (m, 1H), 7,54-7,56 (m, 1H), 7,87-of 8.00 (m, 2H), 8,23-of 8.25 (m, 1H), to 8.57 (m, 1H), 9,83 (ush., 1H).

Example72

Synthesis of N-[3-((4aS,5s,7aS)-2-amino-5-vermeil-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformationen-2-carboxamide

[Formula 165]

Specified in the title compound (27.0 mg) was obtained from the compound obtained in the example of a 25-(13) (25.0 mg), and 5-deformationen-2-carboxylic acid (17,8 mg) according to the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,79-and 2.83 (m, 1H), is 3.08-3,19 (m, 2H), 3,88-3,91 (m, 1H), 4,51-of 4.66 (m, 4H), of 6.65 (t, J=72,0 Hz, 1H), 7,08-7,13 (m, 1H), 7,55-EUR 7.57 (m, 1H), 7,66-of 7.69 (m, 1H), 7.95 is-to 7.99 (m, 1H), 8,31-to 8.34 (m, 1H), of 8.47-8,48 (m, 1H), 9,84 (ush., 1H).

Example 73

Synthesis of N-[3-((4aS,5S,7aS)-2-amino-5-vermeil-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamide

[Formula 166]

Specified in the title compound (16.0 mg) was obtained from the compound obtained in the example of a 25-(13) (25.0 mg), and 5-deformalisation-2-carbon is th acid, received in the sample receiving 17-(5) (16,3 mg), in accordance with the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,80-2,84 (m, 1H), 3,11-3,19 (m, 2H), 3,91-of 3.94 (m, 1H), 4,51-of 4.66 (m, 4H), to 6.80 (t, J=54,4 Hz, 1H), 7,10-7,16 (m, 1H), 7,56-to 7.59 (m, 1H), of 7.96-of 8.00 (m, 1H), to 8.94 (s, 1H), at 9.53 (s, 1H), 9,66 (ush., 1H).

Example 74

Synthesis of N-[3-((4aS,5S,7aS)-2-amino-5-vermeil-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformatsiei-2-carboxamide

[Formula 167]

Specified in the header connection (26,0 mg) was obtained from the compound obtained in the example of a 25-(13) (25.0 mg), and 5-deformatsiei-2-carboxylic acid, obtained in the example of a 14-(2) (17.9 mg), in accordance with the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,79-and 2.83 (m, 1H), 3,09-3,18 (m, 2H), 3,89-to 3.92 (m, 1H), 4,51 with 4.65 (m, 4H), 7,09-7,14 (m, 1H), 7,52 (t, J=71,6 Hz, 1H), 7,52-of 7.55 (m, 1H), 7,94-of 7.97 (m, 1H), 8,35 (s, 1H), 9,07 (s, 1H), 9,49 (ush., 1H).

Example 75

Synthesis of N-[3-((4aS,5s,7aS)-2-amino-5-vermeil-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-formatexpiry-2-carboxamide

[Formula 168]

Specified in the header of the connection (of 28.0 mg) was obtained from the compound obtained in the example of a 25-(13) (25.0 mg), and 5-formatexpiry-2-carboxylic acid obtained in example getting 15-(2) (16.2 mg), in accordance with the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm):2,80-2,84 (m, 1H), 3,11-3,19 (m, 2H), 3,92-3,95 (m, 1H), 4,50-of 4.66 (m, 4H), 6,09-6,10 (m, 1H), 6.22 per 6,23 (m, 1H), 7,08-7,13 (m, 1H), 7,51-7,53 (m, 1H), 7.95 is-to 7.99 (m, 1H), 8.30 to (s, 1H), which is 9.09 (s, 1H), 9,51 (ush., 1H).

Example 76

Synthesis of N-[3-((4aS,5S,7aS)-2-amino-5-vermeil-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]pyrimidine-4-carboxamide

[Formula 169]

Specified in the header connection (15,0 mg) was obtained from the compound obtained in the example of a 25-(13) (20.0 mg), and the pyrimidine-4-carboxylic acid (12,4 mg) according to the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,79-and 2.83 (m, 1H), 3,09-3,18 (m, 2H), a 3.87-3,90 (m, 1H), to 4.52-of 4.66 (m, 4H), 7,09-7,14 (m, 1H), 7,58-to 7.61 (m, 1H), 7.95 is-to 7.99 (m, 1H), 8,21-8,23 (m, 1H), 9,05 (d, J=5.6 Hz, 1H), to 9.32 (d, J=5.6 Hz, 1H), 9,88 (ush., 1H).

Example 77

Synthesis of N-[3-((4aS,5s,7aS)-2-amino-5-vermeil-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]pyridine-2-carboxamide

[Formula 170]

Specified in the header of the connection in (18.0 mg) was obtained from the compound obtained in the example of a 25-(13) (20.0 mg), and pikolinos acid (12.9 mg) according to the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,79-and 2.83 (m, 1H), is 3.08-3,20 (m, 2H), 3,90-to 3.92 (m, 1H), 4,51-of 4.66 (m, 4H), 7,07-7,20 (m, 2H), of 7.48-7,58 (m, 2H), of 7.90 shed 8.01 (m, 1H), 8,28-8,30 (m, 1H), 8,63-8,65 (m, 1H).

Example 78

Synthesis of N-[3-((4aS,5S,7aS)-2-amino-5-vermeil-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-herperidin-2-carboxamide

[Formula is 171]

Specified in the header connection (13,0 mg) was obtained from the compound obtained in the example of a 25-(13) (20.0 mg), and pikolinos acid (15,0 mg) according to the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,78-2,82 (m, 1H), 3,06-3,19 (m, 2H), 3,88-3,90 (m, 1H), 4,51-of 4.67 (m, 4H), 7,07 for 7.12 (m, 1H), 7,55 to 7.62 (m, 1H), 7,93-of 7.97 (m, 1H), 8,31-to 8.45 (m, 2H).

Example 79

Synthesis of N-[3-((4aS*,8aS*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-deformalisation-2-carboxamide

[Formula 172]

Specified in the title compound (29.0 mg) was obtained from the compound obtained in the example of obtaining 8 (30.0 mg)and 5-deformalisation-2-carboxylic acid, obtained in the example of a 17-(5) (22,3 mg), in accordance with the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1.70 to at 1.73 (m, 1H), 2,60-2,70 (m, 2H), 2.93 which was 3.05 (m, 2H), 3,70-3,91 (m, 4H), 4,59 (ush., 1H), 6,79 (t, J=54 Hz, 1H),? 7.04 baby mortality-to 7.09 (m, 1H), 7,45-7,46 (m, 1H), 7,87-7,89 (m, 1H), 8,89 (s, 1H), 9,49 (s, 1H), 9,59 (ush., 1H).

Example 80

Synthesis of N-[3-((4aS*,8aS*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-formatexpiry-2-carboxamide

[Formula 173]

Specified in the header connection (24,0 mg) was obtained from the compound obtained in the example of obtaining 8 (30.0 mg)and 5-formatexpiry-2-carboxylic acid, obtained in the example according to the teachings of the 15-(2) (a 20.3 mg), in accordance with the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,68-1,71 (m, 1H), 2.57 m-2,69 (m, 2H), 2.93 which is a 3.06 (m, 2H), 3,70-3,91 (m, 4H), between 6.08-6,21 (m, 1H), 7,05-7,10 (m, 1H), 7,37-7,38 (m, 1H), 7,89-to 7.93 (m, 1H), of 8.27 (s, 1H), 9,07 (s, 1H), 9,45 (ush., 1H).

Example 81

Synthesis of N-[3-((4aS*,8aS*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-deformationen-2-carboxamide

[Formula 174]

Specified in the header connection (31,0 mg) was obtained from the compound obtained in the example of obtaining 8 (30.0 mg)and 5-deformationen-2-carboxylic acid (21,5 mg) according to the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,69-1,72 (m, 1H), 2,56-a 2.71 (m, 2H), 2,94 was 3.05 (m, 2H), 3,70-3,91 (m, 4H), of 6.65 (t, J=72 Hz, 1H), 7.03 is-to 7.09 (m, 1H), 7,40-7,41 (m, 1H), of 7.64-7,66 (m, 1H), 7,89-to 7.93 (m, 1H), 8,28-8,30 (m, 1H), 8,43-8,43 (m, 1H), 9,77 (ush., 1H).

Examples 82-86

Connection examples 82-86, shown below in table 4, was synthesized in accordance with example 47.

[Table 4]

Table 4
Example 82Chemical structure
ESI-MS m/z 433 [M++H]
Example 83Chemical structure
ES-MS m/z 371 [M ++H]
Example 84Chemical structure
ESI-MS m/z 397 [M++H]
Example 85Chemical structure
ESI-MS m/z 469 [M++H]
Example 86Chemical structure
ESI-MS m/z 434 [M++H]

Examples 87-88

Connection examples 87-88, shown below in table 5, was synthesized in accordance with example 37.

[Table 5]

Table 5
Example 87Chemical structure
ESI-MS m/z 407 [M++H]
Example 88Chemical structure
ESI-MS m/z 424 [M++H]

Example 89

Synthesis of (+)-N-[3-((4aR*,6S*,7aS*)-2-amino-6-ethoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 175]

(1)Synthesis of tert-BU is Il ((4aR*,6S*,7aS*)-7a-{5-[(5-cyano-2-carbonyl)amino]-2-forfinal}-6-ethoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl)carbamate

PyBOP (205 mg) was added to a solution of tert-butyl (±)-[(4aR*,6S*,7aS*)-7a-(5-amino-2-forfinal)-6-ethoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate (52 mg), compound of example, receiving 26-(2) (27.3 mg) and N,N-diisopropylethylamine (of 0.26 ml) in dichloromethane (5.2 ml). The mixture was stirred at room temperature for one hour. The reaction solution was poured into a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on a column of silica gel with obtaining specified in the title compound (45 mg).

ESI-MS; m/z 540 [M++H].

(2) Synthesis of tert-butyl (-)-((4aR*,6S*,7aS*)-7a-{5-[(5-cyano-2-carbonyl)amino]-2-forfinal}-6-ethoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl)carbamate

Complex tert-butyl ester obtained in (1) (45 mg), optically separated using CHIRALPAK™ IB production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 7:3, flow rate: 10 ml/min). Components having a retention time 21-28 minutes, collected by obtaining specified in the header (-)-isomer (17 mg).

Optical rotation (-)

ESI-MS; m/z 540 [M++H].

(3)Synthesis of (+)-N-[3-((4aR*,6S*,7aS*)-amino-6-ethoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

Triperoxonane acid (1.0 ml) was added to a solution of tert-butyl (-)-carbamate obtained in (2) (17 mg), in dichloromethane (1.0 ml), and the reaction solution was stirred at room temperature for one hour. The reaction solution was poured into a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on a column with NH-silica gel with obtaining specified in the title compound (12 mg).

Optical rotation (+)

ESI-MS m/z 440 [M++H]

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,22 (t, J=6.8 Hz, 3H), 1,95 was 2.25 (m, 3H), 2,60-2,70 (m, 1H), 2,78 (DD, J=4,4, 13,2 Hz, 1H), 2,90-3,00 (m, 2H), 3,51 (kV, J=6,8 Hz, 2H), 4,20 is 4.35 (m, 1H), 7,07 (DD, J=8,8, 12.0 Hz, 1H), 7,38 (DD, J=the 2.8, 7.2 Hz, 1H), of 7.90-of 8.00 (m, 1H), to 8.20 (DD, J=2,0, 8.0 Hz, 1H), 8,42 (d, J=8.0 Hz, 1H), 8,86-of 8.92 (m, 1H), 9,82 (s, 1H).

Connection examples 90-103 synthesized in accordance with example 19 using the appropriate carboxylic acid and the appropriate aniline intermediate compounds in the examples received.

Example 90

Synthesis of (+)-N-[3-((4aR*,6R*,7aS*)-2-amino-6-ethoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 176]

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.23 (t, J=7.2 Hz, 3H), 1.85 to 1,95 (m, 1H), of 2.25 to 2.35 (m, 2H), 2.63 in (DD, J=7,2, to 12.8 Hz, 1H), 2,75 (DD, J=3,6, to 12.8 Hz, 1H), 2,99 (DD, J=3,6, to 12.8 Hz, 1H), 3,10-of 3.23 (m, 1H), 3,40-3,55 (m, 2H), 3.95 to 4,05 (m, 1H), was 7.08 (DD, J=8,8, 12.0 Hz, 1H), 7,39 (DD, J=2,8, 7.2 Hz, 1H), 7,88-7,98 (m, 1H), 8,19 (DD, J=2,0, 8.0 Hz, 1H), 8,42 (d, J=8.0 Hz, 1H), 8,84-to 8.94 (m, 1H), 9,82 (s, 1H).

ESI-MS m/z 440 [M++H].

Example 91

Synthesis of (+)-N-[3-((4aR*,6R*,7aS*)-2-amino-6-fluoro-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 177]

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,95-2,60 (m, 3H), 2,75-3,10 (m, 3H), 3.15 and of 3.28 (m, 1H), 5,15 is 5.38 (m, 1H), 7,11 (DD, J=8,8, 12.0 Hz, 1H), 7,42 (DD, J=2,8, 7.2 Hz, 1H), 7,86-of 7.96 (m, 1H), to 8.20 (DD, J=2,0, 8.0 Hz, 1H), 8,42 (d, J=8,0 Hz, 1H), 8,86-of 8.92 (m, 1H), 9,83 (s, 1H).

ESI-MS m/z 414 [M++H].

Example 92

Synthesis of (+)-N-[3-((4aR*,6S*,7aS*)-2-amino-6-methoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamide

[Formula 178]

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,00-and 2.14 (m, 2H), 2,18-of 2.28 (m, 1H), 2,64-to 2.74 (m, 1H), 2,78 (DD, J=4,0, 13,2 Hz, 1H), 2,90-3,00 (m, 2H), 3,34 (s, 3H), 4,08-4,24 (m, 1H), 6,79 (t, J=54,4 Hz, 1H), 7,00-7,13 (m, 1H), 7,39 (DD, J=2,8, 7.2 Hz, 1H), of 7.90-of 8.00 (m, 1H), 8,91 (s, 1H), 9,51 (s, 1H), being 9.61 (s, 1H).

ESI-MS m/z 452 [M++H].

Example 93

Synthesis of (+)-N-[3-((4aR*,6R*,7aS*)-2-amino-6-methoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamide

[Formula 179]

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,85-of 1.94 (m, 1H), 2,24-of 2.38 (m, 2H), 2.63 in (DD, J=6,8, to 12.8 Hz, 1H), was 2.76 (DD, J=3,6, to 12.8 Hz, 1H), 2,99 (DD, J=3,6, to 12.8 Hz, 1H), 3,12-up 3.22 (m, 1H), 3,34 (s, 3H), 3,90-4,00 (m, 1H), 6,79 (t, J=54,8 Hz, 1H), was 7.08 (DD, J=8,8, 12.0 Hz, 1H), 7,43 (DD, J=2,8, 7.2 Hz, 1H), 7,85-to 7.95 (m, 1H), 8,90 (d, J=0.8 Hz, 1H), 9,51 (d, J=0.8 Hz, 1H), 9,62 (s, 1H).

ESI-MS m/z 452 [M++H].

Example 94

Synthesis of (+)-N-[3-((4aR*,7aS*)-2-amino-6,6-debtor-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 180]

1H-NMR (400 MHz, CDCl3) δ (ppm): 2.26 and is 2.44 (m, 1H), 2,46-2,70 (m, 2H), 2,72-and 2.83 (m, 1H), 3,00 (d, J=13,2 Hz, 1H), 3,10-of 3.28 (m, 2H), 7,11 (DD, J=8,8, and 11.6 Hz, 1H), was 7.36-7,46 (m, 1H), of 7.90-of 8.00 (m, 1H), 8,21 (DD, J=2,0, 8.0 Hz, 1H), 8,43 (d, J=8.0 Hz, 1H), 8,90 (d, J=0.8 Hz, 1H), 9,83 (s, 1H).

ESI-MS m/z 432 [M++H].

Example 95

Synthesis of (+)-N-[3-((4aR*,6R*,7aS*)-2-amino-6-methoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamide

[Formula 181]

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,80-of 1.95 (m, 1H), 2,25-to 2.40 (m, 2H), 2,62 (DD, J=6,8, to 12.8 Hz, 1H), was 2.76 (DD, J=3,6, to 12.8 Hz, 1H), 2,99 (DD, J=3,6, to 12.8 Hz, 1H), of 3.10-3.20 (m, 1H), 3,34 (s, 3H), 3,85-4,00 (m, 1H), 7,07 (DD, J=8,8, 12,0 Hz, 1H), 7,38 (DD, J=2,4, 7.2 Hz, 1H), 7,51 (t, J=71,2 Hz, 1H), 7,84-7,94 (m, 1H), 8,32 (d, J=1.2 Hz, 1H), 9,06 (d, J=1.2 Hz, 1H), to 9.45 (s, 1H).

ESI-MS m/z 468 [M++H].

Example 96

Synthesis of (+)-N-[3-((4aR*,6R*,7aS*)-2-amino-6-methoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]enous the n-7a-yl)-4-forfinal]-5-formatexpiry-2-carboxamide

[Formula 182]

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,84-of 1.94 (m, 1H), 2,24-of 2.36 (m, 2H), 2,62 (DD, J=7,2, to 12.8 Hz, 1H), 2,72 is 2.80 (m, 1H), 2,96 totaling 3.04 (m, 1H), 3,12-3,20 (m, 1H), 3,34 (s, 3H), 3,88-3,98 (m, 1H), 6,05 and 6.25 (m, 2H), 7,07 (DD, J=4,8, 12.0 Hz, 1H), 7,37 (DD, J=2,8, 7.2 Hz, 1H), 7,85-to 7.95 (m, 1H), 8,27 (d, J=1.2 Hz, 1H), 9,07 (d, J=1.2 Hz, 1H), 9,46 (s, 1H).

ESI-MS m/z 450 [M++H].

Example 97

Synthesis of (+)-N-[3-((4aR*,6S*,7aS*)-2-amino-6-fluoro-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamide

[Formula 183]

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,20-of 2.50 (m, 3H), 2,73 was 3.05 (m, 4H), 5.25-in of 5.50 (m, 1H), 6,80 (t, J=54,8 Hz, 1H), 7,00-7,10 (m, 1H), 7,41 (DD, J=2,8, 7.2 Hz, 1H), of 7.90-8,02 (m, 1H), of 8.90 (s, 1H), 9,51 (s, 1H), 9,60 (s, 1H).

ESI-MS m/z 440 [M++H].

Example 98

Synthesis of (+)-N-[3-((4aR*,6R*,7aS*)-2-amino-6-fluoro-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformatsiei-2-carboxamide

[Formula 184]

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,00-of 2.20 (m, 1H), 2,25-2,60 (m, 2H), 2,70-3,10 (m, 3H), 3,10-of 3.25 (m, 1H), 5,10 to 5.35 (m, 1H), 7,10 (DD, J=8,8, 12.0 Hz, 1H), 7,38 (DD, J=2,8, 7.2 Hz, 1H), 7,51 (t, J=71,6 Hz, 1H), 7,86-a 7.92 (m, 1H), with 8.33 (d, J=1.2 Hz, 1H), 9,07 (d, J=1.2 Hz, 1H), to 9.45 (s, 1H).

ESI-MS m/z 456 [M++H].

Example 99

Synthesis of (+)-N-[3-((4aR*,6R*,7aS*)-2-amino-6-methoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-chloropyridin-2-carboxamide

[Formula 185]

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,84-of 1.94 (m, 1H), 2,24-of 2.36 (m, 2H), 2,62 (DD, J=7,2, to 12.8 Hz, 1H), 2,75 (DD, J=3,6, to 12.8 Hz, 1H), 3,00 (DD, J=3,6, to 12.8 Hz, 1H), 3,12-3,20 (m, 1H), 3,34 (s, 3H), 3,88-3,98 (m, 1H), 7,07 (DD, J=8,8, 12,0 Hz, 1H), was 7.36 (DD, J=2,8, 7.2 Hz, 1H), 7,87 (DD, J=2,8, and 8.4 Hz, 1H), of 7.90-of 8.00 (m, 1H), 8,24 (d, J=8,4 Hz, 1H), 8,55 (d, J=2.4 Hz, 1H), 9,78 (s, 1H).

ESI-MS m/z 435 [M++H].

Example 100

Synthesis of (+)-N-[3-((4aR*,6R*,7aS*)-2-amino-6-methoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformationen-2-carboxamide

[Formula 186]

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,84 is 1.96 (m, 1H), 2,22-to 2.40 (m, 2H), 2,62 (DD, J=6,8, to 12.8 Hz, 1H), 2,77 (DD, J=3,6, to 12.8 Hz, 1H), 3,01 (DD, J=3,6, to 12.8 Hz, 1H), 3,12-3,24 (m, 1H), 3.33 and (s, 3H), 3,88-3,98 (m, 1H), only 6.64 (t, J=72,0 Hz, 1H), 7,07 (DD, J=8,8, and 12.4 Hz, 1H), 7,40 (DD, J=2,8, 7.2 Hz, 1H), 7,65 (DD, J=2,8, 8,8 Hz, 1H), 7,85-to 7.95 (m, 1H), 8,30 (d, J=8,8 Hz, 1H), 8,45 (d, J=2.0 Hz, 1H), 9,80 (s, 1H).

ESI-MS m/z 467 [M++H].

Example 101

Synthesis of (±)-N-[3-((4aR*,6S*,7aS*)-2-amino-6-methoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-herperidin-2-carboxamide

[Formula 187]

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,98-and 2.14 (m, 2H), 2,16-of 2.26 (m, 1H), 2,62-of 2.72 (m, 1H), 2,78 (DD, J=4,4, to 12.8 Hz, 1H), 2,90-to 3.02 (m, 2H), 3,40 (s, 3H), 4,08-4,24 (m, 1H), 7,05 (DD, J=8,8, 12.0 Hz, 1H), 7,35 (DD, J=2,4, 7.2 Hz, 1H), of 7.60 (dt, J=2,4, 8,8 Hz, 1H), of 7.90-8,02 (m, 1H), with 8.33 (DD, J=4,4, 8,8 Hz, 1H), 8,46 (d, J=2.4 Hz, 1H), made up 9.77 (s, 1H).

ESI-MS m/z 419 [M++H].

Example 102

Synthesis of (±)-N-[3-((4aR*,6S*,7aS*)-2-amino-6-methoxy-4a,5,6,7-is tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]pyridine-2-carboxamide

[Formula 188]

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,96-2,12 (m, 2H), 2,16-of 2.26 (m, 1H), 2,62-to 2.74 (m, 1H), 2,78 (DD, J=4,8, to 12.8 Hz, 1H), 2,90-to 3.02 (m, 2H), 3,34 (s, 3H), 4,08-4,24 (m, 1H), 7,05 (DD, J=8,8, 12.0 Hz, 1H), 7,38 (DD, J=2,8, 7,6 Hz, 1H), 7,45-of 7.55 (m, 1H), 7,85-to 7.95 (m, 1H), 7.95 is-with 8.05 (m, 1H), 8,25-8,35 (m, 1H), 8,60-to 8.70 (m, 1H), 9,99 (s, 1H).

ESI-MS m/z 401 [M++H].

Example 103

Synthesis of (±)-N-[3-((4aR*,6S*,7aS*)-2-amino-6-methoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]pyrimidine-4-carboxamide

[Formula 189]

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,00-and 2.14 (m, 2H), 2,16-of 2.28 (m, 1H), 2,64-to 2.74 (m, 1H), 2,78 (DD, J=4,4, to 12.8 Hz, 1H), 2,90-3,00 (m, 2H), 3,34 (s, 3H), 4,10-4,24 (m, 1H), 7,07 (DD, J=8,8, 12.0 Hz, 1H), 7,40 (DD, J=2,8, 7.2 Hz, 1H), of 7.90-of 8.00 (m, 1H), 8,21 (DD, J=1,6, 4.8 Hz, 1H), 9,04 (d, J=4,8 Hz, 1H), 9,31 (d, J=1.6 Hz, 1H), 9,85 (s, 1H).

ESI-MS m/z 402 [M++H].

Examples 104-107

Connection examples 104-107, shown below in table 6, was synthesized in accordance with example 19 using the appropriate carboxylic acid and the appropriate aniline intermediate compounds in the examples received.

[Table 6]

Table 6
Example 104Chemical structure
Connection name: N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8-is hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-chloropyrazine-2-carboxamide
ESI-MS m/z 420 [M++H]
Example 105Chemical structure
Connection name: N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]for 3,5-differencein-2-carboxamide
ESI-MS m/z 421 [M++H]
Example 106Chemical structure
Connection name: N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-triptorelin-2-carboxamide
ESI-MS m/z 453 [M++H]
Example 107Chemical structure
Connection name: N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-methoxypyrazine-2-carboxamide
ESI-MS m/z 416 [M++H]

Examples 108-110

Connection examples 108-110, shown below in table 7, was synthesized in accordance with example 19 or 89, using the appropriate carboxylic acid and the corresponding aniline compounds in the examples received.

[Tab the Itza 7]

Table 7
Example 108Chemical structure
Connection name: (+)-N-[3-((4aR*,6R*,7aS*)-2-amino-6-butoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide
ESI-MS m/z 468 [M++H]
Example 109Chemical structure
Connection name: (+)-N-[3-((4aR*,6S*,7aS*)-2-amino-6-butoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide
ESI-MS m/z 468 [M++H]
Example 110Chemical structure
Connection name: (+)-N-[3-((4aR*,6S*,7aS*)-2-amino-6-fluoro-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide
ESI-MS m/z 414 [M++H]

Examples 111-125

Connection examples 111-125, shown below in table 8 were synthesized in accordance with example 1 or 19, using appropriate carbó the OIC acid or sulphonylchloride and the compound of example, obtain 1-(8).

[Table 8]

Table 8
Example 111Chemical structure
ESI-MS m/z 436 [M++H]Example 112Chemical structure
ESI-MS m/z 419 [M++H]
Example 113Chemical structure
ESI-MS m/z 448 [M++H]Example 114Chemical structure
ESI-MS m/z 403 [M+]
Example 115Chemical structure
ESI-MS m/z 421 [M++H]Example 116Chemical structure
ESI-MS m/z 420 [M++H]
Example 117Chemical structure
ESI-MS m/z 400 [M++H]Example 118 Chemical structure
ESI-MS m/z 429 [M++H]
Example 119Chemical structure
ESI-MS m/z 378 [M++H]Example 120Chemical structure
ESI-MS m/z 466 [M++H]
Example 121Chemical structure
ESI-MS m/z 386 [M++H]Example 122Chemical structure
ESI-MS m/z 454 [M++H]
Example 123Chemical structure
ESI-MS m/z 388 [M++H]Example 124Chemical structure
ESI-MS m/z 453 [M++H]
Example 125Chemical structure
ESI-MS m/z 388 [M++H]

Examples 126-129

Connection examples 126-129, shown below in table 9, was synthesized in accordance with example 1 or 19, using the appropriate carboxylic acid and connection examples for the preparation of 3-(8).

[Table 9]

Table 9
Example 126Chemical structure
ESI-MS m/z 397 [M++H]Example 127Chemical structure
ESI-MS m/z 428 [M++H]
Example 128Chemical structure
ESI-MS m/z 444 [M++H]Example 129Chemical structure
ESI-MS m/z 414 [M++H]

Example 130

Synthesis of (±)-(4aR*,7aS*)-7a-{5-[(5-chloropyridin-2-yl)amino]-2-forfinal}-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-amine

[Formula 190]

(1)Synthesis of (±)-di-tert-butyl [(4aR*,7aS*)-7a-{5-[(5-chloropyridin-2-yl)amino]-2-forfinal}-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]and is of dodecaborate

2-Bromo-5-chloropyridine (10 mg), (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (4,86 mg), Tris(dibenzylideneacetone)dipalladium(0) (2.38 mg) and tert-butoxylate (6.5 mg) was added to a solution of (±)-di-tert-butyl [(4aR*,7aS*)-7a-(5-amino-2-forfinal)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]iminodicarboxylate (29,1 mg) in toluene (10 ml). The mixture was heated under stirring in nitrogen atmosphere at 100°C for five hours. The reaction solution was brought to room temperature and poured into water, followed by extraction with ethyl acetate. The extract was washed with saturated salt solution and dried over anhydrous magnesium sulfate. Specified in the title compound (60 mg) was obtained by removal of the drying agent and concentrated under reduced pressure.

ESI-MS; m/z 577 [M+].

(2)(±)-(4aR*,7aS*)-7a-{5-[(5-Chloropyridin-2-yl)amino]-2-forfinal}-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-amine

TFOC (0.5 ml) was added to a solution of the condensate obtained at the previous stage (60 mg), in dichloromethane (3 ml)and the mixture was stirred at room temperature for two hours. The reaction solution was poured into a saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extract was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent was removed, followed by concentration under reduced pressure the. The residue was purified column chromatography to obtain specified in the title compound (2.4 mg).

ESI-MS; m/z 377 [M++H].

Example 131

The compound of example 131, shown below in table 10, was obtained according to the method of example 130.

[Table 10]

Table 10
Example 131Chemical structure
ESI-MS m/z 421 [M+]

Examples 132-142

Connection examples 132-142, shown below in table 11, was synthesized in accordance with example 14, using the appropriate carboxylic acid and the compound obtained in example of preparation of 3-(8).

[Table 11]

Table 11
Example 132Chemical structure
Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyclopropylacetylene-2-carboxamide
ESI-MS m/z 435 [M++H]
Example 133Chemical p is the established levels
Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-thiazole-2-espiridion-2-carboxamide
ESI-MS m/z 454 [M++H]

Example 134Chemical structure
ESI-MS m/z 411 [M++H]
Example 135Chemical structure
Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-methylsulfinylphenyl-2-carboxamide
ESI-MS m/z 418 [M++H]
Example 136Chemical structure
Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-(3-methoxypropan-1-yl)pyridine-2-carboxamide
ESI-MS m/z 439 [M++H]
Example 137Chemical structure
On the study of compounds: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]thiazol-2-carboxamide
ESI-MS m/z 377 [M++H]
Example 138Chemical structure
ESI-MS m/z 422 [M++H]
Example 139Chemical structure
ESI-MS m/z 421 [M++H]

Example 140Chemical structure
ESI-MS m/z 422 [M++H]
Example 141Chemical structure
Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-diformylpiridine-2-carboxamide
ESI-MS m/z 421 [M++H]
Example 142Chemical structure
Connection name: N-[3-((4aS*,8aS*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-bromopyridin-2-carboxamide
ESI-MS m/z 467 [M++H]

Connection use the s 143-148, synthesized in accordance with example 14, using the appropriate carboxylic acid and the compound obtained in the example of a 44-(16).

Example 143

Synthesis of N-[3-((4aS*,5S*,8aS*)-2-amino-5-vermeil-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 191]

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,64-1,72 (m, 1H), 2,66-by 2.73 (m, 1H), 2,73-of 2.81 (m, 1H), 2,89-of 2.97 (m, 1H), 2,99-of 3.06 (m, 1H), 3,76-was 4.02 (m, 3H), with 4.64 (DD, J=48,0, 3.8 Hz, 2H), 7,11 (DD, J=11,6, 8,8 Hz, 1H), 7,46 (DD, J=6,8, 2.8 Hz, 1H), 7,88-7,94 (m, 1H), to 8.20 (DD, J=8,0, 2.5 Hz, 1H), to 8.41-to 8.45 (m, 1H), 8,88-of 8.92 (m, 1H), 9,82 (USS, 1H).

ESI-MS m/z 444 [M++H].

Example 144

Synthesis of N-[3-((4aS*,5S*,8aS*)-2-amino-5-vermeil-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-formatexpiry-2-carboxamide

[Formula 192]

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,66-1,72 (m, 1H), 2,66-2,82 (m, 2H), 2,89 are 2.98 (m, 1H), 2,98-of 3.06 (m, 1H), of 3.77-was 4.02 (m, 3H), with 4.64 (USD, J=47,6 Hz, 2H), 6,16 (d, J=51,2 Hz, 2H), 7,05-7,16 (m, 1H), 7,37-7,46 (m, 1H), 7,84-to 7.93 (m, 1H), 8,29 (d, J=1.4 Hz, 1H), remaining 9.08 (d, J=1.4 Hz, 1H), for 9.47 (USS, 1H).

ESI-MS m/z 468 [M++H].

Example 145

Synthesis of N-[3-((4aS*,5S*,8aS*)-2-amino-5-vermeil-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-deformatsiei-2-carboxamide

[Formula 193]

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,63-of 1.73 (m, 1H), 2,65-2,82 (m, 2H), 2,89-2.98 m, 1H), 2,98-of 3.06 (m, 1H), of 3.77-a 4.03 (m, 3H), with 4.64 (DD, J=47,6, 3.5 Hz, 2H), 7,06-to 7.15 (m, 1H), 7,41-7,47 (m, 1H), 7,51 (t, J=71,4 Hz, 1H), 7,84-a 7.92 (m, 1H), 8,32-at 8.36 (m, 1H), 9,05-9,10 (m, 1H), 9,45 (USS, 1H).

ESI-MS m/z 486 [M++H].

Example 146

Synthesis of N-[3-((4aS*,5S*,8aS*)-2-amino-5-vermeil-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-deformalisation-2-carboxamide

[Formula 194]

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,63-of 1.74 (m, 1H), 2,66-2,82 (m, 2H), 2,89 are 2.98 (m, 1H), 2,98-is 3.08 (m, 1H), 3,76-a 4.03 (m, 3H), with 4.64 (DD, J=48,0, 2,8 Hz, 2H), 6,80 (t, J=54,4 Hz, 1H), 7,07-7,17 (m, 1H), 7,45-7,52 (m, 1H), 7,85-7,94 (m, 1H), 8,93 (s, 1H), at 9.53 (s, 1H), 9,62 (USS, 1H).

ESI-MS m/z 470 [M++H].

Example 147

Synthesis of N-[3-((4aS*,5S*,8aS*)-2-amino-5-vermeil-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-deformationen-2-carboxamide

[Formula 195]

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,63-1,72 (m, 1H), 2,67-of 2.81 (m, 2H), 2,88 are 2.98 (m, 1H), 2,98-of 3.07 (m, 1H), 3,76-was 4.02 (m, 3H), with 4.64 (d, J=48,0 Hz, 2H), 6,65 (t, J=72,0 Hz, 1H), 7.03 is-to 7.15 (m, 1H), 7,38-7,47 (m, 1H), 7,62-7,71 (m, 1H), 7,84-to 7.95 (m, 1H), 8,27-at 8.36 (m, 1H), 8,42-of 8.50 (m, 1H), 9,80 (USS, 1H).

ESI-MS m/z 485 [M++H].

Example 148

Synthesis of N-[3-((4aS*,5S*,8aS*)-2-amino-5-vermeil-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-chloropyridin-2-carboxamide

[Formula 196]

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,63-1,72 (m, 1H), 2,67 is 2.80 (m, 2H), 2,90 are 2.98 (m, 1H), 2,98-of 3.06 (m, 1H), of 3.77-4,01 (m, 3H), 464 (DD, J=47,6, 2,8 Hz, 2H), 7,06-7,14 (m, 1H), 7,41-7,47 (m, 1H), 7,86-to 7.93 (m, 2H), by 8.22-of 8.28 (m, 1H), 8,55 at 8.60 (m, 1H), 9,80 (USS, 1H).

ESI-MS m/z 453 [M++H].

Examples 149-151

Connection examples 149-151, shown below in table 12 were synthesized in accordance with example 14, using the appropriate carboxylic acid and the appropriate aniline intermediate compounds in the examples received.

[Table 12]

Table 12
Example 149Chemical structure
ESI-MS m/z 487 [M++H]
Example 150Chemical structure
ESI-MS m/z 412 [M++H]
Example 151Chemical structure
ESI-MS m/z 412 [M++H]

Connection examples 152-157 synthesized in accordance with example 14, using the appropriate carboxylic acid and the compound obtained in the example of a 48-(13).

Example 152

Synthesis of N-[3-((4aS*,5R*,8aS*)-2-amino-5-methyl-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-chloropyridin-2-carboxamide

[Formula 197]

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.34 (d, J=6.4 Hz, 3H), 1,72-to 1.82 (m, 1H), 2,64-2,82 (m, 3H), 2,92-3,00 (m, 1H), 3.75 to 3,86 (m, 2H), 3,92-of 3.97 (m, 1H), 7,08-7,16 (m, 1H), 7,40-7,46 (m, 1H), 7,87-of 7.96 (m, 2H), by 8.22 compared to 8.26 (m, 1H), 8,57 at 8.60 (m, 1H), 9,84 (USS, 1H).

ESI-MS m/z 435 [M++H].

Example 153

Synthesis of N-[3-((4aS*,5R*,8aS*)-2-amino-5-methyl-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-formatexpiry-2-carboxamide

[Formula 198]

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,33 (d, J=6.0 Hz, 3H), 1,75-of 1.84 (m, 1H), 2,62 is 2.80 (m, 3H), 2,89-of 2.97 (m, 1H), 3,74-of 3.85 (m, 2H), 3,89-of 3.97 (m, 1H), 6,06-6,12 (m, 1H), to 6.19 and 6.25 (m, 1H), 7,06-to 7.15 (m, 1H), 7,35-7,41 (m, 1H), 7,88-of 7.96 (m, 1H), 8,30 (d, J=1.2 Hz, 1H), 9,07 (d, J=1.2 Hz, 1H), 9,50 (USS, 1H).

ESI-MS m/z 450 [M++H].

Example 154

Synthesis of N-[3-((4aS*,5R*,8aS*)-2-amino-5-methyl-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-deformatsiei-2-carboxamide

[Formula 199]

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,32 (d, J=6.0 Hz, 3H), 1,68-to 1.77 (m, 1H), 2,59-2,77 (m, 3H), 2,86-to 2.94 (m, 1H), of 3.73-3,86 (m, 2H), a 3.87-3,95 (m, 1H), 7,07-7,14 (m, 1H), was 7.36-7,40 (m, 1H), 7,51 (t, J=71,4 Hz, 1H), 7,88-7,94 (m, 1H), 8,35 (d, J=1.2 Hz, 1H), 9,07 (d, J=1.2 Hz, 1H), for 9.47 (USS, 1H).

ESI-MS m/z 468 [M++H].

Example 155

Synthesis of N-[3-((4aS*,5R*,8aS*)-2-amino-5-methyl-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-deformationen-2-carboxamide

[Formula 200]

H-NMR (400 MHz, CDCl3) δ (ppm): 1,33 (d, J=6.0 Hz, 3H), 1,74 of-1.83 (m, 1H), 2,62-and 2.79 (m, 3H), 2,89-of 2.97 (m, 1H), 3,74-3,86 (m, 2H), 3,88-of 3.96 (m, 1H), 6,65 (t, J=72,0 Hz, 1H), 7,05-7,14 (m, 1H), 7,37-7,42 (m, 1H), of 7.64-of 7.69 (m, 1H), of 7.90-of 7.96 (m, 1H), 8.30 to-a 8.34 (m, 1H), 8,46-of 8.50 (m, 1H), 9,82 (USS, 1H).

ESI-MS m/z 467 [M++H].

Example 156

Synthesis of N-[3-((4aS*,5R*,8aS*)-2-amino-5-methyl-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-deformalisation-2-carboxamide

[Formula 201]

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,33 (d, J=6.4 Hz, 3H), 1,72-of 1.81 (m, 1H), 2,62-and 2.79 (m, 3H), 2,88-2,95 (m, 1H), 3,74-3,86 (m, 2H), 3,89-of 3.96 (m, 1H), 6,79 (t, J=54,4 Hz, 1H), 7,08-7,16 (m, 1H), 7,41-7,46 (m, 1H), 7,88-of 7.96 (m, 1H), 8,92-8,95 (m, 1H), 9,51-9,54 (m, 1H), for 9.64 (USS, 1H).

ESI-MS m/z 452 [M++H].

Example 157

Synthesis of N-[3-((4aS*,5R*,8aS*)-2-amino-5-methyl-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 202]

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,32 (d, J=6.4 Hz, 3H), 1,62 was 1.69 (m, 1H), 2,54-2,62 (m, 1H), 2,65 is 2.75 (m, 2H), 2,84 of 2.92 (m, 1H), of 3.73-3,86 (m, 2H), 3,86-3,93 (m, 1H), 7,06-7,14 (m, 1H), was 7.36-7,42 (m, 1H), 7,92-7,98 (m, 1H), 8,20 (DD, J=8,2, 1.8 Hz, 1H), 8,43 (DD, J=8,2, 1.0 Hz, 1H), 8,90 (DD, J=1,8, 1.0 Hz, 1H), 9,81 (USS, 1H).

ESI-MS m/z 426 [M++H].

Example 158

Synthesis of (±)-N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-5-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 203]

Specified in the title compound (52 what g) was obtained from 5-cyano-2-carboxylic acid, received in the sample receiving 13 (49,3 mg)and the compound obtained in the example of a 55-(11) (85 mg), in accordance with the method of example 14.

ESI-MS; m/z 396 [M++H].

Example 159

Synthesis of N-[3-((4aR*,8aS*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 204]

Specified in the title compound (15 mg) was obtained from 5-cyano-2-carboxylic acid (12.9 mg) and the compound obtained in the example of a 56-(16) (23 mg), in accordance with the method of example 14.

ESI-MS; m/z 412 [M++H].

Example 160

Synthesis of (±)-(4aR*,7aS*)-7a-[2-fluoro-5-(2-herperidin-3-yl)phenyl]-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine

[Formula 205]

(1)Synthesis of benzyl (±)-[(4aR*,7aS*)-7a-(5-bromo-2-forfinal)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]carbamate

Benzylchloride (1,16 ml) was added to a solution of the compound obtained in the example of a 54-(4) (2.24 g)in 1,4-dioxane and a saturated solution of sodium bicarbonate (60 ml/60 ml). The reaction solution was stirred at room temperature for three hours. To the reaction solution were added ethyl acetate and a saturated aqueous solution of sodium chloride and separated the organic layer. The organic layer was again washed with a saturated aqueous solution of sodium chloride. The organization is practical layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on silica gel with obtaining specified in the title compound (2.35 g).

ESI-MS; m/z 463 [M++H].

(2)Synthesis of benzyl (±)-{(4aR*,7aS*)-7a-[2-fluoro-5-(2-herperidin-3-yl)phenyl]-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl}carbamate

1 M aqueous sodium bicarbonate (432 μl), 2-herperidin-3-Bronevoy acid (67,1 mg) and tetrakis(triphenylphosphine)palladium (0) (25.1 mg) was added to a solution of the compound obtained in example 160-(1) (200 mg)in a mixture of toluene (4 ml)/ethanol (2 ml)and the mixture was stirred at 85°C for 16 hours. The reaction solution was brought to room temperature. Was added to the reaction solution, a saturated aqueous solution of sodium chloride and ethyl acetate. The organic layer was separated and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with getting roughly purified product containing specified in the title compound (156 mg).

ESI-MS; m/z 480 [M++H].

(3)Synthesis of (±)-(4aR*,7aS*)-7a-[2-fluoro-5-(2-herperidin-3-yl)phenyl]-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine

Attributively (116 μl) was added to a solution of the compound obtained in example 160-(2) (78 mg)in chloroform (4 ml)and the mixture was stirred at room temperature than is their night. Again added to the reaction solution, attributively (116 μl) and the mixture is boiled under reflux for 20 hours. The reaction solution was brought to room temperature. The reaction solution was podslushivaet 5 N. sodium hydroxide was added chloroform. The organic layer was separated and washed with saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with NH-silica gel with obtaining specified in the title compound (11 mg).

ESI-MS; m/z 346 [M++H].

Example 161

Synthesis of (±)-(4aR*,7aS*)-7a-(4-fluoro-3'-methoxybiphenyl-3-yl)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine

[Formula 206]

Synthesis of (±)-(4aR*,7aS*)-7a-(4-fluoro-3'-methoxybiphenyl-3-yl)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine

Specified in the title compound (1.3 mg) was obtained from the compound obtained in example 160-(1) (100 mg)according to example 160 using appropriate Bronevoy acid.

ESI-MS; m/z 357 [M++H].

Example 162

Synthesis of (+)-(4aR*,7aS*)-7a-(3',5'-dichloro-4-forbiden-3-yl)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine

[Formula 207]

(1)Synthesis of (±)-(4aR*,7aS*)-7a-(3',5'-dichloro-4-forbiden-3-yl)-4,4a,5,6,7,7a-gexa is kotilaine[d][1,3]thiazin-2-ylamine

1 M aqueous sodium bicarbonate (486 μl), 3,5-dichlorophenylamino acid (80.4 mg) and tetrakis(triphenylphosphine)palladium(0) (18,8 mg) was added to a solution of the compound obtained in example 160-(1) (120 mg)in DMF (3 ml)and the mixture was stirred at 110°C for eight hours. The reaction solution was brought to room temperature. To the reaction solution was added saturated aqueous solution of sodium chloride and ethyl acetate. The organic layer was separated and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel with getting roughly purified product containing specified in the title compound (69 mg).

ESI-MS; m/z 395 [M++H].

(2)Synthesis of (+)-(4aR*,7aS*)-7a-(3',5'-dichloro-4-forbiden-3-yl)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine

The compound obtained in example 162-(1) (69 g), washed with a mixed solvent of ethyl acetate (0.5 ml) and heptane (3 ml). The obtained solid substance was diluted in 8 ml of ethanol and the connection is optically separated using CHIRALPAK™ IA production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 7:3, flow rate: 5 ml/min). Component having a retention time of from 24 to 28 minutes, collected by obtaining specified in the title compound (11 mg).

ESI-MS; m/z 395 [M++H].

Example 163

Sin is ez (+)-(4aR*,7aS*)-7a-[2-fluoro-5-(5-methoxypyridine-3-yl)phenyl]-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine

[Formula 208]

(1)Synthesis of (±)-(4aR*,7aS*)-7a-[2-fluoro-5-(5-methoxypyridine-3-yl)phenyl]-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine

Roughly purified product containing specified in the title compound (150 mg), was obtained from the compound obtained in example 160-(1) (200 mg)according to example 162, using the appropriate Bronevoy acid.

ESI-MS; m/z 358 [M++H].

(2)Synthesis of (+)-(4aR*,7aS*)-7a-[2-fluoro-5-(5-methoxypyridine-3-yl)phenyl]-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine

The compound obtained in example 163-(1) (150 mg)was again purified by chromatography on silica gel and the obtained solid substance was diluted in 12 ml of ethanol. The connection is optically separated using CHIRALPAK™ IA production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 1:1, flow rate: 5 ml/min). Component having a retention time of 27 to 30 minutes, collected by obtaining specified in the title compound (18 mg).

ESI-MS; m/z 358 [M++H].

Connection examples 164-167 synthesized in accordance with example 14, using the appropriate carboxylic acid and the appropriate aniline intermediate compounds in the examples received.

Example 164

Synthesis of N-[3-((4aS,5S,7aS)-2-amino-5-vermeil-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula]

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,80 (DD, J=4,0, 13,2 Hz, 1H), 3,05-3,10 (m, 1H), 3.15 in (DD, J=3,6, 13,2 Hz, 1H), a 3.87 (DD, J=2,8, 8,8 Hz, 1H), 4,51-of 4.66 (m, 4H), 7,11 (DD, J=8,8, 12,0H, 1H), 7,58 (DD, J=2,8, 7.2 Hz, 1H), 7,93-of 7.97 (m, 1H), 8,21 (DD, J=2,4, and 8.4 Hz, 1H), 8,42 (DD, J=0,8, 8.0 Hz, 1H), 8,90 (DD, J=0,8, 2.0 Hz, 1H), 9,86 (s, 1H).

ESI-MS m/z 430 [M++H].

Example 165

Synthesis of N-[3-((4aS*,7aS*)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-triptorelin-2-carboxamide

[Formula 210]

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,84 (DD, J=5,6, of 14.0 Hz, 1H), is 3.08-3,13 (m, 2H), 3,83 (DD, J=2.0 a, and 8.4 Hz, 1H), 4,08-to 4.15 (m, 2H), 4,47 (DD, J=1,2, and 8.4 Hz, 1H), 7,10 (DD, J=8,8, 12.0 Hz, 1H), 7,65 (DD, J=2,8, 6,8 Hz, 1H), 7,93-of 7.97 (m, 1H), 8,17 (DD, J=2,4, 8.0 Hz, 1H), 8,43 (d, J=8.0 Hz, 1H), of 8.90 (s, 1H), 9,94 (s, 1H).

ESI-MS m/z 441 [M++H].

Example 166

Synthesis of N-[3-((4aS*,7aS*)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-bromopyridin-2-carboxamide

[Formula 211]

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,84 (DD, J=6,0, of 14.0 Hz, 1H), is 3.08-3,13 (m, 2H), 3,84 (DD, J=2.0 a, 8,8 Hz, 1H), 4,08-to 4.15 (m, 2H), 4,46 (DD, J=1,2, and 8.4 Hz, 1H), to 7.09 (DD, J=8,8, and 11.6 Hz, 1H), to 7.59 (DD, J=2,8, 6,8 Hz, 1H), 7,93-of 7.97 (m, 1H), 8,04 (DD, J=2,4, 8.0 Hz, 1H), 8,18 (d, J=8,4 Hz, 1H), 8,67 (d, J=1.6 Hz, 1H), 9,83 (s, 1H).

ESI-MS m/z 451 [M++H].

Example 167

Synthesis of N-[3-((4aS*,7aS*)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformationen-2-carboxamide

[Formula 212]

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,84 (DD, J=6,4, of 14.0 Hz, 1H), 3,07-of 3.12 (m, 2H), 3,83 (DD, J=2.0 a, 8,8 Hz, 1H), 4,08-4,18 (m, 2H), 4,46 (DD, J=1,2, and 8.4 Hz, 1H), 6,65 (t, J=72,0 Hz, 1H), to 7.09 (DD, J=8,8, 12.0 Hz, 1H), to 7.59 (DD, J=2,8, 7.2 Hz, 1H), to 7.67 (DD, J=2,8, 8,8 Hz, 1H), 7,94-7,98 (m, 1H), 8,32 (d, J=8,8 Hz, 1H), of 8.47 (d, J=2.4 Hz, 1H), 9,83 (s, 1H).

ESI-MS m/z 439 [M++H].

Examples 168-191

Connection examples 168-191, shown below in table 13 were synthesized in accordance with example 14, using the appropriate carboxylic acid and the appropriate aniline intermediate compounds in the examples received.

[Table 13]

Table 13
Example 168Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]for 3,5-differencein-2-carboxamide
ESI-MS m/z 407 [M++H]
Example 169Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-triptorelin-2-carboxamide
1H-NMR (400 MHz, CDCl3) δ (ppm): 1.70 to 2.05 is (m, 5H), 2.57 m-to 2.65 (m, 1H), 2,74-2,84 (m, 2H), 2,9 (d, J=12.0 Hz, 1H), 7,06 (DD, J=10,0, to 10.8 Hz, 1H), 7,42 (d, J=6,8 Hz, 1H), 7,94-of 7.96 (m, 1H), 8,16 (d, J=8.0 Hz, 1H), 8,42 (d, J=8.0 Hz, 1H), 8,88 (s, 1H), 9,90 (s, 1H).
Example 170Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-3-triptorelin-2-carboxamide
1H-NMR (400 MHz, CDCl3) δ (ppm): 1,71 of 1.99 (m, 5H), of 2.56 2.63 in (m, 1H), 2,75 (DD, J=12,4, 4.0 Hz, 1H), 2,82-is 2.88 (m, 1H), 2,99 (DD, J=3.2, and to 12.8 Hz, 1H), 7,05 (DD, J=12,0, 8,8 Hz, 1H), 7,20 (DD, J=2,8, 7.2 Hz, 1H), 7,63 (DD, J=8.0 a, 4,8 Hz, 1H), 8,09-8,13 (m, 1H), 8,23 (d, J=8.0 Hz, 1H), 8,79 (DD, J=1,2, 4,8 Hz, 1H), 9,78 (USS, 1H).

Example 171Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-3-herperidin-2-carboxamide
ESI-MS m/z 389 [M++H]
Example 172Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-bromopyridin-2-carboxamide
ESI-MS m/z 449 [M++H]
Example 173Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-3-bromopyridin-2-carboxamide
ESI-MS m/z 449 [M++H]
Example 174Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-methoxypyridine-2-carboxamide
ESI-MS m/z 401 [M++H]
Example 175Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformationen-2-carboxamide
ESI-MS m/z 437 [M++H]
Example 176Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-bromopyrimidine-2-carboxamide
ESI-MS m/z 472 [M++Na]

Por the measures 177 Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-methoxypyrazine-2-carboxamide
ESI-MS m/z 402 [M++H]
Example 178Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-(2,2,2-triptoreline)pyrazin-2-carboxamide
ESI-MS m/z 470 [M++H]
Example 179Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-(2,2,2-triptoreline)pyridine-2-carboxamide
ESI-MS m/z 469 [M++H]
Example 180Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]for 3,5-dichloropyridine-2-carboxamide
ESI-MS m/z 439 [M++H]
Example 181 Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-(2,2-diflorasone)pyrazin-2-carboxamide
ESI-MS m/z 452 [M++H]
Example 182Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-(2,2-diflorasone)pyridine-2-carboxamide
ESI-MS m/z 451 [M++H]

Example 183Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-(2-floratone)pyrazin-2-carboxamide
ESI-MS m/z 434 [M++H]
Example 184Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-3-chloro-5-triptorelin-2-carboxamide
ESI-MS m/z 473[M++H]
Example 185 Connection name: N-[3-((4aS*,8aS*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]for 3,5-dichloropyridine-2-carboxamide
ESI-MS m/z 455 [M++H]
Example 186Connection name: N-[3-((4aS*,8aS*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-triptorelin-2-carboxamide
ESI-MS m/z 455 [M++H]
Example 187Connection name: N-[3-((4aS*,8aS*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)-4-forfinal]-5-herperidin-2-carboxamide
ESI-MS m/z 405 [M++H]
Example 188Connection name: N-[3-((4aS*,7aS*)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]for 3,5-differencein-2-carboxamide
ESI-MS m/z 409 [M++H]
Example 189Connection name: N-[3-((4aS*,7aS*)-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]for 3,5-dichloropyridine-2-carboxamide
ESI-MS m/z 441 [M++H]

Example 190Connection name: N-[3-((4aS*,7aS*)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-diformylpiridine-2-carboxamide
ESI-MS m/z 423 [M++H]
Example 191Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamide
ESI-MS m/z 422 [M++H]

Examples 192-200

Connection examples 192-200, shown below in table 14 was synthesized in accordance with example 14, using the appropriate carboxylic acid and the appropriate aniline intermediate compounds in the examples received.

[Table 14]

Table 14
Example 192ESI-MS m/z 405 [M++H]
Example 193 ESI-MS m/z 405 [M++H]
Example 194ESI-MS m/z 439 [M++H]

Example 195ESI-MS m/z 386 [M++H]
Example 196ESI-MS m/z 477 [M++H]
Example 197ESI-MS m/z 418 [M++H]
Example 198ESI-MS m/z 372 [M++H]
Example 199ESI-MS m/z 468 [M++H]
Example 200ESI-MS m/z 423 [M++H]

Example 201

Synthesis of N-[3-((4aR*,7S*,8aS*)-2-amino-7-methoxy-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 213]

Tr is t-Butyl (-)-[(4aR*,7S*,8aS*)-8a-(5-amino-2-forfinal)-7-methoxy-4a,5,6,7,8,8a-hydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate, obtained in the example of a 57-(11) (41 mg)was mixed with 5-formatexpiry-2-carboxylic acid (18 mg), N,N-diisopropylethylamine (87 μl, specific gravity: 0,742 g/cm3) and PyBOP (104 mg) in dichloromethane (2 ml)and the mixture was stirred in nitrogen atmosphere at room temperature. After stirring for five hours the reaction solution was immediately purified by chromatography on a column of silica gel. To the resulting amide was added chloroform (0.5 ml) and TFOC (0.5 ml) and the mixture was stirred at room temperature for two hours and 30 minutes. The reaction solution was slowly poured into a saturated solution of sodium bicarbonate, followed by extraction three times with chloroform. The obtained organic layers were dried over anhydrous magnesium sulfate and the solid was removed by filtration. The filtrate was concentrated under reduced pressure and then purified by chromatography on a column with NH-silica gel with obtaining specified in the title compound (34 mg).

ESI-MS; m/z 440 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,40 was 1.43 (m, 1H), 1,69 is 1.75 (m, 1H), 2,08-of 2.28 (m, 3H), 2,32 to 2.35 (m, 1H), 2,61-of 2.64 (m, 1H), was 2.76-and 2.79 (m, 1H), 2,88-only 2.91 (m, 1H), on 3.36 (s, 3H), 3,63 (ush., 1H), 7,05-7,10 (m, 1H), 7,37-7,38 (m, 1H), 8,04-8,07 (m, 1H), 8,19-to 8.20 (m, 1H), to 8.41-8,43 (m, 1H), of 8.90 (s, 1H), 9,84 (s, 1H).

Example 202

Synthesis of N-[3-((4aR*,7R*,8aS*)-2-amino-7-methoxy-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 214]

Specified in the title compound (39 mg) was obtained from tert-butyl (-)-[(4aR*,7R*,8aS*)-8a-(5-amino-2-forfinal)-7-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in example getting 58-(13) (50 mg), in accordance with the method of example 201.

ESI-MS; m/z 440 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,42-of 1.53 (m, 1H), 1,61-of 1.65 (m, 1H), 1.77 in-1,89 (m, 1H), 2,09-of 2.24 (m, 3H), 2,61-of 2.64 (m, 1H), 2.71 to to 2.74 (m, 1H), 2,92 (DD, J=4,0, 12.0 Hz, 1H), on 3.36 (s, 3H), 3,39 is-3.45 (m, 1H), was 7.08 (DD, J=8,8, 12.0 Hz, 1H), 7,32-7,34 (m, 1H), 7,92-to 7.95 (m, 1H), 8,18-8,21 (m, 1H), 8,42 (DD, J=0,8, and 8.4 Hz, 1H), 8,88-8,89 (m, 1H), 9,80 (s, 1H).

Example 203

The compound of example 203, shown below in table 15, was synthesized in accordance with example 202 using the appropriate carboxylic acid.

[Table 15]

Table 15
Example 203Chemical structure
Connection name: N-[3-((4aR*,7R*,8aS*)-2-amino-7-methoxy-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-deformalisation-2-carboxamide
ESI-MS; m/z 466 [M++H]

Example 204

Synthesis of N-[3-((4aR*,6S*,8aS*)-2-amino-6-methoxy-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide/u>

[Formula 215]

Specified in the title compound (37 mg) was obtained from tert-butyl (-)-[(4aR*,6S*,8aS*)-8a-(5-amino-2-forfinal)-6-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in example getting 60-(4) (50 mg), in accordance with the method of example 201.

ESI-MS; m/z 440 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,52-of 1.57 (m, 1H), from 1.66 to 1.76 (m, 1H), 1,82-of 1.92 (m, 3H), 2,52-2,62 (m, 2H), 2.95 and-2,99 (m, 1H), 3,10-3,15 (m, 1H), 3,39 (s, 3H), 3,60-3,62 (m, 1H), 7,07 (DD, J=8,8, and 11.6 Hz, 1H), 7,34 (DD, J=2,8, 7,2 Hz, 1H), to 7.93 (DDD, J=2,8, 4,0, 8,8 Hz, 1H), 8,18-8,21 (m, 1H), 8,42 (DD, J=0,8, 4,4 Hz, 1H), 8,89 (DD, J=0,8, 2.0 Hz, 1H), 9,79 (s, 1H).

The compound of example 205, shown below in table 16 was synthesized in accordance with example 204, using the appropriate carboxylic acid.

[Table 16]

Table 16
Example 205Chemical structure
ESI-MS; m/z 466 [M++H].

Example 206

Synthesis of N-[3-((4aR*,6R*,8aS*)-2-amino-6-methoxy-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 216]

Specified in the title compound (33 mg) was obtained from tert-butyl (-)-[(4aR*,6R*,8aS*)-8a-(5-amino-2-forfinal)-6-methoxy-4a,5,6,7,8,8a-hexa is Idro-4H-benzo[d][1,3]thiazin-2-yl]carbamate, obtained in the example of a 61-(4) (50 mg), in accordance with the method of example 201.

ESI-MS; m/z 440 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,60-of 1.74 (m, 2H), 1,82 is 1.91 (m, 2H), 1,97 is 2.00 (m, 1H), 2,23-of 2.30 (m, 1H), 2,58-2,61 (m, 1H), 2.77-to 2,80 (m, 1H), 2,92-2,95 (m, 1H), 3,41 (s, 3H), 3,41-to 3.49 (m, 1H), 7,05-7,10 (m, 1H), 7,30-to 7.32 (m, 1H), 7,97-of 8.00 (m, 1H), 8,19 (d, J=8,4 Hz, 1H), 8,42 (d, J=8.0 Hz, 1H), of 8.90 (s, 1H), 9,80 (s, 1H).

Examples 207-211

Connection examples 207-211, shown below in table 17 was synthesized according to example 206, using the appropriate carboxylic acid.

[Table 17]

Table 17
Example 207Chemical structure
Connection name: N-[3-((4aR*,6R*,8aS*)-2-amino-6-methoxy-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-deformalisation-2-carboxamide
ESI-MS; m/z 466 [M++H].
Example 208Chemical structure
Connection name: N-[3-((4aR*,6R*,8aS*)-2-amino-6-methoxy-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-formatexpiry-2-carboxamide
1H-NMR (400 MHz, CDCl3 ) δ (ppm): 1,53-to 1.61 (m, 1H), 1,65 is 1.75 (m, 1H), 1,81 is 1.91 (m, 2H), 1,97 of 1.99 (m, 1H), and 2.27 (dt, J=2,4, of 13.6 Hz, 1H), 2,59 (DD, J=2,8, and 12.4 Hz, 1H), was 2.76 is 2.80 (m, 1H), 2,95 (DD, J=4.0 a, and 12.4 Hz, 1H), 3,41-to 3.52 (m, 4H), 6,16 (arcs, J=2,0, a 51.2 Hz, 2H), 7,06 (DD, J=8,8, 12.0 Hz, 1H), 7.23 percent-of 7.25 (m, 1H), 8,00 (DDD, J=2,8, 4,0, 8,8 Hz, 1H), 8,29 (d, J=1.6 Hz, 1H), 9,07 (d, J=1.6 Hz, 1H), 9,44 (ush., 1H).
ESI-MS; m/z 464 [M++H].

Example 209Chemical structure
Connection name: N-[3-((4aR*,6R*,8aS*)-2-amino-6-methoxy-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-deformatsiei-2-carboxamide
ESI-MS; m/z 482 [M++H].
Example 210Chemical structure
Connection name: N-[3-((4aR*,7R*,8aS*)-2-amino-6-methoxy-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-chloropyridin-2-carboxamide
1H-NMR (400 MHz, CDCl3) δ (ppm): 1,52-of 1.75 (m, 2H), 1,81-of 1.92 (m, 2H), 1,96 of 1.99 (m, 1H), 2,23-2,31 (m, 1H), 2.57 m-2,61 (m, 1H), 2,75-of 2.81 (m, 1H) 2,93-of 2.97 (m, 1H), 3,41-to 3.49 (m, 4H), to 4.52 (ush., 2H), 7,05 (DD, J=8,8, 12.0 Hz, 1H), 7,25-7,28 (m, 1H), 7,87 (DD, J=2,4, and 8.4 Hz, 1H), 8,00 (DDD, J=2,8, 4,0, 8,8 Hz, 1H), 8,23 (DD, J=0,4, and 8.4 Hz, 1H), 8,56 (DD, J=0,4, 2.4 Hz, 1H), 9,77 (ush., 1H).
ESI-S; m/z 449 [M++H]
Example 211Chemical structure
Connection name: N-[3-((4aR*,6R*,8aS*)-2-amino-6-methoxy-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-deformationen-2-carboxamide
1H-NMR (400 MHz, CDCl3) δ (ppm): 1,53-to 1.63 (m, 1H), 1,65 is 1.75 (m, 1H), 1,81 is 1.91 (m, 2H), 1,95 for 2.01 (m, 1H), and 2.27 (dt, 2,4, of 13.6 Hz, 1H), 2.57 m-2,60 (m, 1H), 2,75-of 2.81 (m, 1H), 2,95 (DD, J=4.0 a, and 12.4 Hz, 1H), 3,39-to 3.49 (m, 4H), 4,50 (ush., 2H), only 6.64 (t, J=72,0 Hz, 1H), 7,05 (DD, J=8,8, 12.0 Hz, 1H), 7,25-7,27 (m, 1H), 7,65 (DD, J=2,8, 8,8 Hz, 1H), 8,01 (DDD, J=2,8, 4,0, 8,8 Hz, 1H), 8,31 (DD, J=0,8, 8,8 Hz, 1H), 8,46 (DD, J=0,8, 2.8 Hz, 1H), 9,77 (ush., 1H).
ESI-MS; m/z 81 [M++H]

Example 212

Synthesis of N-[3-((4aR*,6R*,8aS*)-2-amino-6-fluoro-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 217]

Specified in the title compound (37 mg) was obtained from tert-butyl (-)-[(4aR*,6R*,8aS*)-8a-(5-amino-2-forfinal)-6-fluoro-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in example obtaining 63-(8) (52 mg), in accordance with the method of example 201.

ESI-MS; m/z 428 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,79 is 1.91 (m, 2H), 1,92-2,07 (m, 3H), 2,24 of-2.32 (m, 1H), 2,61 (DD, J=2,8, 12.0 Hz, 1H), 2,78-2,82 (m, 1H), 2,94 (DDD, J=3.2, and to 4.0, 12.0 Hz, 1H), 4,58 (ush., 2H), 4,68-4,88 (m, 1H), 7,07 (the d, J=8,8, 12.0 Hz, 1H), 7,34 (DD, J=2,8, 7.2 Hz, 1H), 7,97 (DDD, J=2,8, 4,4, 8,8 Hz, 1H), to 8.20 (DD, J=2,4, and 8.4 Hz, 1H), 8,42 (DD, J=1,2, 4,4 Hz, 1H), 8,89 (DD, J=1,2, 2,4 Hz, 1H), 9,80 (ush., 1H).

Examples 213-214

Connection examples 213-214, shown below in table 18 was synthesized in accordance with example 210 using the appropriate carboxylic acid.

[Table 18]

Table 18
Example 213Chemical structure
Connection name: N-[3-((4aR*,6R*,8aS*)-2-amino-6-fluoro-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-deformalisation-2-carboxamide
1H-NMR (400 MHz, CDCl3) δ (ppm): 1,82-1,90 (m, 2H), 1,92-2,07 (m, 3H), 2,25 of-2.32 (m, 1H), 2,59-2,63 (m, 1H), 2,79-2,82 (m, 1H), 2,92-of 2.97 (m, 1H), 4,59 (ush., 2H), 4,68-4,88 (m, 1H), 6,79 (t, J=54,4 Hz, 1H), was 7.08 (DD, J=8,8, 12.0 Hz, 1H), 7,35 (DD, J=2,8, 7.2 Hz, 1H), of 7.96 (DDD, J=2,8, 4,0, 8,8 Hz, 1H), of 8.92 (d, J=1.2 Hz, 1H), 9,52 (d, J=1.2 Hz, 1H), 9,59 (ush., 1H).
ESI-MS; m/z 454 [M++H].
Example 214Chemical structure
Connection name: N-[3-((4aR*,6R*,8aS*)-2-amino-6-methoxy-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-formatexpiry-2-Carbo who Samid
1H-NMR (400 MHz, CDCl3) δ (ppm): 1,82-1,89 (m, 2H), 1,92-to 2.06 (m, 3H), 2,24 of-2.32 (m, 1H), 2,58-2,62 (m, 1H), 2.77-to of 2.81 (m, 1H), 2,92-of 2.97 (m, 1H) 4,59 (ush., 2H), 4,67-4,88 (m, 1H), 6,15 (arcs, J=2,0, a 51.2 Hz, 2H), 7,06 (DD, J=8,8, 12.0 Hz, 1H), 7,29 (DD, J=2,8, 7.2 Hz, 1H), 7,93-of 7.97 (m, 1H), 8,28 (d, J=1.6 Hz, 1H), 9,07 (d, J=1.6 Hz, 1H), 9,44 (ush., 1H).
ESI-MS; m/z 452 [M++H].

Example 215

Synthesis of N-[3-((4aR*,6S*,8aS*)-2-amino-6-fluoro-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

[Formula 218]

Specified in the title compound (22 mg) was obtained from tert-butyl (-)-[(4aR*,6S*,8aS*)-8a-(5-amino-2-forfinal)-6-fluoro-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in example obtain the 64-(8) (36 mg), in accordance with the method of example 201.

ESI-MS; m/z 428 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,51-of 1.66 (m, 1H), 1,72 of-1.83 (m, 1H), 1,87-2,03 (m, 3H), 2.57 m (DD, J=2,8, and 12.4 Hz, 1H), 2,62-2,70 (m, 1H), 3,01 (DD, J=4,0, 12.0 Hz, 1H), 3,16-to 3.34 (m, 1H), 4,99 (d, J=48,8 Hz, 1H) 7,10 (DD, J=8,8, to 11.6 Hz, 1H), was 7.36-7,38 (m, 1H), to $ 7.91-to 7.95 (m, 1H), 8,19-8,21 (m, 1H), 8,42-8,44 (m, 1H), 8,89-of 8.90 (m, 1H), 9,80 (ush., 1H).

Examples 216-219

Connection examples 216-219, shown below in table 19 was synthesized in accordance with example 202 using the appropriate carboxylic acid.

[Table 19]

Table 19
Example 216Chemical structure
Connection name: N-[3-((4aR*,6S*,8aS*)-2-amino-6-fluoro-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-deformalisation-2-carboxamide
ESI-MS; m/z 454 [M++H].
Example 217Chemical structure
Connection name: N-[3-((4aR*,6S*,8aS*)-2-amino-6-fluoro-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-formatexpiry-2-carboxamide
ESI-MS; m/z 452 [M++H].
Example 218Chemical structure
Connection name: N-[3-((4aR*,6S*,8aS*)-2-amino-6-fluoro-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-deformatsiei-2-carboxamide
ESI-MS; m/z 469 [M++H].
Example 219Chemical structure
Connection name: N-[3-((4aR*,6S*,8aS*)-2-amino-6-fluoro-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-chloropyridin-2-carboxamide
1H-NMR (400 MHz, CDCl3) δ (ppm): 1,62-to 1.67 (m, 1H), 1,75-2,04 (m, 4H), 2,54-of 2.58 (m, 1H), 2,66 (dt, J=4,0, 13,2 Hz, 1H), 2,99-3,03 (m, 1H), 3.15 and 3.21-in (m, 1H), 4,55 (ush., 2H), 4,94 (d, J=48,4 Hz, 1H), was 7.08 (DD, J=8,8, and 11.6 Hz, 1H), 7,33 (DD, J=2,8, 6,8 Hz, 1H), 7,87 (DD, J=2.0 a, and 8.4 Hz, 1H), 7,92-of 7.96 (m, 1H), 8,24 (DD, J=0,8, and 8.4 Hz, 1H), 8,56 (DD, J=0,8, 2.4 Hz, 1H), 9,77 (ush., 1H).
ESI-MS; m/z 437 [M++H].

Example 220

Synthesis of (±)-N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]benzamide

[Formula 219]

tert-Butyl (±)-[(4aR*,8aS*)-8a-(5-amino-2-forfinal)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in example obtain 1-(8) (100 mg)was dissolved in THF (5 ml). Then was added pyridine (107 μl, specific gravity 0,978 g/cm3) and the mixture was cooled in an ice bath under nitrogen atmosphere. After sufficient cooling was added benzylchloride (46 μl, specific weight of 1,211 g/cm3), followed by stirring for one hour and 30 minutes. After dilution with ethyl acetate was added a saturated solution of ammonium chloride followed by extraction with ethyl acetate. The resulting organic layer was sequentially washed with a saturated solution of ammonium chloride, water and a saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate and the solid was removed by filtration. The filtrate was concentrated under reduced pressure and was purified ptsh obtaining amide (93 mg). Amide was dissolved in a mixed solvent of ethyl acetate (1 ml) and chloroform (2 ml). Then was added a solution of hydrogen chloride in ethyl acetate (4 ad, 1 ml) and the mixture was stirred at room temperature. Five hours later even added TFOC (2 ml), followed by stirring. After 17 hours, concentrated under reduced pressure the solvent. To the obtained residue was added TFOC (3 ml), followed by stirring. 23 hours and 30 minutes the reaction solution was concentrated under reduced pressure. To the obtained residue were added ethyl acetate and a saturated solution of sodium bicarbonate, followed by extraction three times with ethyl acetate. The obtained organic layers were washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solid was removed by filtration. After concentration under reduced pressure the residue was purified by NH-ptsh obtaining specified in the title compound (40 mg).

ESI-MS; m/z 384 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,47-of 1.81 (m, 7H), 2,20-of 2.27 (m, 1H), 2,55 (DD, J=2,8, and 12.4 Hz, 1H), 2.70 height is 2.75 (m, 1H), equal to 2.94 (DD, J=4,0, 12.0 Hz, 1H), 7,30-to 7.09 (m, 2H), 7,47-7,52 (m, 2H), 7,53-7,58 (m, 1H), 7,84-7,86 (m, 3H), 7,93-7,97 (m, 1H).

Example 221

Synthesis of (±)-N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]furan-2-carboxamide

[Formula 220]

tert-Butyl (±)-[(4aR*,8aS*)-8a-(5-amino-2-CFT is henyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate, obtained in the example of a 1-(8) (100 mg)was dissolved in THF (5 ml). Then was added pyridine (107 μl, specific gravity 0,978 g/cm3) and the mixture was cooled in an ice bath under nitrogen atmosphere. After sufficient cooling was added furan-2-carbonylchloride (39 μl, specific gravity 1,324 g/cm3), followed by stirring for one hour and 30 minutes. After dilution with ethyl acetate was added a saturated solution of ammonium chloride followed by extraction with ethyl acetate. The resulting organic layer was sequentially washed with a saturated solution of ammonium chloride, water and a saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate and the solid was removed by filtration. The filtrate was concentrated under reduced pressure and was purified ptsh obtaining amide (59 mg). Amide was dissolved in a mixed solvent of ethyl acetate (2 ml) and chloroform (2 ml). Then was added a solution of hydrogen chloride in ethyl acetate (4 ad, 2 ml) and the mixture was stirred at room temperature. Five hours later even added TFOC (2 ml), followed by stirring. After 16 hours and 30 minutes, concentrated under reduced pressure the solvent. To the obtained residue were added ethyl acetate and a saturated solution of sodium bicarbonate, followed by extraction three times with ethyl acetate. The obtained organic layers were washed on Ishenim salt solution and dried over anhydrous magnesium sulfate. The solid was removed by filtration. After concentration under reduced pressure the residue was purified by NH-ptsh obtaining specified in the title compound (20 mg).

ESI-MS; m/z 374 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,50-of 1.81 (m, 7H), 2,19-of 2.26 (m, 1H), 2,56 (DD, J=2,4, 12.0 Hz, 1H), 2.71 to to 2.74 (m, 1H), equal to 2.94 (DD, J=4,0, 12.0 Hz, 1H), 6,56 (DD, J=1,6, 3.6 Hz, 1H), 7,05 (DD, J=8,8, 12.0 Hz, 1H), 7,13 (DD, J=2,4, 6,8 Hz, 1H), 7.23 percent-of 7.25 (m, 1H), 7,52 (d, J=1.2 Hz, 1H), 7,89-to 7.93 (m, 1H), 8,07 (USS, 1H).

Examples 222-225

Connection examples 222-225, shown below in table 20 was synthesized according to example 221, using the appropriate carboxylic acid.

[Table 20]

Table 20
Example 222Chemical structure
1H-NMR (400 MHz, CDCl3) δ (ppm): 1,47-and 1.54 (m, 2H), 1,61 (ush., 2H), 1,68-of 1.81 (m, 3H), 2,19-of 2.27 (m, 1H), of 2.51 (s, 3H), of 2.56 (DD, J=2,8, 4.0 Hz, 1H), 2,70 was 2.76 (m, 1H), 2,92 (DD, J=4,0, 12.0 Hz, 1H), of 6.52 (d, J=0.8 Hz, 1H), 7,05 (DD, J=8,8, 12.0 Hz, 1H), 7,20 (DD, J=2,8, 7,2 Hz, 1H), 7,88 (DDD, J=2,8, 4,0, 8,8 Hz, 1H)
Example 223Chemical structure
ESI-MS; m/z 441 [M++H]
Example 224Chemical structure
ESI-MS; m/z 386 [M++H]
Example 225Chemical structure
ESI-MS; m/z 399 [M++H]

Example 226

Synthesis of (±)-(4aR*,7aS*)-6-(4-forfinal)-7a-[3-(2-herperidin-3-yl)phenyl]-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-ylamine

[Formula 221]

(1)Synthesis of tert-butyl (±)-{(4aR*,7aS*)-6-(4-forfinal)-7a-[3-(2-herperidin-3-yl)phenyl]-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-yl}carbamate

tert-Butyl (±)-{(4aR*,7aS*)-7a-[3-(2-herperidin-3-yl)phenyl]-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-yl}carbamate obtained in example getting 18-(9) (72 mg)was mixed with 4-ferbinteanu acid (24,7 mg), copper acetate(II) (6,1 mg), triethylamine (93,2 μl, specific gravity 0,73 g/cm3) and molecular sieves 4A (powder) (57.6 mg) in dichloromethane (3 ml) and the mixture was stirred in nitrogen atmosphere at room temperature for 11 hours and 30 minutes. Additionally added 4-ferbinteanu acid (23,5 mg) and copper acetate(II) (12 mg). The atmosphere was replaced with an open system, followed by stirring. 23 hours and 45 minutes, the reaction suspension was purified by chromatography on a column with NH - silica gel. The resulting product was again purified ptsh obtaining specified in the connection header (15 m is).

1H-NMR (400 MHz, CDCl3) δ (ppm): for 1.49 (s, 9H), 2,28-of 2.93 (m, 1H), 3.00 and-is 3.08 (m, 2H), 3,55-3,59 (m, 1H), 3,64 (d, J=10.0 Hz, 1H), of 3.73-of 3.77 (m, 1H), 3,95 (d, J=10.0 Hz, 1H), 6,47-6,50 (m, 2H), 6,95-7,00 (m, 2H) 7,27-7,31 (m, 1H), 7,41-7,44 (m, 1H), of 7.48-of 7.55 (m, 3H), 7,83-7,88 (m, 1H), they were 8.22 (dt, J=1,6, 4.8 Hz, 1H).

(2)Synthesis of (±)-(4aR*,7aS*)-6-(4-forfinal)-7a-[3-(2-herperidin-3-yl)phenyl]-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-ylamine

Specified in the title compound (7.8 mg) was obtained from tert-butyl (±)-{(4aR*,7aS*)-6-(4-forfinal)-7a-[3-(2-herperidin-3-yl)phenyl]-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-yl}carbamate obtained in example 226-(1) (15 mg)according to example 36-(2).

ESI-MS; m/z 423 [M++H].

Example 227

Synthesis of (±)-(4aR*,7aS*)-7a-[3-(2-herperidin-3-yl)phenyl]-6-o-tolyl-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-ylamine

[Formula 222]

tert-Butyl (±)-{(4aR*,7aS*)-7a-[3-(2-herperidin-3-yl)phenyl]-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-yl}carbamate obtained in example getting 18-(9) (50 mg)was mixed with o-tolylboronic acid (19.1 mg), copper acetate(II) (4.3 mg), triethylamine (64,9 μl, specific gravity 0,73 g/cm3) and molecular sieves 4A (powder) (40 mg) in dichloromethane (2 ml) followed by stirring at room temperature. After 20 hours was added o-tolylboronic acid (12.7mm mg), copper acetate(II) (4.3 mg) and triethylamine (64,9 μl) and the mixture was additionally stirred under oxygen atmosphere. Serezdnoe days added on-tolylboronic acid (31.8 mg), followed by stirring. The next day was added optional on-tolylboronic acid (63,6 mg), triethylamine (130 μl) and dichloromethane (1 ml), followed by stirring. After three days, the reaction suspension was purified by chromatography on a column with NH-silica gel. The resulting product was again purified ptsh obtaining N-aryl compounds. It was dissolved in chloroform (1 ml) and then added TFUK at room temperature with subsequent mixing. After 12 hours the reaction solution was diluted with chloroform and then the excess TFUK neutralized with saturated sodium bicarbonate. The mixture was extracted three times with chloroform. The obtained organic layers were dried over anhydrous magnesium sulfate and the solid was removed by filtration. The filtrate was concentrated under reduced pressure and then purified by chromatography on a column with NH-silica gel with obtaining specified in the title compound (6.4 mg).

ESI-MS; m/z 419 [M++H]

Example 228

The compound of example 228, shown below in table 21 was synthesized in accordance with example 227, using the appropriate carboxylic acid.

[Table 21]

Table 21
Example 228Chemical structure
ESI-MS; m/z 430 [M++H]

Example 229

Synthesis of (±)-3'-((4aR*,7aS*)-2-amino-6-pyrazin-2-yl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-7a-yl) - biphenyl-3-carbonitrile

[Formula 223]

(1)Synthesis of (±)-3'-{(4aR*,7aS*)-2-[N,N-bis(tert-butoxycarbonyl)amino]-6-pyrazin-2-yl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-7a-yl}biphenyl-3-carbonitrile

Specified in the title compound (23 mg) was obtained from (±)-N,N-bis(tert-butoxycarbonyl)[(4aR*,7aS*)-7a-(3-bromophenyl)-6-pyrazin-2-yl-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-yl]amine obtained in the example of a 65-(3) (51 mg), in accordance with the example of getting an 18-(8).

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.41 (s, 18H), 2,99-of 3.07 (m, 2H), 3,20 is 3.23 (m, 1H), a 3.87-3,98 (m, 2H), 4,07-is 4.21 (m, 2H), 7,40-of 7.55 (m, 4H), 7,63-7,66 (m, 1H), 7,83-to 7.84 (m, 2H), 7,88-to 7.93 (m, 2H), of 7.96 (ush., 1H), 8,06 (ush., 1H).

(2)Synthesis of (±)-3'-((4aR*,7aS*)-2-amino-6-pyrazin-2-yl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-7a-yl) - biphenyl-3-carbonitrile

Specified in the title compound (9.8 mg) was obtained from (±)-3'-{(4aR*,7aS*)-2-[N,N-bis(tert-butoxycarbonyl)amino]-6-pyrazin-2-yl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-7a-yl}biphenyl-3-carbonitrile obtained in example 229-(1) (23 mg)according to example 36-(2).

ESI-MS; m/z 413 [M++H].

Example 230

The compound of example 230, shown below in table 22 was synthesized according to example 229 using appropriate carbon is a new acid.

[Table 22]

Table 22
Example 230Chemical structure
ESI-MS; m/z 390 [M++H]

Example 231

The compound of example 231, shown below in table 23 was synthesized from the compound of example getting 66 and the corresponding carboxylic acid in accordance with example 14.

[Table 23]

Table 23
Example 231Chemical structure
ESI-MS; m/z 390 [M++H]

Example 232

The compound of example 232, shown below in table 24 was synthesized from the compound of example, receiving 67 and the corresponding carboxylic acid in accordance with example 14.

[Table 24]

Table 24
Example 232Chemical structure
ESI-MS; m/z 403 [M++H]

Examples 233-239

Connection examples 233-239, are shown in the following table 25, synthesized in accordance with example 14, using the compound of example the preparation of 3-(8) and the corresponding carboxylic acid.

[Table 25]

Table 25
Example 233Chemical structure
ESI-MS m/z 372 [M++H]
Example 234Chemical structure
ESI-MS m/z 385 [M++H]
Example 235Chemical structure
ESI-MS m/z 385 [M++H]
Example 236Chemical structure
ESI-MS m/z 385 [M++H]
Example 237Chemical structure
ESI-MS m/z 413 [M++H]
Example 238Chemical structure
ESI-MS m/z 401 [M++H]
Example 239Chemical structure
ESI-MS m/z 451 [M++H]

Example 240

Synthesis of (±)-N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-5-chlorophenyl]-5-cyanopyridine-2-carboxamide

[Formula 224]

Specified in the title compound (1 mg) was obtained from the compound obtained in the example of a 71-(5) (13 mg), and 5-cyanopyridine-2-carboxylic acid (4,80 mg) according to the method of example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1.70 to 2,03 (m, 5H), 2,25 is 2.33 (m, 1H), 2,41-2,48 (m, 1H), was 2.76 (DD, J=3,6, to 12.8 Hz, 1H), to 3.02 (DD, J=3,6, to 12.8 Hz, 1H), 6,53 (DD, J=0,4, 3.6 Hz, 1H), 7,51 (DD, J=2,0, 3.6 Hz, 1H), 7,86 (t, J=2.0 Hz, 1H), by 8.22 (DD, J=2,0, 8.0 Hz, 1H), 8,43 (DD, J=1,2, 8.0 Hz, 1H), 8,90 (DD, J=1,2, 3.2 Hz, 1H), 9,87 (s, 1H).

Example 241

Synthesis of (±)-(4aR*,7aS*)-7a-[3-chloro-5-(2-herperidin-3-yl)phenyl]-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine

[Formula 225]

2-Herperidin-3-Bronevoy acid (55,8 mg), tetrakis(triphenylphosphine)palladium(0) (22.9 mg) and 1 n sodium carbonate solution (396 μl) was added to solution a by-product (±)-N-(tert-butoxycarbonyl)-N-(methoxycarbonyl)[(4aR*,7aS*)-7a-(3-bromo-5-chlorophenyl)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]amine, obtained in the example of a 71-(2) (100 mg)in DMF (5 ml). After replacement with nitrogen, the mixture was stirred at 85°C for three hours. The reaction solution sufficient for the or to room temperature and evaporated under reduced pressure the solvent. The residue was purified by chromatography on a column with NH-silica gel to obtain the crude product. The crude product was further purified sequentially NH-ptsh and chromatography on a column of silica gel with obtaining specified in the title compound (25.6 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,74-to 2.06 (m, 5H), 2.26 and-of 2.34 (m, 1H), 2,43-2,48 (m, 1H), 2,78 (DD, J=3,6, to 12.8 Hz, 1H), 3.04 from (DD, J=3,6, to 12.8 Hz, 1H), 7,28-7,31 (m, 1H), 7,39 (t, J=2.0 Hz, 1H), 7,41-7,42 (m, 2H), 7,87 (DDD, J=2,0, 7,2 and 9.6 Hz, 1H), they were 8.22 (dt, J=1,6, and 4.4 Hz, 1H).

ESI-MS; m/z 362 [M++H].

Example 242

Synthesis of (±)-5-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]nicotinanilide

[Formula 226]

5-Cyano-3-pyridineboronic acid, or 37.9 mg), tetrakis(triphenylphosphine)palladium and 1 n sodium carbonate solution (256 μl) was added to a solution of (±)-N,N-bis(tert-butoxycarbonyl)[(4aR*,7aS*)-7a-(5-bromo-2-forfinal)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]amine (70.0 mg) in DMF (5 ml). After replacement with nitrogen, the mixture was stirred at 80°C for two hours. After cooling to room temperature was added to the reaction mixture water. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with water and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure the solvent. The residue was dissolved in dihl methane (3 ml). Added triperoxonane acid (1 ml) and the mixture was stirred at room temperature for two hours. The reaction mixture was diluted with water, followed by neutralization with saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column with NH-silica gel with obtaining specified in the connection header.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,74 is 2.01 (m, 5H), 2,59-of 2.66 (m, 1H), 2,78 (DD, J=4.0 a, and 12.4 Hz, 1H), 2,81-2,87 (m, 1H), 2,96 (DD, J=3,2, and 12.4 Hz, 1H), 7,17 (DD, J=8,4, 12.0 Hz, 1H), 7,41 (DDD, J=2,8, to 4.4, and 8.4 Hz, 1H), 7,56 (DD, J=2,8, 7,6 Hz, 1H), 8,09 (t, J=2.0 Hz, 1H), 8,83 (d, J=2.0 Hz, 1H), 8,99 (d, J=2.0 Hz, 1H).

Example 243

Synthesis of (±)-(4aR*,6S*,7aS*)-7a-[2-fluoro-5-(2-herperidin-3-yl)phenyl-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine

[Formula 227]

Specified in the title compound (2.1 mg) was obtained from (±)-N,N-bis(tert-butyloxycarbonyl)[(4aR*,6S*,7aS*)-7a-(5-bromo-2-forfinal)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]amine (22,0 mg) and 2-herperidin-3-Bronevoy acid (11.0 mg) according to example 242.

ESI-MS; m/z 376 [M++H].

Example 244

Synthesis of (4aR,6R,7aS)-7a-[2-fluoro-5-(2-herperidin-3-yl)phenyl-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine

[Formula 28]

The racemate is specified in the header of the compound (30.0 mg) was obtained from (±)-N,N-bis(tert-butyloxycarbonyl)[(4aR*,6R*,7aS*)-7a-(5-bromo-2-forfinal)-6-methoxy-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-yl]amine (92.0 mg) and 2-herperidin-3-Bronevoy acid (46.2 mg) according to example 242. The resulting racemate (10.0 mg) was optically separated using CHIRALPAK™ AD-H production Daicel Chemical Industries, Ltd. (2 cm × 25 cm, mobile phase: hexane:ethanol = 8:2, flow rate 10 ml/min), and the component having a retention time from 33,8 to 38.1 minutes, was collected. This operation was repeated to obtain specified in the connection header (9,9 mg) of racemate (26 mg).

ESI-MS; m/z 376 [M++H].

Example 245

Synthesis of (±)-(4aR*,8aS*)-8a-[2,4-debtor-5-(2-herperidin-3-yl)phenyl]-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-ylamine

[Formula 229]

Isopropyl alcohol (1 ml), 2-fluoro-3-pyridineboronic acid (49,8 mg), 1 n solution of sodium carbonate (354 μl) and bis(tri-tert-butylphosphine)palladium(0) (3,61 mg) was added to a solution of benzyl (±)-[(4aR*,8aS)-8a-(5-bromo-2,4-differenl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate (35 mg) in toluene (2 ml). After replacement with nitrogen, the mixture was stirred at 85°C for 9.5 hours. The reaction solution was cooled to room temperature and evaporated under reduced pressure the solvent. The residue was purified x is matography on a column with NH-silica gel to obtain the intermediate compounds. The obtained intermediate compound was dissolved in chloroform (2 ml). Added attributively (30 μl), followed by stirring for 14 hours. The reaction solution was brought to room temperature and was added to the reaction mixture a solution of sodium bicarbonate. The mixture was diluted with ethyl acetate and was added sodium thiosulfate, followed by stirring for 30 minutes. The reaction mixture when it became clear, were extracted with ethyl acetate. The organic layer was washed with a saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure the solvent. The residue was sequentially purified by NH-ptsh and ptsh obtaining specified in the title compound (2.0 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,43-of 1.81 (m, 7H), 2,18 was 2.25 (m, 1H), 2,58 (DD, J=3,2, and 12.4 Hz, 1H), 2,65-2,69 (m, 1H), 2,85 (DD, J=4.0 a, and 12.4 Hz, 1H), 6,92 (DD, J=9,6, 12.0 Hz, 1H), 7.18 in-7,33 (m, 2H), to 7.77-7,81 (m, 1H), 8,24 (d, J=4,8 Hz, 1H).

ESI-MS; m/z 378 [M++H].

Example 246

Synthesis of (±)-N-[3-((3aS*,7aR*)-2-amino-3a,6,7,7a-tetrahydro-4H-pyrano[4,3-d]thiazole-7a-yl)phenyl]-5-chloropyridin-2-carboxamide

[Formula 230]

Specified in the header connection (to 39.5 mg) was obtained from the compound of example obtaining 75-(9) (99,0 mg) according to the method of example 14.

ESI-MS; m/z 389 [M++H].

Example 247

Synthesis of (±)-(4aS*,8aS*)-8a-[4-(2-ferpi the one-3-yl)thiophene-2-yl]-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-ylamine

[Formula 231]

2-Herperidin-3-Bronevoy acid (15.7 mg), tetrakis(triphenylphosphine)palladium (4.3 mg) and 1 n sodium carbonate solution (112 ml) was added to a solution of (±)-N-tert-butoxycarbonyl-N-[(4aS*,8aS*)-8a-(4-bromothiophene-2-yl)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]benzamide (20.0 mg) in DMF (1 ml). After replacement with nitrogen, the mixture was stirred at 90°C for seven hours. After cooling to room temperature was added to the reaction mixture ethyl acetate. The organic layer was washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue was purified by chromatography on a column with NH-silica gel with obtaining specified in the connection header (4,7 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,98-2,02 (m, 1H), and 2.27 (DDD, J=4,4, 12,8, to 13.6 Hz, 1H), of 2.44-2.50 (m, 1H), 2,59 (DD, J=3,0, to 12.8 Hz, 1H), 3,24 (DD, J=4,4, to 12.8 Hz, 1H), 3,66-to 3.92 (m, 4H), 7,18 (t, J=1.4 Hz, 7,22-7,26 (m, 2H), 7,56 (t, J=1,6 Hz, 1H), 7,95 (DDD, J=1,6, 7,2, 9.6 Hz, 1H), 8,12 (dt, J=1,6, 4.8 Hz, 1H).

ESI-MS; m/z 350 [M++H].

Examples 248-253

Connection examples 248-253, shown below in table 26 was synthesized in accordance with example 33 using the compound of example obtain 7-(8) and the corresponding carboxylic acid.

[Table 26]

Example 248
Table 26
Chemical structure
Connection name: N-[3-((4aR*,9aS*)-2-amino-4a,5,6,7,8,9-hexahydro-4H-cyclohepta[d][1,3]thiazin-9a-yl)-4-forfinal]-5-chloropyridin-2-carboxamide
ESI-MS m/z 433 [M++H]
Example 249Chemical structure
Connection name: N-[3-((4aR*,9aS*)-2-amino-4a,5,6,7,8,9-hexahydro-4H-cyclohepta[d][1,3]thiazin-9a-yl)-4-forfinal]-5-bromopyridin-2-carboxamide
ESI-MS m/z 479 [M++H]
Example 250Chemical structure
Connection name: N-[3-((4aR*,9aS*)-2-amino-4a,5,6,7,8,9-hexahydro-4H-cyclohepta[d][1,3]thiazin-9a-yl)-4-forfinal]-5-triptorelin-2-carboxamide
ESI-MS m/z 467 [M++H]
Example 251Chemical structureESI-MS m/z 417 [M++H]

Example 252Chemical structure
ESI-MS m/z 467 [M++H]
Example 253Chemical structure
ESI-MS m/z 479 [M++H]

Example 254

The compound synthesized from the compound of example, obtain 1-(8) and 5-bromopyridin-2-carboxylic acid in accordance with example 14, optically separated using CHIRALPAK™ OD-H production Daicel Chemical Industries, Ltd. (2.5 cm × 25 cm, mobile phase hexane:ethanol = 8:2, flow rate 20 ml/min), and the component having a retention time of from 4.9 to 5.7 minutes, collected by obtaining compounds of example 254, shown below in table 27.

[Table 27]

Table 27
Example 254Chemical structure
Connection name: N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-bromopyridin-2-carboxamide
ESI-MS m/z 465 [M++H]

Example 255

The compound synthesized from the compound of example, obtain 1-(8) and pyridine-2-carboxylic acid in accordance with example 14, optically separated using CHIRALPAK™ OD-H production Daicel Chemica Industries, Ltd. (2.5 cm × 25 cm, mobile phase hexane:ethanol = 8:2, flow rate 20 ml/min), and the component having a retention time of from 5.1 to 6.4 minutes, collected by obtaining compounds of example 255, as shown below in table 28.

[Table 28]

Table 28
Example 255Chemical structure
ESI-MS m/z 385 [M++H]

Examples 256-261

Connection examples 256-261, shown below in table 29 was synthesized in accordance with example 14, using the compound of example obtaining 2-(2) and the corresponding carboxylic acid.

[Table 29]

Table 29
Example 256Chemical structure
Connection name: N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]-5-herperidin-2-carboxamide
ESI-MS m/z 403 [M++H]
Example 257Chemical structure
The name is soedineniya: N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8a-yl)-4-forfinal]for 3,5-dichloropyridine-2-carboxamide
ESI-MS m/z 453 [M++H]
Example 258Chemical structure
ESI-MS m/z 419 [M++H]
Example 259Chemical structure
ESI-MS m/z 403 [M++H]
Example 260Chemical structure
ESI-MS m/z 465 [M++H]

Example 261Chemical structure
ESI-MS m/z 453 [M++H]

Example 262

Synthesis of N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-2-chlorocresol-4-carboxamide

[Formula 232]

Specified in the header connection (12,4 mg) was obtained from the compound obtained in example of preparation of 3-(8) (20.0 mg)and 2-chlorocresol-4-carboxylic acid (12.1 mg) according to example 14.

ESI-MS; m/z 393, 395 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1.70 to 2,00 (m, 5H), 2,55-to 2.65 (m, 1H), 2.71 to 2,84 (m, 2H), 2,97 (DD, J=3,1, 12,5 Hz, 1H), 7,03 (DD, J=8,8, 12.0 Hz, 1H), 7,30 (DD, J=2,8, 7.2 Hz, 1H), to 7.84 (DDD, a =2,4, 3,9, 8,8 Hz, 1H), 8,24 (s, 1H), and 8.50 (s, 1H).

Examples 263-267

Connection examples 263-267, shown below in table 30 was synthesized in accordance with example 14, using the appropriate carboxylic acid.

[Table 30]

Table 30
Example 263Chemical structure
Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-2-bromocresol-4-carboxamid
ESI-MS; m/z 439 [M++H].
Example 264Chemical structure
Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-2-chlorothiazole-5-carboxamid
ESI-MS; m/z 409 [M++H].
Example 265Chemical structure
Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]methylisoxazol-3-carboxamide
ESI-MS; m/z 375 [M+/sup> +H].
Example 266Chemical structure
Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-2-methyl-5-trifluoromethyl-oxazol-4-carboxamid
1H-NMR (400 MHz, CDCl3) δ (ppm): 1,67-to 1.79 (m, 1H), 1,79 is 2.01 (m, 4H), 2,53 at 2.59 (m, 1H), 2,59 (d, J=0.51 Hz, 3H), was 2.76 (DD, J=3,92, 12,63 Hz, 1H), 2,80-2,87 (m, 1H), 2,97 (DD, J=3,35, 12,69 Hz, 1H), 7,03 (DD, J=8,84, 12.0 Hz, 1H), 7,19 (DD, J=2,84, 7.01 Hz, 1H), 8,02 (DDD, J=2,84, 4,11, 8,84 Hz, 1H), 8,79 (USS, 1H).
ESI-MS m/z 443 [M++H]

Example 267Chemical structure
Connection name: N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-6-chloroimidazo[1,2a]pyridine-2-carboxamide
1H-NMR (400 MHz, CDCl3) δ (ppm): 1,66-2,03 (m, 5H), 2,55-of 2.66 (m, 1H), 2,75 (DD, J=4,04, 12,51 Hz, 1H), 2,78-to 2.85 (m, 1H), 2,98 (DD, J=8,78, 12,06 Hz, 1H),? 7.04 baby mortality (DD, J=8,84, 12.0 Hz, 1H), 7,25 (DD, J=2,02, 9,73 Hz, 1H), 7,41 (DD, J=2,78, 7,20 Hz, 1H), 7,55 (dt, J=9,66, of 0.85 Hz, 1H), 7,94 (DDD, J=0,63 Hz, 1H), 8,24 (DD, J=0,88, 2,02 Hz, 1H), 9,19 (USS, 1H).
ESI-MS m/z 444 [M++H].

Example 268

Synthetic is N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]cyclopentanecarboxylic

[Formula 233]

Specified in the header connection (12,4 mg) was obtained from the compound obtained in example of preparation of 3-(7) (20.0 mg)and 2-chlorocresol-4-carboxylic acid (12.1 mg) according to example 14.

ESI-MS; m/z 334 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 0.79, which is 0.86 (m, 2H), 1,03-of 1.07 (m, 2H), 1,53-of 1.62 (m, 1H), 1,76-2,04 (m, 5H), 2,60 (dt, J=13,4, 8.5 Hz, 1H), and 2.79 (DD, J=3,7, and 12.7 Hz, 1H), 2.91 in-a 3.06 (m, 1H), 6,98 (DD, J=8,8, 12.1 Hz, 1H), to 7.09 (DD, J=2,2, 6,7 Hz, 1H), 7,88 (DD, J=3.3, which is 4.7 Hz, 1H), 8,39 (USS, 1H).

Example 269

Synthesis of (+)-N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-3-bromothiazole-4-carboxamide

[Formula 234]

Specified in the title compound (12.5 mg) was obtained from the compound obtained in example of preparation of 3-(8) (21,0 mg)and 2-bromothiazole-4-carboxylic acid (18,0 mg) according to example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,67-2,02 (m, 5H), of 2.51 of 2.68 (m, 1H), was 2.76 (DD, J=8,72, 12.0 Hz, 1H), 2,78-of 2.86 (m, 1H), 2,99 (DD, J=3,22, 12,57 Hz, 1H),? 7.04 baby mortality (DD, J=8,72, 12,00 Hz, 1H), 7,30 (DD, J=2,84, 7,14 Hz, 1H), 7,87 (DDD, J=2,78, 11,9, 8,78 Hz, 1H), 8,15 (s, 1H), 8,98 (s, 1H).

Example 270

Synthesis of (+)-N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-1-methyl-1H-imidazole-4-carboxamide

[Formula 235]

Specified in the title compound (7 mg) was obtained from the compound obtained in example receiving the Oia 3-(8) (20.0 mg), and 1-methyl-1H-imidazole-4-carboxylic acid (10.0 mg) according to example 14.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,74 is 2.01 (m, 5H), 2,61 (dt, J=12,00, to 8.40 Hz, 1H), 2,74 (DD, J=4,04, 12,13 Hz, 1H), 2.77-to and 2.83 (m, 1H), 2,99 (DD, J=3,03, 12,63 Hz, 1H), of 3.77 (s, 3H), 7,01 (DD, J=8,84, 11.87 per Hz, 1H), 7,30 (DD, J=2,53, 12,63 Hz, 1H), 7,42 (d, of 1.52 Hz, 1H), to 7.61 (d, of 1.52 Hz, 1H), 7,92 (DDD, J=2,78, Android 4.04, 8,84, 1H), 8,89 (s, 1H).

Example 271

Synthesis of (+)-N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-3-methyl-3H-imidazole-4-carboxamide

[Formula 236]

Specified in the title compound (10.5 mg) was obtained from the compound obtained in example of preparation of 3-(8) (15,0 mg)and 3-methyl-3H-imidazole-4-carboxylic acid (10.0 mg) according to example 14.

ESI-MS; m/z 374 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1.70 to a 2.01 (m, 5H), 2,53-of 2.66 (m, 1H), 2,75 (DD, J=4,04, of 12.76 Hz, 1H), 2,79-is 2.88 (m, 1H), 2,97 (DD, J=3,35, 12,69 Hz, 1H), 3,94 (s, 3H), 7,03 (DD, J=8,84, 12,00 Hz, 1H), 7,21 (DD, J=2,78, 7,07 Hz, 1H), 7,53 (s, 1H), to 7.61 (d, J=0,76 Hz, 1H),7,79 (DDD, J=2,78, 4,01, is 8.75 Hz, 1H).

Example 272

Synthesis of (+)-N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-1-methyl-1H-pyrazole-4-carboxamide

[Formula 237]

Specified in the header connection (14,7 mg) was obtained from the compound obtained in example of preparation of 3-(8) (25.0 mg)and 1-methyl-1H-pyrazole-4-carboxylic acid (17,0 mg) according to example 14.

ESI-MS; m/z 374[M ++H].

1H-NMR (400 MHz, CDCl3+ a few drops MeOD) δ (ppm): 1,64-a 2.01 (m, 5H), of 2.51-to 2.65 (m, 1H), 2,73 (DD, J=3,79, 12,63 Hz, 1H), 2,84 of 2.92 (m, 1H), 2,96 (DD, J=3,41, 12,63 Hz, 1H), 3,93 (s, 3H), 6,95? 7.04 baby mortality (m, 2H), 7,97 (m, 3H).

Example 273

Synthesis of (+)-N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-4-chloro-1-methyl-1H-pyrazole-3-carboxamide

[Formula 238]

Specified in the title compound (8.5 mg) was obtained from the compound obtained in example of preparation of 3-(8) (24,0 mg)and 4-chloro-1-methyl-1H-pyrazole-3-carboxylic acid (21,0 mg) according to example 14.

ESI-MS; m/z 408 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 1,66-2,02 (m, 5H), 2,50-of 2.66 (m, 1H), was 2.76 (DD, J=4,04, of 12.76 Hz, 1H), 2,79-2,89 (m, 1H), 2,99 (DD, J=3,28, 12,63 Hz, 1H), 3,93 (s, 3H), 7,02 (DD, J=8,78, 12,06 Hz, 1H), 7,20 (DD, J=2,78, 7,20 Hz, 1H), 7,45 (s, 1H), 7,99 (DDD, J=2,78, 4,11, 8,78 Hz, 1H), 8,58 (s, 1H).

Example 274

Synthesis of (±)-6-{(E)-2-[3-((4aR*,7aS*)-2-amino-4a,5,6,7,7a-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]vinyl}nicotinanilide

[Formula 239]

Triperoxonane acid (0.3 ml) was added to a solution of the compound obtained in the example of getting 77 (17 mg), in dichloromethane (2 ml)and the mixture was stirred at room temperature for 30 minutes. The reaction solution was neutralized with sodium carbonate solution. The reaction mixture was extracted with dichloromethane. The organic layer is dried is over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified preparative HPLC to obtain specified in the title compound (5.1 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,00 (m, 4H), 2,31 (m, 1H), to 2.55 (m, 1H), 2,87 (DD, J=4,0, 12.9 Hz, 1H), of 3.07 (DD, J=4,0, 12.9 Hz, 1H), 3,14 (m, 1H), to 7.09 (DD, J=8,3, and 12.2 Hz, 1H), 7,14 (d, J=16.2 Hz, 1H), 7,49 (DD, J=0,7, 8,3 Hz, 1H), 7,53 (m, 1H), to 7.59 (DD, J=2,2, 8.0 Hz, 1H), 7,78 (d, J=16.2 Hz, 1H), to $ 7.91 (DD, J=2,2, 8,2 Hz, 1H), 8,84 (DD, J=0.5, and 2.1 Hz, 1H).

Example 275

Synthesis of (±)-(4aR*,7aS*)-7a-(5((E)-2-(5-chloropyridin-2-yl)vinyl)-2-pertenece)-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-amine

[Formula 240]

Specified in the header of the connection region (13.4 mg) was obtained from the compound obtained in example getting 72 (200 mg)and 2-bromo-5-chloropyridine (73 mg) according to example 274.

1H-NMR (400 MHz, CDCl3) δ (ppm): 1.70 to 2,00 (m, 4H), 2,19 (m, 1H), 2.40 a (m, 1H), was 2.76 (DD, J=3,8, at 13.0 Hz, 1H), 2,96 (DD, J=3,8, at 13.0 Hz, 1H), 3,06 (m, 1H), 6.90 to (m, 2H), 7,18 (d, J=8.5 Hz, 1H), 7,28 (DD, J=2,1, 8.0 Hz, 1H), 7,34 (m, 1H), 7,39 (d, J=16.1 Hz, 1H), 7,49 (DD, J=2,5,8,4 Hz, 1H), at 8.36 (d, J=2.4 Hz, 1H).

Example 276

Synthesis of (±)-6-{[3-(2-amino-4a,5,6,7,-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a(4H)-yl)-4-forfinal]ethinyl}nicotinanilide

[Formula 241]

The compound obtained in the example of a 78-(2) (135 mg)was mixed with dichloride bis(triphenylphosphine)palladium(II) (35 what g), iodide copper(I) - (9.4 mg) and 2-bromo-5-cyanopyridine (180 mg) in triethylamine (3.5 ml) and tetrahydrofuran (0.45 ml)and the mixture was stirred in nitrogen atmosphere at 90°C for five hours. The reaction suspension was filtered and concentrated. Then the obtained residue was purified preparative LC-MS to obtain specified in the title compound (113 mg).

1H-NMR (400 MHz, CDCl3) δ (ppm): 1.60-to 1,90 (m, 5H), 2,43 (m, 1H), 2,72 (m, 1H), 2,84 (m, 2H), 5,77 (USS, 2H), 7,32 (DD, J=8,5, 12.3 Hz, 1H), 7.62mm (m, 2H), 7,88 (d, J=8,2 Hz, 1H), 8,39 (DD, J=1,8, 8,1 Hz, 1H), 9,06 (s, 1H).

ESI-MS; m/z 377 [M++H].

Example 277

Synthesis of (±)-(4aR*,7aS*)-7a-[2-fluoro-5-(5-herperidin-2-yl)ethinyl]phenyl}-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-amine

[Formula 242]

Specified in the title compound (59 mg) was obtained from the compound obtained in the example of a 78-(2) (200 mg)and 3-bromo-2-herperidin (257 mg) according to example 276.

ESI-MS; m/z 370 [M++H].

Example 278

Synthesis of (±)-(4aR*,7aS*)-7a-{2-fluoro-5-[2-(2-herperidin-3-yl)ethyl]phenyl]-4,4a,5,6,7,7a-hexahydrotriazine[d][1,3]thiazin-2-ylamine

[Formula 243]

The catalyst in the form of 10% palladium hydroxide was added to the mixed solution of the compound obtained in example 277 (20 mg)in methanol (5 ml) and ethyl acetate (5 ml)and the mixture was stirred in hydrogen atmosphere at room temperature for norcio the suspension was filtered through celite and concentrated. Then the obtained residue was purified preparative LC-MS to obtain specified in the title compound (18 mg).

Example 279

The compound of example 279, shown below in table 31 was synthesized in accordance with example 278 using appropriate alcinoe connection.

[Table 31]

Table 31
Example 279Chemical structure
Connection name: (±)-6-{2-[3-(2-amino-4a,5,6,7-tetrahydrocyclopent[d][1,3]thiazin-7a(4H)-yl)-4-forfinal]ethyl}pyridine-3-carbonitrile
ESI-MS; m/z 381 [M++H]

Example 280

Synthesis of N-[3-((4aS,5S,7aS)-2-amino-5-deformity-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-dihydropyridines-2-carboxamide

[Formula 244]

(1)Synthesis of N-[(4aS,5S,7aS)-5-deformity-7a-(2-forfinal)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]benzamide

A solution of DMSO (165 μl) in dichloromethane (0.5 ml) was added dropwise to a solution of oxalicacid (166 μl) in dichloromethane (12 ml) in a nitrogen atmosphere at -78°C. After stirring the mixture for 10 minutes at the same temperature was added dropwise a solution of the compound obtained in the example the floor is to be placed 25-(9) (500 mg), in dichloromethane (2.5 ml). The mixture was stirred for 45 minutes at the same temperature. Diisopropylamine (1,12 ml) was added to the reaction solution at the same temperature and heated the reaction solution to room temperature. The reaction solution was stirred for one hour at room temperature. Was added an aqueous solution of ammonium chloride and ethyl acetate and the organic layer was separated. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to obtain the crude aldehyde dry residue. To the crude aldehyde dry residue was added dichloromethane (10 ml) and the mixture was cooled with ice. To the mixture was added dropwise TRIFLUORIDE diethylaminoethyl (676 μl) and the mixture was stirred for 30 minutes followed by warming to room temperature. The reaction solution was further stirred for two hours. To the reaction solution was added saturated aqueous sodium bicarbonate solution and chloroform, and separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel with obtaining specified in the title compound (170 mg).

The reaction as described above, conducted the ri same parameters, using TRIFLUORIDE [bis(2-methoxyethyl)amino]sulfur (0.95 ml) instead of the TRIFLUORIDE diethylaminoethyl, obtaining specified in the title compound (140 mg).

ESI-MS; m/z 407 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,85-only 2.91 (m, 1H), 3,14-3,29 (m, 1H), 3,51-of 3.60 (m, 1H), EUR 4.00-4.09 to (m, 1H), 4,53 (d, J=9,2 Hz, 1H), 4,60-4,70 (m, 1H), 5,86-x 6.15 (m, 1H), 7,12-7,27 (m, 2H), 7,35-7,53 (m, 5H), 8,00-8,18 (m, 2H).

(2)Synthesis of (4aS,5S,7aS)-5-debtor-7a-(2-forfinal)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-ylamine

Hydrazinehydrate (738 μl) was added to a solution of the compound obtained in example 280-(1) (310 mg)in ethanol (8 ml) and the mixture was stirred for three hours at room temperature. To the reaction solution was added saturated aqueous solution of sodium chloride and ethyl acetate and the separated organic layer. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel with obtaining specified in the title compound (185 mg).

ESI-MS; m/z 303 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): 2,84 (DD, J=3,6, 13,2 Hz, 1H), 3,10 (DD, J=3,6, 13,2 Hz, 1H), 3,23-of 3.27 (m, 1H), 3,85-3,88 (m, 1H), 4,45-4,58 (m, 4H), 5,77-6,07 (m, 1H), 7,06 (DDD, J=1,2, 8,4, to 12.8 Hz, 1H), 7,13-to 7.18 (m, 1H), 7,28-7,31 (m, 1H), 7,41 was 7.45 (m, 1H).

(3)Synthesis of tert-butyl [(4aS,5S,7aS)-deformity-7a-(2-fluoro-5-nitrophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

White fuming nitric acid (39,7 ml) was added dropwise to the Astaro connection obtained in example 280-(2) (185 mg)under ice cooling. The reaction solution was stirred for 30 minutes at room temperature and then poured into ice. The resulting mixture was podslushivaet 5 N. sodium hydroxide under ice cooling. To the reaction solution was added chloroform, and separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in THF (801 ml), was added triethylamine (0,85 ml) and di-tert-BUTYLCARBAMATE (801 mg) and the resulting mixture was stirred for twelve hours. To the reaction solution was again added triethylamine (0,85 ml) and di-tert-BUTYLCARBAMATE (801 mg) and the mixture was stirred for five hours. To the reaction solution was added saturated aqueous solution of sodium chloride and ethyl acetate and the separated organic layer. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel with obtaining specified in the title compound (213 mg).

ESI-MS; m/z 448 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): of 1.53 (s, 9H), 2,78 (DD, J=3,6, of 14.0 Hz, 1H), 2.91 in are 2.98 (m, 1H), 3,37-3,44 (m, 1H), 3,79-a-3.84 (m, 1H), 4,46 (d, J=8.0 Hz, 1H), 4,58 with 4.64 (m, 1H), of 5.83-6,13 (m, 1H), 7,27-7,33 (m, 1H), 8,21-of 8.25 (m, 1H), 8,31 (DD, J=2,8, 6,8 Hz, 1H).

(4)Synthesis of tert-butyl [(4aS,5S,7aS)-7a-(5-amino-2-forfinal)-5-deformity-4a,5,7,7a-tetrahydro is-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

A saturated aqueous solution of ammonium chloride (2 ml) and iron powder (276 mg) was added to a solution of the compound obtained in example 280-(3) (210 mg)in ethanol (10 ml) and boiled under reflux for 30 minutes. The temperature of the reaction solution was brought to room temperature and was diluted reaction solution with ethyl acetate. Substances insoluble in the reaction solution were removed by filtration through celite. To the filtrate was added a saturated aqueous solution of sodium chloride and ethyl acetate and the separated organic layer. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on NH-silica gel with obtaining specified in the title compound (144 mg).

ESI-MS; m/z 418 [M++H].

1H-NMR (400 MHz, CDCl3) δ (ppm): is 1.51 (s, 9H), was 2.76 (DD, J=3,6, of 14.0 Hz, 1H), 3.04 from-of 3.12 (m, 1H), 3.33 and-of 3.42 (m, 1H), 3,62 (USS, 2H), 3,80-of 3.85 (m, 1H), 4,50 (d, J=8,4 Hz, 1H), 4,49-4,59 (m, 1H), 5,94 (dt, J=3,6, 55,6 Hz, 1H), 6,55-6,62 (m, 2H), 6.87 in (DD, J=8,4, and 12.4 Hz, 1H).

(5)Synthesis of N-[3-((4aS,5S,7aS)-2-amino-5-deformity-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide

Specified in the title compound (15 mg) was obtained in accordance with the methods of example 14 from the compound obtained in example 280-(4) (28 mg)and the compound obtained in the example of a 13-(2) (19 mg).

ESI-MS; m/z 448 [M++H].

1H-NMR (400 MHz, DCl 3) δ (ppm): 3,05 (DD, J=3,6, of 14.0 Hz, 1H), 3,40 (DD, J=3,6, to 13.6 Hz, 1H), 3,70 is 3.76 (m, 1H), 4,27-to 4.33 (m, 1H), 4,47-of 4.57 (m, 2H), equal to 6.05 (dt, J=3.2, and of 54.8 Hz, 1H), 7,19 (DD, J=9,2, 12.0 Hz, 1H), of 7.70 (DD, J=2,8, 7,2 Hz, 1H), 7,94-7,98 (m, 1H), they were 8.22 (DD, J=2,0, 8.0 Hz, 1H), to 8.41 (DD, J=0,8, 8.0 Hz, 1H), of 8.92 (DD, J=0,8, 2.0 Hz, 1H), 9,96 (s, 1H).

Examples 281-284

Connection examples 281-284, shown below in table 32 was synthesized pursuant to methods of example 280, using the appropriate carboxylic acid.

[Table 32]

Table 32
Example 281Connection name: N-[3-((4aS,5S,7aS)-2-amino-5-deformity-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamide
1H-NMR (400 MHz, CDCl3) δ (ppm): 2,87 (DD, J=2,0, 13,2 Hz, 1H), 3,14 (DD, J=3.2, and to 13.6 Hz, 1H), 3,29-to 3.34 (m, 1H), 3,86-to 3.89 (m, 1H), 4,48-of 4.57 (m, 2H), 5,81-6,10 (m, 1H), 6,80 (t, J=54,4 Hz, 1H), 7,13 (DD, J=8,4, and 11.6 Hz, 1H), 7.62mm (DD, J=2,8, 7.2 Hz, 1H), 7,93-of 7.97 (m, 1H), of 8.92 (d, J=1.2 Hz, 1H), at 9.53 (d, J=0.8 Hz, 1H), 9,65 (s, 1H).
ESI-MS; m/z 474 [M++H]

Example 282Connection name: N-[3-((4aS,5S,7aS)-2-amino-5-deformity-4a,5-dihydro-4H-f the ro[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-chloropyridin-2-carboxamide
1H-NMR (400 MHz, CDCl3) δ (ppm): 3,01 totaling 3.04 (m, 1H), 3,35-to 3.41 (m, 1H), 3,63-and 3.72 (m, 1H), 4,24-or 4.31 (m, 1H), 4,45-4,58 (m, 2H), of 5.89-6,18 (m, 1H), 7,17 (DD, J=8,8, 12.0 Hz, 1H), 7,66 (DD, J=2,8, 7.2 Hz, 1H), of 7.90 (DD, J=2,4, and 8.4 Hz, 1H), to 7.93-to 7.99 (m, 1H), 8,23 (d, J=8,4 Hz, 1H), 8,59 (d, J=2.4 Hz, 1H), 9,19 (s, 2H).
ESI-MS; m/z 457 [M++H].
Example 283Connection name: N-[3-((4aS,5S,7aS)-2-amino-5-deformity-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-triptorelin-2-carboxamide
1H-NMR (400 MHz, CDCl3) δ (ppm): 2,87 (DD, J=4,0, to 13.6 Hz, 1H), 3.15 in (DD, J=3.2, and to 13.6 Hz, 1H), 3,29-to 3.33 (m, 1H), 3,86-3,90 (m, 1H), 4,49-of 4.57 (m, 2H), 5,95 (dt, J=4,0, 55,6 Hz, 1H), 7,12 (DD, J=8,8, 12.0 Hz, 1H), 7.62mm (DD, J=2,8, 7,2 Hz, 1H), 7,94-to 7.99 (m, 1H), 8,18 (DD, J=2,8, 8.0 Hz, 1H), 8,43 (d, J=8.0 Hz, 1H), 8,89 (d, J=0.8 Hz, 1H), 9,94 (s, 1H).
ESI-MS; m/z 491 [M++H]
Example 284Connection name: N-[3-((4aS,5S,7aS)-2-amino-5-deformity-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformationen-2-carboxamide
1H-NMR (400 MHz, CDCl3) δ (ppm): 2,86 (DD, J=4,0, to 13.6 Hz, 1H), 3,13 (DD, J=3.2, and up to 13.2 Hz, 1H), 3,28-of 3.32 (m, 1H), 3,86-to 3.89 (m, 1H), 4,48-4,56 (m, 2H), 5,94 (dt, J=4,4, 55,6 Hz, 1H), 6,65 (t, J=72,0 Hz, 1H), 7,10 (DD, J=8,8, and 11.6 Hz, 1H), 7,60 (DD, J=2,8, 6,8 Hz, 1H) 7,66 (DD, J=2,4, 8,8 Hz, 1H), 7,92-of 7.96 (m, 1H), 8,31 (d, J=8,4 Hz, 1H), 8,45 (d, J=2,8 Hz, 1H), 9,84 (s, 1H).
ESI-MS; m/z 489 [M++H]

Example 285

Synthesis of (±)-N-[5-((4aS*,5R*,7aR*)-2-amino-5-methyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)thiophene-3-yl]-5-cyanopyridine-2-carboxamide

[Formula 245]

(1)Synthesis of (±)-(3aR*,4R*,6aR*)-6a-(4-bromothiophene-2-yl)-4-methyltetrahydro-furo[3,4-c]isoxazol

Specified in the header connection (956 mg) was obtained in accordance with the methods of example getting 76 from the compound obtained in the example of a 22-(2)(410 mg)and 2,4-dibromothiophene (1.64 g).

ESI-NS; m/z 290 [M++H].

(2)Synthesis of (±)-(4aS*,5R*,7aR*)-7a-(4-bromo-2-thienyl)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-ylamine

Specified in the title compound (270 mg) was obtained in accordance with the methods of example, receiving 22 of (±)-(3aR*,4R*,6aR*)-6a-(4-bromothiophene-2-yl)-4-methyltetrahydro-flo[3,4-c]isoxazol. However, the reaction dibenzoylmethane corresponding to the example of getting 22-(7), conducted in accordance with the methods of example obtaining 19-(9).

ESI-MS; m/z 335 [M++H].

(3)Synthesis of (±)-di-tert-butyl[(4aS*,5R*,7aR*)-7a-(4-azido-2-thienyl)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]iminodicarboxylate

Specified in the title compound (75 mg) was obtained in accordance with the methods of example, receiving 71 of (±)-(4aS*,5R*,7aR*)-7a-(4-bromo-2-thienyl)-5-methyl-4a,5,7,7a-tetrahydro-4H-flo[3,4-d][1,3]thiazin-2-lamina.

ESI-MS; m/z 496 [M++H].

(4)Synthesis of (±)-tert-butyl [(4aS*,5R*,7aR*)-7a-(4-aminothiophene-2-yl)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate

Zinc (19.7 mg) and ammonium formate were added to a solution of (±)-di-tert-butyl[(4aS*,5R*,7aR*)-7a-(4-azido-2-thienyl)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]iminodicarboxylate (75 mg) in methanol (5 ml). The mixture was stirred for three days at room temperature. It was further added to the reaction mixture, methanol (50 ml), zinc (197 mg) and ammonium formate (476 mg) and the mixture is then stirred for three hours. The excess ethanol is evaporated under reduced pressure. To the residue were added water and ethyl acetate to dissolve the insoluble substances. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure the solvent. The residue was purified by chromatography on NH-silica gel with obtaining specified in the title compound (35 mg).

ESI-MS; m/z 370 [M++H].

(5)Synthesis of (±)-N-[5-((4aS*,5R*,7aR*)-2-amino-5-methyl-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)thiophene-3-yl]-5-cyanopyridine-2-carboxamide

Specified in the title compound (27 mg) was obtained in accordance with the methods of example 14 from the compound obtained in example 285-(4), and the compound obtained in the example of a 13-(2).

ESI-MS; m/z 400 [M++H].

Example 286

Synthesis of (±)-N-[5-((4aS*,8aR*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)thiophene-3-yl]-5-cyanopyridine-2-carboxamide

[Formula 246]

(1)Synthesis of tert-butyl (±)-[(4aS*,8aR*)-8a-(4-aminothiophene-2-yl)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azonaphthalene-2-yl]carbamate

Specified in the title compound (89 mg) was obtained in accordance with the methods of example 285 from the compound obtained in example obtain 8-(2), and 2,4-dibromothiophene.

ESI-MS; m/z 370 [M++H].

(2)Synthesis of (±)-N-[5-((4aS*,8aR*)-2-amino-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8a-yl)thiophene-3-yl]-5-cyanopyridine-2-carboxamide

Specified in the title compound (23 mg) was obtained in accordance with the methods of example 14 from the compound obtained in example 286-(1), and the compound obtained in the example of a 13-(2).

ESI-MS; m/z 400 [M++H].

The test example 1

Quantification of Aβ peptide in the culture of neurons from the brain of a fetus of the rat

(1)Primary culture of neural cells of the rat

Primary cultures of neurons were obtained from the cerebral cortex 18-day-old embryos of Wistar rats (Charles River Japan, Yokohama, Japan). In particular, the embryos were aseptically extracted from pregnant rats under ether anesthesia. The brain was removed from the embryo and immersed in a cooled ice medium L-15 (such as Invitrogen Corp. Cat #11415-064,Carlsbad, CA, USA or SIGMA L1518). The cerebral cortex was isolated from the extracted brain under stereoscopic microscope. The collected fragments of the cortex of the brain enzyme was treated in an enzyme solution containing 0.25% trypsin (Invitrogen Corp. Cat #15050-065, Carlsbad, CA, USA) and 0.01% DNase has (Sigma D5025, St. Louis, MO, USA), at 37°C for 30 minutes to disperse the cells. Then the enzymatic reaction was stopped by addition of inactivated horse serum to the solution. Enzyme treated solution was centrifuged at 1500 rpm for five minutes to remove the supernatant. To the resulting cell mass is added 5-10 ml of medium. As the medium (Neurobasal/B27/2-ME) was used neuropathology medium (Invitrogen Corp. Cat #21103-049, Carlsbad, CA, USA), supplemented with 2% B27 Supplement (Invitrogen Corp. Cat #17504-044, Carlsbad, CA, USA), 25 μm 2-mercaptoethanol (2-ME, WAKO Cat #139-06861, Osaka, Japan), 0.5 mm L-glutamine (Invitrogen Corp. Cat #25030-081, Carlsbad, CA, USA) and antibiotics and antimycotics (Invitrogen Corp. Cat #15240-062, Carlsbad, CA, USA). However, for the analysis used above neuropathology environment, not supplemented with 2-ME (Neurobasal/B27). Cells were again dispersible moderate treatment with a pipette and cell mass, to which was added the specified environment. The cell dispersion was filtered through a 40-μm nylon mesh (Cell Strainer, Cat #35-2340, Becton Dickinson Labware, Franklin Lakes, NJ, USA) to remove any remaining cell mass and as a result received the suspension of nerve cells. Suspension of nerve cells was diluted described environment and then were sown in the amount of 100 μl/well at an initial density of cells 5×105cells/cm2on 96-well polystyrene culture tablet, pre-coated with poly-L-or D-lysine (Falcon Cat #35-3075, Becton Dickinson Labware, Franklin Lakes, NJ, USA, coated with poly-L-lysine using the method described below, or BIOCOAT™ cell environments Poly-D-lysine cell ware 96-well plate, Cat #35-6461, Becton Dickinson Labware, Franklin Lakes, NJ, USA). Coating of poly-L-lysine was carried out as follows. Aseptically prepared using 0.15 M borate buffer (pH 8.5), 100 µg/ml poly-L-lysine (SIGMA P2636, St. Louis, MO, USA). 100 μg/well of the obtained solution was made in the wells of 96-well polystyrene culture of the tablet, and incubated at room temperature for one or more hours or at 4°C over night or more. After this is provided by coating 96-well polystyrene culture the tablet was washed with sterile water four times or more and then was dried or rinsed, for example, sterile PBS or medium and used for seeding cells. Seeded cells were grown on a culture plate at 37°C in an atmosphere of 5% CO2-95% air for one day. Then all the medium was replaced with fresh medium Neurobasal™/B27/2-ME, after which cells were cultured for another three days.

(2)Making connections

p> On day 4 of cultivation in wells contributed medicinal substance as follows. All medium was removed from the wells and brought them in 180 µl/well neuropathology environment, not containing 2-ME and containing 2% B-27 (Neurobasal/B27). The solution of the test compound in dimethyl sulfoxide (hereinafter abbreviated as DMSO) was diluted with medium Neurobasal/B27 concentrations up to 10 times the final concentration. Located in the holes of medium were added to 20 μl/well of the obtained diluted solution and sufficiently mixed it environment. The final concentration of DMSO was 1% or less. The control group was only added DMSO.

(3)Sample

After adding the connection, the cells were cultured for three days and the whole environment was collected. The resulting environment was used as a sample for ELISA. The sample was not diluted for measurement of Aβx-42 by ELISA method and diluted to 5-fold dilution with the diluent supplied with the ELISA kit, ELISA measurements of Aβx-40.

(4)Evaluation of the survival rate of cells

Cell survival was assessed by MTT analysis according to the following procedure. After collecting medium in the wells was made 100 μl/well of pre-warmed medium. Then the wells were added to 8 μl/well of a solution of 8 mg/ml MTT (SIGMA M2128, St. Louis, MO, USA) in D-PBS(-) (Dulbecco''s phosphate buffered Saline, SIGMA D8537, St. Louis, MO, USA). 96-well polystyrene culture p is unset incubated in the incubator at 37°C in an atmosphere of 5% CO 2-95% air for 20 minutes. Added 100 μl/well buffer for MTT lysis and the MTT crystals formazan sufficiently dissolved in the buffer in an incubator at 37°C in an atmosphere of 5% CO2-95% air. Then measured the optical density at 550 nm in each well. Buffer for MTT lysis was prepared as follows. 100 g of SDS (sodium dodecyl sulphate (sodium lauryl sulphate), WAKO 191-07145, Osaka, Japan) was dissolved in a mixed solution of 250 ml of N,N'-dimethylformamide (WAKO 045-02916, Osaka, Japan) with 250 ml of distilled water. Then to the solution was added 350 μl of concentrated chloride-hydrogen acid and acetic acid to provide the final pH of approximately 4.7.

When measuring wells not containing seeded cells containing only medium and MTT solution was considered background (bkg). The measured values are respectively used in the following formula, subtracting from them bkg values. So, for comparison and evaluation activity in relation to the survival rate of cells was calculated percentage to the control group (group not treated with the drug, CTRL) (% of CTRL).

% CTRL=(A550_sample-A550_bkg)/(A550_CTRL-bkg)×100

(A550_sample: optical density at 550 nm of the wells with the sample, A550_bkg: optical density at 550 nm background wells, A550_CTRL: optical density at 550 nm of the wells of the control group).

(5)Aβ ELISA

To determine Aβ ELISA method used a set of Human/Rat β Amyloid (42) ELISA Kt Wako (#290-62601) and a set of Human/Rat β Amyloid (40) ELISA Kit Wako (#294-62501) from Wako Pure Chemical Industries, Ltd. Analysis of Aβ ELISA was carried out according to the instructions recommended by the manufacturer (the techniques described in the attached documents). However, Aβ calibration curve was obtained using beta-amyloid peptide 1-42, rat and beta-amyloid peptide 1-40, rat (Calbiochem, #171596 [Aβ42], #171593 [Aβ40]). The results are shown below in tables 33, 34 and 35 in the form of a percentage of the concentration of Aβ in the medium control group (% of CTRL).

[Table 33]

Table 33
Test connectionThe effect of reducing the production of Aβ42
IC50 (μm)
Test connectionThe effect of reducing the production of Aβ42
IC50 (μm)
30,009260,0069
50,003270,011
60,088280,012
90,028290,004
19 0,045300,011
200,005310,004
210,013320,0011
220,005330,01
230,01340,115
240,0043360,384
250,0061370,029

Table 34
Test connectionThe effect of reducing the production of Aβ42
IC50 (μm)
Test connectionThe effect of reducing the production of Aβ42
IC50 (μm)
380,006900,0025
39 0,007910,0014
400,026920,005
410,006930,003
420,004940,002
430,019950,001
480,575960,001
490,0008980,001
500,0009990,001
510,00161000,002
520,0021040,212
530,0021050,121
540,00171060,088
550,00111070,017
560,0031080,001
570,0031090,0018
580,0071100,005
590,0021170,158
600,0121200,038
630,011121to 0.263
640,0081220,123
650,0381260,07
660,0013127 0,214
670,00141280,231
680,0061290,065
690,0021320,044
700,0021330,063
710,0011340,086
720,0021350,015

730,0071360,025
750,0031370,047
790,0281380,063
800,0081390,169
810,0141400,067
820,4251410,016
840,8931420,01
870,0621430,016
880,0751440,011
890,00321450,003

Table 35
Test connectionThe effect of reducing the production of Aβ42
IC50 (μm)
Test connectionThe effect of reducing the production of Aβ42
IC50 (μm)
146to 0.0321970,22
1470,0121980,129
1480,0091990,012
1490,4142000,044
1510,1672020,003
1580,0532040,023
1600,5212050,025
1630,3672060,002
1640,0012070,003
1650,0122150,01
1660,0042230,316
1670,0062240,271
1680,016 2250,198
1690,0272260,233
1700,212290,544
1710,0892300,202
1720,0072330,086
1730,0722360,059

1740,0112370,08
1750,0092380,35
1760,012390,238
1770,0182400,039
1780,044243 0,069
1790,0982451,159
1800,0032480,016
1810,0472490,018
1820,092500,027
1830,0282510,12
1840,0132520,187
1850,012530,171
1860,032540,043
1870,0542550,158
1880,0222560,038
1890,008 2570,017
1900,0122580,376
1910,0092590,372
1950,0682600,17
1960,9772610,277

From the results shown in the tables, it is clear that the compound of the present invention has the effect of reducing the production of Aβ42.

Industrial applicability

The compound of General formula (I) or its pharmaceutically acceptable salt or MES according to the present invention has the effect of reducing the production of Aβ42. Therefore, the present invention can, in particular, to provide a therapeutic or prophylactic agent against neurodegenerative disease caused by Aβ such as dementia Alzheimer's disease or down's syndrome.

1. The compound represented by formula (I)
[Formula 1]

or its pharmaceutically acceptable salt,
where ring a is a phenyl group which may contain 1-3 is the", selected from the group of substituents α, or thienyl group, which may contain 1-3 substituent selected from the group of substituents α,
L represents a single bond or a group of the formula-NReCO- (where Rerepresents a hydrogen atom),
the ring represents a C6-14aryl group, which may contain 1-3 substituent selected from the group of substituents α, or 5-10-membered heterocyclic group, which may contain 1-3 substituent selected from the group of substituents α,
X represents a methylene group which may contain 1 or 2 substituent selected from the group of substituents α,
Y represents a single bond, -NRY- (where RYrepresents a hydrogen atom, a C6-14aryl group, which may contain 1-3 substituent selected from the group of substituents α, or 5-10-membered heterocyclic group, which may contain 1-3 substituent selected from the group of substituents α), or an oxygen atom,
Z represents a single bond or C1-3alkylenes group, which may contain 1-3 substituent selected from the group of substituents α,
R1and R2represent hydrogen atoms, and
R3, R4, R5and R6independently represent a hydrogen atom, halogen atom, or hydroxy-group1-6Alki is inuu group, which may contain 1-3 substituent selected from the group of substituents α,
[the group of substituents α: a halogen atom, a C1-6allylthiourea, cyano, C3-8cycloalkyl group2-6Alchemilla group, which may contain 1-3 substituent selected from the group of substituents β, C1-6alkoxygroup, which may contain 1-3 substituent selected from the group of substituents β, C1-6alkyl group which may contain 1-3 substituent selected from the group of substituents β, and a 5-10 membered heterocyclic group, which may contain 1-3 substituent selected from the group of substituents β,
the group of substituents β: halogen atom, cyano, hydroxy-group, C1-6alkoxygroup, C1-6alkyl group, a C3-8cycloalkyl group and oxoprop].

2. The compound or its pharmaceutically acceptable salt according to claim 1, where Y represents a single bond and Z represents a C1-3alkylene, which may contain 1-3 substituent selected from the group of substituents α.

3. The compound or its pharmaceutically acceptable salt according to claim 1, where Y represents an oxygen atom and Z represents a C1-3alkylene, which may contain 1-3 substituent selected from the group of substituents α.

4. The compound or its pharmaceutically acceptable salt according to claim 1, where Y submitted is an oxygen atom and Z represents a single bond.

5. The compound or its pharmaceutically acceptable salt according to claim 1, where Y is-NRY- (where RYrepresents a C6-14aryl group, which may contain 1-3 substituent selected from the group of substituents α, or 5-10-membered heterocyclic group, which may contain 1-3 substituent selected from the group of substituents α), and Z represents a single bond.

6. The compound or its pharmaceutically acceptable salt according to claim 1, where L represents a group of formula-NReCO- (where Rerepresents a hydrogen atom).

7. The compound or its pharmaceutically acceptable salt according to claim 1, where L represents a single bond.

8. The compound or its pharmaceutically acceptable salt according to claim 1, which is selected from the following compounds:
1) (+)-N-{3-[(4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8A-yl]-4-forfinal}-5-chloropyridin-2-carboxamid,
2) (+)-N-{3-[(4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl]-4-forfinal}-5-chloropyridin-2-carboxamid,
3) N-{3-[(4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl]-4-forfinal}pyridine-2-carboxamide,
4) N-{3-[(4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[(1][1,3]thiazin-7a-yl]-4-forfinal}-5-herperidin-2-carboxamid,
5) N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8-hexahydrobenzo[d][1,3]thiazin-8A-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,
6) N-[3-((4R*,7S*)-2-am is but-4A,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformatsiei-2-carboxamid,
7) N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[(1][1,3]thiazin-7a-yl)-4-forfinal]-5-formatexpiry-2-carboxamid,
8) N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,
9) N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-formatexception-2-carboxamid,
10) N-[3-((4S*,7aS*)-2-amino-4A,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,
11) N-[3-((4S*,7S*)-2-amino-4A,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformatsiei-2-carboxamid,
12) N-[3-((4S*,7S*)-2-amino-4A,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-chloropyridin-2-carboxamid,
13) N-[3-((7S*,7S*)-2-amino-4A,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-formatexpiry-2-carboxamid,
14) N-[3-((4S*,8S*)-2-amino-4A,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8A-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,
15) N-[3-((4S*,8S*)-2-amino-4A,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8A-yl)-4-forfinal]-5-deformatsiei-2-carboxamid,
16) N-[3-((4S*,8S*)-2-amino-4A,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8A-yl)-4-forfinal]-5-chloropyridin-2-carboxamid,
17) (+)-N-[3-((4aR*,6S*,7aS*)-2-amino-6-methoxy-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,
18) (+)-N-[3-((4R*,6R*,7S*)-2-amino-6-methoxy-4A,5,6,7-tetrahydro-4H-Cyclops the NTA[(1][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2 carboxamide,
19) (+)-N-[3-((4aR*,9aS*)-2-amino-4a,5,6,7,8,9-hexahydro-4H-cyclohepta[(1][1,3]thiazin-9a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,
20) N-[3-((4aR*,7aS*)-2-amino-4a,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-methoxyphenyl]-5-chloropyridin-2-carboxamid,
21) N-[3-((4S*,7S*)-2-amino-4A,5,7,7a-tetrahydro-4H-furo[3,4-a][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamid,
22) (4aR,7aS)-7a-[3-(2-herperidin-3-yl)phenyl]-6-phenyl-4,4a,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-ylamine,
23) (4aR*,7aS*)-7a-[3-(2-herperidin-3-yl)phenyl]-6-pyrimidine-2-yl-4,4A,5,6,7,7a-hexahydrofuro[3,4-d][1,3]thiazin-2-ylamine,
24) N-[3-((4aS*,5R*,7aS*)-2-amino-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,
25) N-[3-((4aS*,5R*,7aS*)-2-amino-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamid,
26) N-[3-((4S*,8S*)-2-amino-4A,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8A-yl)-4-forfinal]-5-formatexpiry-2-carboxamid,
27) N-[3-((4aS*,5R*,7aS*)-2-amino-5-ethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformatsiei-2-carboxamid,
28) N-[3-((4S,5S,7S)-2-amino-5-vermeil-4A,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamid,
29) N-[3-((4S,5S,7S)-2-amino-5-vermeil-4A,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-formatexpiry-2-carboxamid,
30) N-[3-((4aS*,5S*,7aS*)-2-amino-5-vermeil-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-forfinal]-5-C is aloperidin-2-carboxamid,
31) N-[3-((4S*,5S*,8S*)-2-amino-5-vermeil-4A,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8A-yl)-4-forfinal]-5-cyanopyridine-2-carboxamide,
32) N-[3-((4aS*,5S*,8aS*)-2-amino-5-vermeil-4a,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8A-yl)-4-forfinal]-5-formatexpiry-2-carboxamid,
33) N-[3-((4S*,5S*,8S*)-2-amino-5-vermeil-4A,5,7,8-tetrahydro-4H-6-oxa-3-thia-1-azonaphthalene-8A-yl)-4-forfinal]-5-chloropyridin-2-carboxamid,
34) N-[3-((4S*,6S*,7S*)-2-amino-6-methoxy-4A,5,6,7-tetrahydro-4H-cyclopent[e][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamid,
35) N-[3-((4R*,6R*,7S*)-2-amino-6-methoxy-4A,5,6,7-tetrahydro-4H-cyclopent[d][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamide and
36) N-[3-((4aR*,6S*,7aS*)-2-amino-6-fluoro-4a,5,6,7-tetrahydro-4H-cyclopent[(1][1,3]thiazin-7a-yl)-4-forfinal]-5-deformalisation-2-carboxamide.

9. Pharmaceutical composition having an effect of inhibiting the production of β-amyloid protein, containing the compound or its pharmaceutically acceptable salt according to any one of claims 1 to 8 as an active ingredient.

10. The pharmaceutical composition according to claim 9 for inhibiting the production of β-amyloid protein.

11. The pharmaceutical composition according to claim 9 for the inhibition of enzyme cleavage of beta-site of the protein precursor of β-amyloid type 1 (BASE).

12. The pharmaceutical composition according to any one of p-11 for the treatment of neurodegenerative diseases.

13. The pharmaceutical composition according to item 12, where the specified neurodegenerative disease is dementia Alzheimer's disease or down syndrome.



 

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36 cl, 303 ex

FIELD: chemistry.

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9 cl, 1 tbl, 85 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new antibacterial compounds of formula I

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8 cl, 6 tbl, 9 ex

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12 cl, 1 dwg, 3 tbl, 5 ex

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29 cl, 178 ex

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