Method of synthesising e1-activating enzyme inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining a formula compound. The method includes a stage of binding a formula compound with a formula compound in the presence of a base with the formation of the formula (I) compound. In formula (I) stereochemical configurations in the positions, marked with asterisks, are relative; Rb represents hydrogen; R00 represents a C1-10 aliphatic group or a C6-14 aryl group, including one-three rings; Rd, Re, Re', Rf, Rh, Rh', Rk represent hydrogen; Rg represents chlorine, fluorine, iodine or bromine; Rm represents a protective hydroxyl group; values of radicals Ra, R*, Rc are given in the invention formula. In formulas (II) and (III) Ra, Rb, Rc, Rd, Re, Re', Rf, Rg, Rh, Rh', Rj, Rk and Rm are such as determined in formula (I) and R1 represents -CH2CHO. The invention also relates to methods of obtaining compounds of formulae (V), (VI), (VId) and to a compound of the structural formula (IIa). Structural formulae of compounds (V), (VI), (VId), (IIa) are given in the invention formula.

EFFECT: method makes it possible to carry out synthesis in a regioselective way and use the obtained product without purification.

15 cl, 1 tbl, 26 ex

 

Requested priority

According to this application claims priority under provisional patent application U.S. No. 60/963008, filed August 2, 2007, provisional application for U.S. patent No. 61/062378, filed January 25, 2008, each of which is incorporated herein by reference in its entirety.

The technical field to which the invention relates

The present invention relates to methods of synthesis of inhibitors of the enzyme that activates E1, and the intermediates used in such methods.

The level of technology

Posttranslational modification of proteins by ubiquitin-like molecule (ubl) is an important regulatory process within cells that plays a key role in regulating many biological processes, including cell division, transmission of cellular signals and immune response. Ubl are small proteins that are covalently joined to a lysine of the target protein through isopeptide connection with the C-terminal glycine ubl. Ubiquitin-like molecule changes the molecular surface of the target protein and can affect properties such as protein-protein interaction, enzymatic activity, stability and cellular localization of the target.

Ubiquitin and other ubls are activated by a specific enzyme E1, which catalyzes about�education alldaylong intermediate compounds with the C-terminal glycine. The activated ubl molecule is then transferred to the catalytic cysteine residue in the enzyme E1 via the formation of intermediate compounds with thioether bond. An intermediate connection E1-ubl forms associate with E2, resulting in thioether exchange in which ubl is transferred to the active site cysteine of E2. Then ubl forms a conjugate with protein-targeted - directly or through its E3 ligase through education isopeptides connection with the amino group of the side chain of lysine in the protein target.

Targeting of E1-activating enzymes provides a unique opportunity to intervene in the functioning of the various biochemical pathways that are important for the maintenance of normal cell division and transmission of cellular signals. E1-activating enzymes function in the first stage of ways of ubl conjugation; thus, the inhibition of E1-activating enzyme will specifically modulate further biological consequences of ubl modifications. As such, the inhibition of such activating enzymes and the subsequent inhibition effects of ubl conjugation occurring as a result of this, is a way of intervention in normal cell division, transmission of cellular signals and in some aspects of cell physiology that are critical to disease mechanisms. In particular, E1-Fe�cops, as UAE, NAE and SAE, as regulators of diverse cellular functions, are potentially important therapeutic targets in the search for new approaches to the treatment of diseases and disorders.

Langston S. et al. in a patent application in the USA under serial number 11/700614, which in its entirety is incorporated herein by reference, disclose compounds that are effective inhibitors of E1 activating enzymes, in particular, NAE. These compounds can be used for inhibiting the activity of E1 in vitro and in vivo and can be used in the treatment of disorders of cell proliferation, particularly cancer, and other disorders associated with the activity of E1. One of the classes of compounds described by Langston et al., are 4-substituted ((1S,2S,4R)-2-hydroxy-4-{7H-imidazo[2,3-d]pyrimidine-7-yl}cyclopentyl)methylsulfonate. Efficient chemical synthesis of such compounds can be very difficult due to the presence in these compounds of multiple stereogenic centers. Therefore there is a need for additional methods of obtaining 4-substituted ((1S,2S,4R)-2-hydroxy-4-{7H-imidazo[2,3-d]pyrimidine-7-yl}cyclopentyl)methylsulfonate.

Description of the invention

The present invention relates to methods and intermediate compounds for the synthesis of 4-substituted ((1S,2S,4R)-2-hydroxy-4-{7H-imidazo[2,3-d]pyrimidine-7-yl}cyclopentyl)methylsulfonate which can be used as inhibitors of E1 activating enzyme.

In one aspect, the present invention relates to a method of synthesis of a compound of formula (I):

or its salts;

where:

stereochemistry at the position marked with asterisks are relative;

Rarepresents hydrogen or a protective group of hydroxyl; or Rataken together with Rjand the intermediate atoms forms a cyclic diol-protective group; or Rataken together with Rmand the intermediate atoms forms a cyclic diol-protective group;

Rbrepresents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rcrepresents hydrogen, fluorine, chlorine, -OH, -O-Rmor optionally substituted C1-4aliphatic group;

Rdrepresents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rerepresents hydrogen or C1-4aliphatic group;

Re'represents hydrogen or C1-4aliphatic group;

each Rfindependently represents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rgrepresents chlorine, fluorine, iodine or bromine;

Rhrepresents hydrogen, fluorine, C 1-4aliphatic group or a C1-4forlifetime group;

Rh'represents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rjrepresents hydrogen or a protective group of hydroxyl; or Rjtaken together with Raand the intermediate atoms forms a cyclic diol-protective group;

Rkrepresents hydrogen or C1-4aliphatic group;

Rmrepresents a protective group of hydroxyl; or Rmtaken together with Raand the intermediate atoms forms a cyclic diol-protective group;

comprising the step of binding the compound of formula (II) or its salt with a compound of formula (III), to produce a compound of formula (I):

where:

stereochemistry at the position marked with asterisks are relative;

each of the radicals Ra, Rb, Rc, Rd, Re, Re', Rf, Rg, Rh, Rh', Rj, Rkand Rmin formulas (II) and (III) is as defined in formula (I);

Rlrepresents-CH2CHO or-CH2CH(ORl')2; and

each Rl'independently represents an aliphatic group, or two Rl'taken together with the interim at�Mami oxygen and carbon, form an optionally substituted 5 - or 6-membered cyclic acutally fragment.

In some embodiments, the method additionally includes the stage:

c) treatment of a compound of formula (I) with an amine of the formula HNRnRoto produce a compound of formula (V) or salts thereof:

where:

stereochemistry at the position marked with asterisks are relative;

each of the radicals Ra, Rb, Rc, Rd, Re, Re', Rf, Rh, Rh', Rj, Rkand Rmin the formula (V) is as defined in formula (I);

Rnrepresents H or C1-4aliphatic group; and

Rois an optionally substituted C1-10the aliphatic group, aryl, heteroaryl or heterocyclic radical.

In some embodiments, the method additionally includes the stage:

(d) sulfanilamide of a compound of formula (V), where Rjrepresents hydrogen, with a compound of formula (VI) or salts thereof;

where:

stereochemistry at the position marked with asterisks are relative;

each of the radicals Ra, Rb, Rc, Rd, Re, Re', Rf, Rh, Rh', Rk , Rm, Rnand Roin the formula (VI) is as defined in formula (V).

Another aspect of the present invention relates to another method of obtaining compounds of formula (I):

or its salts;

where:

stereochemistry at the position marked with asterisks are relative;

Rarepresents hydrogen or a protective group; or Rataken together with Rjand the intermediate atoms forms a cyclic diol-protective group; or Rataken together with Rmand the intermediate atoms forms a cyclic diol-protective group;

Rbrepresents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rcrepresents hydrogen, fluorine, chlorine, -OH, -O-Rmor optionally substituted C1-4aliphatic group;

Rdrepresents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rerepresents hydrogen or an aliphatic group;

Re'represents hydrogen or C1-4aliphatic group;

each Rfindependently represents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rgis the FDS�th chlorine, fluorine, iodine or bromine;

Rhrepresents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rh'represents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rjrepresents hydrogen or a protective group; or Rjtaken together with Raand the intermediate atoms forms a cyclic diol-protective group;

Rkrepresents hydrogen or C1-4aliphatic group;

Rmrepresents a protective group of hydroxyl; or Rmtaken together with Raand the intermediate atoms forms a cyclic diol-protective group;

comprising treating the compound of formula (IV):

Acid, to produce a compound of formula (I),

where:

each of the radicals Ra, Rb, Rc, Rd, Re, Re', Rf, Rg, Rh, Rh', Rj, Rkand Rmin the formula (IV) is as defined in formula (I);

Rlrepresents-CH2CH(ORl')2; and

each Rl'independently represents C1-6aliphatic group, or two Rl'taken together with the intermediate atoms of oxygen and carbon, form an optionally substituted 5 - or 6-membered cyclic�cue acutally fragment.

Another aspect of the present invention relates to a method of obtaining compounds of formula (V):

or its salts;

where:

stereochemistry at the position marked with asterisks are relative;

Rarepresents hydrogen or a protective group; or Rataken together with Rjand the intermediate atoms forms a cyclic diol-protective group; or Rataken together with Rmand the intermediate atoms forms a cyclic diol-protective group;

Rbrepresents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rcrepresents hydrogen, fluorine, chlorine, -OH, -O-Rmor optionally substituted C1-4aliphatic group;

Rdrepresents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rerepresents hydrogen or C1-4aliphatic group;

Re'represents hydrogen or C1-4aliphatic group;

each Rfindependently represents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rhrepresents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime GRU�PU;

Rh'represents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rjrepresents hydrogen or a protective group of hydroxyl; or Rjtaken together with Raand the intermediate atoms forms a cyclic diol-protective group;

Rkrepresents hydrogen or C1-4aliphatic group;

Rmrepresents a protective group of hydroxyl; or Rmtaken together with Raand the intermediate atoms forms a cyclic diol-protective group;

Rnrepresents H or C1-4aliphatic group;

Rois an optionally substituted C1-10the aliphatic group, aryl, heteroaryl or heterocyclic radical;

comprising treating the compound of formula (Ia):

an amine of the formula HNRnRo,

where:

each of the radicals Ra, Rb, Rc, Rd, Re, Re', Rf, Rh, Rh', Rj, Rkand Rmin the formula (Ia) is as defined in formula (V); and

Rg'represents a leaving group.

Another aspect of the present invention relates to compounds of formula (Ia):

or salts thereof;

where:

stereochemical configurations�and the regulations asterisks, are absolute;

Rarepresents hydrogen or a protective group; or Rataken together with Rjand the intermediate atoms forms a cyclic diol-protective group; or Rataken together with Rmand the intermediate atoms forms a cyclic diol-protective group;

Rbrepresents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rcrepresents hydrogen, fluorine, chlorine, -OH, -O-Rmor optionally substituted C1-4aliphatic group;

Rdrepresents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rerepresents hydrogen or C1-4aliphatic group;

Re'represents hydrogen or C1-4aliphatic group;

each Rfindependently represents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rg'represents a leaving group;

Rhrepresents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rh'represents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rjrepresents salavador or a protective group of hydroxyl; or Rjtaken together with Raand the intermediate atoms forms a cyclic diol-protective group;

Rkrepresents hydrogen or C1-4aliphatic group; and

Rmrepresents a protective group of hydroxyl; or Rmtaken together with Raand the intermediate atoms forms a cyclic diol-protective group.

Another aspect of the present invention relates to compounds of formula (IIa):

or salts thereof;

where:

stereochemistry at the position marked with asterisks are absolute;

Rarepresents hydrogen or a protective group; or Rataken together with Rjand the intermediate atoms forms a cyclic diol-protective group; or Rataken together with Rmand the intermediate atoms forms a cyclic diol-protective group;

Rbrepresents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rcrepresents hydrogen, fluorine, chlorine, -OH, -O-Rmor optionally substituted C1-4aliphatic group;

Rd'represents hydrogen, fluorine, bromine, C1-4aliphatic group or a C1-4forlifetime group;

Rerepresents hydrogen or C1-4and�efficency group;

Re'represents hydrogen or C1-4aliphatic group;

Rhrepresents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rh'represents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rjrepresents hydrogen or a protective group of hydroxyl; or Rjtaken together with Raand the intermediate atoms forms a cyclic diol-protective group;

Rmrepresents a protective group of hydroxyl; or Rmtaken together with Raand intermediate carbon atoms forms a cyclic diol-protective group; and

Rrrepresents hydrogen or a protective group of the amine.

Compounds and methods of the present invention include compounds and methods described above and further illustrated by a detailed description of the methods and compounds shown below. Terms used in this description should be consistent with the following specific values, unless otherwise indicated.

As used in this description, the term "E1", "E1-enzyme" or "E1-activating enzyme" refers to any one of a family of related ATP-dependent activating enzymes, involved in activating or stimuleren�of the conjugation of ubiquitin or ubiquitin-like proteins (collectively referred to as "ubl") target molecules. E1-activating enzymes function via the formation of intermediate product attilireari/thioether transfer corresponding to the corresponding E2-conjugating enzyme by the reaction of transstilbene. The resulting activated ubl-E2 stimulates the final ubl conjugation with the protein target. Substrates for conjugation, ubl, adjustable E1-activating enzymes (e.g., NAE, UAE, SAE) are a diverse array of cellular proteins that play a role in cell signaling, cell cycle and metabolism of proteins. Unless the context otherwise indicated, the term "E1-enzyme" is considered to relate to any of E1-activating enzyme protein, including, but without limitation, nedd8-activating enzyme (NAE (APPBP1/Uba3)), ubiquitin-activating enzyme (UAE (Ubal)), sumo-activating enzyme (SAE (Aosl/Uba2)) or ISG15-activating enzyme (UbelL), preferably human NAE, SAE or UAE and, more preferably, NAE.

The term "E1 inhibitor-enzyme or inhibitor of the enzyme E1" is used to refer to compounds having the structure, as defined herein, which is able to interact with E1 enzyme and inhibit its enzymatic activity. The inhibition of E1-enzymatic activity means reducing the ability of E1 enzymes activate ubiquitin-like (ubl) conjugation with the substrate �OPTICOM or protein (e.g., the ubiquitination, adilibria, suveliaane).

The term "aliphatic" or "aliphatic group", as used herein, means a substituted or unsubstituted linear, branched or cyclic C1-12the hydrocarbon that is completely saturated or which contains one or more units of unsaturation, but which is not aromatic. For example, suitable aliphatic groups include substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl, alkyline groups and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. In various embodiments, the aliphatic group has 1-12, 1-8, 1-6, 1-4 or 1-3 carbon.

The terms "alkyl", "alkenyl" and "alkynyl", used alone or as part of a larger fragment, refers to an aliphatic group with a straight or branched chain, having from 1 to 12 carbon atoms. For the purposes of the present invention, the term "alkyl" will be used in cases when the carbon atom attaching the aliphatic group to the rest of the molecule is a saturated carbon atom. However, the alkyl group may include unsaturation at other carbon atoms. Thus, the alkyl groups include, but are not limited to, methyl, ethyl, propyl, allyl, prop�Rhyl, butyl, pentyl and hexyl.

For the purposes of the present invention, the term "alkenyl" is used in cases when the carbon atom attaching the aliphatic group to the rest of the molecule forms part of a carbon-carbon double bond. Alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 1-butenyl, 1-pentenyl and 1-hexenyl.

For the purposes of the present invention, the term "alkynyl" will be used in cases when the carbon atom attaching the aliphatic group to the rest of the molecule forms part of a carbon-carbon triple bond. Alkyline groups include, but without limitation, ethinyl, 1-PROPYNYL, 1-butynyl, 1-pentenyl and 1-hexenyl.

The term "cycloaliphatic group", used alone or as part of a larger fragment, refers to a saturated or partially unsaturated cyclic aliphatic ring system having from 3 to about 14 members, where the aliphatic ring system is optionally substituted. In some embodiments, the cycloaliphatic compound is a monocyclic hydrocarbon having 3-8 or 3-6 carbon atoms in the ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctanol cyclooctadiene. In some embodiments, the cycloaliphatic compound is a bridged or condensed bicyclic hydrocarbon having 6-12, 6-10, or 6-8 carbon atoms in the ring, where any individual ring in the bicyclic ring system is a 3-8-membered.

In some embodiments, two adjacent substituents on the cycloaliphatic ring, taken together with intermediate ring atoms, form an optionally substituted condensed 5-6-membered aromatic or a 3-8-membered non-aromatic ring having 0-3 heteroatom in the ring selected from the group consisting of O, N and S. Thus, the term "cycloaliphatic" includes aliphatic rings that are fused with one or more aryl, heteroaryl or heterocyclic rings. Non-limiting examples include indolyl, 5,6,7,8-tetrahydroquinoxaline, decahydronaphthalene or tetrahydronaphthyl, where the radical or point of connection is located on the aliphatic ring. The term "cycloaliphatic" can be used interchangeably with the terms "carbocycle", "carbocyclic", "carbocycle" or "carbocyclic".

The terms "aryl" and "ar", used alone or as part of a larger fragment, such as "aralkyl", "arakaki" or "aryloxyalkyl" refer to C6-C14the aromatic�whom the hydrocarbon, comprising 1-3 rings, each of which is optionally substituted. Preferably, the aryl group is a C6-10the aryl group. Aryl groups include, but are not limited to, phenyl, naphthyl and anthracene. In some embodiments, two adjacent substituents on the aryl ring, taken together with intermediate ring atoms, form an optionally substituted 5-6-membered aromatic or 4-to 8-membered non-aromatic ring having 0-3 heteroatom selected from the group consisting of O, N and S. Thus, the term "aryl" as used herein, includes groups in which an aromatic ring condensed with one or more heteroaryl, cycloaliphatic or heterocyclic rings, where the radical or point of connection is located on the aromatic ring. Non-limiting examples of such condensed ring systems include indole, isoindole, benzothiazyl, benzofuranyl, dibenzofurans, indazoles, benzimidazoles, benzothiazoles, hinely, ethanolic, cinnoline, phthalazine, hintline, honokalani, carbazolyl, acridines, phenazines, phenothiazines, phenoxazines, tetrahydroquinolines, tetrahydroisoquinolines, fluorenyl, indolyl, phenanthridines, tetrahydronaphthyl, indolinyl, phenoxazines, benzodioxane and benzodioxolyl. Aryl group may �be mono-, bi-, tri - or polycyclic, preferably mono-, bi - or tricyclic, more preferably mono - or bicyclic. The term "aryl" can be used interchangeably with the terms "aryl group", "aryl moiety", and "aryl ring".

"Aralkyl" or "arylalkyl" group comprises an aryl group covalently attached to an alkyl group, each of which independently is optionally substituted. Preferably, kalkilya group is a C6-10aryl(C1-6)alkyl, C6-10aryl(C1-4)alkyl or C6-10aryl(C1-3)alkyl, including, but without limitation, benzyl, phenethyl and naphthylmethyl.

The terms "heteroaryl" and "heteroa", used alone or as part of a larger fragment, such as "heteroalkyl" or "heteroanalogues" refer to groups having 5 to 14 atoms in the ring, preferably 5, 6, 9, or 10 atoms in the ring; having 6, 10 or 14 π electrons, socialized in a cyclic array; and having, in addition to carbon atoms, from one to four heteroatoms. The term "heteroatom" refers to nitrogen, oxygen or sulfur and includes any oxidized form of nitrogen or sulfur, and any quaternion the form of a basic nitrogen. Heteroaryl groups include, but without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, Tria�of ail, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolin, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinol, naphthyridines and pteridinyl. In some embodiments, two adjacent substituents on heteroaryl, taken together with intermediate ring atoms, form an optionally substituted condensed 5-6-membered aromatic or 4-to 8-membered non-aromatic ring having 0-3 heteroatom in the ring selected from the group consisting of O, N and S. Thus, the terms "heteroaryl" and "heteroa -" as used herein, also include groups in which a heteroaromatic ring is fused with one or more aryl, cycloaliphatic or heterocyclic rings, where the radical or point of connection is located on the heteroaromatic ring. Non-limiting examples include indole, isoindole, benzothiazyl, benzofuranyl, dibenzofurans, indazoles, benzimidazoles, benzothiazoles, hinely, ethanolic, cinnoline, phthalazine, hintline, honokalani, 4H-hemolysins, carbazolyl, acridines, phenazines, phenothiazines, phenoxazines, tetrahydroquinolines, tetrahydroisoquinolines and pyrido[2,3-b]-1,4-oxazine Serie-3(4H)-it. Heteroaryl group can be mono-, bi-, tri - or polycyclic, preferably mono-, bi - or tricyclic, more PR�doctitle, mono - or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic group", and any of such terms include rings that are optionally are substituted. The term "heteroalkyl" refers to an alkyl group substituted by heteroaryl, where alkyl and heteroaryl portion is independently optionally are substituted.

As used in this description, the terms "heterocycle", "heterocyclic group", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a stable 3-to 7-membered monocyclic or 7-10-membered condensed, or 6-10-membered bridged bicyclic heterocyclic fragment, which is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. The term "nitrogen" when used in respect of the atom in the ring of the heterocycle comprises a substituted nitrogen. For example, in heterocyclic ring having 1-3 heteroatom selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or+NR (as in N-substituted Pirro�denile). The heterocyclic ring may be attached to the side group at any heteroatom or carbon atom which ensures the formation of a stable structure, and any of the atoms in the ring may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrofuryl, pyrrolidinyl, pyrrolidinyl, piperidinyl, pyrrolidyl, tetrahydropyranyl, tetrahydroisoquinoline, decahydroquinoline, oxazolidinyl, piperazinyl, dioxane, dioxolane, diazepines, oxazepines, thiazepines, morpholinyl and hinokitiol.

In some embodiments, two adjacent substituents on the heterocyclic ring, taken together with intermediate ring atoms, form an optionally substituted 5-6-membered aromatic or a 3-8-membered non-aromatic ring having 0-3 heteroatom in the ring selected from the group consisting of O, N and S. Thus, in the present description the terms "heterocycle", "heterocyclyl", "heterocyclic ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical" are used interchangeably; they include groups, in which the heterocyclic ring condensed with one or more aryl, heteroaryl, or cycloaliphatic rings�, such as indolinyl, 3H-indole, bromanil, phenanthridine or tetrahydroquinoline, where the radical or point of connection is located on the heterocyclic ring. Heterocyclic group may be mono-, bi-, tri - or polycyclic, preferably mono-, bi - or tricyclic, more preferably mono - or bicyclic. The term "heteroseksualci" refers to an alkyl group substituted by heterocyclyl, where the alkyl and heterocyclyl parts independently are optionally substituted.

As used in this description, the term "partially unsaturated" refers to the fragment of the ring that includes at least one double or triple bond between the atoms in the ring. The term "partially unsaturated" should encompass rings having multiple centres of unsaturation, but it should not include aryl or heteroaryl fragments, as defined in this specification.

The terms "aliphatic halogen", "halogenated", "halogenoalkanes and halogenoalkane", depending on the circumstances, refer to an aliphatic group, alkyl, alkenyl or alkoxygroup that are substituted by one or more halogen atoms. The term "halogen" or "halo" as used herein, denote F, Cl, Br or I. the Term "forlifetime" refers to aliphatic halogen group, where the halogen is f�op. Non-limiting examples floralities groups include-CH2F, -CHF2, -CF3-CH2CF3, -CF2CH3and-CF2CF3.

The term "linker group" or "linker" means an organic group that links the two parts of the connection. Typically, the linkers include atom such as oxygen or sulfur, a unit, as-NH-, -CH2-, -C(O)-, -C(O)NH-, or a chain of atoms, such as Allenova chain. The molecular mass of a linker is typically in the range of from about 14 to 200, preferably in the range 14-96, at a length corresponding to about six atoms. In some embodiments, the linker is a C1-6alkylenes chain.

The term "alkylene" refers to a divalent alkyl group. "Allenova chain" is a polymethene group, i.e.,- (CH2)n-, where n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2 or from 2 to 3. Substituted Allenova chain represents the polymethene the group in which one or more methylene hydrogen atoms are replaced by any substitute. Suitable substituents include the substituents described below for a substituted aliphatic group. Allenova chain can also be substituted in one or more of the provisions aliphatic group or substituted alipac�cal group.

Allenova chain can also be optionally interrupted by a functional group. Allenova chain is "interrupted" with functional group in the case where the internal methylene link is replaced by a functional group. Examples of suitable "interrupting functional groups" include-C(R*)=C(R*)-, -C≡C-, -O-, -S-, -S(O)-, -S(O)2-, -S(O)2N(R+)-, -N(R*)-, -N(R+)CO-, -N(R+)C(O)N(R+)-, -N(R+)2-, -C(O)N(R+)-, -C(O)-, -C(O)-C(O)-, -CO2-, -OC(O)-, -OC(O)O-, -OC(O)N(R+)-, -C(NR+)=N, -C(OR*)=N-, -N(R+)-N(R+)- or-N(R+)S(Oh)2-. Each R+, independently, represents hydrogen or optionally substituted aliphatic, aryl, heteroaryl or heterocyclyl group, or two R+when the same nitrogen atom, taken together with that nitrogen atom, form a 5-8-membered aromatic or non-aromatic ring having, in addition to the nitrogen atom, 0-2 heteroatom in the ring selected from N, O, and S. Each R* independently represents hydrogen or optionally substituted aliphatic, aryl, heteroaryl or heterocyclyl group.

Examples of C3-6alkilinity chains that are "interrupted" -O -,- CH2OCH2-, -CH2O(CH2)2-, -CH2O(CH2)3-, -CH2O(CH2)4-, -(CH2)2OCH2-, -(CH2)2�(CH 2)2-, -(CH2)2O(CH2)3-, -(CH2)3O(CH2)-, -(CH2)3O(CH2)2- and -(CH2)4O(CH2)-. Other examples alkilinity chains that are "interrupted" with functional groups include-CH2ZCH2-, -CH2Z(CH2)2-, -CH2Z(CH2)3-, -CH2Z(CH2)4-, -(CH2)2ZCH2-, -(CH2)2Z(CH2)2-, -(CH2)2Z(CH2)3-, -(CH2)3Z(CH2)-, -(CH2)3Z(CH2)2- and -(CH2)4Z(CH2)-, where Z represents one of the "interrupting" functional groups listed above.

The person skilled in the art it will be obvious that in cases where Allenova circuit having a gap that is attached to the functional group, certain combinations are not sufficiently stable for pharmaceutical use. In the scope of the present invention includes only a stable or chemically acceptable connection. A stable or chemically acceptable compound is such a compound, a chemical structure which does not change significantly while keeping a temperature from about -80°C to approximately +40°C in the absence of moisture or other chemically reactive conditions for at least weeks, or compound that retains a�the density long enough so it can be used for therapeutic or prophylactic administration to a patient.

The term "substituted", as used herein, means that a hydrogen radical, a specific fragment is replaced by the radical of a specified substituent, provided that such substitution results in a stable or chemically acceptable connection. The expression "one or more substituents", as used herein, refers to the number of substituents that equals the number in the interval from one to the maximum number of substituents possible based on the number of available binding sites, provided that you have met the above conditions of stability and chemical admissibility. Unless otherwise specified, optionally substituted group may have a substituent in each position of this group in which the possible substitution, the substituents may be the same or different.

The term "independently selected", as used herein, means that the same or different values may be chosen for many occasions refer to this radical in the same connection.

Aryl group (including the aryl fragment in aralkyl, Alcochete, aryloxyalkyl, etc.) or heteroaryl group (including the heteroaryl fragment in heteroalkyl and heteroaryl�shrope, etc.) may contain one or more substituents. Examples of suitable substituents on the unsaturated carbon atom aryl or heteroaryl group include-halo, -NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SRoo, -S(O)Roo, -SO2Roo, -SO3Roo, -SO2N(R+)2, -N(R+)2, -NR+C(O)R*, -NR+C(O)N(R+)2, -NR+CO2Roo, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2Roo, -NR+SO2N(R+)2, -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, and-P(O)(NR+)-N(R+)2where Roorepresents an optionally substituted aliphatic or aryl group, and R+and R* are as defined above, or two adjacent substituent taken together with their intermediate atoms, form a 5-6-membered unsaturated or partially saturated ring having 0-3 atom in the ring selected from the group consisting of N, O and S.

Aliphatic group or non-aromatic heterocyclic ring may be substituted by one or more substituents. Examples of suitable for�of entitely on the saturated carbon of an aliphatic group or non-aromatic heterocyclic rings include, but without limitation, such substituents as listed above for the unsaturated carbon on the aryl or heteroaryl group and the following: =O, =S, =C(R*)2, =N-N(R*)2, =N-OR*, =N-NHC(O)R*, =N-NHCO2Roo, =N-NHSO2Rooor =N-R* where each R* and Roois such as defined above.

Suitable substituents on the nitrogen atom non-aromatic heterocyclic ring include-R*, -N(R*)2, -C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)CH2C(O)R*, -SO2R*, -SO2N(R*)2, -C(=S)N(R*)2, -C(=NH)-N(R*)2and-NR*SO2R*; each R* is as defined above.

The term "about" used in this description, means "approximately", "in", "approximately" or "about". When the term "about" is used in conjunction with a numerical range, it modifies that range, expanding its borders above and below the preset numeric values. Generally, the term "about" is used herein to modify a numerical value above and below the intended value with a deviation of 10%.

The term "contain" as used in this description, means "includes, but is not limited to this."

Unless otherwise stated, structures depicted herein, are also considered to include compounds that differ only in the presence of one or more isotopes�nbut enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen atom by a deuterium atom or tritium, or the replacement of a carbon atom13With - or14C-enriched carbon, are included in the scope of the present invention.

The person skilled in the art will also be obvious that certain compounds according to the present invention may exist in tautomeric forms, all such tautomeric forms of the compounds included in the scope of the present invention. If the stereochemical configuration is not specified explicitly, the structure depicted in this description, is considered to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, unless specified otherwise, single stereochemical isomers as well as enantiomeric and diastereomeric mixture of compounds according to the present invention, included in the scope of the present invention. For example, compounds of formula (VI), where Rcrepresents-OH, can have the R - or S-configuration at the carbon atom bearing Rc. As R-or S-stereochemical isomers, as well as all mixtures thereof, are included in the scope of the present invention.

Where the stereochemical configuration at a given asymmetric center of defined structure, the depicted configuration is relative to other� asymmetric centers in the molecule, if not specified otherwise. Where the stereochemical configuration is determined by the chemical name, designation (rel), (R*) and (S*) indicate relative stereochemistry, whereas the symbol (R), (S), (+), (-) and (abs) indicate absolute stereochemistry.

In the compounds of formulas (I) to(VI) stereochemical configurations depicted at positions marked with asterisks are relative, unless explicitly indicated absolute stereochemistry. Preferably, diastereomeric purity of the compound is at least 80%, more preferably at least 90%, even more preferably at least 95% and most preferably at least 99%. The term "diastereomer cleanliness", as used herein, refers to compounds having the depicted relative stereochemistry, expressed in percentage of the total number of all diastereomers present.

In some embodiments, the stereochemical configuration at the position marked with asterisks are the absolute and relative configurations. Preferably, the enantiomeric purity of the compound is at least 80%, more preferably at least 90%, even more preferably at least 95% and most preferably at least 99%. The term "enantiomeric purity", as used in this description refers to to�the number of connections, having depicted relative stereochemistry, expressed in percentage of the total number of the depicted compound and its enantiomer.

Methods of determining diastereomeric and enantiomeric purity are well known in this field. Diastereomer purity can be determined by any analytical method that can identify the differences between the Union and its diastereomers. Examples of suitable analytical methods include, but are not limited to, nuclear magnetic resonance spectroscopy (NMR), gas chromatography (GC) and high performance liquid chromatography (HPLC). Similarly, enantiomeric purity can be determined by any analytical method that can identify the differences between the compound and its enantiomer. Examples of suitable analytical methods include, but are not limited to, GC or HPLC using chiral material that fills the column. Enantiomers may also be distinguished by GC or HPLC using achiral material that fills the column, if prior to derivatization of optically enriched derivateservlet means, for example, Mosher acid. Similarly, the enantiomers may also be distinguished by NMR, if prior to derivatization of optically enriched derivatization agent.

The term "�itna hydroxyl group", as used herein, refers to a chemical group that: (i) interacts with the hydroxyl functional group of the substrate, forming a protected substrate; (ii) stable under reaction conditions, which will be subjected to the protected substrate; and (iii) can be removed from the protected substrate to release of hydroxyl functional groups under conditions that are compatible with other functional groups present in the substrate. The term "cyclic diol-protective group" as used herein, refers to a chemical group that: (i) is reacted with a diol functional group of the substrate, forming a protected substrate; (ii) stable under reaction conditions, which will be subjected to the protected substrate; and (iii) can be removed from the protected substrate with the release of the diol functional group under conditions that are compatible with other functional groups present in the substrate. The hydroxyl group of 1,2 - and 1,3-diols can be protected individually protective hydroxyl groups or can be protected together a cyclic diol-protective group.

The term "acid-labile protective group" as used herein, refers to a chemical group that: (i) interacts with the functional group of the substrate, forming a protected sub�Trad; (ii) is stable under reaction conditions, which will be subjected to the protected substrate; and (iii) can be removed from the protected substrate to release of functional groups in acidic conditions that are compatible with other functional groups present in the substrate. Amine and hydroxyl groups include such functional groups, which can protect the acid-labile protective group.

The term "protective group of an amine", as used herein, refers to a chemical group that: (i) interacts with the amine functional group in the substrate, forming a protected substrate; (ii) stable under reaction conditions, which will be subjected to the protected substrate; and (iii) can be removed from the protected substrate with the release of the amine in acidic conditions that are compatible with other functional groups present in the substrate.

Protective hydroxyl groups, cyclic diol protecting groups, acid-labile protective group and the protective group of the amine suitable for use in the methods and compounds of the present invention, well-known specialists in this field. Chemical properties of such protective groups, methods for their introduction and removal can be found in P. G. M. Wuts and T. W. Greene, Greene's Protective Groups in Organic Synthesis (4thed.), John Wiley & Sons, NJ (2007).

Ways and link� of the present invention is additionally illustrated by a detailed description and illustrative examples, below.

In a first aspect the present invention relates to a method for producing compounds of formula (I) by binding of a compound of formula (II) with a compound of formula (III). In one embodiment, the implementation, where Rlrepresents-CH2CH(ORl')2and each Rl'independently represents C1-6aliphatic group, or two Rl'taken together with the intermediate atoms of oxygen and carbon, form an optionally substituted 5 - or 6-membered cyclic acutally fragment, the method comprises the steps:

(a) treatment of a compound of formula (II) or its salts compound of formula (III) in the presence of base, to produce a compound of formula (IV); and

(b) processing the reaction mixture containing the compound of formula (IV), acid, to produce a compound of formula (I).

Step a) involves the nucleophilic substitution reaction between the compound of formula (II) and compound of formula (III), to obtain compounds of formula (IV). Compounds of the formula (IV) can then be converted into compounds of formula (I) without isolation in the conditions of stage (b). Alternatively, compounds of formula (IV) can be isolated and/or purified by methods known to experts in this field, and converted into compounds of formula (I) in separate reactions. (Cm. J. A. Secrist et al. J. Med. Chem., 1984, 27, 534-536; R. B. Talekar and R. H. Wightman Tetrahedron, 1997, 53, 38313842). Step b) includes treatment with an acid, leading to acid-catalyzed removal acetylenic groups simultaneously with the cyclization and formation of 7H-imidazo[2,3-d]pyrimidine-7-yl ring system.

Stage (a) can be conveniently carried out in the presence of a base, as the base is an alkaline earth metal or organic amine. Examples of alkaline earth metal bases include, but are not limited to, potassium carbonate, sodium carbonate, calcium carbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, lithium bicarbonate, potassium bicarbonate, sodium bicarbonate, lithium hydride, potassium hydride, sodium hydride, tert-butoxide, lithium, tert-butoxide and potassium tert-butoxide sodium. Other alkaline earth metal bases include, but are not limited to, sodium carbonate, cesium hydroxide and cesium. Base organic amines include, but are not limited to, trialkylamines, cyclic amines, pyridine and substituted pyridine. Examples of such substances include, but are not limited to, triethylamine, triethylenediamine, pyridine, collidin, 2,6-lutidine, 4-dimethylaminopyridine, di-tert-butylpyridinium, N-methylmorpholin, N-demerol, tetramethylguanidine, diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene and N,N'-diisopropylethylamine. Other base organic amines in�exclude, but are not limited to, 1-azabicyclo[2.2.2]octane, tributylamine and Tripropylamine. Preferably, the base used in stage a) is selected from potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, N,N'-diisopropylethylamine, pyridine and 2,6-lutidine.

The processing at the stage a) can be carried out at ambient temperature or at an elevated temperature of reaction, although the result of elevated temperatures may be shorter reaction time. The choice of the appropriate reaction temperature and reaction time largely depends on the base and solvent. The person skilled in the art can select a suitable reaction temperature and reaction time to the applied reaction conditions.

In some embodiments, the implementation of stage a) can be carried out at reaction temperatures not lower than about 20°C, 45°C or 60°C. In some embodiments, the implementation of stage a) can be carried out at reaction temperatures not higher than 120°C, 105°C or 90°C. Any range encompassing these high and low temperatures, included in the scope of the present invention. Stage a) is preferably carried out at reaction temperatures in the range of from about 20°C to about 120°C, from about 45°C to about 105°C or from about 60°C to �rimero 90°C.

The acid used in stage b), is a mineral acid or organic acid. Examples of mineral acids include, but are not limited to, hydrochloric acid, sulfuric acid, Hydrobromic acid, nitric acid and phosphoric acid. Examples of organic acids include, but are not limited to, acetic acid, propionic acid, benzoic acid, formic acid, oxalic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluensulfonate acid and triftormetilfullerenov acid. Preferably, the acid at the stage b) is selected from the group consisting of hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluensulfonate acid, trichloroacetic acid, acetic acid and formic acid.

The processing at the stage b) is preferably carried out at ambient temperature or at an elevated temperature of reaction, although the result of elevated temperatures may be shorter reaction time. The choice of the appropriate reaction temperature and reaction time largely depends on nature of acid and solvent. The person skilled in the art can select a suitable reaction temperature and reaction time to the applied reaction conditions.

In some vari�ntah the implementation of stage b) can be carried out at reaction temperatures not lower than about 20°C, 40°C or 50°C. In some embodiments, the implementation of stage b) can be carried out at reaction temperatures not higher than about 90°C, 70°C, 60°C or 50°C. Any range encompassing these high and low temperatures, included in the scope of the present invention. Preferably, stage (b) is carried out at reaction temperatures in the range of from about 20°C to about 90°C, from about 40°C to about 60°C or from about 50°C to about 60°C. In some other embodiments, the implementation of stage b) is preferably carried out at a reaction temperature in the range of from about 45°C to about 60°C.

In some embodiments, the implementation of stage a) and stage b) are independently carried out in a solvent or diluent containing one or more of the following: ethanol, isopropanol, sec-butanol, ethyl acetate, methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, 1,4-dioxane, toluene, anisole, acetonitrile, N,N'-dimethylformamide, N,N'-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide or mixtures thereof. In certain embodiments, each of the stages a) and b) is carried out in a solvent containing aqueous ethanol, aqueous isopropanol, aqueous sec-butanol, aqueous tetrahydrofuran, aqueous 1,4-dioxane or mixtures thereof. In some embodiments, each of the stages a) and b) is carried out in a dissolved�Le, containing ethanol, isopropanol, sec-butanol, tetrahydrofuran or 1,4-dioxane or a mixture thereof.

In some embodiments, after completion of the reaction, the reaction mixture is allowed the opportunity to cool to ambient temperature, then concentrated and added to the aqueous solution, after which the resulting product is separated by filtration and dried. In some embodiments, the concentrated reaction mixture is added to the water. In some other embodiments, the concentrated reaction mixture was added to the aqueous solution of sodium chloride. In another group some other embodiments of the concentrated reaction mixture was added to the aqueous solution of the base to neutralize the acid is introduced at the stage b). Examples of aqueous bases include, but are not limited to, aqueous sodium carbonate, aqueous potassium carbonate and aqueous sodium bicarbonate.

Preferably, the method comprising the stages a) and b) obtain the compounds of formula (I), where Rlrepresents-CH2CH(ORl')2characterized by at least one of the following features:

(i) the base in stage (a) represents triethylamine;

(ii) processing at the stage a) is carried out in aqueous isopropanol;

(iii) processing at the stage b) is carried out in aqueous isopropanol;

(iv) acid in stage (b) is hydrochloric acid;

(v) processing at the stage a) is carried out at a reaction temperature in the range of from about 60°C to about 90°C; and

(vi) processing at the stage b) is carried out at a reaction temperature in the range of from about 40°C to about 60°C.

In some embodiments, where Rlrepresents-CH2CH(ORl')2, compounds of formula (IV) can be isolated and optionally purifying methods known to experts in this field, and be converted into compounds of formula (I) in separate reactions. In such embodiments, the conditions are as described above for stage (b). Preferably, the method of obtaining compounds of formula (I) from compounds of formula (IV), where Rlrepresents-CH2CH(ORl')2characterized by at least one of the following features:

(i) the treatment is carried out in aqueous isopropanol;

(ii) the acid is a hydrochloric acid; and

(iii) the treatment is carried out at the reaction temperature in the range of from about 50°C to about 60°C.

In another embodiment of the method of obtaining compounds of formula (I) comprises treating the compound of formula (II) compound of formula (III), where Rlrepresents-CH2CHO, in the presence of base. In this embodiment, the implementation�ing the binding of a compound of formula (II) and formula (III), to produce a compound of formula (I), occurs in one stage, the stage aa):

aa) treatment of a compound of formula (II) or its salts compound of formula (III) in the presence of base.

Suitable and preferred bases, solvents and reaction temperature for step (aa) are as described above for stage (a).

Preferably, the method of obtaining compounds of formula (I), comprising treating the compound of formula (II) compound of formula (III), where Rlrepresents-CH2CHO, in the presence of base, characterized at least one of the following:

(i) stage Foundation aa) represents triethylamine;

(ii) processing stage (aa) is carried out in isopropanol; and

(iii) processing stage (aa) is carried out at a reaction temperature in the range of from about 60°C to about 90°C.

In some embodiments, after completion of the reaction, the reaction mixture is allowed the opportunity to cool to ambient temperature, then concentrated and added to the aqueous solution, after which the resulting product is separated by filtration and dried. In some embodiments, the concentrated reaction mixture is added to the water. In some other embodiments, the concentrated reaction mixture was added to the aqueous solution of sodium chloride. In another group some�contain other variants of implementation of the concentrated reaction mixture was added to the aqueous solution of the base. Examples of aqueous bases include, but are not limited to, aqueous sodium carbonate, aqueous potassium carbonate and aqueous sodium bicarbonate.

In some embodiments, the method described above further includes a step

c) treatment of a compound of formula (I) with an amine of the formula HNRnRoto produce a compound of formula (V) or its salt.

In some embodiments, the implementation stage (c) can be conveniently carried out in the presence of acid or base. In some embodiments, the base is an alkaline earth metal base or the base is an organic amine. Examples of such bases described above for stage (a). Preferably, the base is at the stage (C) is selected from potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, N,N'-diisopropylethylamine, pyridine and 2,6-lutidine. The base can be used in equimolar amounts, in excess or, if appropriate, as solvent for the reaction.

In some embodiments, the processing at the stage c) is carried out in a solvent or diluent containing one or more of the following: ethanol, isopropanol, sec-butanol, n-butanol, ethyl acetate, methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, 2-methyltetrahydro�furan, dimethoxyethane, 1,4-dioxane, toluene, anisole, N,N'-dimethylformamide, N,N'-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, digim or mixtures thereof. In some embodiments, the implementation stage (c) can be performed in water or in a mixture of aqueous solvents containing one or more of the solvents listed above. In some embodiments, the implementation stage (c) can be carried out without solvent or diluent, using excess amine HNRnRo. In some embodiments, the processing at the stage c) is carried out in a solvent or diluent comprising one or more of the following: toluene, anisole, N,N'-dimethylformamide, sec-butanol, diglis, dimethylacetamide or N-methylpyrrolidinone.

Preferably, the processing at the stage c) is carried out at ambient temperature or at elevated temperatures of the reaction. In some embodiments, the processing at the stage c) is carried out under conditions of microwave irradiation. The choice of the appropriate reaction temperature and reaction time will greatly depend on the used base and solvent. The person skilled in the art can select a suitable reaction temperature and reaction time with regard to the applicable conditions of the reaction.

In some embodiments, the implementation stage (c) can be carried out at reaction temperatures not lower th� about 50°C, 90°C or 130°C. In some embodiments, the implementation stage (c) can be carried out at reaction temperatures not higher than about 160°C or 145°C. Any range encompassing these high and low temperatures, included in the scope of the present invention. Preferably, stage (C) is carried out at reaction temperatures in the range of from about 50°C to about 160°C, from about 90°C to about 145°C or from about 130°C to about 145°C.

The processing at the stage (c) can be optionally carried out at elevated reaction pressure. The person skilled in the art can choose suitable reaction pressure with regard to the applicable conditions of the reaction. In some embodiments, the implementation stage (c) can be carried out at reaction pressure of not lower than about 3.4 ATM or 4.8 ATM. In some embodiments, the implementation stage (c) the reaction can be carried out at a pressure not higher than approximately 8.2 ATM or 7.5 ATM. Any ranges encompassing these high and low reaction pressure, is included in the scope of the present invention. If at the stage (C) apply the increased reaction pressure, this stage is preferably carried out at a reaction pressure in the range of from about 3.4 ATM to about 8.2 ATM or from about 4.8 atmospheres to about 6.8 bar. In some other embodiments, if at the stage (C) apply the increased reaction�TES the pressure such pressure is preferably in the range of from about 4.8 atmospheres to about 6.8 bar.

In some embodiments, after stage C), the reaction mixture was cooled to ambient temperature and pressure, and extracted with a solvent such as ethyl acetate, isopropylacetate, methyl ethyl ketone, methyl isobutyl ketone, toluene or tert-butylmethylamine ether. In some other embodiments, after stage c), the reaction mixture was cooled to ambient temperature and pressure, concentrated and added directly to water or a solvent such as ethyl acetate, methylene chloride, acetone, isopropylacetate, methyl ethyl ketone, methyl isobutyl ketone, toluene, tert-butylmethylamine ether, diethyl ether or acetonitrile, to precipitate the product. The product is then separated by filtration and dried.

Preferably, the method of obtaining compounds of formula (V) from compounds of formula (I) comprising a stage (c), characterized by at least one of the following features:

(i) a specified base to stage C) is an N,N'-diisopropylethylamine;

(ii) processing at the stage c) is carried out in sec-butanol;

(iii) processing at the stage c) is carried out at a reaction temperature in the range of from about 130°C to about 145°C; and

(iv) processing at the stage c) is carried out at a reaction pressure in �the range from about 4.8 atmospheres to about 6.8 bar.

The present invention also relates to a method of obtaining compounds of formula (V) as defined above, comprising treating the compound of formula (Ia) as defined above, an amine of the formula HNRnRo. In some embodiments, Rg'represents halogen, -O-Rs, -S-Rt, -S(O)Rtor-S(O)2Rt; where Rsrepresents C1-4aliphatic group, alkylsulfonyl, peralkaline, optionally substituted aryl or optionally substituted arylsulfonyl, and Rtis an optionally substituted C1-4aliphatic group or optionally substituted aryl.

Compounds of formula (Ia), where Rg'represents-O-Rs, -S-Rt, -S(O)Rtor-S(O)2Rt, can be obtained from compounds of formula (I) by methods known to experts in this field. For example, Rgin the compound of the formula (I) can be replaced by alkoxide or thiol, to produce a compound of formula (Ia), where Rg'represents-O-Rs, -S-Rtwhere Rsis an optionally substituted C1-4aliphatic group or optionally substituted aryl, or Rtis an optionally substituted C1-4aliphatic group or optionally substituted aryl. Compounds, where Rg'submitted�is-S-R tcan optionally be oxidized, with the formation of compounds, where Rg'represents-S(O)Rtor-S(O)2Rt.

To obtain the compound of formula (Ia), where Rg'represents-O-Rswhen Rsis alkylsulfonyl, peralkaline or optionally substituted arylsulfonyl, Rgin the compound of formula (I) must first be converted into a hydroxyl group, with subsequent treatment of the corresponding sulphonylchloride or anhydride. The transformation of Rgin hydroxyl group can be carried out directly by the processing in the presence of base, such as NaOH, or, alternatively, from compounds of formula (Ia), where Rg'represents-OCH3that can hydrolyze to the corresponding alcohol by treatment with an aqueous NaOH or trimethylsilylpropyne with sodium iodide.

Substitution of Rg'in the compounds of formula (Ia) compound HNRnRocan be conveniently carried out in the presence of base such as an alkaline earth metal base or the base is an organic amine. Examples of suitable bases described above for stage (c). The base can be used in equimolar amounts, in excess or, if appropriate, as solvent for the reaction.

Substitution of Rg'in the compounds of formula (Ia) compounds�of HNR nRocan be conveniently carried out in the presence of a suitable solvent or diluent. Examples of suitable solvents described above for stage (c). In some embodiments, the substitution Rg'can be carried out without solvent or diluent, using excess amine HNRnRo.

Substitution of Rg'in the compounds of formula (Ia) compound HNRnRois preferably carried out at ambient temperature or at elevated temperatures of the reaction. Suitable temperatures and temperature ranges are as described above for stage (c).

Substitution of Rg'in the compounds of formula (Ia) compound HNRnRoyou can optionally carried out at elevated pressure reactions. Suitable pressures and ranges of pressures are as described above for stage (c).

In some embodiments, the substitution Rg'in the compounds of formula (Ia) compound HNRnRoyou can also hold in the presence of a palladium catalyst and/or ligand system. Appropriate systems metal catalysts are described in publications D. Prim et al. Tetrahedron, 2002, 58, 20412 and P. Gunda et al. Angew. Chem. Intl. Ed., 2004, 43, 6372. Suitable bases include, but are not limited to, tert-butoxide sodium, sodium carbonate, cesium and K3PO4. Suitable solvents�and include, but are not limited to, toluene, 1,4-dioxane, tert-butanol and mixtures thereof.

In some embodiments, when using a palladium catalyst and/or ligand, Rg'represents chloride, bromide, iodide, or triflic-O-Rswhere Rsrepresents an optionally substituted arylsulfonyl. In certain such embodiments, Rg'represents chloride, bromide or triflic.

In some embodiments, the method of the present invention additionally includes the stage:

(d) sulfanilamide of a compound of formula (V), where Rjrepresents hydrogen, with a compound of formula (VI) or its salt:

where:

stereochemistry at the position marked with asterisks are relative; and

each of the radicals Ra, Rb, Rc, Rd, Re, Re', Rf, Rh, Rh', Rk, Rm, Rnand Roin the formula (VI) is as defined in formula (V).

Compounds of the formula (VI), which are effective inhibitors of E1 activating enzymes, in particular, NAE, Langston reveals S. et al. in the patent application U.S. serial number 11/700614, which is incorporated herein by reference in its entirety, including all formulas and described�I all genera and subgenera, disclosed in the specified application.

If Rjin the compound of formula (V) is different from hydrogen, i.e. if Rjrepresents a protective group of hydroxyl, it must be deleted before the conversion to the compound of formula (VI). Stage of deprotection can be carried out by methods known to the person skilled in the art.

In some embodiments, the implementation stage of sulfanilamide (d) comprises the steps:

(I-A) treatment of the base in the solvent solution of RuNHS(O)2Cl, where Rurepresents hydrogen or acid labile protective group;

II-A) treatment of the reaction mixture formed in stage (I-A), a compound of formula (V); and

III-A) optional treatment of the reaction mixture formed in stage (II-A), acid.

Stage (d) (I-A), II-A and III-A) can be conveniently carried out in the presence of a suitable solvent or diluent, which may be the same or different for each of the stages (d) (I-A), II-A and III-A). Examples of suitable solvents include, but are not limited to, ethyl acetate, methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane, toluene, anisole, acetonitrile, N,N'-dimethylformamide, N,N'-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, and mixtures thereof. In some embodiments, each of d) (I-A), II-A) and HI (A) is carried out in a solvent containing ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, acetonitrile, N,N'-dimethylacetamide, N-methylpyrrolidinone, DME, or mixtures thereof.

Stage Foundation (d) (I-A) is a basis of an organic amine. Examples of organic bases amines include, but are not limited to, trialkylamine, pyridine and substituted pyridine. Examples of such substances include, but are not limited to, trimethylamine, triethylamine, triethylenediamine, pyridine, collidin, 2,6-lutidine, 4-dimethylaminopyridine, 2,6-di-tert-butylpyrazine, 2,6-di-tert-butyl-4-methylpyridine, 1-azabicyclo[2.2.2]octane, tributylamine, Tripropylamine, diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, sparteine and N,N'-diisopropylethylamine.

In some embodiments, at stage (d) (I-A) RuNHS(O)2Cl is added to the solvent at a speed sufficient to maintain the reaction temperature below about 15°C; and at the stage (d) (II-A), the reaction mixture is cooled, preferably to a temperature of from about -10°C and 0°C, and then adding the compound of formula (V) in pure form or in the form of a solution in a solvent.

In other embodiments, the implementation stage (d) (I-A) is carried out at ambient temperature and at the stage (d) (II-A), the reaction mixture is cooled, preferably to a temperature t�around -10°C and 0°C and then adding the compound of formula (V) in pure form or in the form of a solution in a solvent. In some embodiments, the implementation stage (d) (I-A) is carried out at ambient temperature and then adding the compound of formula (V) in pure form or in the form of a solution in a solvent at ambient temperature in stage (d) (II-A). In some embodiments, after addition of a compound of formula (V), the reaction mixture is allowed the opportunity to warm to ambient temperature.

In some other embodiments, the implementation stage of sulfanilamide (d) comprises the steps:

I-B) treatment of a compound of formula (V) base;

II-B) processing the reaction mixture formed in stage (I-B), a solution of RuNHS(O)2Cl, where Rurepresents hydrogen or acid labile protective group; and

III-B) optionally, treatment of the reaction mixture formed in stage (III-B), acid.

Stage (d) I-B, II-B and III-B) can be conveniently carried out in the presence of a suitable solvent or diluent, which may be the same or different for each of the stages (d) I-B, II-B and III-B). Examples of suitable solvents are as described above for stages d) (I-A), (II-A) and IH-A).

Stage Foundation (d) (I-B) is a strong base. Examples of strong bases include, but are not limited to, n-butyllithium, tert-butyllithium, diisopropylamide lithium, diisopropylamide potassium, hexamethyldisilazane lit�I, hexamethyldisilazane potassium, hexamethyldisilazane sodium and tert-butoxide potassium.

In the compounds of the formula RuNHS(O)2Cl, Rurepresents hydrogen or a protective group of the amine. In some embodiments, Rurepresents hydrogen. In other embodiments, Rurepresents an acid-labile protective group. In certain specific embodiments, Rurepresents-C(O)N(Ph)2. In other specific embodiments, Rurepresents-C(O)OC(Rv)2(Rw), where each Rvindependently selected from optionally substituted C1-10aliphatic group or optionally substituted aryl, and Rwis an optionally substituted C1-10aliphatic group or optionally substituted aryl. In some other specific embodiments, Rurepresents-C(O)OC(Rv)2(Rw), where each Rvindependently selected from hydrogen or optionally substituted C1-10aliphatic group, and Rwis an optionally substituted C1-10aliphatic group or optionally substituted aryl. In another group of embodiments, Rurepresents-C(O)OC(Rv)2(Rw) where Rv is an optionally substituted C1-10the aliphatic group and the other Rvtaken together with Rw, forms an optionally substituted C3-6cycloaliphatic ring.

In some embodiments, Rwis methyl or phenyl. In some embodiments, each Rvindependently is methyl, ethyl, butyl, hexyl, octyl or phenyl. In some other embodiments, each Rvindependently represents hydrogen, methyl or ethyl. In some other embodiments, one of Rvtaken together with Rwrepresents cyclopropyl or cyclohexyl. In preferred embodiments, Rurepresents-C(O)OCMe3, -C(O)OC(Me)2Ph, -C(O)OC(Et)2Ph or-C(O)OC(octyl)2Ph. In other preferred embodiments, Rurepresents-C(O)OCH2Ph or-C(O)OCH(Me)Ph. In another group of preferred embodiments Rurepresents C(O)OC(Me)2Et,

or

In certain preferred embodiments, Ruselected from the group consisting of-C(O)OCMe3, -C(O)OCH2Ph, -C(O)OCH(Me)Ph, C(O)OC(Me)2Et,

and

In some�x other embodiments, the implementation stage of sulfanilamide (d) comprises the steps:

I-C) treatment of a compound of formula (V) sulfanilimide reagent RuN--S(O)2X+and acid; and

II-C) optional treatment of the reaction mixture formed in stage (I-C), acid; where Ruhas the values and preferred values as described above.

In the compounds of the formula RuN--S(O)2X+X is a tertiary amine or a nitrogen-containing heteroaryl. In some embodiments, X is a tertiary amine. Examples of suitable tertiary amines include, but are not limited to, trimethylamine, triethylamine, triethylenediamine, diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, sparteine and N,N'-diisopropylethylamine. Other examples of suitable tertiary amines include, but are not limited to, tributylamine, 1-azabicyclo[2.2.2]octane, N,N'-dimethylpiperazine, N-ethylmorpholine and Tripropylamine.

In some other embodiments, X represents a nitrogen-containing heteroaryl. Examples of suitable nitrogen-containing heteroaryl include, but are not limited to, unsubstituted or substituted pyridine, unsubstituted or substituted imidazole and unsubstituted or substituted pyrrole.

In some other embodiments, X is a pyridine or substituted pyridine. Examples of pyridines Il� substituted pyridines include, but are not limited to, pyridine, collidin, 2,6-lutidine, 4-dimethylaminopyridine, 2,6-di-tert-butylpyrazine and 2,6-di-tert-butyl-4-methylpyridine.

In preferred embodiments, X is selected from the group consisting of triethylamine, triethylenediamine, 1-azabicyclo[2.2.2]octane, N,N'-dimethylpiperazine, N-ethylmorpholine and pyridine. In certain preferred embodiments, X is triethylenediamine.

Stage (d) I-C and II-C) can be conveniently carried out in the presence of a suitable solvent or diluent. Examples of suitable solvents are as described above for stages d) (I-A), H-A and III-A).

The acid used in stage (d) I-C) may be mineral or organic acid. Examples of mineral acids include, but are not limited to, hydrochloric acid, sulfuric acid, Hydrobromic acid, nitric acid and phosphoric acid. Examples of organic acids include, but are not limited to, acetic acid, propionic acid, isobutyric acid, benzoic acid, formic acid, oxalic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluensulfonate acid and triftormetilfullerenov acid.

In some embodiments, at stage (d) I-C) treatment is conducted at such a speed that�to keep the reaction temperature below than about 10°C. In some embodiments, at stage (d) I-C), the processing is carried out at ambient temperature. In some other embodiments, in stage (d) I-C) the reaction mixture was treated with additional portions sulfanilimide reagent and acid until then, until the reaction is complete. In some such embodiments, additional processing portions is carried out at room temperature. In other such embodiments, additional processing portions is carried out at reaction temperatures lower than about 10°C.

In some embodiments, the implementation stage of sulfanilamide (d) comprises the steps:

I-D) treatment of a compound of formula (V) sulfanilimide reagent RuN--S(O)2X+; and

II-D) optionally, treatment of the reaction mixture formed in stage (d) I-D), acid;

where Ruand X have the values and preferred values as described above.

In some embodiments, the processing at the stage (d) I-D) happens when a mixed compound of the formula (V) and the compound of the formula RuN--S(O)2X+and then add a suitable solvent or diluent. In some other embodiments, the processing at the stage (d) I-D) occurs when the compound of the formula RuN--S(O) X+added to the compound of formula (V) in a suitable solvent or diluent. In another group some other embodiments, the processing at the stage (d) I-D) occurs when the compound of formula (V) is added to the compound of the formula RuN--S(O)2X+in a suitable solvent or diluent.

Stage (d) I-D and II-D) can be conveniently carried out in the presence of a suitable solvent or diluent, which may be the same or different for each of the stages (d) I-D and II-D). Examples of suitable solvents are as described above for stages d) I-A, II-A and III-A). In some embodiments, the implementation stage (d) I-D and II-D) is carried out in a solvent containing acetonitrile, N,N'-dimethylacetamide, N,N'-dimethylformamide, N-methylpyrrolidinone, dimethylsulfoxide or mixtures thereof.

The processing at the stage (d) I-D) is preferably carried out at ambient temperature or at an elevated temperature reaction. The person skilled in the art can select a suitable reaction temperature and reaction time with regard to the applicable conditions of the reaction.

In some embodiments, the implementation stage (d) I-D) can be carried out at reaction temperatures not lower than about 0°C, 25°C or 40°C. In some embodiments, the implementation stage (d) I-D) can be carried out at reaction temperatures not higher than 55°C, 65°C �whether 95°C. Any range encompassing these high and low temperature reactions, is included in the scope of the present invention. Preferably, stage (d) I-D) is carried out at reaction temperatures in the range of from about 0°C to about 95°C, about 25°C to about 65°C or from about 40°C to about 55°C.

Preferably, the method of obtaining compounds of formula (VI) from a compound of formula (V), which includes stages (d) I-D and II-D, characterized by at least one of the following features:

(i) processing at the stage (d) I-D) is carried out in acetonitrile; and

(ii) processing at the stage (d) I-D) is carried out at a reaction temperature in the range of from about 40°C to about 55°C.

In some embodiments, the compound of the formula RuN--S(O)2X+formed in situ before the treatment stage (d) I-C) or in stage d) I-D).

In some other embodiments, the compound of the formula RuN--S(O)2X+allocate before using it on stage (d) I-C) or in stage d) I-D). In some such embodiments, the preparation of the compound of the formula RuN--S(O)2X+where Rurepresents-C(O)OC(Rv)2(Rw), comprising the following steps:

I-E) treatment with (Rw)(Rv)2C-OH chlorosulfonylisocyanate;

II-(E) treating the reaction mixture formed in stage (I-E), substance X; and

III-E) allocation sulfanilimide reagent RuN--S(O)2X+;

where Rv, Rwand X have the values and preferred values as described above.

Stage I-E), II-E and III-E) can be conveniently carried out in the presence of a suitable solvent or diluent. Examples of suitable solvents are as described above for stages d) I-A, II-A and III-A).

In some embodiments, at stage (I-E) chlorosulfonylisocyanate was added to a chilled solution (Rw)(Rv)2C-OH in a suitable solvent at such a speed as to keep the temperature below about 10°C. In some embodiments, at stage (I-E), (Rw)(Rv)2C-OH was added to a chilled solution chlorosulfonylisocyanate in a suitable solvent at such a speed as to keep the temperature below about 15°C. In some embodiments, the implementation in phase II-E), X is added to the reaction mixture formed in stage (I-E), with the speed to keep the temperature below about 15°C. In some embodiments, sulfanilimide the reagent is isolated by concentrating the reaction mixture. In some other embodiments, sulfanilimide the reagent is isolated by concentrating the reaction mixture of stage (III-E), followed by stirring mod�and in another solvent, to form a solid precipitate which can be isolated by filtration and dried. In some embodiments, sulfanilamide reagent allocate directly to stage III-E) by filtration from the reaction mixture of stage (II-E).

In some embodiments, the compound of the formula RuN--S(O)2X+isolated in the form of the complex, further comprising hydrochloride salt X. In some embodiments, the ratio of the compound of formula RuN--S(O)2X+to hydrochloride salt X in the complex is less than unity. In some other embodiments, the ratio of the compound of formula RuN--S(O)2X+to hydrochloride salt X in the complex is approximately one. In some other embodiments, the ratio of the compound of formula RuN--S(O)2X+to hydrochloride salt X in the complex is greater than one.

In some embodiments, when Rurepresents hydrogen, the compound of formula (VI) can be directly isolated and optionally purified after stage (d) (II-A) or stage (d) (II-B) by methods known to the person skilled in the art.

In other embodiments, when Rurepresents an acid-labile protective group, the reaction mixture is processed�Thibaut acid in stage (d) (III-A) or stage (d) (III-B) or stage (d) (II-C) or in stage d) (II-D). For use in the reaction of suitable mineral acids, Lewis acids and organic acids. Examples of mineral acids include, but are not limited to, hydrochloric acid, sulfuric acid, Hydrobromic acid, nitric acid and phosphoric acid. Examples of suitable Lewis acids include, but are not limited to, SnCl4, (CH3)3SiI, Mg(ClO4)2, BF3, ZnBr2Sn(OTf)2and Ti(OiPr)4. Examples of organic acids include, but are not limited to, acetic acid, propionic acid, benzoic acid, formic acid, oxalic acid, trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluensulfonate acid and triftormetilfullerenov acid.

In some other embodiments, when Rurepresents an acid-labile protective group, the compound is characterized by formula (VIa), where each of the radicals Ra, Rb, Rc, Rd, Re, Re', Rf, Rh, Rh', Rk, Rm, Rnand Roin the formula (VIa) is such as defined above in formula (VI) may be directly isolated and optionally purified after stage (d) (II-A) or stage (d) (II-B), or stage d) I-C), or stage d) I-D) by methods known to the person skilled in the art. Then connect the�their formula (VIa) in separate reactions treated with acid to remove the protective group, R uby applying the same reactions as described in this description for the stage (d) (III-A) or stage (d) (III-B) or stage (d) (II-C) or in stage d) (II-D), to obtain the compound of formula (VI). The person skilled in the art it will be obvious that in those cases where Ruin the compounds of formula (VIa) is an acid-labile protective group can be alternative conditions of deprotection, which will remove the group Ruto produce a compound of formula (VI):

In some embodiments, where Rurepresents an acid-labile protective group, after removal of acid-labile protective group by treatment with acid, the reaction mixture is neutralized in the final processing and the compound of formula (VI) is isolated in the form of the free base. In such embodiments, the compound of formula (VI) can be allocated in the form of a solid substance after post-processing by concentrating the solvent or diluent and treatment with methylene chloride, triptoreline or their mixture. The resulting solid may be removed by filtration. In some other embodiments, the compound of formula (VI) may be isolated as salts.

In some other embodiments, when Rurepresents a protective group of the amine, compound, product�risueno formula (VIa), where each of the radicals Ra, Rb, Rc, Rd, Re, Re', Rf, Rh, Rh', Rk, Rm, Rnand Roin the formula (VIa) is such as defined above in formula (VI) may be directly isolated and optionally purified after stage (d) (II-A) or stage (d) (II-B), or stage d) I-C), or stage d) I-D) by methods known to the person skilled in the art. Then the compound of formula (VIa) can be converted into a compound of formula (VI) by removing the protective group of the amine Ru, by methods known to those skilled in this field.

In relation to the compounds and methods described herein, is applicable to the following preferred values.

In formulas (I), (Ia), (II), (IIa), (IV), (V) and (VI) each of Rb, Rhand Rh'independently represents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group. In some embodiments, each of Rb, Rhand Rh'independently represents hydrogen, fluorine, methyl, ethyl or trifluoromethyl. In preferred embodiments, each of Rb, Rhand Rh'represents hydrogen.

In formulas (I), (Ia), (II), (IV), (V) and (VI) Rdrepresents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group. In some var�the ants implementation of R drepresents hydrogen, fluorine, methyl, ethyl or trifluoromethyl. In preferred embodiments, Rdrepresents hydrogen.

In the formula (IIa) Rd'represents hydrogen, fluorine, bromine, C1-4aliphatic group or a C1-4forlifetime group. In some embodiments, Rd'represents hydrogen, fluorine, methyl, ethyl or trifluoromethyl. In other embodiments, Rd'represents hydrogen or bromine. In some preferred embodiments, Rd'represents hydrogen. In some other preferred embodiments, Rd'represents bromine.

In formulas (I), (Ia), (II), (IV), (V) and (VI) each Rfindependently represents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group. In some embodiments, each Rfindependently represents hydrogen, fluorine, methyl, ethyl or trifluoromethyl. In preferred embodiments, each Rfrepresents hydrogen.

In formulas (I), (Ia), (II), (IIa), (IV), (V), (VI) each of Reand Re'independently represents hydrogen or C1-4aliphatic group. In some embodiments, each of Reand Re'independently represents hydrogen, methyl �whether ethyl. In preferred embodiments, each of Reand Re'represents hydrogen.

In formulas (I), (Ia), (III), (IV), (V) and (VI) Rkrepresents hydrogen or C1-4aliphatic group. In some embodiments, Rkrepresents hydrogen, methyl or ethyl. In preferred embodiments, Rkrepresents hydrogen.

In formulas (I), (Ia), (II), (IIa), (IV), (V) and (VI) Rcrepresents hydrogen, fluorine, chlorine, -OH, -ORmor optionally substituted C1-4aliphatic group. In some embodiments, Rcrepresents hydrogen, -OH, fluorine or methyl. In preferred embodiments, Rcrepresents hydrogen, -OH or-O-Rm. In more preferred embodiments, Rcrepresents hydrogen or-OH. In other more preferred embodiments, Rcrepresents hydrogen.

In formulas (I), (Ia), (II), (IIa), (IV), (V) and (VI), each Raand Rjindependently represents hydrogen or a protective group of hydroxyl, and Rmrepresents a protective group of hydroxyl. Rataken together with Rjand the intermediate atoms, may form a cyclic diol-protective group, or Rataken together with Rmand the intermediate atoms, can clicks�should be organized the cyclic diol-protective group, or Rjtaken together with Rmmay form a cyclic diol-protective group. Preferred values for the protective groups of hydroxyl and cyclic diol protective groups is given below.

In some embodiments, Rarepresents hydrogen. In some embodiments, Rjrepresents hydrogen. In certain specific embodiments, Raand Rjrepresent hydrogen.

In some embodiments, the protective hydroxyl group selected from the group consisting of a silyl protective group, an optionally substituted aliphatic group, -C(O)-Raaand-C(O)-O-Raawhere Raais an optionally substituted C1-4aliphatic group or optionally substituted aryl.

In some embodiments, the silyl protective group is selected from trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS) and tert-butyldiphenylsilyl (TBDPS). In some embodiments, optionally substituted C1-4aliphatic protective group selected from methoxymethyl, benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), diphenylmethyl (benzhydryl, DPM), etc. In some embodiments, the protective group-C(O)-Raachoose from AC�teel the formyl, pivaloyl, benzoyl, etc. In some embodiments, the protective group-C(O)-O-Raachoose from benzyloxycarbonyl (Cbz), methoxycarbonyl, tert-butoxycarbonyl (t-Boc), fluorenylmethoxycarbonyl (Fmoc), etc.

In some embodiments, the cyclic diol-protective group is a 1,2-cyclic diol-protective group. In some embodiments, the cyclic diol-protective group is a 1,3-cyclic diol-protective group. In some other embodiments, the cyclic diol-protective group is a-C(Raa)(Rbb)-, where Raais optionally substituted C1-4aliphatic group or optionally substituted aryl, and Rbbrepresents hydrogen or optionally substituted C1-4aliphatic group. In some preferred embodiments, Raarepresents hydrogen or methyl. In some preferred embodiments, Rbbis methyl, phenyl or 4-methoxyphenyl.

In formulas (I), (III) and (IV) Rgrepresents chlorine, fluorine, iodine or bromine. In some preferred embodiments, Rgrepresents a chlorine or fluorine. In certain preferred embodiments, Rgperformance�ulation of a chlorine.

In the formula (Ia) Rg'represents halogen, -O-Rs, -S-Rt, -S(O)Rtor-S(O)2Rt; where Rsrepresents C1-4aliphatic group, alkylsulfonyl, peralkaline optionally substituted aryl or optionally substituted arylsulfonyl, and Rtis an optionally substituted C1-4aliphatic group or optionally substituted aryl. In some embodiments, Rg'represents chlorine, fluorine, iodine, a methoxy group, an ethoxy group, a substituted or unsubstituted fenoxaprop, mesilate (OSO2CH3), tosylate (-OSO2C6H4CH3), triflic (OSO2CF3), and methyl-sulfonyl benzolsulfonat. In preferred embodiments, Rg'represents chlorine, fluorine, bromine, mesilate, tosylate or triflic.

In formulas (III) and (IV) Rlrepresents-CH2-CHO or-CH2CH(ORl')2where each Rl'independently represents C1-6aliphatic group, or two Rl'taken together with the intermediate atoms of oxygen and carbon, form an optionally substituted 5 - or 6-membered cyclic acutally fragment. In some embodiments, two Rl'taken together with the intermediate atoms of oxygen and carbon, form neobyazatelnostyu 5 - or 6-membered cyclic acutally fragment. In some such embodiments, two Rl'taken together with the intermediate atoms of oxygen and carbon, form an optionally substituted 1,3-dioxane or 1,3-DIOXOLANYL fragment. In some other embodiments, each Rl'independently represents C1-3aliphatic group. In certain specific embodiments, each Rl'is methyl or ethyl.

In amino formula HNRnRoand in the compounds of formulas (V) and (VI), Rnrepresents hydrogen or C1-4aliphatic group. In some embodiments, Rnrepresents hydrogen, methyl or ethyl. In preferred embodiments, Rnrepresents hydrogen.

In amino formula HNRnRoand in formulas (V) and (VI) Rois an optionally substituted C1-10the aliphatic group, aryl, heteroaryl or heterocyclic group. In some embodiments, Rois an optionally substituted C1-10aliphatic group. In some embodiments, Rorepresents an optionally substituted cycloaliphatic or heterocyclic ring. In other embodiments, Rorepresents an aryl or heteroaryl ring. At�nnyh embodiments, R orepresents a mono-, bi - or tricyclic ring system. In some other specific embodiments, Rorepresents a mono - or bicyclic ring system.

In some such embodiments, the ring represented by Roselected from the group consisting of furanyl, teinila, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazoline, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, naftel, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, indazole, benzimidazole, benzthiazole, benzothiazyl, benzofuranyl, purine, chinoline, izochinolina, cinnoline, phthalazine, hintline, chinoxalin, naphthyridine, pteridine, tetrahydrofuranyl, tetrahydrofuryl, pyrrolidinyl, pyrrolidinyl, piperidinyl, pyrrolidyl, tetrahydropyranyl, tetrahydroisoquinoline, decahydroquinoline, oxazolidinyl, piperazinyl, dioxane, dioxolane, diazepine, oxazepine, thiazepine, morpholinyl, hinokitiol, tetrahydroquinoline, tetrahydroisoquinoline, indlela, phenanthridine, tetrahydronaphthyl, indolinyl, benzodioxolyl, benzodioxolyl, Romania, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexene�La, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctene, cyclooctadiene, bicycloheptane and bicyclobutane. In certain embodiments, the ring represented by Rorepresents an optionally substituted indolyl, tetrahydronaphthyl or chromanol.

In such embodiments, the ring or the ring system, represented by Romay be optionally substituted on any of them ring component or on both of them, and the substituents may be the same or different. In particular, each capable of substituting unsaturated carbon in the ring is unsubstituted or substituted by 0-2 groups Rpand each capable of substitution on a saturated carbon in the ring is unsubstituted or substituted by 0-2 groups Rq. The radicals Rpand Rqhave the values described below.

Each Rpindependently selected from the group consisting of fluoro, -OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4y), or C1-4aliphatic group or a C1-4forlifetime group, an optionally substituted-OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4y).

Each Rqindependently selected from the group consisting of fluoro, -OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4y), or C1-4Ali�interactive group or C1-4forlifetime group, an optionally substituted-OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4y), provided that when two Rqattached to the same carbon atom, one of them must be selected from the group consisting of fluoro, -CO2R5x, -C(O)N(R4x)(R4y) and C1-4aliphatic group or a C1-4forlifetime group, an optionally substituted-OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4y); or two Rqat one and the same carbon atom together form =O or =C(R5x)2.

R4xrepresents hydrogen, C1-4alkyl, C1-4foralkyl or C6-10ar(C1-4)alkyl, the aryl portion of which may be optionally substituted, and R4yrepresents hydrogen, C1-4alkyl, C1-4foralkyl or C6-10ar(C1-4)alkyl, the aryl portion of which may be optionally substituted, or optionally substituted 5 - or 6-membered aryl, heteroaryl or heterocyclyl ring; or R4xand R4ytaken together with the nitrogen atom to which they are attached, form an optionally substituted 4-8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 heteroatom in the ring, independently selected from N, O, and S. Each R5xillegal�isimo represents hydrogen, C1-4alkyl, C1-4foralkyl or optionally substituted C6-10aryl or C6-10ar(C1-4)alkyl.

In some embodiments, in Aminah formula HNRnRoand in formulas (V), (VI), (VIa) and (VIb) ring or ring system, represented by Rorepresented by the formula (VII):

where the radicals Rpand Rqhave the meanings described above.

In some other embodiments, in Aminah formula HNRnRoand in formulas (V), (Va), (VI), (VIa), (VIb), (VIc) and (VId) ring or ring system, represented by Roselected from the group consisting of:

and

In certain specific embodiments, in Aminah formula HNRnRoand in formulas (V), (Va), (VI), (VIa), (VIb), (VIc) and (VId) ring or ring system, represented by Roselected from the group consisting of:

and

In a specific embodiment of the present invention relates to a method for producing the subgenus of compounds of formula (VI), characterized by formula (VIb):

or their pharmaceutically acceptable salts;

where:

stereochemistry at the position marked with asterisks are relative;

the radicals Ra, Rb, Rc, Rd, Rnand Rohave the values and preferred values described above for formulae (I) to(VII); and

which includes stages (a) to(d) as described above to obtain a compound of formula (VI). Preferred conditions for each of the stages (a) to(d) are as described above to obtain compounds of formulas (I) to(VI).

In another specific embodiment of the present invention relates to a method for producing the subgenus of compounds of formula (VI), characterized by formula (VIc):

or their pharmaceutically acceptable salts;

where:

stereochemistry at the position marked with asterisks are relative;

the radicals Ra, Rb, Rc, Rd, Rpand Rqhave the values and preferred values described above for formulae (I) to(VII); and

which includes stages a) to d) as described above to obtain a compound of formula (VI). Preferred conditions for each of the stages a) to d) are as described above to obtain compounds of formulas (I) to(VI).

In another specific embodiment of the present invention relates to a method for producing the subgenus of compounds of formula (VI), characterized by f�rmulas (VId):

or their pharmaceutically acceptable salts;

where:

stereochemistry at the position marked with asterisks are relative;

the radicals Ra, Rb, Rc, Rd, Re, Re', Rf, Rh, Rh', Rk, Rpand Rqhave the values and preferred values described above for formulae (I) to(VII); and

which includes stages a) to d) as described above to obtain a compound of formula (VI). Preferred conditions for each of the stages a) to d) are as described above to obtain compounds of formulas (I) to(VI).

Another aspect of the present invention relates to compounds, which are useful intermediate compounds in the manner described above, such as compounds of formula (Ia) and formula (IIa).

One variant of implementation relates to compounds of formula (Ia):

or salts thereof;

where the stereochemistry at the position marked with asterisks are absolute;

Rarepresents hydrogen or a protective group; or Rataken together with Rjand the intermediate atoms forms a cyclic diol-protective group; or Rataken together with Rmand the intermediate atoms forms a cyclic diol-protective group;

R brepresents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rcrepresents hydrogen, fluorine, chlorine, -OH, -O-Rmor optionally substituted C1-4aliphatic group;

Rdrepresents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rerepresents hydrogen or C1-4aliphatic group;

Re'represents hydrogen or C1-4aliphatic group;

each Rfindependently represents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rg'represents a leaving group;

Rhrepresents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rh'represents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rjrepresents hydrogen or a protective group of hydroxyl; or Rjtaken together with Raand the intermediate atoms forms a cyclic diol-protective group;

Rkrepresents hydrogen or C1-4aliphatic group; and

Rmrepresents a protective group of hydroxyl; or Rmtaken together with Raand premeiotic�bubbled atoms, forms a cyclic diol-protective group.

In some embodiments, the compound of formula (Ia) characterized by the formula (Iaa):

where the stereochemistry at the position marked with asterisks are absolute;

Rg'represents chlorine, bromine, fluorine, iodine, -O-Rs, -S-Rt, -S(O)Rtor-S(O)2Rt;

where Rsrepresents C1-4aliphatic group, alkylsulfonyl, peralkaline, optionally substituted aryl or optionally substituted arylsulfonyl; and

Rtis an optionally substituted C1-4aliphatic group or optionally substituted aryl.

In certain embodiments, the compound of formula (Ia) characterized by the formula (Iaa), where Rcrepresents hydrogen, -OH or-O-Rm;

Rarepresents hydrogen or a protective group of hydroxyl, selected from the group consisting of a silyl protective group, an optionally substituted aliphatic group, -C(O)-Raaand-C(O)-O-Raaor Rataken together with Rjand the intermediate atoms forms a cyclic diol-protective group- (C(Raa)(Rbb)-; or Rataken together with Rmand the intermediate atoms forms a cyclic diol-protective group�y-C(R aa)(Rbb)-;

Rjrepresents hydrogen or a protective group of hydroxyl, selected the group consisting of silyl protective group, an optionally substituted aliphatic group, -C(O)-Raaand-C(O)-O-Raa; or Rjtaken together with Raand the intermediate atoms forms a cyclic diol-protective group- (C(Raa)(Rbb)-;

Rmrepresents a protective group of hydroxyl, selected from the group consisting of a silyl protective group, an optionally substituted aliphatic group, -C(O)-Raaand-C(O)-O-Raa; or Rmtaken together with Raand the intermediate atoms forms a cyclic diol-protective group- (C(Raa)(Rbb)-;

Raais an optionally substituted C1-4aliphatic group or optionally substituted aryl; and

Rbbrepresents hydrogen or optionally substituted C1-4aliphatic group.

In certain other preferred embodiments, the compound of formula (Ia) characterized by the formula (Iaa), and the values and preferred values for Ra, Rj, Rm, Rcand Rg'are as described above.

Another aspect of the present invention relates to compounds of formula (IIa):

or salts thereof;

where

stereochemistry at the position marked with asterisks are absolute;

Rarepresents hydrogen or a protective group; or Rataken together with Rjand the intermediate atoms forms a cyclic diol-protective group; or Rataken together with Rmand the intermediate atoms forms a cyclic diol-protective group;

Rbrepresents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rcrepresents hydrogen, fluorine, chlorine, -OH, -ORmor optionally substituted C1-4aliphatic group;

Rd'represents hydrogen, fluorine, bromine, C1-4aliphatic group or a C1-4forlifetime group;

Rerepresents hydrogen or C1-4aliphatic group;

Re'represents hydrogen or C1-4aliphatic group;

Rhrepresents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rh'represents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;

Rjrepresents hydrogen or a protective group of hydroxyl; or Rjtaken together with Raand the intermediate atoms, form a cyclic Dialin�Yoo protective group;

Rmrepresents a protective group of hydroxyl; or Rmtaken together with Raand intermediate carbon atoms forms a cyclic diol-protective group; and

Rrrepresents hydrogen or a protective group of the amine.

In some embodiments, the compound of formula (IIa) is characterized by formula (IIaa):

where the stereochemistry at the position marked with asterisks are absolute; and

Rcrepresents hydrogen, -OH or-O-Rm;

Rarepresents hydrogen or a protective group of hydroxyl, selected from the group consisting of a silyl protective group, an optionally substituted aliphatic group, -C(O)-Raaand-C(O)-O-Raaor Rataken together with Rjand the intermediate atoms forms a cyclic diol-protective group- (C(Raa)(Rbb)-; or Rataken together with Rmand the intermediate atoms forms a cyclic diol-protective group- (C(Raa)(Rbb)-;

Rjrepresents hydrogen or a protective group of hydroxyl, selected from the group consisting of a silyl protective group, an optionally substituted aliphatic group, -C(O)-Raaand-C(O)-O-Raa; or Rjtaken together with Raand the intermediate atoms, form a C�Klionsky diol-protective group- (C(R aa)(Rbb)-;

Rmrepresents a protective group of hydroxyl, selected from the group consisting of a silyl protective group, an optionally substituted aliphatic group, -C(O)-Raaand-C(O)-O-Raa; or Rmtaken together with Raand the intermediate atoms forms a cyclic diol-protective group- (C(Raa)(Rbb)-;

Raais an optionally substituted C1-4aliphatic group or optionally substituted aryl;

Rbbrepresents hydrogen or optionally substituted C1-4aliphatic group; and

Rrrepresents hydrogen or a protective group of the amine.

In some other embodiments, the compound of formula (IIa) is characterized by formula (IIbb):

where the stereochemistry at the position marked with asterisks are absolute; and

Rd'represents bromine;

Rarepresents hydrogen or a protective group of hydroxyl, selected from the group consisting of a silyl protective group, an optionally substituted aliphatic group, -C(O)-Raaand-C(O)-O-Rbbor Rataken together with Rjand the intermediate atoms forms a cyclic diol-protective group- (C(Raa)(Rbb)-; or Rataken together with Rm and the intermediate atoms forms a cyclic diol-protective group- (C(Raa)(Rbb)-;

Rjrepresents hydrogen or a protective group of hydroxyl, selected from the group consisting of a silyl protective group, an optionally substituted aliphatic group, -C(O)-Raaand-C(O)-O-Raa; or Rjtaken together with Raand the intermediate atoms forms a cyclic diol-protective group- (C(Raa)(Rbb)-;

Rmrepresents a protective group of hydroxyl, selected from the group consisting of a silyl protective group, an optionally substituted aliphatic group, -C(O)-Raaand-C(O)-O-Raa; or Rmtaken together with Raand the intermediate atoms forms a cyclic diol-protective group- (C(Raa)(Rbb)-;

Raais an optionally substituted C1-4aliphatic group or optionally substituted aryl;

Rbbrepresents hydrogen or optionally substituted C1-4aliphatic group; and

Rrrepresents hydrogen or a protective group of the amine.

In certain preferred embodiments, the compound of formula (IIa) is characterized by formula (IIaa) or (IIbb), and the values and preferred values for Ra, Rj, Rm, Rcand Rd'are to�described above.

In formulas (IIa), (IIaa) and (IIbb) Rrrepresents hydrogen or a protective group of the amine. In some embodiments, Rrrepresents hydrogen. In other embodiments, Rrrepresents a protective group of an amine selected from-C(O)Rcc, -C(O)-ORcc, -CH2Rccand-C(Rcc)3where Rccis an optionally substituted C1-4aliphatic group or optionally substituted aryl. In preferred embodiments, Rrrepresents hydrogen, benzyl, 4-methoxybenzyl, tert-butoxycarbonyl, triphenylmethyl or (4-methoxyphenyl)diphenylmethyl. In certain preferred embodiments, Rrrepresents a tert-butoxycarbonyl or triphenylmethyl.

In specific embodiments, the present invention relates to a compound selected from the group consisting of:

and;

where the stereochemistry at the position marked with asterisks are absolute; and

Rrrepresents-C(O)Rcc, -C(O)-ORcc, -CH2Rccor-C(Rcc)3where Rccis an optionally substituted C1-4aliphatic group or optionally substituted aryl.

In some embodiments, the compound of formula (IIa) has diastereoisomeric purity of at least 80%, 90%, 95% or 99%. In some other embodiments, the compound of formula (IIa) has an enantiomeric purity of at least 80%, 90%, 95% or 99%.

In some embodiments, the stereochemical configuration at the position marked with asterisks in any of the preceding claims, are relative. In other embodiments, the stereochemical configuration at the position marked with asterisks are absolute. In certain specific embodiments, the present invention relates to compounds of formula, where the stereochemistry at the position marked with asterisks are absolute.

General synthesis technique

Compounds of formula (II), (IIa), (III) and RuNHS(O)2Cl can be obtained by methods known to the person skilled in the art and/or by reference to the schemes shown below and the following examples of synthesis. Specific ways of synthesis described below in schemes 1, 2 and 3, and in the examples.

Scheme 1: General way of synthesis of (1S,2S,4R)-4-amino-2-hydroxymethyl)Cyclopentanol

Schemes 1 and 2 show the General ways of obtaining the compounds of formula (IIa), where each of Rb, Rd, Re, Re' , Rhand Rh'represents hydrogen. Specialists in this field will be clear that the compounds of the formula (IIa), where one or more of Rb, Rd, Re, Re', Rhand Rh'is different from hydrogen, can also be obtained in a similar way, based on the corresponding starting compounds, similar to the substance i.

The lactams, such as (-)-i, are commercially available, and the conversion of a compound of formula i into compounds of the formula iii is carried out by the methods specified in detail in scheme 1 (see Smith et al. Tetrahedron. Lett., 2001, 41, 1347). Treatment of the lactam i thionylchloride in methanol gives compound ii, which then protect with suitable protective group of the amine Rrto produce a compound of formula iii (method A). Alternatively, it is possible first to carry out protection of the amino group with subsequent acid catalyzed ring opening by means of a suitable acid, such as hydrochloric acid in methanol, yielding the compound of formula iii (method B; see Bray et al. Tetrahedron Lett., 1995, 36, 4483). Compounds of formula iii also serve as the starting material in an alternative General synthesis of compounds of formula (IIa), as detailed below in scheme 2.

It is mediated by base hydrolysis of the ester in compounds of formula iii by epimerization leads to the compound of formula iv. Such converted�e can be performed using an appropriate base, such as sodium hydroxide, in an appropriate solvent, such as tetrahydrofuran and methanol (method C). Bromination and lactonization with obtaining the compounds of formula v (method D) can be carried out by treatment of compounds of formula iv hydroxide of tetrabutylammonium, followed by treatment with bromine in an appropriate solvent, such as methylene chloride or tetrahydrofuran. Before treatment with bromine the reaction mixture was cooled to the appropriate temperature in the range of from about 0°C to -70°C. the Reaction mixture was kept at a temperature lower than about 20°C during the reaction. Other reagents that can be used instead of the hydroxide of tetrabutylammonium prior to the addition of bromine include, but are not limited to, sodium bicarbonate, potassium phosphate, pyridine, or mixtures thereof. Other suitable solvents for this transformation include, but are not limited to, ethyl acetate, methanol, water, dimethoxyethane or mixtures thereof.

The restoration of the lactone in the compounds of formula v with a reducing agent provides a compound of formula vi (method E). Suitable reducing agents for this transformation include tetrahydroborate lithium. Appropriate solvents for this transformation include tetrahydrofuran, diethyl ether, etc. Before adding the reducing agent to the Sol�R compounds of the formula v is usually cooled, preferably, to a temperature in the range of from about -20°C to 0°C. in Addition tetrahydroborate lithium you can use the second reagent, such as, but not limited to, copper chloride or palladium chloride. Other reagents suitable for converting compounds of the formula v into compounds of formula vi include alumoweld lithium, diisobutylaluminium and sodium borohydride. Other solvents suitable for this transformation include isopropanol, methanol and dimethylsulfoxide, which may contain up to about 10% water. Other temperature ranges appropriate for this conversion are in the range of from about 0°C to about 40°C.

The removal of the protective group, Rrand debromination in the compounds of formula vi (method F) then give the compound vii. Such conversion can be accomplished in several ways known to the person skilled in the art, depending on the protective group, Rr. In some embodiments, Rris a hydrogen-labile protective group. In such embodiments, removing protection and debromination is carried out in one stage. This stage can include treatment with hydrogen gas in the presence of a palladium catalyst in an appropriate solvent, such as methanol. Such transformations give compounds�Oia formula vii in the form of their hydrobromide salts. In other embodiments, the removal of the protective group, Rrand debromination can be carried out in separate stages. In some embodiments, may be formed hydrochloride salt of a compound of formula vii.

When the protective group, Rris acid-labile, after its removal under the action of HBr or HCl formed hydrobromide or hydrochloride salt of a compound of formula vi, where Rrrepresents N. The resulting compound is then treated with hydrogen for the implementation of debromination and obtaining the compound of formula vii. The debromination can be performed using a suitable palladium catalyst, a suitable base and a suitable solvent. Suitable catalysts include Pd/C. Suitable bases include, but are not limited to, triethylamine, N,N'-diisopropylethylamine, pyridine, hydroxide of tetrabutylammonium and sodium bicarbonate. Suitable solvents include, but are not limited to, isopropyl alcohol and methanol.

Scheme 2: Alternative common way of synthesis of (1S,2S,4R)-4-amino-2-hydroxymethyl)Cyclopentanol

Scheme 2 presents the details of an alternative total way of synthesis of compounds of the General formula (IIa), where each of Rb, Rd, Re, Re', Rh and R represents hydrogen. The starting material iii can be obtained, as described above in scheme 1. The conversion of compounds of formula iii into compounds of formula viii can be realized by processing diazabicyclo[5.4.0]undec-7-ene (method G) in an appropriate solvent, such as methylene chloride (see Bray et al. Tetrahedron Lett., 1995, 36, 4483).

The reduction of the ester group in compounds of formula viii, to obtain compounds of the formula ix, conduct an appropriate reducing agent, such as diisobutylaluminium or the like in an appropriate solvent, such as toluene or tetrahydrofuran (method H). Before adding the reducing agent solution of compounds of the formula viii is cooled, preferably to a temperature in the range of from about -20°C to about 0°C.

Epoxidation of the double bond in compounds of the formula ix to produce a compound of formula x, reach by known methods (method J) (see Gao et al. J. Am. Chem. Soc., 1987, 5765). A solution of a compound of formula ix is slowly added to the cooled mixture of (+)-diethyl-1-tartrate and isopropoxide titanium (IV) in methylene chloride. Choose the speed of adding compounds of the formula ix, the reaction temperature is maintained in the range of from about -25°C to about -45°C. tert-butylhydroperoxide is added slowly to the reaction temperature supports� in the range of from about -25°C to about -45°C.

Regiospecifically ring-opening of epoxide in the compounds of formula x, to obtain compounds of formula xi can be carried out by treatment of a solution of compounds of the formula x with sodium borohydride and borane-THF (see Brown and Yoon J. Am. Chem. Soc, 1968, 90, 2686) in an appropriate solvent, such as methylene chloride (method K).

The reaction of formation of a compound of formula xi can also lead to the formation of a certain number of compounds of the formula xii as a by-product. The primary alcohol in compounds of formula xi can be selectively protected with bulky protective group (Rj), such as triisopropylsilyl or tert-butyldiphenylsilyl, to obtain compounds of the formula xiii, which can be separated from compounds of formula xii purification methods known to the person skilled in the art, such as column chromatography. The introduction of a silyl protective group can be carried out by known methods, such as processing corresponding similiarites in the presence of base, such as triethylamine or N,N'-diisopropylethylamine, in a solvent such as methylene chloride (method L).

After cleaning silyl protective group can be selectively removed from compounds of formula xiii for the compounds of formula xiv. This conversion can be carried out by treating a cooled solution �of soedinenii formula xiii with a solution of tetrabutylammonium (TBAF) in an appropriate solvent, such as tetrahydrofuran (method M).

The removal of the protective group, Rrgives the compound of formula vii (method F). This conversion can be performed in several ways known to the person skilled in the art, depending upon the protective group, Rr. For example, in some embodiments, the protective group Rrsubjected to hydrogenolysis and unprotection can be accomplished by treatment with gaseous hydrogen in the presence of palladium catalyst (method F) in an appropriate solvent, such as methanol. In some other embodiments, the protective group Rris acid-labile, and unprotection can be accomplished by acid.

Any hydroxyl group or both hydroxy groups in the compounds of formulae vi, vii or xiv in schemes 1 or 2 can be protected with protective groups of the hydroxyl, or cyclic diol-protective group using methods known to the person skilled in the art.

Compounds of the formula (III) can be obtained according to such methods, as described by J. A. Montgomery and K. Hewson, J. Med. Chem., 1967, 10, 665.

Figure 3: a Common way of synthesis of substituted (chlorosulfonyl)carbamates RuNHS(O)2Cl

Scheme 3 shows a General route for obtaining compounds of formula RuNHS(O)2Cl, where Ruthe performance�t a-C(O)OC(R v)2(Rw), and Rwrepresents phenyl. Specialists in this field will be clear that the compounds of the formula RuNHS(O)2Cl, where Rwis different from phenyl, can also be obtained similarly, based on the appropriate source of a substance analogous compound xv.

Proceeding from commercially available methylbenzoate xv, treatment with Grignard reagent RvMgCl in a suitable solvent, such as tetrahydrofuran, gives the compound of formula xvi (method N). A solution of compounds of the formula xv is cooled to about 0°C before the addition of the Grignard reagent, which is added at a rate sufficient to maintain the temperature of the reaction mixture is lower than about 10°C. a Solution of xvi was then added to a chilled solution chlorosulfonylisocyanate in an appropriate solvent, such as tetrahydrofuran, yielding the compound of formula xvii. The addition of a solution of compounds of the formula xvi is carried out at a speed sufficient to maintain the temperature of the reaction mixture is lower than about 10°C (method O). The resulting substituted (chlorosulfonyl)carbamate reagent xvii then stored until use in the form of a solution in an appropriate solvent, such as tetrahydrofuran.

The compound of the formula RuNHS(O)2Cl, where Rurepresents-C(O)OC(CH3) , can be obtained according to the methods as described by Hirayama et al. in Bioorg. Med. Chem., 2002, 10, 1509-1523. The compound of the formula RuNHS(O)2Cl, where Rurepresents-C(O)N(Ph)2, can be obtained by a method similar to that described in published patent application U.S. (2005), US 2005282797 A1.

Amines used in example 18 can be obtained by methods disclosed in S. Langston et al. in a patent application in the USA under serial number 11/700614, which in its entirety is included in this description by reference.

For a more complete understanding of the present invention represented by the following preparative examples and examples of tests. These examples illustrate how to obtain or to test specific compounds, and they should not be construed as restricting any way the scope of the present invention.

Examples

liquid chromatography with reversed phase and mass spectrometry
Reduction
AcOHacetic acid
BINAP2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
Boctert-butoxycarbonyl
DCMmethylene chloride
DI deionised
DMAP4-dimethylaminopyridine
DMFAdimethylformamide
DMF-DMAdimethylformamide-dimethylacetal
DMSOdimethyl sulfoxide
EtOActhe ethyl acetate
EtOHethanol
iPrOAcisopropylacetate
MCPBAmeta chloroperbenzoic acid
MeOHmethanol
MTBEmethyl tert-butyl ether
THFtetrahydrofuran
hwatch
HRMSthe mass spectrum of high resolution
minminutes
m/zthe mass-to-charge
MSthe mass spectrum
OF LC-MS
TLCthin-layer chromatography

The spectra of proton nuclear magnetic resonance was obtained on spectrometer Varian Mercury 300 at 300 MHz on a Bruker AVANCE 300 at 300 MHz or on a Bruker AVANCE 500 at 500 MHz.

Conditions JHMS: spectra were obtained using column Phenomenex Luna 5 μm C18(2) 150×4.6 mm, Agilent 1100 series, with 1 ml/min for 20-minute expiration, using the following gradients:

Technique with formic acid (FA): Mobile phase A, consisting of 99% V/V water, 1% V/V acetonitrile and 0.1% V/V formic acid. Mobile phase B consisting of 95% V/V acetonitrile, 5% V/V water, with 0.1% V/V formic acid. The methodology follows the gradient from 5% B to 100% B over 12 minutes, maintaining 100% phase B for 3 minutes, returning to 5% phase B for 1 minute, and supporting such a composition before the end of expiration.

Method ammonium acetate (AA): Mobile phase A, consisting of 100% water (10 mm ammonium acetate, pH 4.5). Mobile phase B consisting of 95% V/V acetonitrile, 5% V/V water (10 mm ammonium acetate, pH 4.5). The methodology follows the gradient from 5% B to 100% B over 12 minutes, maintaining at 100% phase B for 3 minutes, returning to 5% phase B for 1 minute, maintaining 5% B until the end of expiration.

Thin�layer chromatography (TLC) was performed, using plate EMD silica gel 60, visualized by ultraviolet (UV) light.

The HPLC analyses were performed on column (Phenomenex Luna 5 μm C18(2) 150×4.6 mm, Agilent 1100 series at 1.0 ml/min for the 30 minute expiry using the following gradients:

Technique with ammonium acetate (AA2): Mobile phase A, consisting of 100% water (10 mm ammonium acetate, pH 4.5). Mobile phase B consisting of 95% V/V acetonitrile, 5% V/V water (10 mm ammonium acetate, pH 4.5). The methodology follows the gradient from 30% phase B to 70% phase B over 12 minutes, from 70% phase B to 100% phase B for 5 minutes, maintaining at 100% phase B for 3 minutes, returning to 30% phase B over 5 minutes, maintaining the 30% phase B before the end of expiration.

Example 1: the Hydrochloride of methyl-(1S,4R)-4-aminocyclopent-2-ene-1-carboxylate

(-)-2-Azabicyclo[2.2.1]hept-5-ene-3-one (20,00 g, 0,1833 mmol) was dissolved in MeOH (140 ml) and the resulting mixture was cooled to 0°C. Then was added dropwise thionylchloride (29.4 ml, 0,403 mol), maintaining the temperature below 15°C. After complete addition the mixture was allowed to stir at 5°C for 2 hours. The solvent was removed under reduced pressure, obtaining oil, which is then dried in a high vacuum over night at 35°C, obtaining specified in the title compound as a white solid (33 g) which was used without further purification.

1H NMR (300 MHz, DMSO, δ): to 8.45 (s, 3H), 6,03 (m, 1H), 5,87 (m, 1H), 4,13 (m, 1H), 3,60 (m, 4H), 2,53 (m, 1H) and 1.89 (m, 1H).

Example 2: Methyl(1S,4R)-4-(trailmen)cyclopent-2-ene-1-carboxylate

Hydrochloride methyl-(1S,4R)-4-aminocyclopent-2-ene-1-carboxylate (5,50 g) was suspended in methylene chloride (60 ml), to which was added triphenylmethylchloride (9,06 g, 0,0325 mol). Then the mixture was cooled to 0°C. Then was added dropwise triethylamine (10.8 ml, 0,0774 mol), maintaining the temperature below 10°C. After complete addition the mixture was allowed to warm to 20-25°C. the Mixture was allowed to stir at 20-25°C for 17 hours. Then the mixture was washed with water (3×50 ml). The washings were combined and extracted with DCM (50 ml). The organic solutions were combined, washed with saturated brine (20 ml) and the solvent was removed under reduced pressure, obtaining specified in the title compound as brown oil (12.5 g) which was used without further purification.

1H NMR (300 MHz, CDCl3, δ): 7,58 (m, 6H), 7,27 (m, 6H), 7,18 (m, 3H), to 5.57 (m, 1H), is 4.93 (m, 1H), 3,76 (m, 1H), 3,65 (s, 3H), 3,18 (m, 1H), 2,11 (m, 1H), 1,90 (m, 1H) and 1.53 (m, 1H).

Example 3: (1R,4R)-4-(trailmen)cyclopent-2-ene-1-carboxylic acid

Methyl (1S,4R)-4-(trailmen)cyclopent-2-ene-1-carboxylate (11,00 g, 0,02868 mol) was dissolved in tetrahydrofuran (50 ml) and methanol (50 ml). Was added sodium hydroxide (of 2.06 g, 0,0516 mol) in water (60 ml) and the mixture stirred at ambient �Reda for 18 hours. TLC (20% EtOAc/hexane) showed no starting materials. When ambient temperature was added dropwise a 20% (weight/volume) citric acid in water until the pH of the mixture was equal to 6. Then the mixture was extracted with methylene chloride (3×100 ml). The organic layers were combined and dried over Na2SO4, filtered and concentrated, yielding a white foam (10 g). TLC (50% EtOAc/hexane) showed 2 of diastereoisomer. The mixture was purified by column chromatography with the elution with a mixture of 50% EtOAc/hexane, obtaining specified in the title compound (1.3 g) as a white solid.

1H NMR (300 MHz, DMSO, δ): 7,47 (m, 6H), 7,30 (m, 6H), 7,17 (m, 3H), 5,49 (m, 1H), of 4.88 (m, 1H), 3,70 (m, 1H), 3,35 (m, 1H), of 1.84 (m, 1H) and 1.43 (m, 1H). JHMS: Rf=12,95 min, ES+=370 (AA).

Example 4: (1R,3R,4R,5R)-4-bromo-3-(trailmen)-6-oxabicyclo[3.2.0]heptane-7-he

To (1R,4R)-4-(trailmen)cyclopent-2-ene-1-carboxylic acid (0.9 g, 0,0024360 mol) dissolved in methylene chloride (20 ml) was added 31% hydroxide of tetrabutylammonium in MeOH (2,579 ml) and the mixture was stirred for 30 minutes at ambient temperature. The mixture was concentrated under reduced pressure. Then the obtained residue was dissolved in methylene chloride (20 ml, 0.3 mole) and cooled to -70°C in an atmosphere of N2. Then was added dropwise bromine (251 μl, 0,00487 mol) in 5 ml of methylene chloride and the mixture was stirred at -70°C for 1 hour, then was warmed to 0°C After reaching 0°C was added dropwise 20 ml of a 5% (weight/volume) Na 2SO3in water and the mixture was allowed to warm to ambient temperature. The reaction mixture was extracted with methylene chloride (3×10 ml), organic layers were combined and dried over Na2SO4, filtered and concentrated, obtaining a red residue. The resulting residue was filtered through a loose layer of silica gel, elwira 0-30% mixture of EtOAc/hexane, to remove inorganic substances and contaminants, receiving specified in the title compound (0.73 g) as a white solid.

1H NMR (300 MHz, DMSO, δ): 7,49 (m, 6H), 7,24 (m, 9H), 4.95 points (d, 1H), of 3.91 (m, 1H), 3,65 (m, 1H), 2,97 (m, 1H), 2,66 (m, 1H), 1,62 (m, 1H) and 1.20 (m, 1H). JHMS: Rf=14,40 min, ES+Na=470 (AA).

Example 5: (1R,2R,3R,5S)-2-bromo-5-(gidroximetil)-3-(trailmen)Cyclopentanol

(1R,3R,4R,5R)-4-bromo-3-(trailmen)-6-oxabicyclo[3.2.0]heptane-7-he (0.6 g, 0,0013382 mol) was dissolved in diethyl ether (20 ml) and the mixture was cooled to 0°C. Tetrahydroborate lithium (0,087 g, 0,004015 mol) was added in one portion and the mixture was stirred at 0°C for 1 hour, and then gave her the opportunity to warm to ambient temperature and stirred for another 1 hour. TLC (20% mixture of EtOAc/hexane) showed no starting materials. The reaction mixture was cooled to 0°C, then was added dropwise a saturated aqueous NH4Cl (20 ml), keeping the temperature below 5°C. the Mixture was allowed to warm to a temperature of�s environment and was extracted with methylene chloride (3×20 ml). The organic solutions were combined and dried over Na2SO4, filtered and concentrated, obtaining specified in the header connection (0,61 g) as a white solid which was used without further purification.

1H NMR (300 MHz, CD3OD, δ): 7,56 (m, 6H), 7,25 (m, 9H), 4,15 (m, 1H), 3,55 (m, 1H), 3,40 (m, 2H), 2,90 (m, 1H), 2,53 (m, 1H), and 1.63 (m, 2H). JHMS: Rf=13,30 min, ES+Na=474 (AA).

Example 6: (1S,2S,4R)-4-amino-2-(gidroximetil)Cyclopentanol∙HBr

(1R,2R,3R,5S)-2-bromo-5-(gidroximetil)-3-(trailmen)Cyclopentanol (0.4 g, 0,0008842 mol) was dissolved in MeOH (10.0 ml). To this mixture was added 5% palladium on carbon (0.28 g). The resulting mixture was stirred in hydrogen atmosphere (1000 ml, 0.04 mole) for 18 hours at 40°C. an Aliquot was filtered into the syringe and concentrated.1H NMR showed that the reaction was completed, so the whole reaction mixture was filtered through a layer of celite and the filtrate concentrated. The obtained sticky solid was triturated with 5 ml THF, filtered and the remaining layer was washed with tert-butylmethylamine ether. The resulting solid was dried in vacuo at ambient temperature, receiving specified in the title compound (0.125 g) as a white solid which was used without further purification.

1H NMR (300 MHz, CD3OD, δ): 4,38 (t, J=4,08 Hz, 1H), 3,82 (m, 1H), and 3.72 (m, 1H), 3,60 (m, 1H), 2,31 (m, 1H), 2,22 (m, H), 2,03 (m, 1H) and 1,78 (m, 2H).

Example 7: Methyl(4S)-4-(trailmen)cyclopent-1-ene-1-carboxylate

To the reactor was loaded a solution of methyl(1S,4R)-4-(trailmen)cyclopent-2-ene-1-carboxylate (4,75 kg, 12.4 mol) in methylene chloride. The same reactor was loaded with additional methylene chloride (15 l), bringing the total to 23.8 L. To a stirred solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4,82 l, of 32.2 mol). The reaction mixture was heated to 40°C with stirring for 16 to 22 h. Analysis of a small sample of the reaction mixture, is accomplished by means of1H NMR (CDCl3), confirmed the formation of product. The reaction mixture was washed with 10% aqueous citric acid solution (2×7 l). The organic phase was concentrated under reduced pressure, obtaining specified in the title compound as an oil. The resulting oil was diluted with anhydrous toluene and concentrated to remove residual water and was used without further purification.

1H NMR (300 MHz, CDCl3δ): 7,60-7,54 (m, 5H), 7,34-7,17 (m, 10H), a 6.53-6,50 (m, 1H), 3,70 (s, 3H), 3,50 is 3.40 (m, 1H), 2,60-to 2.52 (DD, J=16,6, 8,3 Hz, 1H), 2,24-of 2.20 (m, 1H), 2,16-of 2.05 (m, 1H) and 1.91-1,80 (m, 1H).

Example 8: [(4S)-4-(trailmen)cyclopent-1-Yong-1-yl]methanol

To the reactor was loaded methyl-(4S)-4-(trailmen)cyclopent-1-ene-1-carboxylate (4,75 kg, 12.4 mol). The same reactor was loaded with anhydrous toluene (9.5 liters), cooled to a temperature of from -5 to -10°C and started stirring�. While maintaining a temperature of from -10°C to +10°C, was added diisobutylaluminium (1M solution in toluene, 23.4 kg, and 27.3 mol). After completion of the addition, the reaction mixture was analyzed by HPLC, which confirmed complete conversion of the starting materials in the product. The reaction mixture was quenched with cold 2n NaOH solution (-5 to -10°C) at a speed necessary to maintain the internal temperature below 20°C. the Organic phase was separated and was filtered through a layer of diatomaceous earth. This layer was washed with toluene (2×1 l) and the filtrate was concentrated under reduced pressure, obtaining specified in the title compound as a thick oil (5.15 kg). The product was diluted with methylene chloride and kept in solution at 0-5°C.

1H NMR (300 MHz, CDCl3, δ): 7,60-7,56 (m, 5H), 7,35-7,17 (m, 10H), 5,38 (SHS, 1H), 4,03-was 4.02 (d, J=3.7 Hz, 2H), 3,49-3,36 (m, 1H), 2,40 (s, 2H), 2,19-to 1.79 (m, 4H), 1,32-of 1.29 (t, J=5.8 Hz, 1H).

Example 9: [(1S,3S,5S)-3-(trailmen)-6-oxabicyclo[3.1.0]hex-1-yl]methanol

To the reactor was loaded with (+)-diethyl-L-tartrate (2,23 l, of 13.0 mol) and methylene chloride (10.5 l). Started stirring, and the mixture was cooled to a temperature of from -30 to -40°C. was Slowly added isopropoxide titanium (IV) (3,93 l, 13.4 moles), keeping the internal temperature between -30 to -40°C. To the reaction mixture was slowly added a solution of [(4S)-4-(trailmen)cyclopent-1-EN-1-yl]methanol (4.2 kg, of 11.8 mol) in methylene chloride (19 l), maintaining the temperature from -0 to -40°C. After stirring for 20 minutes was slowly added tert-butylhydroperoxide (5-6M in decane, 3,3 l, 16.3 mol), maintaining the temperature between -30 to -40°C. After complete addition the reaction mixture was analyzed by HPLC, which confirmed the formation of product and the presence of 3% (AUC) of the original substances. The reaction mixture was carefully quenched with 100-l reactor containing a cold (0 to 5°C) aqueous solution of heptahydrate of iron (II) sulphate (10.5 kg) and tartaric acid (6,3 kg) in DI-water (42 l). After stirring for 15 minutes the organic phase was separated and was filtered through a layer of diatomaceous earth. This layer was washed with methylene chloride (2×2 l) and the filtrate was transferred into a 100-l reactor. To the reaction mixture, stir gently, slowly added to a cold (0-5°C) solution of solid sodium hydroxide (3,36 kg) in saline solution (42 l). After 1 hour the organic phase was separated, dried over anhydrous sodium sulfate, filtered through a layer of diatomaceous earth and concentrated under reduced pressure, obtaining a brown oil. The resulting oil was purified by chromatography on silica gel, using five columns. Each column was treated as follows. A glass column (20 cm in diameter was loaded with a thick slurry of silica gel (5 kg) in 30% mixture of ethyl acetate/heptane with addition of 0.5% triethylamine. The crude product (~1.2 kg) were absorbed by Sealy�agile (1.5 kg) and loaded on the column. Gradually increased polarity from 30% to 40% ethyl acetate in heptane with 0.5% triethylamine. The purified product, combined with all of the speakers, gave specified in the header connection (3,93 kg, yield 89%) as a yellow-brown oil.

1H NMR (300 MHz, CDCl3, δ) 7,54-7,50 (m, 5H), 7,32-to 7.18 (m, 10H), 3,80-to 3.76 (d, J=12,5 Hz, 1H), 3,65-3,61 (d, J=12,5 Hz, 1H), and 3.31 (s, 1H), 3,03-of 2.92 (m, 1H), 1,77-to 1.69 (m, 2H) and 1.37 and 1.13 (m, 2H).

Example 10: (1S,2S,4R)-2-(gidroximetil)-4-(trailmen)Cyclopentanol and (1S,3S)-1-(gidroximetil)-3-(trailmen)Cyclopentanol

To the reactor was loaded methylenchloride a solution of [(1S,3S,5S)-3-(trailmen)-6-oxabicyclo[3.1.0]hex-1-yl]methanol (2,76 kg, 7.4 mole). To the reactor was loaded with additional methylene chloride (5 l), leading to 13.8 l Stirred reaction mixture was heated to 35-40°C. Using a system of adding solids portions was added sodium borohydride (281 g, 7.4 mol), maintaining the temperature from 35°C to 45°C. was Slowly added a complex of borane-THF (1M solution in THF, 6.7 kg, 7.4 mol), maintaining the temperature from 35 to 45°C. the Temperature was maintained at 35-45°C for 1 hour and then the reaction mixture was analyzed by HPLC. The reaction was considered complete when the amount of the starting materials was less than 2%. The reaction mixture was cooled to a temperature below 30°C, then carefully quenched in 100-l reactor containing cold DI-water (28 l). After stirring for 3 cha�s and the organic phase separated and dried over anhydrous magnesium sulfate, was filtered through a layer of diatomaceous earth and concentrated under reduced pressure, yielding a mixture of (1S,2S,4R)-2-(gidroximetil)-4-(trailmen)Cyclopentanol and (1S,3S)-1-(gidroximetil)-3-(trailmen)Cyclopentanol (2,74 kg) in the form of a brown oil which was used without further purification.

Example 11: (1S,2S,4R)-2-{[(triisopropylsilyl)oxy]methyl}-4-(trailmen)Cyclopentanol

To the reactor was loaded with a mixture of (1S,2S,4R)-2-(gidroximetil)-4-(trailmen)Cyclopentanol and (1S,3S)-1-(gidroximetil)-3-(trailmen)Cyclopentanol (only 1.87 kg, ~280 g of (1S,2S,4R)-2-(gidroximetil)-4-(trailmen)Cyclopentanol, 0.75 mole). In the same reactor was loaded with methylene chloride (7.4 liter) and started mixing. Maintaining the temperature below 25°C, was added triethylamine (210 ml, 1.5 mole). Maintaining the temperature below 25°C, was slowly added triisopropylsilane (402 ml, 1.9 mol). The reaction mixture was allowed to stir at 20-22°C for ~48 hours. The reaction mixture was analyzed by TLC (50% ethyl acetate/heptane, UV visualization), which showed the formation of product (Rf0.70) and the presence of unreacted (1S,3S)-1-(gidroximetil)-3-(trailmen)Cyclopentanol (Rf0,15). Clear pale yellow solution was cooled to 5-10°C, was slowly quenched with DI-water (7.5 liters) and the resulting layers were separated. The aqueous phase was extracted with methylene chloride (3 l) and the combined body�ical phase was dried over anhydrous magnesium sulfate, was filtered through a layer of diatomaceous earth and concentrated under reduced pressure, obtaining a brown oil (4,06 kg), which was purified by chromatography on silica gel, using multiple columns. Each column was treated as follows. In a glass column (20 cm in diameter was loaded with a heavy suspension of silica gel (4.5 kg) in 10% mixture of ethyl acetate/heptane. Oil (~1.2 kg) were loaded on the column. The purified product, combined with all of the speakers, gave specified in the header connection (2,94 kg) in the form of a clear oil which was used without further purification.

1H NMR (300 MHz, CDCl3, δ): 7,56-7,54 (m, 5H), 7,34-7,13 (m, 10H), 4,26 (SHS, 1H), 3,86-of 3.81 (DD, J=10,0, and 4.5 Hz, 1H), 3,65-of 3.60 (DD, J=10,1, 7,2 Hz, 1H), 3,41-3,37 (m, 1H), of 3.07 (SHS, 1H), 2,16-2,07 (m, 1H), 1,69-to 1.63 (m, 3H), 1,47-of 1.20 (m, 4H) and 1,08-of 1.03 (2s, 18H).

Example 12: (1S,2S,4R)-2-(gidroximetil)-4-(trailmen)Cyclopentanol

To the reactor was loaded (1S,2S,4R)-2-{[(triisopropylsilyl)oxy]methyl}-4-(trailmen)Cyclopentanol (2,94 kg, ~1.6 kg supposedly pure substance 3,02 mol). To the reactor was loaded THF (6 l) and started mixing. Maintaining the temperature below 25°C, was added tetrabutylammonium (1M solution in THF, 3,02 l, 3.0 mole). The reaction mixture was allowed to stir at 20-22°C for 3 hours. TLC (50% ethyl acetate/heptane, UV visualization) confirmed full conversion of starting materials to product. The reaction �rity concentrated under reduced pressure to a volume of ~2 l and transferred to the second reactor. The concentrate was diluted with methylene chloride (16 l), washed with saturated aqueous ammonium chloride (8 l) and DI-water (8 l). The organic phase was dried over anhydrous magnesium sulfate, was filtered through a layer of diatomaceous earth and concentrated under reduced pressure, yielding a yellow-brown oil (3,88 kg), which was purified by chromatography on silica gel. Two columns were processed as follows. In a glass column (20 cm in diameter was loaded with a heavy suspension of silica gel (5 kg) in a 10% mixture of ethyl acetate/heptane. Approximately 1.9 kg of oil were absorbed on silica gel (1.5 kg), were loaded on the column and gradually increasing the polarity to 10% to 50% ethyl acetate in heptane. Pure fractions were combined and concentrated under reduced pressure, obtaining specified in the title compound (800 g) as a white solid.

1H NMR (300 MHz, CDCl3, δ): EUR 7.57-7,53 (m, 5H), 7,32-to 7.18 (m, 10H), 4,26-to 4.23 (m, 1H), 3,65-of 3.46 (m, 2H), 3,36-3,29 (m, 1H), 2,17-2,07 (m, 2H), 1,65-1,62 (d, 1H), 1,51-of 1.39 (m, 2H), 1,37-of 1.26 (m, 1H) and 1,2-1,17-1,11 (m, 1H).

Example 13: (1S,2S,4R)-4-amino-2-(gidroximetil)Cyclopentanol

The hydrogenation reactor was purged with argon, it was loaded with 5% palladium on carbon (50% water, 80 g, 20% mol) and the reactor sealed. Using the vacuum in the reactor was added a solution of (1S,2S,4R)-2-(gidroximetil)-4-(trailmen)Cyclopentanol (400 g, 1.07 mole) in methanol (2.7 l). The reactor was purged with argon, was filled with hydrogen �ri pressure from 2.4 to 3.1 ATM and heated to 35°C for 72 h. The reaction mixture was filtered through a layer of diatomaceous earth, washed with methanol (32 l) and concentrated under reduced pressure to a volume of ~1 liter of a mixture Of precipitated was filtered triphenylmethane, and the filtrate was further concentrated, obtaining a yellow-brown oil. The crude substance was purified by chromatography on silica gel. The column was treated as follows. A glass column (15 cm diameter was loaded with a thick slurry of silica gel (1.6 kg) in methylene chloride. Yellow-orange oil was absorbed on silica gel (200 g) and loaded on the column. Gradually increased polarity from 100% methylene chloride to 50% methylene chloride in methanol. Pure fractions were combined and concentrated under reduced pressure, obtaining specified in the title compound (118 g) as a waxy yellow solid.

1H NMR (300 MHz, CD3OD, δ): 4,35-4,32 (m, 1H), 3,76-3,70 (m, 1H), 3,64-to 3.56 (m, 2H), 2,34 and 2.26 (m, 1H), 2,10-2,03 (m, 1H), 1.93 and-to 1.82 (m, 1H), and 1.63-1,46 (m, 2H).

Example 14: (1S,2S,4R)-4-(4-chloro-7H-imidazo[2,3-d]pyrimidine-7-yl)-2-(gidroximetil)Cyclopentanol

To the thick slurry of 4,6-dichloro-5-(2,2-diatexite)pyrimidine (10.0 g, 0,0377 mol) and (1S,2S,4R)-4-amino-2-(gidroximetil)Cyclopentanol∙HBr (8,00 g) in isopropyl alcohol (82 ml, 1.1 mol) and water (11 ml of 0.59 mol) was added triethylamine (13 ml, 0,094 mol). Then the mixture was heated to 85°C for 23 hours. The mixture was cooled� to 50°C, then slowly added 4M hydrochloric acid in water (20 ml). Then, the resulting mixture was stirred at 50°C for 3 hours. HPLC showed that the reaction was completed. The reaction mixture was cooled to ambient temperature and the portions was added sodium bicarbonate (10 g, 0.1 mol). Excess solids were filtered; the filter cake was washed with isopropyl alcohol (20 ml) and the filtrate was concentrated to ~70 ml) was Added ethyl acetate (150 ml), the mixture is then saturated aqueous NaHCO3(35 ml) and water (35 ml). The layers were separated, the aqueous phase was extracted with ethyl acetate (2×50 ml) and filtered. The organic layers were pooled, washed with saturated aqueous NaCl (50 ml) and then concentrated, obtaining specified in the title compound (9.3 g) as brown solids.

1H NMR (300 MHz, CD3OD, δ): of 8.56 (s, 1H), 7,67 (d, 1H), 6,65 (d, 1H), 5,52 (m, 1H), 4,50 (m, 1H), 3,79 (m, 1H), 3,66 (m, 1H), 2,63 (m, 1H), 2,25 (m, 3H) and 2.02 (m, 1H).

Example 15: (1S,2S,4R)-4-(4-chloro-7H-imidazo[2,3-d]pyrimidine-7-yl)-2-(gidroximetil)Cyclopentanol

A solution of (1S,2S,4R)-4-amino-2-(gidroximetil)Cyclopentanol (250 mg, 1,90 mmol) and triethylamine (380 mg, of 3.80 mmol) in 2-propanol (30 ml) was treated with 2-(4,6-dichloropyrimidine-5-yl)acetaldehyde (330 mg, 1,71 mmol) at 80°C. the Reaction was monitored by HPLC and it was found that all the aldehyde was consumed after 19 h. the Reaction mixture was cooled to temperatures� environment. Approximately 80% of the solvent was removed under reduced pressure and the obtained brown solution was added with stirring to water (30 ml). The resulting clear solution was cooled in a bath of ice water, the resulting formed product of crystallization. The obtained thick suspension was stirred at a temperature below 5°C for thirty minutes and filtered. Layer on the filter was washed with cold water (10 ml) and dried in a vacuum oven at 40°C for 14 h, receiving specified in the title compound as brown solid (311 mg, yield 68%).

1H NMR (500 MHz, CDCl3) δ 8,54 (s, 1H), 7,68 (d, J=3.7 Hz, 1H), 6,66 (d, J=3,6 Hz, 1H), 5,54 (m, 1H), 4,52 (m, 1H), 3,82 (DD, J=10,7, 7,2 Hz, 1H), 3,68 (DD, J=10,8, 6,5 Hz, 1H), 2,64 (m, 1H), 2,32 (m, 2H), 2,24 (m, 1H), 2,05 (m, 1H).

Example 16: 9-phenylheptane-9-ol

Methylbenzoate (14,34 g, to 105.3 mmol) was dissolved in anhydrous THF (43 ml) and the resulting mixture was cooled to 0°C. Then was added dropwise a solution of n-octylaniline in THF (200.0 ml, 2.0 M, 400 mmol), maintaining the temperature below 10°C. After complete addition the mixture was allowed to stir at 0°C for 2 hours. Then dropwise added a solution of hydrochloric acid in water (400 ml, 1.0 M), maintaining the temperature below 25°C. the Mixture was diluted with iPrOAc (420 ml), the resulting organic layer was washed with 1.0 M HCl (1×ml), washed with saturated brine (1×70 ml), dried over sulph�including sodium and evaporated, getting colorless liquid. The crude product was purified by chromatography on a column of silica gel, receiving a clear colourless liquid (21,0 g).

1H NMR (300 MHz, CDCl3, δ): 7,41-7,30 (m, 4H), 7,28-7,20 (m, 1H), 1,90-1,70 (m, 4H), 1,35-of 1.20 (m, 23H), 1,11-to 0.96 (m, 2H) and from 0.92 to 0.83 (m, 6H).

Example 17: 1-octyl-1-feilner(chlorosulfonyl)carbamate

Chlorosulfonylisocyanate (1,30 ml 14,95 mmol) was dissolved in anhydrous THF (10 ml) and the resulting mixture was cooled to 0°C. was dropwise added a solution of 9-phenylheptane-9-ol (4,972 g, 14,95 mmol) in anhydrous THF (18.5 ml), maintaining the temperature below 10°C. After complete addition the mixture was allowed to stir at 0°C for 1 hour. Obtained approximately 0.5 M solution of 1-octyl-1-feilner(chlorosulfonyl)carbamate was kept at 0°C until use.

Example 18: General method of obtaining 4-aminotoluene (1S,2S,4R)-(7H-imidazo[2,3-d]pyrimidine-7-yl)-2-(gidroximetil)Cyclopentanol

(1S,2S,4R)-4-(4-chloro-7H-imidazo[2,3-d]pyrimidine-7-yl-2-(gidroximetil)Cyclopentanol (1 equiv.), Amin, as listed below in table 1 (1.1 equiv.), and N,N'-diisopropylethylamine (1.3 equiv.) mixed in 2-butanol (approximately 6 volumes). The reaction vessel was purged with nitrogen and then heated under pressure (5.4 ATM) at 135°C for about 40 hours or up until HPLC will not show a small amount of remaining starting materials or the lack thereof. Mixture� cooled to ambient temperature and pressure. To the reaction mixture are added ethyl acetate, separated and washed with water the organic layer. The aqueous layer is separated and washed with ethyl acetate. The combined organic layers washed with saturated NaCl solution and dried over Na2SO4, filtered and concentrated. To the mixture was added methylene chloride and the mixture cooled to 0°C for about one hour. The resulting solid is filtered off and washed with cold methylene chloride. The solid is dried in vacuo at ambient temperature.

Table 1
Amines suitable for use in example 18

Amin-i

Amin-ii

Amin-iii

Amin-iv

Amin-v

Amin-vi

Amin-vii

Amin-viii

Amin-ix

Amin-x


Amin-xi

Amin-xii

Amin-xiii

Amin-xiv

Amin-xv

Amin-xvi

Amin-xvii

Example 19: General conditions of sulfanilamide 1

In the reaction vessel is added triethylenediamine (approximately 4 equiv. regarding the input of the product of example 18) and tetrahydrofuran (approximately 12 volumes relative to the input of the product of example 18). The mixture is cooled to 0°C and when cooled add 0,866 M tert-butyl(chlorosulfonyl)carbamate (obtained by adding tert-butyl alcohol to a molar equivalent chlorosulfonylisocyanate in an appropriate amount of anhydrous THF under stirring for about 1 hour, maintaining the temperature below about 15°C) in tetrahydrofuran (approx�flax 3 equiv. regarding the input of the product of example 18) with such a rate that the internal temperature remained below or equal to 15°C. the Suspension was warmed to ambient temperature and stirred for about 30 minutes, then cooled to -20°C. One portion add the product of example 18, then add additional tetrahydrofuran (approximately 3 volume relative to the input of the product of example 18). The reaction mixture is heated to 0°C and give her the opportunity to stir until then, until HPLC shows that there is less than 1% by area of the original substances. The reaction mixture was cooled to 0°C and slowly add 9M hydrochloric acid in water (approximately 25 volumes relative to the input of the product of example 18), keeping the temperature below 25°C. Then, the resulting mixture is allowed the opportunity to warm to ambient temperature and stirred for about 4 hours or until until HPLC indicates a full removal of the BOC protection. After removal of the protecting portions add sodium bicarbonate to achieve a pH of ~8. If there is a two-phase mixture, the excess solid is filtered off and the filter cake was washed with ethyl acetate. Separate the organic layer. The aqueous layer was extracted with ethyl acetate, all organic solutions were combined, washed with saturated aqueous NaCl and the concentration�irout, getting the crude product which is purified column chromatography. The product is further purified by crystallization from appropriate solvent.

Example 20: a General method of obtaining sulfanilimide reagent 1

In the reaction vessel add alcohol of the formula (Rw)(Rv)2C-OH (1.1 equiv.) and anhydrous methylene chloride (about 20 volumes) and the mixture is cooled to about 0-10°C. Add chlorosulfonylisocyanate (1 equiv.) at such a speed as to keep the temperature below 10°C, and the mixture was stirred for about 1 hour. Portions add base (2.6 equiv.), maintaining the temperature below about 15°C and the mixture is then stirred for about 1 hour at a temperature of from 0°C to 15°C. the Solids were removed by filtration and the filter cake washed with methylene chloride (approximately 5 volumes). The solvent was removed under reduced pressure, the residue was added acetonitrile (about 5 volumes) and the resulting suspension was stirred at room temperature for about 3 hours. Sulfanilamide reagent is separated by filtration, washed with acetonitrile (1 volume) and dried in vacuum.

Example 21: General conditions of sulfanilamide 2

In the reaction vessel is added the product of example 18 (1 equiv.) and NMP (approximately 9 volumes relative to the injected product� example 18). The mixture is cooled to a temperature of about 0-10°C and stirred for about 15 minutes. Add sulfanilamide reagent obtained in example 20 (1 equiv. regarding the input of the product of example 18) and acid (1 equiv. regarding the input of the product of example 18) and the mixture was stirred at a temperature of from about 0°C to 10°C. the Reaction track HPLC. Additional 1-equivalent portion sulfanilimide reagent obtained in example 20, and acid add approximately one hour to complete the reaction. Add water (approximately 2.5 volume relative to the input of the product of example 18) and the mixture was stirred at a temperature of about 15°C for about 16 hours. Add ethyl acetate (approximately 15 of the volume relative to the input of the product of example 18) and water (10 volumes relative to the input of the product of example 18), the resulting mixture was stirred for about 10 minutes and divide the formed layers. Then the organic phase was washed with water (3×15 volumes relative to the input of the product of example 18). Then the organic phase is dried over anhydrous sodium sulfate and the solvent removed under reduced pressure.

The crude product is dried under vacuum and then redissolved in acetonitrile (6.5 volume relative to the input of the product of example 18). Add hydrochloric acid (2,4 volume on�individual input of the product of example 18), maintaining the reaction temperature below about 20°C. the Reaction track HPLC until complete removal of the protective group. Add water (approximately 14 volumes relative to the input of the product of example 18), then the sodium bicarbonate to achieve a pH of 7-8. Add ethyl acetate (approximately 15 of the volume relative to the input of the product of example 18) and after stirring for about 10 minutes, separated the layers. The organic layer was washed with water (approximately 3×15 volumes relative to the input of the product of example 18) and dried over anhydrous sodium sulfate. The solvent was removed, the residue dissolved in 7% acetonitrile in methylene chloride (approximately 11 volumes relative to the input of the product of example 18) and stirred for about 18 hours. The product is separated by filtration and dried in vacuo at a temperature of 30-35°C.

Example 22: General method of obtaining sulfanilimide reagent 2

In the reaction vessel is added chlorosulfonylisocyanate (1 equiv.) and anhydrous toluene (about 20 volumes) and the mixture is cooled to about 0-10°C. Add tert-butyl alcohol (1 equiv.) with such a rate that the reaction temperature is kept below about 10°C, and the mixture was stirred for about 1 hour. Portions add triethylenediamine (2 equiv.), maintaining the temperature below about 15°C, and the mixture is then ne�amerivault for about two hours at a temperature of from about 15°C to about 25°C. Sulfanilamide reagent is separated by filtration in a nitrogen atmosphere and dried in vacuum.

Example 23: General conditions of sulfanilamide 3

In the reaction vessel is added the product of example 18 (1 equiv.) and acetonitrile (approximately 7 volumes relative to the input of the product of example 18). Add sulfanilamide reagent obtained in example 22 (2 equiv. regarding the input of the product of example 18), and the mixture was stirred at a temperature of about 50°C. the Reaction track HPLC. Heating was continued until the completion of the reaction. After cooling to room temperature, add 0.5 n HCl (approximately 5.5 per volume relative to the input of the product of example 18) and the mixture was stirred at a temperature of about 23°C for about 5-6 hours. The aqueous phase is separated from the resulting two-phase solution and extracted into MTBE (approximately 5 volumes relative to the input of the product of example 18). Extract in MTBE combined with the previously separated organic phase and add additional MTBE (about 2 volume relative to the input of the product of example 18). The resulting mixture was stirred with water (approximately 10 volumes relative to the input of the product of example 18) for 10 minutes. The organic phase is separated. To the organic phase is added acetonitrile (about 10 volumes relative to the input of the product of example 18) and when the low�nom pressure reduce the volume of the solution to 10 volumes, relative to the input of the product of example 18. Add additional acetonitrile (approximately 8 volumes relative to the input of the product of example 18) and again under reduced pressure reduce the volume of the solution to 10 volumes, relative to the input of the product of example 18.

To acetonitrile solution of the crude product slowly add concentrated hydrochloric acid (3 volume relative to the input of the product of example 18), maintaining the reaction temperature below about 5°C. the Reaction track HPLC until complete removal of the protective group. Add water (approximately 10 volumes relative to the input of the product of example 18), then the sodium bicarbonate to achieve a pH of 7-8. Add ethyl acetate (approximately 10 volumes relative to the input of the product of example 18) and after stirring for about 10 minutes, the layers were separated. The organic layer was washed with water (approximately 3×10 volumes relative to the input of the product of example 18). To facilitate the separation of phases at 2-m and 3-m flushing optional add saturated salt solution (about 5% V/V). A solution of crude product are not necessarily given the opportunity to pass through a layer of activated charcoal or silica gel (approximately 250%-25% by weight relative to the input of the product of example 18). For washing the layer of activated carbon or silica gel using EtOAc (approximately 2-10 about�on what to enter in the extent of the product of example 18). The resulting solution was concentrated to approximately 3 volumes relative to the input of the product of example 18 and then heated at 35-40°C. Slowly add dichloro methane (20 volumes relative to the input of the product of example 18), maintaining the internal temperature at 35-40°C. After the addition of DCM, the suspension was stirred at 35-40°C for 1 hour, giving her the opportunity to cool to room temperature and then was stirred at room temperature for about 18 hours. The obtained solid substance separated by filtration and dried in vacuo at 30-35°C to constant weight.

Example 24: Tert-butyl[(1R,3R,4R,5R)-4-bromo-7-oxo-6-oxabicyclo[3.2.0]hept-3-yl]carbamate

To (1R,4R)-4-[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylic acid (400,00 g, 1,7601 mol; obtained by methods similar to those described above in examples 1-3), dissolved in methylene chloride (6 l) was added, the hydroxide of tetrabutylammonium in methanol (1.0 M, 1800 ml) and the mixture stirred at ambient temperature for 60 minutes. Then the reaction mixture was cooled to -25°C in a nitrogen atmosphere. Then within 60 minutes was slowly added bromine (181 ml, 3,52 mol) in methylene chloride (2 l), maintaining the internal temperature at -20°C. After complete addition of bromine, the mixture was stirred at -25°C for further 30 minutes and then for 30 minutes slowly heating�to 0°C. Then the mixture was allowed to stir at 0°C for 1 hour. At 0°C for 30 minutes was slowly added a mixture of sodium salts of L-ascorbic acid (523,0 g, 2,640 mol) in water (3 l) and saturated sodium bicarbonate in water (3 l), maintaining the internal temperature below 10°C. the Obtained two-phase mixture was stirred and gave her the opportunity to warm to ambient temperature for 1 h. Separated the methylene chloride layer and extracted the aqueous layer with methylene chloride (2 l). Layers of methylene chloride were combined and concentrated to volume of about 4 L. was Added ethyl acetate (8 l) and the mixture was concentrated to a volume of about 5 liters was Added ethyl acetate (5 l) and the resulting mixture was 3 times washed with water (4 l). Then the organic layer was washed with saturated sodium chloride in water (2 l) and concentrated, obtaining specified in the title compound (460 g, 85%) as a white solid.

1H NMR (300 MHz, CDCl3): δ 5,09 (d, 1H), 4,80 (m, 1H), 4,71 (m, 1H), 4,47 (m, 1H), of 4.04 (m, 1H), 2,39 (m, 1H), 1,89 (m, 1H) and 1.46 in (SS, 9H).

Example 25: Tert-butyl[(1R,2R,3R,4S)-2-bromo-3-hydroxy-4-(gidroximetil)cyclopentyl]carbamate

Tert-butyl[(1R,3R,4R,5R)-4-bromo-7-oxo-6-oxabicyclo[3.2.0]hept-3-yl]carbamate (450,0 g, 1,470 mol) was dissolved in THF (6 l) and the mixture was cooled to 0°C. was Slowly added 2.0 M tetrahydroborate lithium in THF (730 ml), maintaining the internal temperature below 10°C. the mixture is Then �eremetical at 0°C for 30 minutes, after which HPLC showed that the starting materials were consumed. At 0°C was slowly added a mixture of saturated ammonium chloride in water (2.5 l) and water (2.5 l), maintaining the internal temperature below 10°C. Then the mixture was allowed to warm to ambient temperature, followed by the separation layer THF. The THF layer was concentrated to about 2 l and the aqueous layer was twice extracted with ethyl acetate (4 l). The organic layers were combined and washed twice with water (4 l). Then the organic layer was washed with saturated sodium chloride in water (4 l) and concentrated, obtaining specified in the title compound (452 g, 99%) as a yellow residue.

1H NMR (300 MHz, CDCl3): δ of 4.83 (m, 1H), of 4.54 (m, 1H), 4,43 (m, 1H), 4,31 (m, 1H), a 3.87 (m, 1H), 3,74 (m, 1H), 2,71 (m, 1H), 2,02 (m, 1H), 1,70 (m, 1H) and 1.41 (SS, 9H).

Example 26: (1S,2S,4R)-4-amino-2-(gidroximetil)Cyclopentanol·HBr

Tert-butyl[(1R,2R,3R,4S)-2-bromo-3-hydroxy-4-(gidroximetil)cyclopentyl]carbamate (444,0 g, 1,431 mol) was dissolved in isopropyl alcohol (2000 ml). To the resulting solution was added 4.0 M hydrochloric acid in 1,4-dioxane (2000 ml) and the mixture stirred at ambient temperature for 3 hours. An aliquot was concentrated and analyzed1H NMR, which showed that raw materials were consumed. The rest of the reaction mixture was concentrated under reduced pressure at 35°C, yielding transparent�th residue. The obtained residue was dissolved in a mixture of methanol (2000 ml) and isopropyl alcohol (2000 ml) was added 10 wt%. Pd/C (76 g of 2.5% mol) and sodium bicarbonate (360 g, 4.3 mol). The obtained heterogeneous mixture was subjected to hydrogen (1.4 bar) at ambient temperature for 18 hours. An aliquot of the reaction mixture was filtered in a syringe and concentrated;1H-NMR analysis showed complete consumption of the starting materials. The rest of the reaction mixture was filtered through a layer of celite (250 g). The filter cake was washed with methanol (2000 ml) and the filtrate was concentrated under reduced pressure at 35°C, obtaining specified in the title compound (310 g, quantitative) as an orange solid substance.

1H NMR (300 MHz, CD3OD): δ 4,17 (t, 1H), 3,83 (m, 1H), and 3.72 (m, 1H), 3,60 (m, 1H), 2,33 (m, 1H), of 2.21 (m, 1H), 2,03 (m, 1H) and 1.79 (m, 2H).

Although the invention above has been described in some detail for purposes of clarity and understanding, such a specific implementation options should be considered as illustrative and non-limiting. From reading the present description, the skilled in the art it will be obvious that in form and details may be made various changes without departing beyond the true scope of the present invention, which is defined by the attached claims and not the specific embodiments be implemented thr�deposits.

The patent and scientific literature that is referred to in this description, shall provide such information that is available to experts in this field. Unless otherwise indicated, all technical and scientific terms used herein have the same meaning, as it is usually understood by the expert in that area to which belongs the present invention. The issued patents, patent applications and references cited herein, thereby incorporated herein by reference to the same extent as if each was specifically and individually indicated as incorporated by reference. In case of conflict, will be effective the present disclosure, including definitions.

1. The method of obtaining compounds of formula (I):

or its salts,
where:
stereochemistry at the position marked with asterisks are relative;
Rarepresents hydrogen or a protective group of hydroxyl; or Rataken together with Rjand the intermediate atoms forms a cyclic diol-protective group; or Rataken together with Rmand the intermediate atoms forms a cyclic diol-protective group;
Rbrepresents hydrogen; Rcrepresents hydrogen, fluorine, chlorine, -OH, -O-Rmor C1-4aliphatic �the Rupp, optionally substituted by halogen, -NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, -P(O)(NR+)-N(R+)2, =O, =S, =C(R*)2, =N-N(R*)2, =N-OR*, =N-NHC(O)R*, =N-NHCO2R00, =N-NHSO2R00or =N-R*;
R00represents C1-10aliphatic group or a C6-14aryl group comprising one to three rings;
each R* is independently selected from hydrogen, C1-10aliphatic group, C6-14aryl groups containing 1-3 rings, the heteroaryl group including 5 to 14 atoms in the ring comprising in addition to carbon atom 1 to 4 heteroatoms selected from O, N, S, and oxidized forms of S and N or quaternionic form N, or heterocyclyl the group including a stable 3-to 7-membered monocycle, condensed 7-10-membered bicyclic ring or a bridged 6-10-membered� bicyclic heterocyclic moiety, moreover, the group is saturated or partially saturated and include besides carbon atoms one or more heteroatoms selected from O, N, S, and oxidized forms of S and N or quaternionic forms of N, and each R+independently selected from hydrogen, C1-10aliphatic group, C6-14aryl groups containing 1-3 rings, the heteroaryl group including 5 to 14 atoms in the ring comprising in addition to carbon atom 1 to 4 heteroatoms selected from O, N, S, and oxidized forms of S and N or quaternionic form N, or heterocyclyl the group including a stable 3-to 7-membered monocycle, condensed 7-10-membered bicyclic ring or a bridged 6-10-membered bicyclic heterocyclic moiety, and the group is saturated or partially saturated and include besides carbon atoms one or more heteroatoms selected from O, N, S, oxidized forms of S and N or quaternionic forms of N, or two R+on the same nitrogen atom together with the nitrogen atom form a 5-8 membered aromatic or non-aromatic ring having in addition to the nitrogen atom 0-2 heteroatom in the ring selected from N, O and S;
Rdrepresents hydrogen;
Rerepresents hydrogen;
Re`represents hydrogen;
each Rfrepresents hydrogen;
Rgrepresents chlorine, fluorine, iodine or bromine;
R represents hydrogen;
Rh`represents hydrogen;
Rjrepresents hydrogen or a protective group of hydroxyl; or Rjtaken together with Raand the intermediate atoms forms a cyclic diol-protective group;
Rkrepresents hydrogen;
Rmrepresents a protective group of hydroxyl; or Rmtaken together with Raand the intermediate atoms forms a cyclic diol-protective group;
and each aryl and each heteroaryl optionally substituted by substituents selected from halogen,- NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, and-P(O)(NR+)-N(R+)2or two adjacent Deputy together with the intermediate atoms form a 5-6 membered unsaturated or partially saturated ring having 0-3 and�Ohm in the ring, selected from N, O and S;
where at least one carbon atom of each heterocyclyl optionally substituted Deputy, selected from halogen, -NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, -P(O)(NR+)-N(R+)2, =O, =S, =C(R*)2, =N-N(R*)2, =N-OR*, =N-NHC(O)R*, =N-NHCO2R00, =N-NHSO2R00or=N-R*; and
where at least one nitrogen atom, if present, each heterocyclyl optionally substituted Deputy selected from-R*, -N(R*)2, C(O)R*, CO2R*,
C(O)C(O)R*C(O)CH2C(O)R*, -SO2R*, -SO2N(R*)2, -C(=S)N(R*)2, -C(=NH)-N(R*)2and NR*SO2R*;
comprising the step of binding the compound of formula (II) or its salt with a compound of formula (III) in the presence of base to form a compound of formula (I):

where:
stereochemical�Chia configuration in the regulations asterisks, are relative;
each of the radicals Ra, Rb, Rc, Rd, Re, Re`, Rf, Rg, Rh, Rh`, RjRkand Rmin formulas (II) and (III) is as defined in formula (I); and
R1represents-CH2SSS.

2. A method according to claim 1, where Rgrepresents a chlorine or fluorine.

3. A method for producing a compound of formula (V)

or its salt, comprising the stage of:
a) combining the compound of formula (II) or its salt with a compound of formula (III) or its salt in the presence of base to form a compound of formula (I);

(b) treatment of a compound of formula (I) with an amine of the formula HNRnRowith the formation of a compound of formula (V) or its salts;
where:
stereochemistry at the position marked with asterisks are relative;
Rarepresents hydrogen or a protective group of hydroxyl; or Rataken together with Rjand the intermediate atoms forms a cyclic diol-protective group; or Rataken together with Rmand the intermediate atoms forms a cyclic diol-protective group;
Rbrepresents hydrogen;
Rcrepresents hydrogen, fluorine, chlorine, -OH, -O-Rmor C1-4�officesyou group;
Rdrepresents hydrogen;
Rerepresents hydrogen;
Re`represents hydrogen;
each Rfrepresents hydrogen;
Rgrepresents chlorine, fluorine, iodine or bromine;
Rhrepresents hydrogen;
Rh`represents hydrogen;
Rjrepresents hydrogen or a protective group of hydroxyl; or Rjtaken together with Raand the intermediate atoms forms a cyclic diol-protective group;
Rkrepresents hydrogen;
Rmrepresents a protective group of hydroxyl; or Rmtaken together with Raand the intermediate atoms forms a cyclic diol-protective group;
R1represents-CH2SSS;
Rnrepresents hydrogen or C1-4aliphatic group; and R0selected from furanyl, teinila, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazoline, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, naftel, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, indazole, benzimidazole, benzthiazole, benzothiazyl, benzofuranyl, purine, chinoline, izochinolina, cinnoline, phthalazine, hintline, chinoxalin, naphthyridine, pteridine, Tetra�of droperidol, tetrahydrothieno, pyrrolidinyl, pyrrolidinyl, piperidinyl, pyrrolidyl, tetrahydropyranyl, tetrahydroisoquinoline, decahydroquinoline, oxazolidinyl, piperazinyl, dioxane, dioxolane, diazepine, oxazepine, thiazepine, morpholinyl, hinokitiol, tetrahydroquinoline, tetrahydroisoquinoline, indlela, phenanthridine, tetrahydronaphthyl, indolinyl, benzodioxolyl, benzodioxolyl, Romania, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctene, cyclooctadiene, bicycloheptane and bicyclobutane; and where the
R0may be optionally substituted on any of them ring component or on both of them, each capable of substituting unsaturated carbon in the ring is optionally substituted with 1-2 groups Rpand each capable of substitution on a saturated carbon ring optionally substituted by 1-2 groups Rq; where
each Rpindependently selected from the group consisting of fluoro, -OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4y), or C1-4aliphatic group, or C1-4forlifetime group, an optionally substituted-OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4y),
each Rqindependent� selected from the group consisting of fluoro, -OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4y), or C1-4aliphatic group, or C1-4forlifetime group, an optionally substituted-OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4y), provided that when two Rqattached to the same carbon atom, one of them must be selected from the group consisting of fluoro, -CO2R5x, -C(O)N(R4x)(R4y) and C1-4aliphatic group or a C1-4forlifetime group, an optionally substituted-OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4y); or two Rqat one and the same carbon atom together form =O or =C(R5x)2
R4xrepresents hydrogen, C1-4alkyl, C1-4foralkyl or C6-10ar(C1-4)alkyl,
R4yrepresents hydrogen, C1-4alkyl, C1-4foralkyl or C6-10ar(C1-4)alkyl, or 5 - or 6-membered aryl, 5 - or 6-membered heteroaryl having 1-4 heteroatom selected from O, N or S or 5 - or 6-membered heterocyclic ring having 1-4 heteroatom selected from O, N or S; or
R4xand R4ytaken together with the nitrogen atom to which they are attached, form an optionally substituted 4-8-membered heterocyclyl ring having,in addition to the nitrogen atom, 0-2 heteroatom in the ring, independently selected from N, O and S;
each R5xindependently represents hydrogen, C1-4alkyl, C1-4foralkyl or optionally substituted C6-10aryl or C6-10ar(C1-4)alkyl;
wherein each aliphatic group optionally substituted with substituents selected from halogen,- NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, -P(O)(NR+)-N(R+)2, =O, =S, =C(R*)2, =N-N(R*)2, =N-OR*, =N-NHC(O)R*, =N-NHCO2R00, =N-NHSO2R00or =N-R*, where
R00represents C1-10aliphatic group or a C6-14aryl group comprising one to three rings;
each R* is independently selected from hydrogen, C1-10aliphatic group, C6-14aryl groups containing 1-3 rings, the heteroaryl group, including 5-1 atoms in the ring, comprising in addition to carbon atom 1 to 4 heteroatoms selected from O, N, S, and oxidized forms of S and N, or quaternionic form N, or heterocyclyl the group including a stable 3-to 7-membered monocycle, condensed 7-10-membered bicyclic ring or a bridged 6-10-membered bicyclic heterocyclic moiety, and the group is saturated or partially saturated and include besides carbon atoms one or more heteroatoms selected from O, N, S, and oxidized forms of S and N or quaternionic forms of N, and
each R+independently selected from hydrogen, C1-10aliphatic group, C6-14aryl groups containing 1-3 rings, the heteroaryl group including 5 to 14 atoms in the ring comprising in addition to carbon atom 1 to 4 heteroatoms selected from O, N, S, and oxidized forms of S and N, or quaternionic form N, or heterocyclyl the group including a stable 3-to 7-membered monocycle, condensed 7-10-membered bicyclic ring or a bridged 6-10-membered bicyclic heterocyclic moiety, and the group is saturated or partially saturated and include besides carbon atoms one or more heteroatoms selected from O, N, S, oxidized forms of S and N or quaternionic forms of N, or two R+on the same nitrogen atom together with the nitrogen atom form a 5-8 membered aromatic Il� non-aromatic ring, having in addition to the nitrogen atom 0-2 heteroatom in the ring selected from N, O and S;
and each aryl and each heteroaryl optionally substituted by substituents selected from halogen,- NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, and-P(O)(NR+)-N(R+)2or two adjacent Deputy together with the intermediate atoms form a 5-6 membered unsaturated or partially saturated ring having 0-3 atoms in the ring selected from N, O and S;
where at least one carbon atom of each heterocyclyl optionally substituted Deputy, selected from halogen, -NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(OR*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, -P(O)(NR+)-N(R+)2, =O, =S, =C(R*)2, =N-N(R*)2, =N-OR*, =N-NHC(O)R*, =N-NHCO2R00, =N-NHSO2R00or=N-R*; and
where at least one nitrogen atom, if present, each heterocyclyl optionally substituted Deputy selected from-R*, -N(R*)2, C(O)R*, CO2R*, C(O)C(O)R*C(O)CH2C(O)R*, -SO2R*, -SO2N(R*)2, -C(=S)N(R*)2, -C(=NH)-N(R*)2and NR*SO2R*.

4. A method for producing a compound of formula (VI)

or its salt, comprising the stage of:
(a) combining the compound of formula (II) or its salt with a compound of formula (III) in the presence of base to produce a compound of formula (I);

(b) treatment of a compound of formula (I) with an amine of the formula HNRnRowith the formation of a compound of formula (V) or its salt

(C) sulamericana of a compound of formula (V), where Rjrepresents hydrogen, with formation of a compound of formula (VI) or salts thereof, where:
stereochemical�their configuration in the regulations asterisks, are relative; where Rarepresents hydrogen or a protective group of hydroxyl; or Rataken together with Rjand the intermediate atoms forms a cyclic diol-protective group; or Rataken together with Rmand the intermediate atoms forms a cyclic diol-protective group;
Rbrepresents hydrogen;
Rcrepresents hydrogen, fluorine, chlorine, -OH, -O-Rmor C1-4aliphatic group;
Rdrepresents hydrogen;
Rerepresents hydrogen;
Re`represents hydrogen;
each Rfrepresents hydrogen;
Rgrepresents chlorine, fluorine, iodine or bromine;
Rhrepresents hydrogen;
Rh`represents hydrogen;
Rjrepresents hydrogen or a protective group of hydroxyl; or Rjtaken together with Raand the intermediate atoms forms a cyclic diol-protective group;
Rkrepresents hydrogen;
Rmrepresents a protective group of hydroxyl; or Rmtaken together with Raand the intermediate atoms forms a cyclic diol-protective group;
R1represents-CH2SSS;
Rnrepresents hydrogen or C1-4aliphatic group; and
R0selected from furanyl, teinila, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazoline, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, naftel, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, indazole, benzimidazole, benzthiazole, benzothiazyl, benzofuranyl, purine, chinoline, izochinolina, cinnoline, phthalazine, hintline, chinoxalin, naphthyridine, pteridine, tetrahydrofuranyl, tetrahydrofuryl, pyrrolidinyl, pyrrolidinyl, piperidinyl, pyrrolidyl, tetrahydropyranyl, tetrahydroisoquinoline, decahydroquinoline, oxazolidinyl, piperazinyl, dioxane, DIOXOLANYL, diazepine, oxazepine, thiazepine, morpholinyl, hinokitiol, tetrahydroquinoline, tetrahydroisoquinoline, indlela, phenanthridine, tetrahydronaphthyl, indolinyl, benzodioxolyl, benzodioxolyl, Romania, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctene, cyclooctadiene, bicycloheptane and bicyclobutane; and where the
R0may be optionally substituted on any of them ring component or on both of them, each capable of substituting unsaturated carbon ring neo�Astelin substituted by 1-2 groups R pand each capable of substitution on a saturated carbon ring optionally substituted by 1-2 groups Rq; where
each Rpindependently selected from the group consisting of fluoro, -OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4y), or C1-4aliphatic group or a C1-4forlifetime group, an optionally substituted-OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4y),
each Rqindependently selected from the group consisting of fluoro, -OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4y), or C1-4aliphatic group, or C1-4forlifetime group, an optionally substituted-OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4y), provided that when two Rqattached to the same carbon atom, one of them must be selected from the group consisting of fluoro, -CO2R5x, -C(O)N(R4x)(R4y) and C1-4aliphatic group or a C1-4forlifetime group, an optionally substituted-OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4y); or two Rqat one and the same carbon atom together form =O or =C(R5x)2
R4xrepresents hydrogen, C1-4alkyl, C1-4foralkyl or C6-1 ar(C1-4)alkyl,
R4yrepresents hydrogen, C1-4alkyl, C1-4foralkyl or C6-10ar(C1-4)alkyl, or 5 - or 6-membered aryl, 5 - or 6-membered heteroaryl having 1-4 heteroatom selected from O, N or S, or 5 - or 6-membered heterocyclic ring having 1-4 heteroatom selected from O, N or S; or
R4xand R4ytaken together with the nitrogen atom to which they are attached, form an optionally substituted 4-8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 heteroatom in the ring, independently selected from N, O and S;
each R5xindependently represents hydrogen, C1-4alkyl, C1-4foralkyl or optionally substituted C6-10aryl or C6-10ar(C1-4)alkyl;
wherein each aliphatic group optionally substituted with substituents selected from halogen,- NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+) 2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, -P(O)(NR+)-N(R+)2, =O, =S, =C(R*)2, =N-N(R*)2, =N-OR*, =N-NHC(O)R*, =N-NHCO2R00=N-NHSO2R00or=N-R*, where
R00represents C1-10aliphatic group or a C6-14aryl group comprising one to three rings;
each R* is independently selected from hydrogen, C1-10aliphatic group, C6-14aryl groups containing 1-3 rings, the heteroaryl group including 5 to 14 atoms in the ring comprising in addition to carbon atom 1 to 4 heteroatoms selected from O, N, S, and oxidized forms of S and N or quaternionic form N, or heterocyclyl the group including a stable 3-to 7-membered monocycle, condensed 7-10-membered bicyclic ring or a bridged 6-10-membered bicyclic heterocyclic moiety, and the group is saturated or partially saturated and include besides carbon atoms one or more heteroatoms selected from O, N, S, and oxidized forms of S and N, or quaternionic forms of N, and
each R+independently selected from hydrogen, C1-10aliphatic group, C6-14aryl groups containing 1-3 rings, the heteroaryl group including 5 to 14 atoms in the ring comprising in addition to carbon atom 1 to 4 heteroatoms selected from O, N, S, oxidized�Oh form S and N, or quaternionic form N, or heterocyclyl the group including a stable 3-to 7-membered monocycle, condensed 7-10-membered bicyclic ring or a bridged 6-10-membered bicyclic heterocyclic moiety, and the group is saturated or partially saturated and include besides carbon atoms one or more heteroatoms selected from O, N, S, and oxidized forms of S and N or quaternionic forms of N, or two R+ on the same nitrogen atom together with the nitrogen atom form a 5-8 membered aromatic or non-aromatic ring having in addition to the nitrogen atom 0-2 heteroatom in the ring, selected from N, O, and S;
and each aryl and each heteroaryl optionally substituted by substituents selected from halogen,- NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, and-P(O)(NR+)-N(R+)2, �whether two adjacent Deputy together with the intermediate atoms form a 5-6 membered unsaturated or partially saturated ring, having 0-3 atoms in the ring selected from N, O and S;
where at least one carbon atom of each heterocyclyl optionally substituted Deputy, selected from halogen, -NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, -P(O)(NR+)-N(R+)2, =O, =S, =C(R*)2, =N-N(R*)2, =N-OR*, =N-NHC(O)R*, =N-NHCO2R00, =N-NHSO2R00or =N-R*; and
where at least one nitrogen atom, if present, each heterocyclyl optionally substituted Deputy selected from-R*, -N(R*)2, C(O)R*, CO2R*, C(O)C(O)R*C(O)CH2C(O)R*, -SO2R*, -SO2N(R*)2, -C(=S)N(R*)2, -C(=NH)-N(R*)2and NR*SO2R*.

5. A method according to claim 4, wherein stage C) comprises the steps:
I-C) treatment of a compound of formula (V) sulfanilimide reagent RUN--S(O)2X+;
II-C) optional processing �actionnow mixture, formed at the stage (I-C), acid; where:
Rurepresents-C(O)OC(Rv)2(Rw);
each Rvindependently selected from hydrogen, C1-10aliphatic group or a C6-14aryl comprising 1-3 rings;
Rwrepresents C1-10aliphatic group or a C6-14aryl comprising 1-3 rings;
or one of Rvrepresents C1-10the aliphatic group and the other Rvtaken together with Rwforms With3-6cycloaliphatic ring; and
X is selected from:
the tertiary amine is selected from trimethylamine, triethylamine, triethylenediamine, diazabicyclo[5.4.0]undec-7-Jena (DBU), 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-Yung, sparteina, N,N`-diisopropylethylamine, tributylamine, 1-azabicyclo[2.2.2]octane, N,N`-dimethylpiperazine, N-ethylmorpholine and Tripropylamine; or
nitrogen-containing heteroaryl selected from pyridine, imidazole, pyrrole, collidine, 2,6-lutidine, 4-dimethylaminopyridine, 2,6-di-tert-butylpyrazine and 2,6-di-tert-butyl-4-methylpyridine, 1-azabicyclo[2.2.2]octane, N,N`-dimethylpiperazine and N-ethylmorpholine;
where each aliphatic and each cycloaliphatic group optionally substituted by a Deputy selected from halogen,- NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R ), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, -P(O)(NR+)-N(R+)2, =O, =S, =C(R*)2, =N-N(R*)2, =N-OR*, =N-NHC(O)R*, =N-NHCO2R00, =N-NHSO2R00or =N-R; where
each aryl and each heteroaryl optionally substituted Deputy, selected from halogen, -NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, and-P(O)(NR+)-N(R+), or two adjacent Deputy together with the intermediate�face-to-face atoms form a 5-6 membered unsaturated or partially unsaturated ring, having 0-3 heteroatoms in the ring selected from N, O and S; where
at least one carbon atom of each heterocycle optionally substituted by substituent selected from halogen, -NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, -P(O)(NR+)-N(R+)2, =O, =S, =C(R*)2, =N-N(R*)2, =N-OR*, =N-NHC(O)R*, =N-NHCO2R00, =N-NHSO2R00or =N-R*; and
where at least one nitrogen atom, if present, each heterocycle optionally substituted Deputy selected from-R*, -N(R*)2, C(O)R*, CO2R*, C(O)C(O)R*C(O)CH2C(O)R*, -SO2R*, -SO2N(R*)2, -C(=S)N(R*)2, -C(=NH)-N(R*)2and NR*SO2R*; and
where each of R00, R* and R+defined in paragraph 4.

6. A method according to claim 3, where:
HNRnRorepresented by a compound of formula (VIIa) and forms a compound of formula (Va):

where:
stereochemistry at the position marked with asterisks are relative;
each of the radicals Ra, Rb, Rc, Rd, Re, Re`, Rf, Rh, Rh`, Rj, Rkand Rmin the formula (Va) is the same as defined in formula (V);
each Rpindependently selected from fluoro, -OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4y) or (C1-4aliphatic group or a C1-4forlifetime group, an optionally substituted-OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4y);
each Rqindependently selected from fluoro, -OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4y), or C1-4aliphatic group or a C1-4forlifetime group, an optionally substituted-OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4y), provided that when two Rqattached to the same carbon atom, one must be selected from fluorine, -CO2R5x, -C(O)N(R4x)(R4y) and C1-4aliphatic group or a C1-4forlifetime group, an optionally substituted-OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4y); or two Rqat one and the same carbon atom, together�STN form =O or =C(R 5x)2;
R4xrepresents hydrogen, C1-4alkyl, C1-4foralkyl or C6-10ar(C1-4)alkyl;
R4yrepresents hydrogen, C1-4alkyl, C1-4foralkyl, S6-10ar(C1-4)alkyl or 5 - or 6-membered aryl, 5 - or 6-membered heteroaryl having 1-4 heteroatom selected from O, N or S; or a 5 - or 6-membered heterocyclyl ring having 1-4 heteroatom selected from O, N or S; or
R4xand R4ytaken together with the nitrogen atom to which they are attached, form a 4-8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatom independently selected from N, O and S; and
each R5xindependently represents hydrogen, C1-4alkyl, C1-4foralkyl or C6-10aryl or C6-10ar(C1-4)alkyl, where
each aryl and each heteroaryl optionally substituted Deputy, selected from halogen, -NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+-N(R +)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, and-P(O)(NR+)-N(R+), or two adjacent Deputy together with the intermediate atoms form a 5-6 membered unsaturated or partially unsaturated ring having 0-3 heteroatoms in the ring selected from N, O and S; where
at least one carbon atom of each heterocycle optionally substituted by substituent selected from halogen, -NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, -P(O)(NR+)-N(R+)2, =O, =S, =C(R*)2, =N-N(R*)2, =N-OR*, =N-NHC(O)R*, =N-NHCO2R00, =N-NHSO2R00or =N-R*; and
where at least one nitrogen atom, if present, each heterocycle optionally substituted Deputy selected from-R*, -N(R*)sub> 2, C(O)R*, CO2R*, C(O)C(O)R*C(O)CH2C(O)R*, -SO2R*, -SO2N(R*)2, -C(=S)N(R*)2, -C(=NH)-N(R*)2and NR*SO2R*; and
where each of R00, R* and R+defined in paragraph 3.

7. A method of obtaining a compound (VId)

or its salt, comprising the stage of:
(a) combining the compound of formula (II) or its salt with a compound of formula (III) in the presence of base to produce a compound of formula (I);

(b) treatment of a compound of formula (I) with an amine of the formula (VIIa) with the formation of a compound of formula (Va) or its salts;

(VIIa)

(C) sulamericana of a compound of formula (Va), where Rjrepresents hydrogen, with formation of a compound of formula (VId):
where the stereochemistry at the position marked with asterisks are relative; Rarepresents hydrogen or a protective group of hydroxyl; or Rataken together with Rjand the intermediate atoms forms a cyclic diol-protective group; or Rataken together with Rmand the intermediate atoms forms a cyclic diol-protective group;
Rbrepresents hydrogen;
Rcrepresents hydrogen, fluorine, chlorine, -OH, -O-Rmor C1-4aliphatic group;
Rdperformance�et a hydrogen;
Rerepresents hydrogen;
Re`represents hydrogen;
each Rfrepresents hydrogen;
Rgrepresents chlorine, fluorine, iodine or bromine;
Rhrepresents hydrogen;
Rh`represents hydrogen;
Rjrepresents hydrogen or a protective group of hydroxyl; or Rjtaken together with Raand the intermediate atoms forms a cyclic diol-protective group;
Rkrepresents hydrogen;
Rmrepresents a protective group of hydroxyl; or Rmtaken together with Raand the intermediate atoms forms a cyclic diol-protective group;
R1represents-CH2SSS;
each Rpindependently selected from the group consisting of fluoro, -OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4y), or C1-4aliphatic group or a C1-4forlifetime group, an optionally substituted-OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4y),
each Rqindependently selected from the group consisting of fluoro, -OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4v), or C1-4aliphatic group, or C1-4forlifetime group, an optionally substituted-OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4y), provided that when two Rqattached to the same carbon atom, one of them must be selected from the group consisting of fluoro, -CO2R5x, -C(O)N(R4x)(R4y) and C1-4aliphatic group or a C1-4forlifetime group, an optionally substituted-OR5x, -N(R4x)(R4y), -CO2R5xor-C(O)N(R4x)(R4y); or two Rqat one and the same carbon atom together form =O or =C(R5x)2
R4xrepresents hydrogen, C1-4alkyl, C1-4foralkyl or C6-10ar(C1-4)alkyl,
R4yrepresents hydrogen, C1-4alkyl, C1-4foralkyl or C6-10ar(C1-4)alkyl, or 5 - or 6-membered aryl, 5 - or 6-membered heteroaryl having 1-4 heteroatom selected from O, N or S, or 5 - or 6-membered heterocyclic ring having 1-4 heteroatom selected from O, N or S; or
R4xand R4ytaken together with the nitrogen atom to which they are attached, form an optionally substituted 4-8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 heteroatom in the ring, independently selected from N, O and S;
each R5xindependently represents hydrogen, C1-4alkyl, C1-4foralkyl or optionally substituted C6-10aryl or C610 ar(C1-4)alkyl;
wherein each aliphatic group optionally substituted with substituents selected from halogen,- NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, -P(O)(NR+)-N(R+)2, =O, =S, =C(R*)2, =N-N(R*)2, =N-OR*, =N-NHC(O)R*, =N-NHCO2R00, =N-NHSO2R00or =N-R*, where
R00represents C1-10aliphatic group or a C6-14aryl group comprising one to three rings;
each R* is independently selected from hydrogen, C1-10aliphatic group, C6-14aryl groups containing 1-3 rings, the heteroaryl group including 5 to 14 atoms in the ring comprising in addition to carbon atom 1 to 4 heteroatoms selected from O, N, S, and oxidized forms of S and N, or quaternionic form N, or heterocyclyl the group including stable 3-7-cinnamoroll, condensed 7-10-membered bicyclic ring or a bridged 6-10-membered bicyclic heterocyclic moiety, and the group is saturated or partially saturated and include besides carbon atoms one or more heteroatoms selected from O, N, S, and oxidized forms of S and N, or quaternionic forms of N, and
each R+independently selected from hydrogen, C1-10aliphatic group, C6-14aryl groups containing 1-3 rings, the heteroaryl group including 5 to 14 atoms in the ring comprising in addition to carbon atom, 1 to 4 heteroatoms selected from O, N, S, and oxidized forms of S and N or quaternionic form N, or heterocyclyl the group including a stable 3-to 7-membered monocycle, condensed 7-10-membered bicyclic ring or a bridged 6-10-membered bicyclic heterocyclic moiety, and the group is saturated or partially saturated and include besides carbon atoms one or more heteroatoms selected from O, N, S, and oxidized forms of S and N, or quaternionic forms of N, or two R+ on the same nitrogen atom together with the nitrogen atom form a 5-8 membered aromatic or non-aromatic ring having in addition to the nitrogen atom 0-2 heteroatom in the ring selected from N, O, and S;
and each aryl and each heteroaryl optionally substituted by substituents selected from halogen,- NO2 , -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, and-P(O)(NR+)-N(R+)2or two adjacent Deputy together with the intermediate atoms form a 5-6 membered unsaturated or partially saturated ring having 0-3 atoms in the ring selected from N, O and S;
where at least one carbon atom of each heterocyclyl optionally substituted Deputy, selected from halogen, -NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-(R +)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, -P(O)(NR+)-N(R+)2, =O, =S, =C(R*)2, =N-N(R*)2, =N-OR*, =N-NHC(O)R*, =N-NHCO2R00, =N-NHSO2R00or =N-R*; and
where at least one nitrogen atom, if present, each heterocyclyl optionally substituted Deputy selected from-R*, -N(R*)2, C(O)R*, CO2R*, C(O)C(O)R*C(O)CH2C(O)R*, -SO2R*, -SO2N(R*)2, -C(=S)N(R*)2, -C(=NH)-N(R*)2and NR*SO2R*.

8. A method according to claim 7, where stage C) comprises the steps:
I-C) treatment of a compound of formula (V) sulfanilimide reagent RUN--S(O)2X+;
II-C) optional treatment of the reaction mixture formed in stage (I-C), acid;
Where Rurepresents-C(O)OC(Rv)2(Rw);
each Rvindependently selected from hydrogen, C1-10aliphatic group or a C6-14aryl comprising 1-3 rings;
Rwrepresents C1-10aliphatic group or a C6-14aryl comprising 1-3 rings;
or one of Rvrepresents C1-10the aliphatic group and the other Rvtaken together with Rwforms With3-6cycloaliphatic ring; and
X is selected from:
the tertiary amine is selected from trimethylamine, triethylamine, �of rietlanden, diazabicyclo[5.4.0]undec-7-Jena (DBU), 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-Yung, sparteina, N,N`-diisopropylethylamine, tributylamine, 1-azabicyclo[2.2.2]octane, N,N`-dimethylpiperazine, N-ethylmorpholine and Tripropylamine; or nitrogen-containing heteroaryl selected from pyridine, imidazole, pyrrole, collidine, 2,6-lutidine, 4-dimethylaminopyridine, 2,6-di-tert-butylpyrazine and 2,6-di-tert-butyl-4-methylpyridine, 1-azabicyclo[2.2.2]octane, N,N`-dimethylpiperazine and N-ethylmorpholine;
where each aliphatic and each cycloaliphatic group optionally substituted by a Deputy selected from halogen,- NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, -P(O)(NR+)-N(R+)2, =O, =S, =C(R*)2, =N-N(R*)2, =N-OR*, =N-NHC(O)R*, =N-NHCO2R00, =N-NHSO2R00or =N-R; where each�th aryl and each heteroaryl optionally substituted Deputy,selected from halogen, -NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, and-P(O)(NR+)-N(R+), or two adjacent Deputy together with the intermediate atoms form a 5-6 membered unsaturated or partially unsaturated ring having 0-3 heteroatoms in the ring selected from N, O and S; where
at least one carbon atom of each heterocycle optionally substituted by substituent selected from halogen, -NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, N(R +)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, -P(O)(NR+)-N(R+)2, =O, =S, =C(R*)2, =N-N(R*)2, =N-OR*, =N-NHC(O)R*, =N-NHCO2R00, =N-NHSO2R00or =N-R*; and
where at least one nitrogen atom, if present, each heterocycle optionally substituted Deputy selected from-R*, -N(R*)2, C(O)R*, CO2R*, C(O)C(O)R*C(O)CH2C(O)R*, -SO2R*, -SO2N(R*)2, -C(=S)N(R*)2, -C(=NH)-N(R*)2and NR*SO2R*; and
where each of R00, R* and R+defined in clause 7.

9. A method according to any one of claims. 1-8, where:
Rcrepresents hydrogen, -HE or-O-Rm;
Rarepresents hydrogen or a protective group of hydroxyl, selected from a silyl protective group, C1-10aliphatic group, -C(O)Raaand-C(O)-O-Raaor Rataken together with Rjand the intermediate atoms forms a cyclic diol-protective group- (C(Raa)(Rbb)-; or Rataken together with Rmand the intermediate atoms forms a cyclic diol-protective group- (C(Raa)(Rbb)-;
Rjrepresents hydrogen or a protective group of hydroxyl, selected from a silyl protective group, C1-10aliphatic group, -C(O)-Raaand-C(O)-O-Raa; or Rj/sup> taken together with Raand the intermediate atoms forms a cyclic diol-protective group- (C(Raa)(Rbb)-;
Rmrepresents a protective group of hydroxyl, selected from a silyl protective group, C1-10aliphatic group, -C(O)-Raaand-C(O)-O-Raaor Rmtaken together with Raand the intermediate atoms forms a cyclic diol-protective group-(C(Raa)(Rbb)-;
Raarepresents C1-4aliphatic group or a C6-14aryl comprising 1-3 rings; and
Rbbrepresents hydrogen or C1-4aliphatic group, where
each aliphatic group optionally substituted Deputy, selected from halogen, -NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, -P(O)(NR+)-N(R+)2, =O, =S, =C(R*)2, =N-N(R*)2, =N-OR*, =N-NHC(O)R*, =N-NHCO2R00, =N-NHSO2R00or =N-R; wherein each aryl and each heteroaryl optionally substituted Deputy, selected from halogen, -NO2;-CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, and-P(O)(NR+)-N(R+), or two adjacent Deputy together with the intermediate atoms form a 5-6 membered unsaturated or partially unsaturated ring having 0-3 heteroatoms in the ring selected from N, O and S; where
at least one carbon atom of each heterocycle optionally substituted by substituent selected from halogen, -NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -O 2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, -P(O)(NR+)-N(R+)2, =O, =S, =C(R*)2, =N-N(R*)2, =N-OR*, =N-NHC(O)R*, =N-NHCO2R00, =N-NHSO2R00or =N-R*; and
where at least one nitrogen atom, if present, each heterocycle optionally substituted Deputy selected from-R*, -N(R*)2, C(O)R*, CO2R*, C(O)C(O)R*C(O)CH2C(O)R*, -SO2R*, -SO2N(R*)2, -C(=S)N(R*)2, -C(=NH)-N(R*)2and NR*SO2R*; and
where each of R00, R* and R+defined in the PP. 1-8.

10. The compound of formula (IIa):

or its salt; where:
stereochemistry at the position marked with asterisks are absolute;
Rarepresents hydrogen or a protective group of hydroxyl, selected from a silyl protective group, aliphatic group, -C(O)-Raaand-C(O)-O-Raa; or Rataken together with Rjand the intermediate atoms forms a cyclic diol-protective group- (C(Raa)(Rbb)-; or Rataken together with Rmand the intermediate atoms, obra�should cyclic diol-protective group- (C(R aa)(Rbb)-;
Rbrepresents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;
Rcrepresents hydrogen, fluorine, chlorine, -OH, -O-Rmor C1-4aliphatic group, optionally substituted Deputy selected from halogen,- NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, -P(O)(NR+)-N(R+)2, =O, =S, =C(R*)2, =N-N(R*)2, =N-OR*, =N-NHC(O)R*, =N-NHCO2R00, =N-NHSO2R00or =N-R, where each R00, R* and R+defined in the PP. 1-8;
Rd`represents hydrogen, fluorine, bromine, C1-4aliphatic group or a C1-4forlifetime group;
Rerepresents hydrogen or C1-4aliphatic group;
Re`represents hydrogen or C1-4aliphatic gr�SPF;
Rhrepresents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;
Rh`represents hydrogen, fluorine, C1-4aliphatic group or a C1-4forlifetime group;
Rjrepresents hydrogen or a protective group of hydroxyl, selected from a silyl protective group, aliphatic group, -C(O)-Raaand-C(O)-O-Raa; or Rjtaken together with Raand the intermediate atoms forms a cyclic diol-protective group- (C(Raa)(Rbb)-;
Rmrepresents a protective group of hydroxyl, selected from a silyl protective group, aliphatic group, -C(O)-Raaand-C(O)-O-Raa; or Rmtaken together with Raand intermediate carbon atoms forms a cyclic diol-protective group-(C(Raa)(Rbb)-;
Raarepresents C1-4aliphatic group or a C6-10aryl;
Rbbrepresents hydrogen or C1-4aliphatic group, and
Rrrepresents hydrogen or a protective group of the amine,
each aliphatic group optionally substituted Deputy, selected from halogen, -NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+ ), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, -P(O)(NR+)-N(R+)2, =O, =S, =C(R*)2, =N-N(R*)2, =N-OR*, =N-NHC(O)R*, =N-NHCO2R00, =N-NHSO2R00or =N-R; wherein each aryl optionally substituted Deputy, selected from halogen, -NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, and-P(O)(NR+)-N(R+), or two adjacent Deputy together with the intermediate atoms form a 5-6 membered unsaturated or partially nemasys�TES the ring, having 0-3 heteroatoms in the ring selected from N, O and S; and where each of R00, R* and R+defined in the PP. 1-8.

11. The compound according to claim 10, where:
each of Rb, Re, Re`, Rhand Rh`represents hydrogen; Rd`represents hydrogen or bromine; and Rcrepresents hydrogen, -HE or-ORm.

12. The compound according to claim 11, where:
Rarepresents hydrogen or a protective group of hydroxyl, selected from a silyl protective group, aliphatic group, -C(O)-Raaand-C(O)-O-Raaor Rataken together with Rjand the intermediate atoms forms a cyclic diol-protective group- (C(Raa)(Rbb)-; or Rataken together with Rmand the intermediate atoms forms a cyclic diol-protective group- (C(Raa)(Rbb)-;
Rjrepresents hydrogen or a protective group of hydroxyl, selected from a silyl protective group, aliphatic group, -C(O)-Raaand-C(O)-O-Raaor Rjtaken together with Raand the intermediate atoms forms a cyclic diol-protective group- (C(Raa)(Rbb)-;
Rmrepresents a protective group of hydroxyl, selected from a silyl protective group, aliphatic group, -C(O)-Raaand-C(O)-O-Raaor Rmtaken together with Raand the intermediate atoms, form a qi�chip metallic diol-protective group- (C(R aa)(Rbb)-;
Raarepresents C1-4aliphatic group or a C6-10aryl; and
Rbbrepresents hydrogen or C1-4aliphatic group, wherein each aliphatic group optionally substituted Deputy, selected from halogen, -NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, -P(O)(NR+)-N(R+)2, =O, =S, =C(R*)2, =N-N(R*)2, =N-OR*, =N-NHC(O)R*, =N-NHCO2R00, =N-NHSO2R00or =N-R; wherein each aryl optionally substituted Deputy, selected from halogen, -NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+ )2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, and-P(O)(NR+)-N(R+), or two adjacent Deputy together with the intermediate atoms form a 5-6 membered unsaturated or partially unsaturated ring having 0-3 heteroatoms in the ring selected from N, O and S; and where each of R00, R* and R+defined in the PP. 1-8.

13. Compound selected from the group:

or salts thereof; where:
stereochemistry at the position marked with asterisks are absolute; and
Rrrepresents-C(O)Rcc, -C(O)-ORcc, -CH2Rccor-C(Rcc)3where Rccrepresents C1-4aliphatic group or a C6-14aryl, where C1-4aliphatic group optionally substituted Deputy, selected from halogen, -NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, C(O)N(R +)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(OR*)2, -O-P(O)-OR*, -P(O)(NR+)-N(R+)2, =O, =S, =C(R*)2, =N-N(R*)2, =N-OR*, =N-NHC(O)R*, =N-NHCO2R00, =N-NHSO2R00or =N-R;
where aryl optionally substituted by a Deputy selected from halogen,- NO2, -CN, -R*, -C(R*)=C(R*)2, -C≡C-R*, -OR*, -SR00, -S(O)R00, -SO2R00, -SO3R00, -SO2N(R+), -N(R+), -NR+C(O)R*, -NR+C(O)N(R+), -NR+CO2R00, -O-CO2R*, -OC(O)N(R+)2, -O-C(O)R*, -CO2R*, -C(O)-C(O)R*, -C(O)R*, -C(O)N(R+)2, -C(O)N(R+)C(=NR+)-N(R+)2, -N(R+)C(=NR+)-N(R+)-C(O)R*, -C(=NR+)-N(R+)2, -C(=NR+)-OR*, -N(R+)-N(R+)2, -N(R+)C(=NR+)-N(R+)2, -NR+SO2R00, -NR+SO2N(R+), -P(O)(R*)2, -P(O)(0R*)2, -O-P(O)-OR*, and-P(O)(NR+)-N(R+), or two adjacent Deputy together with the intermediate atoms form a 5-6 membered unsaturated or partially saturated ring having 0-3 atoms in the ring selected from N, O and S;
and where each of R00, R* and R+defined in the PP. 1-8.

14. Ability� according to claim 4 or 5, where
Rarepresents hydrogen;
Rcrepresents hydrogen;
Rgrepresents chlorine;
Rjrepresents hydrogen;
Rnand Roin HNRnRorepresents hydrogen and indanyl, respectively; where the next stage C) comprises the steps:
I-C) treatment of a compound of formula (V) with a reagent of sulfanilamide RuN--S(O)2X+;
II-C) optional processing of the reaction mixture formed in stage (I-C) acid; where
Rurepresents-C(O)OC(Rv)2(Rw);
each Rvindependently selected from hydrogen or C1-10aliphatic group;
Rwrepresents C1-10aliphatic group;
X is selected from tertiary amine is selected from trimethylamine, triethylamine, triethylenediamine, diazabicyclo[5.4.0]undec-7-Jena (DBU), 1,5-diazabicyclo[4.3.0]non-5-Yung, sparteina, N,N`-diisopropylethylamine, tributylamine, 1-azabicyclo[2.2.2]octane, N,N`-dimethylpiperazine, N-ethylmorpholine and Tripropylamine.

15. A method according to claim 14, where the stereochemistry at the position marked with asterisks are relative;
Rvrepresents methyl;
Rwrepresents methyl;
X represents triethylenediamine;
HNRnRois a



 

Same patents:

Ethinyl derivatives // 2553461

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to ethinyl derivatives of formula I, where X represents N or C-R1; Y represents N or C-R2; Z represents CH or N; R4 represents 6-membered ring, containing 0, 1 or 2 nitrogen atoms, possibly substituted with 1-2 groups, selected from halogen, lower alkyl, lower alkoxy or NRR'; R1 represents hydrogen, lower alkyl, lower hydroxyalkyl, lower cycloalkyl or represents 5-6-membered heterocycloalkyl, containing 1-2 heteroatoms, selected from O and N; R2 represents hydrogen, CN; R and R' independently on each other represent hydrogen; or their pharmaceutically acceptable salts or acid-addition salts. Invention also relates to pharmaceutical composition, possessing activity of positive allosteric modulator of mGluR5 receptor, including effective quantity of at least one invention compound, and to application of invention compounds for manufacturing medication for treatment or prevention of diseases, associated with positive allosteric modulators of mGluR5 receptor.

EFFECT: obtained are novel compounds, which can be applied as positive allosteric modulator of mGluR5 receptor.

14 cl, 51 ex

FIELD: chemistry.

SUBSTANCE: invention describes a method of producing and a method of purifying dialkyl pemetrexed of formula (I) , having antifolate action. The compound can be used to treat non-small-cell cancer and, coupled with cisplatin, to treat malignant pleural mesothelioma of the lungs. The method includes reacting a carboxylic acid of formula (II) with a diester of glutamic acid of formula (III) or an acid-addition salt thereof. The process is carried out in the presence of a substituted triphenyl phosphate of formula (IV) , a base and a solvent. In formulae (I) and (III) each R1 and R2 independently represents alkyl groups. In formula (IV) X, Y and Z assume values given in the claim.

EFFECT: use of safe, mild, cheap, non-oxidising and easy to handle triphenyl phosphate simplifies the process and enables to obtain, for example, diethyl pemetrexed with purity higher than 99%.

14 cl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry, namely to novel heterocyclic compounds of formula (1) and/or to their pharmaceutically acceptable salts, where A1 represents CH; A4and A5 independently represent CR2 or N; A2 and A3 together with ring B represent 5-membered heteroaryl or heterocycle, with said 5-membered heteroaryl or heterocycle being selected from where t represents 1 or 2; and R3 is independently selected from H, C1-C6 alkyl, C6-aryl, C3-C6-membered cycloalkyl, C(O)NRcRd, -ORb, heteroaryl, representing pyridine, and heterocycle, representing piperidine and tetrahydropyran; and each of said alkyl, aryl, cycloalkyl, heteroaryl and heterocycle can be substituted with one group, independently selected from C1-C6 alkyl, possibly substituted with one substituent, selected from -CONMe2, C3-membered cycloalkyl, -CN, -OMe, -pyridine, tetrahydropyran, -CO-morpholine, -CO-pyrrolidine, (3-methyl)oxetane; -OH; -C(O)Ra; -CN; -C(O)NRcRd; -NRcRd; -ORb; -S(O)nRe; halogen, and substituted with one group -COMe heterocycle, representing piperidine, on condition that when A4 represents CR2, A2 and A3 together with ring B are selected from structure (3), (5) or (6); represents single bond or double bond; R1 represents heteroaryl, representing 6-membered or 9-10-membered aromatic mono- or bicyclic ring, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur; possibly substituted with one or two groups, independently selected from C1alkyl, C2alkinyl, -NRcRd, -NRcS(O)nRe, -ORb, halogen, halogenalkyl; R2 is independently selected from H; each Ra, Rb, Rc, Rd, and Re is independently selected from H; C1-C4alkyl, possibly substituted with one substituent, selected from -OH, -OMe, -CN, -NH2, -NMe2, C3-cycloalkyl; C2-C3alkenyl; C3alkinyl; C6aryl, possibly substituted with one or more substituents, selected from fluorine or methyl group; C3-membered cycloalkyl, possibly substituted with one substituent, selected from -OH and -CN; halogenalkyl; heteroaryl, representing pyridine; and substituted with one methyl group heterocycle, representing piperidine, or Rc and Rd together with atom (atoms) which they are bound to form 5-6-membered heterocyclic ring, representing pyrrolidine or morpholine; and in each case n is independently equal 2. Invention also relates to particular compounds, pharmaceutical composition, based on claimed compounds; method of inhibiting PI3K and/or mTOR activity and to application of claimed compounds.

EFFECT: novel compounds, useful for inhibiting PI3K and/or mTOR activity have been obtained.

15 cl, 16 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to a method of obtaining methyl ether of 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propionic acid and benzosulphonate of methyl ether of 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propionic acid, which includes the interaction of methyl ether of 3-[(S)-7-bromo-2-((R and/or S)-2-hydroxypropylamino)-5-pyridin-2-yl-3H-benzo[e][1,4]diazepin-3-yl]propionic acid with an oxidiser and, optionally, processing the reaction product in acidic conditions, as well as to intermediate compounds and .

EFFECT: simplification and reduction of the price of the obtaining method due to the reduction of the number of stages.

13 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to a compound of formula (I), or its tautomer, or a pharmaceutically acceptable salt, where each of Z1 and Z2: N and CR, where at least, one of Z1 and Z2 represents CR, and each R: H, C1-C4 alkyl and -N(R3)(R3); W: -O-, -N(C1-C4) alkyl and -C(R6)(R6) -, and each R6: H and C1-C4 alkyl, or two R6, bound with the same carbon atom, are taken together with the formation of =O, R1: a phenyl and heterocycle, which represents a saturated or unsaturated 5-6-member monocyclic ring, containing 1-3 heteroatoms, selected from atoms N, S and O, or a 8-12-member bicyclic ring, each cycle of which is selected from a saturated, unsaturated and aromatic cycle, containing 1-2 nitrogen atoms, where R1 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4 alkyl, =O, fluorosubstituted C1-C2 alkyl, -O-R3, -(C1-C4 alkyl)-N(R3)(R3), -N(R3)(R3) and -C(O)-N(R3)(R3), R2: a phenyl and heterocycle, which represents an unsaturated 5-6-member monocyclic ring, containing 1-2 heteroatoms, selected from atoms N and O, or represents dihydrobenzofuranyl, where R2 is optionally substituted with 1-2 substituents, independently selected from a halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorosubstituted alkyl, -O-R3, -(C1-C4 alkyl)-N(R3)(R3) and -N(R3)(R3); each R3: -C1-C4 alkyl; or two R3 are taken together with a nitrogen atom, which they are bound with, with the formation of a 4-8-member unsaturated heterocycle, optionally containing one additional heteroatom, selected from N and O, where in case when R3 represents an alkyl, the said alkyl is optionally substituted with two -OH groups, and when two R3 are taken together with a nitrogen atom, which they are bound with, with the formation of a 4-8-member saturated heterocycle, the said saturated heterocycle is optionally substituted with fluorine by any carbon atom; and is substituted with hydrogen by any capable of substitution nitrogen atom; p equals 1, 2 or 3; X2 is selected from -C(=O)-♣, -C(=O)-O-♣, -C(=O)-NH-♣, -S(=O)2-NH-♣ and -C(=O)-NH-CR4R5-♣, where: ♣ represents a site, by which X2 is bound with R1; and each R4 and R5 represents hydrogen. The invention also relates to compounds of formulas (IV), (V), (VI), particular the compounds, a pharmaceutical composition based on the compound of formulas (I), (IV)-(VI) and to a method of treatment, based on the application of the said compounds.

EFFECT: novel heterocyclic compounds, possessing sirtuin-modelling activity are obtained.

26 cl, 2 tbl, 40 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new substituted aminotetrahydropyranes of structural formula or to their pharmaceutically acceptable salts , and , wherein V is specified in groups having the formulas below, Ar represents phenyl unsubstituted or substituted by one to five halogen atoms, each of R1 and R2 is independently specified in C1-C6alkyl; R3 is specified in a group consisting of C1-C6alkyl; cyano; tetrazolyl; -C(O)OC1-C6alkyl and -C(O)NH2; wherein C1-C6alkyl is substituted by 1-4 substitutes independently specified in a group consisting of OH; -C(O)NH2 and -CO2H. The declared compounds can be dipeptidylpeptidase-IV inhibitors and can be applicable in treating or preventing diseases involving the enzyme dipeptidylpeptidase-IV, such as diabetes, and especially type 2 diabetes mellitus.

EFFECT: invention also refers to a pharmaceutical composition containing the above compounds, and using the above compounds and compositions for preventing or treating the diseases involving the enzyme dipeptidylpeptidase-IV.

12 cl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new chemical compounds of general formula I wherein LA, LB, LC, cycle A, cycle B, RA, RB, RC, RD, RE and RF have the values specified in the patent claim. The compounds of formula (I) are protein kinase inhibitors.

EFFECT: invention refers to pharmaceutical compositions containing the above compounds, as well as to using the above compounds for treating and/or preventing the diseases related to aberrant protein kinase activity, particularly oncological diseases.

10 cl, 14 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) such as below, or to their pharmaceutically acceptable salts, wherein R1 means H, C1-8alkyl morpholinyl, haloC1-8alkylamino, C1-8alkyloxadiazolyl, hydroxyl, halopyrrolidinyl, azetidinyl, C1-8alkylamino, amino, cyano C1-8alkylamino, halophenylC1-8alkylamino or cyanoC3-8cycloalkylamino; R2, R3, R4, R5 and R6 independently mean H, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, haloC1-8alkyloxy, halogen, hydroxyl, cyanopyrazinyloxy, halogen, hydroxyl, cyanopyrazinyloxy, pyrazolyl, C1-8alkylpyrazolyl, imidazolyl, benzimidazolyl, 6-oxo-6H-piridazinyl, C1-8alkyl-6-oxo-6H-pyridazinyl, piperazinyl, N-C1-8alkylpiperazinyl, piperidinyl, difluoropyrrolidinyl, phenylimidazolyl, oxo-pyrrolidinyl, oxo-oxazolidinyl, morpholinyl, oxo-morpholinyl, oxo-pyridinyl, 2-oxo-2H-pyrazinyl, difluoropiperidinyl, haloC1-8alkylpiperidinyl, piperidinylC1-8alkoxy, oxetanyloxy, C1-8alkylpyrazolyl, halopyridinyl, C1-8alkylpyridinyl, C3-8cycloalkyl, C3-8 cycloalkylC1-8alkyl, halophanyl, C1-8alkylcarbonylamino-C3-8-cycloalkyl-C1-8alkyl, haloC1-8alkylpiperazinyl, C1-8alkylamino, C1-8alkoxy-C1-8alkylpiperazinyl, C3-8cycloalkylpiperazinyl, hexahydropyrrolo[1,2-a]pyrazinyl, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl, C1-8alkylimidazolyl, azetidinyl, C3-8cycloalkylpiperazinyl, C1-8alkylimidazolyl, C1-8alkoxy C1-8alkoxy, imidazo[4,5-c]pyridinyl, C1-8alkylpiperazinyl, hexahydro-pyrrolo[1,2-a]pyrazinyl, haloazetidinyl, pyrimidinyl and C2-8alkenyloxy; A1 means -CH2-, carbonyl, -C(O)O- or is absence; A2 means N, CR7; A3 means N, CR8; A4 means N, CR9; R7 means H, C1-8alkyl, haloC1-8alkyl, halogen, hydroxyl, haloC1-8alkylaminocarbonyl; halophenylC1-8alkylaminocarbonyl, phenyl-C3-8-cycloalkylaminocarbonyl, haloC1-8alkylphenylC1-8alkylaminocarbonyl, halophenylC3-8 cycloalkylaminocarbonyl, halophenylC3-8cycloalkylC1-8alkylaminocarbonyl; R8 means H, C1-8alkyl, haloC1-8alkyl, halogen or hydroxyl; or R7 and R8 together with a carbon atom they are attached to, form C3-8cycloalkyl or substituted pyrrolidine, wherein substituted pyrrolidine represents pyrrolidine, N-substituted haloC1-8alkyl or formyl; R9 means H, C1-8alkyl, haloC1-8alkyl, halogen or nitro; or R8 and R9 together with a carbon atom they are attached to, form C3-8cycloalkyl; or its pharmaceutically acceptable salt

EFFECT: compounds inhibit the enzyme catepsin that enables using them in pharmaceutical compositions.

27 cl, 8 dwg, 1 tbl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry, namely to novel hetericyclic compounds of general formula or to its tautometric form, or to its pharmaceutically acceptable salt, where 1-2 of X1, X2, X3, X4, X5, X6 is selected from N, and the remaining ones represent C, X7 is selected from N or CH; each of X8, X9, X10 and X11 is independently selected from N or CH on condition that fragment can simultaneously contain one or two nitrogen atoms; R1, R2, R3 and R4 are selected from H, 6-memberedaryl, CF3, halogen; R5, R6, R7 represent C1-alkyl on condition that X9, X10 or X11 in this case respectively equals C; "A" can represent simple bond or bridging ethyne moiety; Y can represent simple bond or is independently selected from methylene or ethylene bridging moieties; moiety Z is independently selected from no-substituted or substituted in nitrogen atom heterocycloalkyl or is non-substituted or substituted cycloalkyl on condition that N (nitrogen) equals C (carbon): , where R9 is selected from CH2OH, CON(R15, R16), where R15, R16 can independently represent H, C1-alkyl, Het represents N, n=1, n1=3; R8 is selected from H, C1-6-alkyl, C1-alkylcarbonyl, derivetives of arylacetic acid of general structure: , where methylheteroaryls of general structure: , where derivatives of alkylsulphonyls of general structure where R14=Alk, with Alk representing C1-alkyl, or to 2-methylamino-1-{3-[6-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyridin-2-ylmethyl]-1-oxa-8-azaspiro]4.5]decan-8-yl}-ethanol dihydrochloride, or to 6-(6- chloroimidazo[1,2-a]pyridin-3-yl)-1',4',5',6'-tetrahydro-2'H-[2,3']bipyridinyl-3'-carboxylic acid dihydrochloride, or to 6-(6- chloroimidazo[1,2-a]pyridin-3-yl)-1',4',5',6'-tetrahydro-2'H-[2,3']bipyridinyl-3'-carboxylic acid dimethylamine dihydrochloride. Invention also relates to pharmaceutical composition based on claimed compound and to method of Haspin kinase inhibition.

EFFECT: obtained are novel compounds, possessing useful biological properties.

5 cl, 7 tbl, 35 ex

FIELD: chemistry.

SUBSTANCE: invention relates to azoloazine salts of compounds of a fluoroquinolone line of formulae 4a-c , 5a-c , 7a-b and 8a-b , possessing antibacterial and antiviral properties. The claimed compounds can be applied for the creation of a medication for the emergency prevention and treatment of infections, caused by pathogens of both the bacterial and viral origin, including especially dangerous ones. In general formulae 4 and 5 R=CH3, R1=C2H5; R=H, R1=C2H5; R=C2H5, R1=cyclo-C3H7, in formulae 7 and 8 R=H (7a, 8a); R=CH3 (7b, 8b).

EFFECT: increased efficiency of the compound application.

8 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to compounds of formula or a pharmaceutically acceptable salt of such a compound, where - X is a carbon atom and R1a and R2a together form a bond; or - X is a carbon atom, R1a and R2a together form a bond, and R1 and R2 together form a moiety , where the asterisk shows the bonding site of R2; or - X is a carbon atom, R1a is hydrogen or (C1-4)alkoxy, and R2a is hydrogen; and R1 and R2, unless indicated otherwise, independently denote hydrogen; (C1-5)alkyl; aryl, where aryl denotes naphthyl or phenyl, where said aryl is unsubstituted or independently mono- or disubstituted, where the substitutes are independently selected from a group consisting of (C1-4)alkyl, (C1-4) alkoxy and halogen; or heteroaryl, selected from pyridyl, thienyl, oxazolyl or thiazolyl, where said heteroaryl is unsubstituted; under the condition that if R2 is aryl or heteroaryl, R1 cannot be aryl or heteroaryl, where the aryl and heteroaryl are independently unsubstituted or substituted as defined above; R3 is hydrogen or -CO-R31; R31 is (C1-5)alkyl, (C1-3)fluoroalkyl or (C3-6)cycloalkyl; n equals 1, 2, 3 or 4; B is a -(CH2)m- group, where m equals an integer from 1 to 3; A is-(CH2)P-, where p equals 2 or 3; R4 is (C1-5)alkyl; W is , where R5 is hydrogen or (C1-5)alkyl; R8, R9 and R10 is independently hydrogen, halogen, (C1-5)alkyl, hydroxy, -(C1-5)alkoxy, -O-CO-(C1-5)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, -CO-(C1-5)alkoxy, (C1-2)alkoxy-(C1-4)alkoxy or -NH-CO-(C1-5)alkyl. The invention also relates to a pharmaceutical composition based on a compound of formula (I).

EFFECT: novel compounds which are useful as calcium channel blockers are obtained.

11 cl, 2 tbl, 166 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of the formula (I) that are characterized by the properties of M3 muscarine receptor antagonist that is applicable in treatment or prevention of the disease or state (the abnormity of) which includes activity of the M3 muscarine receptor such as respiratory diseases. In the formula (I) A is represented by the oxygen atom or the group -N(R12)-; (i) R1 is represented by C1-C6-alkyl or the hydrogen atom; and R2 is represented by the hydrogen atom or the group -R5, -Z-Y-R5, -Z-NR9R10, -Z-NR9CO-R5 or -Z-CO2H; and R3 is absent or is represented by C1-C6-alkyl, and in this case the nitrogen atom to which it is bound is represented by tetradic nitrogen and bears a positive charge; or (ii) R1 and R2 together with nitrogen to which they are bound form heterocycloalkyl ring; the mentioned ring is displaced by the group -Y-R5 or -Z-Y-R5, and R3 is absent or is represented by C1-C6-alkyl, and in this case the nitrogen atom to which it is bound is represented by tetradic nitrogen and bears a positive charge; R4 is represented by the formula group (a), (b), (c) or (d); Z is represented by C1-C16-alkylene group; Y is represented by the link or the oxygen atom; R5 is represented by C1-C6-alkyl, aryl, phenyl condensed with C3-C6cycloalkyl, phenyl condensed with heterocycloalkyl, heteroaryl, aryl(C1-C8-alkyl)-, heteroaryl(C1-C8-alkyl)-, C3-C6cycloalkyl or heteroC3-C6cycloalkyl group; R6 is represented by C1-C6-alkyl or the hydrogen atom; n and m equal 0; R8a and R8b are independently chosen from the group consisting of aryl, phenyl condensed with heterocycloalkyl, heteroaryl, C1-C6-alkyl, C3-C6cycloalkyl; R8c is represented by -OH or C1-C6-alkyl; R9 and R10 are represented independently by the hydrogen atom, C1-C6-alkyl, aryl, phenyl condensed with heterocycloalkyl and other components mentioned in the invention formula.

EFFECT: new compounds applicable in treatment or prevention of the disease or state (the abnormity of) which includes activity of the M3 muscarine receptor such as respiratory diseases.

10 cl, 49 ex

FIELD: chemistry.

SUBSTANCE: compound has formula (I):

The compound is obtained through arylamination of 2-(4-methoxyphenyl)-6-hydroxy-6-methyl-4-oxocyclohexane-1,3-dicarboxylate with phenylethylamine in the presence of acetic acid in ethanol. The compound is a yellow crystalline substance with Tm=130°C, which is soluble in dimethyl sulphoxide (DMSO) and dimethyl formamide (DMFA) but not soluble in water. LD50 during intraperitoneal administration to white mice was greater than 10000 mg/kg.

EFFECT: high anti-inflammatory action of the compound.

1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), optical isomers or pharmaceutically acceptable salts thereof which can be used to inhibit or block reuptake of 5-hydroxytryptamine (5HT) and/or norepinephrine (NA), as well as for treating diseases associated with the central nervous system, a pharmaceutical composition based on said compounds and use thereof in preparing a medicinal agent. (I), where the chiral centre (*) can be R or S or RS (racemic mixture), R3 and R4 are independently selected from saturated alkyl, having 1-6 carbon atoms, and R1 and R2 are as described in the formula of invention.

EFFECT: high effectiveness of the compounds.

12 cl, 10 tbl, 3 dwg, 15 ex

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

New drugs // 2237057
The invention relates to organic chemistry and can find application in medicine

The invention relates to new cycloalkenyl exhibiting the properties of inhibitors of the biosynthesis of cholesterol, in particular, inhibitors of the enzyme 2,3-amoxicilin-lanosterol-cyclase activity and can find application in the treatment and prevention of, for example, hyperlipidemia, hypercholesterinemia, atherosclerosis, and pharmaceuticals based on them

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel cyclic compounds of general formula which possess properties of CaSR modulator. In general formula I group represents cycloalkyl, which contains 4-7 carbon atoms, optionally substituted with one or several similar or different substituents, selected from R2, R3, R4 or R5; A represents 1-naphthyl; R1 represents methyl, ethyl or n-propyl, each of which is optionally substituted with one or several, similar or different substituents, selected from halogen and hydroxy; R2 and R3 represent hydrogen; R4 represents hydrogen, halogen, hydroxy or C1-6alkyl; each R5 represents independently one or several similar or different substituents, represented by hydrogen or C1-6alkyl; G represents -C(O)NH2, C3-8cycloalkyl, C1-6heterocycloalkyl, C1-6heterocycloalkenyl, C3-8cycloalkenyl, C6-14aryl, C1-10heteroaryl, C6-10arylamino, hydroxyaminocarbonyl, C6-10arylaminocarbonyl, C1-4aminocarbonyl, C1-6heterocycloalkylcarbonyl, C1-10heteroarylaminocarbonyl, C6-10arylsulfonylaminocarbonyl, C6-14aryloxy, or C1-4alkoxycarbonyl, where said substituents are optionally additionally substituted with one or several, similar or different substituents. Other values of radicals are given in the formula of invention.

EFFECT: compounds can be applied in treatment, relief or prevention of physiological disorders or diseases, associated with impairment of activity of CaSR, such as hyperparathyreosis, and other diseases.

23 cl, 9 dwg, 3 tbl, 315 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing optically active compounds: (S)-(-)-2-(N-propylamino)-5-methoxytetraline and (S)-(-)-2-(N-propylamino)-5-hydroxytetraline. Said method involves optical separation of a mixture of enantimers of 2-(N-propylamino)-5-methoxytetraline and 2-(N-propylamino)-5-hydroxytetraline in the presence of an optically active form of N-(3,5-dinitrobenzoyl)-α-phenylglycine. The method enables to obtain a product with high optical purity.

EFFECT: invention also relates to use of salts of (S)-(-)-2-(N-propylamino)-5-methoxytetraline and (S)-(-)-2-(N-propylamino)-5-hydroxytetraline as intermediate compounds when producing rotigotine.

7 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of cycloalkylamines, possessing inhibiting activity with respect to, at least, one monoamine transporter, selected from group, consisting of serotonin transporter, dopamine transporter and norepinephrine transporter. In formula (IV): n equals 1; s equals 1; Y and Z each independently represents halogen; X represents OR5; where R5 stands for H or non-substituted C1-C10alkyl; A represents H, non-substituted C1-C10alkyl or halogen; R1 and R2 each independently represents H; R3 and R4 each independently represents H or on-substituted C1-C10alkyl.

EFFECT: invention relates to pharmaceutical composition, containing said compounds and to method of treatment or prevention of neurological disorder or eating disorder, mediated by activity of monoamine transporter, selected from group, consisting of serotonin transporter, dopamine transporter and norepinephrine transporter, such as depression, neurodegenerative disease, abuse with psychoactive substances, fibromyalgia, pain, sleep disorder, syndrome of attention-deficit disorder, syndrome of attention-deficit disorder with hyperactivity, restless legs syndrome, schizophrenia, anxiety, obsessive-compulsive disorder, panic disorder, post-traumatic stress, premenstrual dysphoria.

35 cl, 6 dwg, 8 ex

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