Pharmaceutical compounds

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to their pharmaceutically acceptable salts exhibiting PI3 kinase inhibitor activity. In the formula (I), A represents a thiophen ring; n=1; R1 represents , where m=1; R30 represents H; R4 And R5 together with N atom whereto attached form a 5- or 6-members N-containing heterocyclic group which includes 0 or 1 additional heteroatom selected from N and O which is unsubstituted or substituted by one or more substitutes selected from C1-6alkyl, C1-6alkoxy, -N(R"')-alk-OR, -alk-OR, -O-alk-OR, -alk-C(O)NR2, -C(O)NR2, -alk-Het, -N(R)-Het, -O-Het, -N(R)-C(O)- alk-OR, -NR-S(O)2R, -N(R)-alk-S(O)2R, -N(R)-alk-OR, -alk-NR'R", -N(R"')-S(O)2R, S(O)2R"', -S(O)2-alk-ORf 5- or 6-members N-containing heterocyclic group, 5- or 6-members N-containing heteroaryl group which includes 0 or 1 additional heteroatom selected from N, O or S, oxo(=O), -SO2NR2, -SO2-alk-NR2 where alk means a C1-6alkylene chain; Het means a 5- or 6-members N-containing heteroaryl group or furan optionally substituted by C1-6alkyl; R means H or C1-6alkyl, or when 2 groups R are bound with N, they together with N atom form a saturated 5- or 6-members N-containing heterocyclic group; each R' and R" means independently H, C1-6alkyl or C1-6alkoxy; R'" represents C1-6alkyl, a 5- or 6-merous saturated N-containing heterocyclic group, or a 5- or 6-merous N-containing heteroaryl group; R2 means where R6 and R7 together with N atom whereto attached form a morpholine group; R3 represents an indazole group.

EFFECT: development of the effective method of preparing the compounds of formula (I), and their application for preparing a drug, a pharmaceutical composition, and a method of inhibition.

10 cl, 6 ex

 

The present invention relates to pyrimidine derivatives and their use as inhibitors of phosphatidylinositol-3-kinase (PI3K).

Phosphatidylinositol (hereinafter defined abbreviation “PI”) is one of several phospholipids found in cell membranes. In recent years it has become clear that PI plays an important role in intracellular signal transduction. In the late 1980s, it was found that the PI3 kinase (RK) is an enzyme that phosphorylates position 3 inonitoring ring phosphatidylinositol (D. Whitman et al., 1988, Nature, 332, 664).

Originally RK considered a single enzyme, but now it turned out that in RC there are many subtypes. Each subtype has its own mechanism for regulating activity. 3 main classes RK were identified on the basis of specificity for their substrate in vitro (B. Vanhaesebroeck, 1997, the Trend in Biol. Sci., 22, 267). Substrates for RC class I is PI, PI-4-phosphate (RR) and PI-4,5-phosphate (PI(4,5)P2). RC class I, also divided into 2 groups, class Ia and class Ib from the point of view of the mechanism of their activation. PI3K class Ia include PI3K subtypes 110α, 110β and 110δ that transmit signals from receptors connected with the receptor. PI3K class Ib includes the subtype 110γ-activated receptor connected with protein G. PI and PI(4)P is known as the substrates of PI3K class II. PI3K Klah the CA II include the PI3K subtypes 2α, 2β and 2γ, which are characterized by a content of C2 domains at the C-end. The substrate for PI3K class III represents only PI.

In the PI3K subtypes to date, the most extensively been studied subtype of class Ia. 3 subtype of class Ia are heterodimeric catalytic subunit 110 kDa regulatory subunit of 85 kDa or 55 kDa. The regulatory subunits contain SH2 domains and contact tyrosinemia residues phosphorylated by the receptors of growth factors with tyrosine kinase activity or the product of an oncogene, thereby causing the activity of the PI3K catalytic subunit R, which phosphorylates its lipid substrate. Thus, subtypes of class Ia are associated with cell proliferation and carcinogenesis.

WO 01/083456 describes the number of condensed heteroaryl derivatives, which have activity as inhibitors of PI3K and which inhibit the growth of cancer cells.

A brief description of the invention

Currently, it was discovered that a new class of condensed pyrimidine compounds are effective inhibitors of PI3K with physico-chemical and pharmacokinetic properties similar to drugs. The compounds exhibit selectivity for PI3K class Ia versus Ib class, in particular, the relation subtype p110α.

Accordingly, the present invention relates to a compound, which is a condensed pyrimidine of the formula (I):

where

A represents a thiophene or furan ring;

n=1 or 2;

R1represents a group of the formula:

where

m=0 or 1;

R30represents hydrogen or C1-C6alkyl;

R4and R5form together with the N atom to which they are attached, a 5 - or 6-membered saturated N-containing heterocyclic group which includes 0 or 1 additional heteroatom selected from N, S and O, which may be condensed with a benzene ring and which is unsubstituted or substituted; or one of R4and R5is an alkyl and the other represents a 5 - or 6-membered saturated N-containing heterocyclic group as defined above, or alkyl group which is substituted 5 - or 6-membered saturated N-containing heterocyclic group as defined above;

R2selected from the

(a)

where R6and R7form together with the nitrogen atom to which they are attached, morpholino, thiomorpholine, piperidine, pieperazinove, oxazepine or diazepambuy group, which is unsubstituted what does substituted; and

(b)

where Y represents a chain C2-C4alkylene, which contains between the constituent atoms of the carbon chain and/or at one or both ends of the chain 1 or 2 heteroatoms selected from O, N and S and which is unsubstituted or substituted;

and R3represents indazol group, which is unsubstituted or substituted;

or its pharmaceutically acceptable salt.

Detailed description of the invention

Thiophene or furan ring in the formula (I) takes any of the two existing regional chemical orientations. Thus, the formula (I) covers thieno[3,2-d]pyrimidines and furano[3,2-d]pyrimidine of the following formula (Ia), and thieno[2,3-d]pyrimidines and furano[2,3-d]pyrimidine of the following formula (Ib):

where each of R1-R3and n have the meanings defined above, and X represents S or O.

In the formula (I) the group or groups R1that are the same or different, in this connection, when n=2, can be associated with any or both of the two available positions of the rings on the thiophene or furan ring A. Therefore, referring to the above structures (Ia) and (Ib), when n=1, furan or thiophene ring is monosubstituted by a radical R1in position 2 or state is 3. When n=2, thiophene or furan ring is disubstituted by the radical R1in positions 2 and 3.

As defined in the description, the alkyl group represents an unbranched or branched saturated hydrocarbon radical, which is unsubstituted or substituted. Usually it represents a C1-C20alkyl, for example, C1-C10alkyl, such as C1-C6alkyl or C1-C4alkyl, for example methyl, ethyl, isopropyl, n-propyl, tert-butyl, sec-butyl or n-butyl. It can also represent pentyl, hexyl, heptyl, octyl and its various branched isomers.

When an alkyl group is substituted it typically bears one or more substituents R20selected from halogen, alkoxy, carbocycle, 5 - or 6-membered saturated N-containing heterocyclic group as defined above, OH, SR, CN, nitro, NR2, -COOR, -C(O)R, -CH2OR, S(O)mR, -NRC(O)R, -S(O)mNR2, -OC(O)R, -OC(O)NR2, NRS(O)mR, NRC(O)NR2and-CONR2where each R represents H, unsubstituted alkyl or C3-C10cycloalkyl and m represents 1 or 2.

Usually R20selected from halogen, alkoxy, carbocycle, 5 - or 6-membered saturated N-containing heterocyclic group as defined above, OH, CN, NR2, -COOR, and-CONR2where each R represents Neely unsubstituted alkyl, as specified above.

Substituted alkyl may represent, for example, halogenation group or a group-ALK-N(R4)(R5), where ALK represents alkylenes chain, and R4and R5form together with the N atom to which they are attached, a 5 - or 6-membered saturated N-containing heterocyclic group which includes 0 or 1 additional heteroatom selected from N, S or O, which may be condensed with a benzene ring and which is unsubstituted or substituted. Often it is halogenating group-ALK-N(R4)(R5), where ALK represents alkylenes chain, and R4and R5form together with the N atom to which they are attached, a 5 - or 6-membered saturated N-containing heterocyclic group as defined above.

Allenova group is an unsubstituted or substituted, unbranched or branched saturated divalent hydrocarbon group. Usually it represents a C1-C8alkylen, for example, C1-C6alkylen. Preferably, it represents a C1-C4alkylen, for example, C2-C4alkylene, such as methylene, ethylene, isopropylene, n-propylene, t-butylene, sec-butylene, or n-butylene. It can also be pentile, hexylen, reptile, octile andtheir various branched isomers. When Allenova group is substituted, it is substituted by a group R20as defined above, or alkyl, which is unsubstituted or substituted by a group R20as specified above.

Alchemilla group is an unsubstituted or substituted, unbranched or branched hydrocarbon radical having one or more double bonds. Usually it represents a C2-C8alkenyl, for example, C2-C6alkenyl, such as allyl, butenyl, butadienyl, pentenyl or hexenyl. When Alchemilla group is substituted, it is substituted by a group R20as defined above, or alkyl, which is unsubstituted or substituted by a group R20as specified above.

Alchemilla group is an unsubstituted or substituted, unbranched or branched hydrocarbon radical having one or more triple bonds. Usually it represents a C2-C8quinil, for example, C2-C6quinil, such as ethinyl, PROPYNYL or butynyl. When Alchemilla group is substituted, it is substituted by a group R20as defined above, or alkyl, which is unsubstituted or substituted by a group R20as specified above.

Halogenation group represents an alkyl group, as defined above, substituted by one or is more halogen atoms. It can represent perhalogenated group, for example, trifluoromethyl or perferences.

Halogen represents chlorine, fluorine, bromine or iodine. He usually represents bromine or iodine.

Alkoxygroup is unbranched or branched. It usually represents C1-C6alkoxy, for example, C1-C4alkoxy, such as methoxy, ethoxy, isopropoxy, n-propoxy, tert-butoxy, n-butoxy or second-butoxy. She is unsubstituted or substituted, for example, the group R20having the values defined above, or alkyl, which is unsubstituted or substituted, as defined above, the group R20. Usually it is replaced by carbocyclic, morpholino, OH, CN, NR2, -COOR, or-CONR2where each R represents H or unsubstituted alkyl, as defined above.

The carbocyclic group is a non-aromatic saturated or unsaturated monocyclic hydrocarbon ring, usually with 3 to 10 carbon atoms. It can be a C3-C8cycloalkyl group or a C5-C10cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Alternatively, it can represent cycloalkenyl group, usually C4-C8cycloalkenyl, for example, qi is lofentanil, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene, cyclooctene or cyclooctadiene. The carbocyclic group may be unsubstituted or substituted, for example, the group R20as defined above, or alkyl, which is unsubstituted or substituted by a group R20as defined above. Usually, she substituted alkoxy, metroline, OH, CN, NR2, -COOR, or-CONR2where each R represents H or unsubstituted alkyl, as defined above.

5 - or 6-membered saturated N-containing heterocyclic group which includes 0 or 1 additional heteroatom selected from N, S and O, which may be condensed with a benzene ring and which is unsubstituted or substituted, typically selected from the research, piperidine, piperazine, pyrrolidine, thiomorpholine, quinoline, isoquinoline, diazepan, oxazepan and diazepan.

When the 5 - or 6-membered saturated N-containing heterocyclic group as defined above, is usually substituted by one or more substituents, for example 1, 2 or 3 substituents, typically 1 or 2 substituents. Typically, the substituents selected from alkyl, which is unsubstituted or substituted, alkoxy which is unsubstituted or substituted, -NR2, -N(R”')-ALK-OR, -O-ALK-OR-ALK-C(O)NR2, -C(O)NR2, -ALK-Het, -N(R)-Het, -O-Het, -N(R)-C(O)-ALK-OR, -C(O)-N(R)-ALK-OR-ALK-S(O)2R-N(R)-ALK-OR, -ALK-R NR'r”, -N(R'”)-S(O)2R, S(O)2R'”, -ALK-N(R)-ALK-OR, -S(O)2-ALK-OR, the second 5 - or 6-membered saturated N-containing heterocyclic group as defined above, 5 - or 6-membered N-containing heteroaryl group which is unsubstituted or substituted and which may be condensed with a benzene ring, -COOR, -CONR2, oxo(=O), -SO2NR2, -SO2-ALK-NR2and-CO-ALK-OR, where ALK represents alkylenes chain, as defined above; Het represents a 5 - or 6-membered N-containing heteroaryl group, as defined above, which is unsubstituted or substituted; R represents H or alkyl, or when 2 groups R are associated with N, they may form, together with the N atom, a saturated 5 - or 6-membered N-containing heterocyclic group as defined above which is unsubstituted or substituted; each of R' and R” represents independently H, alkyl, or alkoxy; and R”' represents alkyl, which is unsubstituted or substituted, for example, CF3, NR2OR 5 - or 6-membered saturated N-containing heterocyclic group as defined above, or a 5 - or 6-membered N-containing heteroaryl group, as defined above, and the specified heterocyclic and heteroaryl groups are unsubstituted or substituted.

5-, 6 - or 7-membered assistsappearancescats group, which contains 1 or 2 heteroatoms selected from N, S and O and which is unsubstituted or substituted, typically selected from tetrahydropyran, tetrahydrothiopyran, tetrahydrofuran and tetrahydrothiophene.

When 5-, 6 - or 7-membered saturated heterocyclic group which contains 1 or 2 heteroatoms selected from N, S and O, is substituted it may be substituted by a group R20as defined above. It usually substituted by one or more substituents selected from alkyl as defined above which is unsubstituted or substituted, for example, R20as defined above, or alkyl, which is unsubstituted or substituted by a group R20as defined above, halogenoalkane, as defined above, alkoxy as defined above, which is unsubstituted or substituted, halogen, hydroxy, CN, nitro, amino, oxo(=O), and-NR'r R”where each R' and R” is independently H or alkyl.

Heteroaryl group is a heteroaryl group which contains 1, 2, 3 or 4 ring nitrogen atom and 0, 1 or 2 additional heteroatoms selected from O, N and S, and the group is monocyclic or bicyclic and unsubstituted or substituted. It is usually a 5-12-membered ring. Examples of heteroaryl groups include pyrrole, pyrazole nucleus, triazole, t is trusolino, indazol, thiazole, isothiazol, oxazoline, isooxazolyl, indole, isoindoline, 1,3-dihydroindol-2-about, pyridine-2-about, pyridine, pyridine-3-Aulnay, imidazole, 1,3-dihydropyrimidinase, benzimidazole, benzothiazole, benzothiadiazole, quinoline, isoquinoline, hinoksalinovym, pyrazolidinone, aminopyrazoles, imidazopyridines, pyrimidine, pyridazinone, pyrazinone and Stanovoy group. Preferred examples include indazol, indole, pyrazole nucleus and tetrazolo group. These groups can be unsubstituted or substituted, for example, the group R20as defined above, or alkyl, which is unsubstituted or substituted by a group R20as specified above.

5 - or 6-membered N-containing heteroaryl group which may be condensed with a benzene ring, usually selected from pyrrole, pyrazole, triazole, tetrazole, indazole, thiazole, isothiazole, oxazole, etoxazole, indole, isoindole, 1,3-dihydroindol-2-it, pyridine-2-it, pyridine, pyridine-3-ol, imidazole, 1,3-dihydropyrimidone, benzimidazole, benzothiazole, benzothiadiazole, quinoline, isoquinoline, cinoxacin, pyrazolidine, aminopyrazoles, imidazopyridine, pyrimidine, pyridazine and pyrazine. When such heteroaryl group is substituted, it can be C Medina group, R 20as defined above, or alkyl, which is unsubstituted or substituted by a group R20as specified above.

In R1m represents 0 or 1, usually 1. R30is a usually N. R4and R5usually form together with the N atom to which they are attached, a saturated N-containing heterocyclic group selected from the research, thiomorpholine, piperidine, piperazine, pyrrolidine, quinoline, isoquinoline, diazepan, oxazepan and diazepan. Heterocyclic group formed by R4and R5is unsubstituted or substituted, for example, by one or more substituents selected from alkyl, which is unsubstituted or substituted, alkoxy which is unsubstituted or substituted, -N(R”')-ALK-OR-ALK-OR, -O-ALK-OR-ALK-C(O)NR2, -C(O)NR2, -ALK-Het, -N(R)-Het, -O-Het, -N(R)-C(O)-ALK-OR, -NR-S(O)2R, -N(R)-ALK-S(O)2R, -N(R)-ALK-OR-ALK-R NR'r”, -N(R'”)-S(O)2R, S(O)2R'”, -ALK-N(R)-ALK-OR, -S(O)2-ALK-OR, and 5 - or 6-membered N-containing heteroaryl group, and which may be condensed with a benzene ring, -COOR, -CONR2, oxo(=O), -SO2NR2, -SO2-ALK-NR2and-CO-ALK-OR, where ALK represents alkylenes chain, as defined above; Het represents a 5 - or 6-membered N-containing heteroaryl group, as defined above, which is resumes is authorized or substituted; R represents H or alkyl, or when 2 groups R are associated with N, they may form, together with the N atom, a saturated 5 - or 6-membered N-containing heterocyclic group as defined above which is unsubstituted or substituted; each of R' and R” is independently H, alkyl, or alkoxy; and R”' represents alkyl, which is unsubstituted or substituted, for example, CF3, NR2OR 5 - or 6-membered N-containing saturated heterocyclic group, as defined above, or a 5 - or 6-membered N-containing heteroaryl group, as defined above, and the specified heterocyclic and heteroaryl groups are unsubstituted or substituted.

In this definition, R1Het is usually selected from pyridines (e.g. pyridine-1-yl, pyridine-2-yl or pyridin-3-yl)pyrimidine, imidazole, furan, oxazole, isoxazol, and thiazole, each of which is unsubstituted or substituted. Part of the "ALK" represents an unbranched1-C4alkylenes group, typical,1-C3alkylene, such as-CH2-, -CH2CH2or-CH2CH2CH2-.

In determining (a) R2in the formula (I), the ring formed by R6and R7is usually a morpholine, which is unsubstituted or substituted, for example, the group R20to whom to defined above. Alternative it can represent a group selected from tetrahydropyran, tetrahydrothiopyran, tetrahydrofuran and tetrahydrothiophene, each of which is unsubstituted or substituted, for example, the group R20as defined above. When the ring formed by R6and R7is substituted it may be substituted on any ring heteroatom or a ring carbon atom, for example, the group R20as defined above, or alkyl group which is unsubstituted or substituted, for example, the group R20as specified above.

In definition (b) R2in the formula (I) Allenova chain represented by Y forms together with the carbon atoms to which they are attached, a saturated 5-, 6 - or 7-membered heterocyclic ring which contains 1 or 2 heteroatoms selected from O, N and S and which is unsubstituted or substituted. Examples of heterocyclic rings include tetrahydropyran, tetrahydrofuran, tetrahydrothiopyran, tetrahydrothiopyran and morpholine. When the heterocyclic ring is substituted, it is usually substituted by one or more substituents, for example 1, 2 or 3 substituents selected from halogen, alkyl, halogenoalkane (for example, trifloromethyl), alkoxy, OH, CN, NR2, oxo (=O), -COOR, and-CONR2where each R represents H or unsubstituted alkyl, ka is defined above.

Indazol group R3is unsubstituted or substituted. If it is substituted it may be substituted by one or more substituents selected from the group Z, where Z is selected from OR, CH2OR, CO2R, CF2OH, CH(CF3)OH, C(CF3)OH, -(CH2)qOR2and -(CH2)qNR2where each R is independently H or alkyl, and q=0, 1, or 2; one or more substituents selected from halogen, alkyl, alkenyl, quinil, CN, NO2, OR, SR, NR2C(O)R, SOR, SO2R, SO2NR2, NC(O)R and CO2R, where each R is independently H or alkyl; and oxoprop (=About). Usually when replacing indazol group substituted HE, NH2or exography. In one embodiment, indazol group is unsubstituted.

Indazol group R3represents isostere 3-hydroxyproline or 4-hydroxyproline group. Used in the description of the term "isostere" represents a functional group that has the properties of the binding, which is the same as or similar to the 3-hydroxyproline or 4-hydroxyproline group, in the context of the structural formula (I).

In one embodiment, the condensed pyrimidine is of formula (Ic):

where

R2and R3have the meanings given above

n=1; and

R1represent a group of the formula:

where

m=0 or 1;

R4and R5together with the N atom to which they are attached, form a 5 - or 6-membered saturated N-containing heterocyclic group which includes 0 or 1 additional heteroatom selected from N, S or O and which is unsubstituted or substituted by one or more substituents selected from alkyl, which is unsubstituted or substituted, alkoxy which is unsubstituted or substituted, -NR2, -N(R”')-ALK-OR-ALK-OR, -O-ALK-OR-ALK-C(O)NR2, -C(O)NR2, -ALK-Het, -N(R)-Het, -O-Het, -N(R)-C(O)-ALK-OR, -C(O)-NR-ALK-OR-ALK-S(O)2R, -N(R)-ALK-OR-ALK-R NR'r”, -N(R'”)-S(O)2R, S(O)2R'”, -ALK-N(R)-ALK-OR, -S(O)2-ALK-OR, and 5 - or 6-membered N-containing heteroaryl group which is unsubstituted or substituted and which may be condensed with a benzene ring, where ALK represents alkylenes chain, as defined above; Het represents a 5 - or 6-membered N-containing heteroaryl group, as defined in the description, which is unsubstituted or substituted; R represents H or alkyl, or when 2 groups R are associated with N, they can form together with the N atom a saturated 5 - or 6-membered N-containing heterocyclic group as defined above, which is nezam the seal or substituted; each of R' and R” is independently H, alkyl, or alkoxy; and R”' represents alkyl, which is unsubstituted or substituted, or one of R4and R5is an alkyl and the other represents a 5 - or 6-membered saturated N-containing heterocyclic group as defined above which is unsubstituted or substituted as defined above, or alkyl group which is substituted 5 - or 6-membered saturated N-containing heterocyclic group as defined above; or their pharmaceutically acceptable salt.

In the formula (Ic), part of the "ALK" represents a usually unbranched1-C4alkylenes group, typical,1-C3alkylene, such as-CH2-, -CH2CH2or-CH2CH2CH2-. Heterocyclic group formed by R4and R5usually chosen from the research, piperidine and piperazine, each of which is unsubstituted or substituted as defined above. R2usually represents morpholine. R3is a usually indazol group, which is unsubstituted.

Specific examples of compounds according to the invention include

2-(1H-indazol-4-yl)-6-(4-methylpiperazin-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine;

dimethylamide 4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrim the DIN-6-ylmethyl]piperazine-1-sulfonic acid;

{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-yl}morpholine-4-ylmethanone;

(2-methoxyethyl)methylamide 4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-carboxylic acid;

{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-yl}-N,N-dimethylacetamide;

dimethylamide 4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-carboxylic acid;

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-[4-(3-morpholine-4-improper-1-sulfonyl)piperazine-1-ylmethyl]thieno[3,2-d]pyrimidine;

{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-1-yl}-(2-methoxyethyl)methylamine;

(3-{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-sulfonyl}propyl)dimethylamine;

2-{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-yl}-2-methylpropan-1-ol;

1'-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-[1,4']bipyridinyl;

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-(morpholine-4-reparacin-1-ylmethyl)thieno[3,2-d]pyrimidine;

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-(pyrimidine-2-reparation-1-ylmethyl)thieno[3,2-d]pyrimidine;

1-(2-hydroxyethyl)-4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-2-he;

6-(4-cyclopropylamines-1-ylmethyl)-2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine;

p> 2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-pyridine-2-reparation-1-ylmethyl)thieno[3,2-d]pyrimidine;

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-[4-(2,2,2-triptorelin)piperazine-1-ylmethyl]thieno[3,2-d]pyrimidine;

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-thiazol-2-reparation-1-ylmethyl)thieno[3,2-d]pyrimidine;

2-(6-fluoro-1H-indazol-4-yl)-6-(4-methylpiperazin-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine;

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-pyridine-2-iletileri-1-ylmethyl)thieno[3,2-d]pyrimidine;

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-thiazol-2-iletileri-1-ylmethyl)thieno[3,2-d]pyrimidine;

2-(1H-indazol-4-yl)-6-[4-(5-methylfuran-2-ylmethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine;

amide 1-[2-(1H-indazol-4-yl)4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-carboxylic acid;

2-(1H-indazol-4-yl)-6-[4-(2-methoxy-1,1-dimethylethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine;

2-(1H-indazol-4-yl)-6-[(3R,5S)-4-(2-methoxyethyl)for 3,5-dimethylpiperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine;

(2-methoxyethyl)methylamide 1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-carboxylic acid;

dimethylamide 1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-carboxylic acid;

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-pyridine-3-iletileri-1-ylmethyl)thieno[3,2-d]pyrimidine;

methylamide 1-[2-(1H-indazol-4-yl) - morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-carboxylic acid;

2-{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-yl}-N-methylisoleucine;

2-{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-yl}-2-methyl-1-pyrrolidin-1-improper-1-it;

2-(1H-indazol-4-yl)-6-[4-(1-methyl-1H-imidazol-2-ylmethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine;

2-(1H-indazol-4-yl)-6-[4-(5-methylisoxazol-3-ylmethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine;

1-{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-yl}-2-methylpropan-2-ol;

Cyclopropylmethyl-{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}-(2-methoxyethyl)amine;

6-[4-(1-ethyl-1-methoxymethyl)piperazine-1-ylmethyl]-2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine;

2-(1H-indazol-4-yl)-6-[4-(1-methoxyoestradiol)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine;

{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}-(2-methoxyethyl)-(2,2,2-triptorelin)amine;

2-(1H-indazol-4-yl)-6-[4-(2-methoxyethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine;

{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}methanol;

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-pyridin-4-iletileri-1-ylmethyl)thieno[3,2-d]pyrimidine;

2-(1H-indazol-4-yl)-6-[4-(6-methylpyridin-2-ylmethyl)piperazine-1-ILM is Teal]-4-morpholine-4-illiano[3,2-d]pyrimidine;

2-(1H-indazol-4-yl)-6-[4-(4-methylthiazole-2-ylmethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine;

{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}pyridine-2-ylamine;

N-{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}-2-methoxy-N-methylacetamide;

N-{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}-N-methylmethanesulfonamide;

{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}-(3-methoxypropyl)methylamine;

6-((3S,5R) - for 3,5-dimethyl-4-pyridin-2-iletileri-1-ylmethyl)-2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine;

2-(1H-indazol-4-yl)-6-(4-methoxypiperidine-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine;

{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}-(2-methoxyethyl)thiazol-2-ylmethylamino;

1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-4-pyridine-2-iletilerini-4-ol;

{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]pyridine-4-yl}isopropyl-(2-methoxyethyl)amine;

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-[4-(pyridine-2-yloxy)piperidine-1-ylmethyl]thieno[3,2-d]pyrimidine;

N-{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}-N-(2-methoxyethyl)methanesulfonamide;

2-{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-and the methyl]piperidine-4-yl}propan-2-ol;

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-[4-(1-oxypyridine-3-ylmethyl)piperazine-1-ylmethyl]thieno[3,2-d]pyrimidine;

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-(morpholine-4-iletilerini-1-ylmethyl)thieno[3,2-d]pyrimidine;

{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-ylmethyl}-(2-methoxyethyl)methylamine;

{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-ylmethyl}dimethylamine;

{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-3-yl}-(2-methoxyethyl)methylamine;

methylamide 1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-3-carboxylic acid;

2-(1H-indazol-4-yl)-6-(3-methoxypiperidine-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine;

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-pyridine-2-iletilerini-1-ylmethyl)thieno[3,2-d]pyrimidine;

2-(1H-indazol-4-yl)-6-[4-(2-methoxyethoxy)piperidine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine;

6-((3R,5S) - for 3,5-dimethyl-4-thiazol-2-iletileri-1-ylmethyl)-2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine;

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-[4-(1-oxypyridine-2-ylmethyl)piperazine-1-ylmethyl]thieno[3,2-d]pyrimidine;

2-(1H-indazol-4-yl)-6-[4-(2-methoxyethyl)piperidine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine;

2-(1H-indazol-4-yl)-6-(4-methanesulfonamido-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine;

{1-[2-(1H-indazol-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}-(3-methanesulfonyl)methylamine;

2-(1H-indazol-4-yl)-6-[4-(3-methoxypropan-1-sulfonyl)piperidine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine;

methylamide (R)-1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-3-carboxylic acid;

methylamide (S)-1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-3-carboxylic acid;

6-(4-imidazol-1-iletilerini-1-ylmethyl)-2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine;

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-morpholine-4-ilmatieteen[3,2-d]pyrimidine;

2-(1H-indazol-4-yl)-6-(3-methylpiperidin-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine;

{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-3-yl}methanol;

2-{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}ethanol;

1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-4-thiazole-2-reparacin-4-ol;

2-(1-methyl-1H-indazol-4-yl)-6-(4-methylpiperazin-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine;

2-(2-methyl-2H-indazol-4-yl)-6-(4-methylpiperazin-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine;

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-thiazole-4-iletileri-1-ylmethyl)thieno[3,2-d]pyrimidine;

1-{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-yl}-3-phenoxypropan-2-ol;

6-{4-(1H-imidazol-2-ylmethyl)piperazine-1-ylmethyl]-2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]p is rimidine;

6-{4-(3H-imidazol-4-ylmethyl)piperazine-1-ylmethyl]-2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine;

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-((2S,6R)-2,4,6-trimethylpyrazine-1-ylmethyl)thieno[3,2-d]pyrimidine;

{4-[2-1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-1-methanesulfonylaminoethyl-2-yl}methanol; and

2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-3-methoxypiperidine-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine;

and their pharmaceutically acceptable salts.

The compounds of formula (I) can exist in the form of geometric isomers or tautomers depending on species groups substituents, and these isomers in their isolated forms or mixtures can be used in the present invention. When compounds have asymmetric carbon atoms can exist as optical isomeric forms with different configuration of such carbon atoms. All mixtures and isolated forms of these optical isomers can be used in the present invention.

Suitable synthesis method of obtaining compounds of formula (I)in which m=1, uses as a source of product carboxyaldehyde formula (II):

where a and R2have the meanings given above. From this precursor, the synthesis involves performing in any order using palladium reactions Suzuki cross-coupling and restore the positive amination. Therefore, the present invention also relates to a method for obtaining compounds of formula (I)as defined above in which m=1, and the method includes

(a) treatment of compounds of formula (II):

where a and R2have the meanings given above, Bronevoy acid or a complex ester of the formula R3B(OR15)2in which R3shall have the meaning given above, and each R15represents N or C1-C6alkyl or 2 groups OR15together with the boron atom to which they are attached, form the group of ester of penatration in the presence of a palladium catalyst; and processing the obtained compound of the formula (III):

where A, R2and R3have the meanings defined above, an amine of the formula with other4R5in which R4and R5have the meanings given above, in the presence of a suitable reducing agent; or

(b) treatment of compounds of formula (II), as defined above, an amine of the formula with other4R5where R4and R5have the meanings given above, in the presence of a suitable reducing agent; and processing the obtained compound of the formula (IV):

where A, R2R4and R5have the meanings defined above, with Boro the OIC acid or a complex ester of the formula R 3B(OR15)2in which R3has the values defined above, and each R15represents N or C1-C6alkyl or 2 groups OR15together with the boron atom to which they are attached, form the group of ester of penatration in the presence of palladium catalyst.

And stage amination, and stage cross-combination with the use of Pd occurs in normal conditions. The palladium catalyst may be any commonly used for cross-combination of Suzuki type, such as PdCl2(PPh3)2. Reducing agent is usually a borohydride, for example, NaBH(OAc)3, NaBH4or NaCNBH4in particular, NaBH(OAc)3.

Ester of penatration can, for example, be obtained as described in any of the reference examples 5 and 6 below.

The compound of formula (II), as defined above, where R2represents-NR6R7you can get a method that includes processing the compounds of formula (IX):

where A, R6and R7have the meanings given above, literalism agent, followed by treatment of N,N'-dimethylformamide (DMF), DMF). The reaction is usually carried out by adding a solution otherwisehe agent in a nonpolar organic solvent, for example, hydrocarbon solvent, that is ω as hexane, to a suspension of compounds of formula (IX) in an organic solvent, such as tetrahydrofuran (THF, THF). If THF is used, the addition occurs at a low of about -78°C temperature. Literaly agent is a normally alkality, for example, n-utility.

The compound of formula (IX)as defined above, can be obtained by a method that includes processing the compounds of formula (X):

with an amine of the formula with other6R7where R6and R7have the meanings defined above, in an organic solvent. The solvent is usually an alcohol, such as methanol. The reaction is generally carried out at room temperature.

The compound of formula (X) can be obtained by the method described in reference example 1, to obtain 2,4-dichlorethene[3,2-d]pyrimidine, or by analogy with this method.

The compound of formula (II), as defined above, where R2has the formula

you can get a method that includes the effects of the compound of formula (XI):

where a and R3have the meanings defined above, with a compound of formula (XII):

where L represents H or a group selected from halogen, -OSO2CF3, -B(OR)2, -Sn(R)3and-Si(R)3where R represents the or alkyl, as defined above, followed by reduction, to obtain the compounds of the following formula (XIII):

where A, R3and Y have the meanings given above.

The compound of formula (XIII) can be converted into the corresponding carboxaldehyde processing literalism agent, followed by treatment of N,N'-dimethylformamide (DMF), for example, in the conditions described above for the conversion of compounds of formula (IX) into the compound of the formula (II). Literaly agent shall have the meaning given above. Then the obtained carboxaldehyde can be converted into the desired final compound of formula (I)as defined above in which m=1, by treatment with the amine of the formula with other4R5where R4and R5have the meanings given above, in the presence of a suitable reducing agent, for example, borohydride, as defined above, in particular, NaBH(Ac)3.

The compound of formula (I)as defined above in which m=0, can be obtained by Buchwald reaction in the presence of palladium by incorporating nitrogen. Such a method may include processing the compounds of formula (XIV):

where A, R2and R3have the meanings defined above, and W represents a halogen selected from Br and I, an amine of the formula with other4R5where R4and R5have the meanings given above, in Pris is accordance palladium catalyst.

The compound of formula (XIV) can be obtained by treating compound of formula (XV):

where A, R2and R3have the meanings given above, literaure agent, and a halogen selected from bromine and iodine. Literaly agent is usually alkality, for example utility. Halogen represents usually iodine, which provides obtaining the compounds of formula (XIV)in which W represents a I.

The compound of formula (I)as defined above in which m=0, can also be obtained by the reaction of polar aromatic substitution (SNAr), for example, under the conditions described D. Prim and G. Kirsch in Tetrahedron 1999, 55 (21), 6511-6526. This method includes processing the compounds of formula (XIV)as defined above, in which W represents Br, with an amine of the formula with other4R5where R4and R5have the meanings defined above, in water while boiling under reflux for 12 hours.

The alternate connection of the formula (I)as defined above in which m=0, can be obtained by treating compound of formula (XIV)as defined above, in which W is an I, an amine of the formula with other4R5where R4and R5have the meanings defined above, 1,4-dioxane, in the presence of CuI/En and K3PO4. The reaction is carried out at a temperature of about 110°C for 24 hours. This procedure is described Kang S-K et al, Synlett, (3), 427-430, 2002.

Condensed pyrimidine of the formula (I) can be converted into a pharmaceutically acceptable salt and salt can be converted into the free compound by conventional means. Examples of pharmaceutically acceptable salts include the acid additive salts with inorganic acids such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, nitric acid and phosphoric acid; and organic acids such as formic acid, acetic acid, triperoxonane acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonate acid, econsultancy acid, aspartic acid and glutamic acid. In the case of compounds according to the invention, the bearing free carboxyl Deputy, salt include salts of alkali and alkaline earth metals and ammonium, for example, salts of sodium, potassium, magnesium, calcium and ammonium. Last receive treatment free of condensed pyrimidine of the formula (I) or its acid additive salts of the corresponding metal base or ammonia. The compounds of formula (I) and their salts may exist in the form of hydrate or solvate.

In biological tests was obnarujeno, the compounds of the present invention are inhibitors of PI3 kinase. These compounds are selective in relation to PI3 kinase, class Ia, in comparison with the Ib class, and usually are, at least, the selectivity in respect of the class Ia 20 times the selectivity for PI3 kinase class Ib. In particular, these compounds are selective about their isoforms p110α.

Thus, the connection of the present invention can be used as an inhibitor of PI3 kinase, in particular class Ia PI3. Accordingly, the compound of the present invention can be used to treat diseases or disorders caused by abnormal cell growth, function or behaviour associated with PI3 kinase. Examples of such diseases and disorders discussed Drees et al. in Expert Opin. Ther. Patents (2004) 14(5): 703-732. They include cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolic/endocrine disorders and neurological disorders. Examples of metabolic/endocrine disorders include diabetes and obesity. Examples of cancers for which treatment can be applied to these connections include leukemia, brain tumors, kidney cancer, stomach cancer and cancer of the skin, bladder, breast, uterus, lung, colon, prostate, ovarian and pagelog who offered gland. Thus, the patient is human or animal suffering from an immune disorder, cancer, cardiovascular disease, viral infection, inflammation, metabolic/endocrine disorder or neurological disorders, can be treated by the process comprising introducing him to the compounds of the present invention, as defined above. Thus, it is possible to improve or alleviate the patient's condition.

In addition to the biochemical activity of the compounds according to the invention exhibit physico-chemical and pharmacokinetic properties, which makes them particularly suitable for use as medicines. This is shown, for example, in the results of the biological assays described in the following example 3. In particular, the compounds have a high solubility in water at physiological pH; many of them have a solubility of at least 40 μm, and a significant amount has a solubility of more than 100 μm. High solubility at physiological pH is desirable because it promotes biological availability. These compounds also have a high metabolic stability, as shown, in particular, the analysis of the clearance of hepatocytes described in example 3, in which it was shown that most of the tested compounds have a low clearance hepatocyte is. Low clearance hepatocytes correlates with a low rate of hepatic metabolism. Therefore, it is seen that the compounds of the present invention have improved physical-chemical and pharmacokinetic properties, at the same time preserving the biochemical activity as inhibitors of PI3 kinase.

The compound of the present invention can be introduced in a variety of dosage forms, e.g. orally, for example in the form of tablets, capsules, pills, coated with sugar or film of liquid solutions or suspensions, or parenterally, e.g. intramuscularly, intravenously or subcutaneously. Therefore, the connection can be activated by injection or infusion.

The dosage depends on various factors, including the age, weight and condition of the patient and route of administration. The daily dosage may vary within wide limits and should be chosen in accordance with the individual requirements in each particular case. Usually, however, the dosage selected for each route of administration when the connection is introduced separately to adults, from 0.0001 to 50 mg/kg, most often in the range of from 0.001 to 10 mg/kg of body weight, for example, from 0.01 to 1 mg/kg, This dose can be entered, for example, from 1 to 5 times/day. For intravenous injection, a suitable daily dose is from 0.0001 to 1 mg/kg body weight, preferably from 0.0001 to 0.1 mg/kg of body weight. The daily dose can be administered as a single dosage or in accordance with the scheme of introduction of fractional doses.

The connection is included in the formulation for use as a pharmaceutical or veterinary composition also includes a pharmaceutically or acceptable in the veterinary carrier or diluent. Songs are usually obtained in accordance with customary methods and injected into pharmaceutically or veterinary suitable form. The connection can be entered in any conventional form, for example, in the following form:

A) oral administration, for example, in the form of tablets, coated tablets, pills, lozenges, pellets, aqueous or oily suspensions, liquid solutions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be obtained in accordance with any method known in this field, for the manufacture of pharmaceutical compositions and such compositions may contain one or more means selected from the group consisting of sweeteners, flavoring agents, coloring agents and preserving drugs, to provide a pharmaceutically acceptable and palatable preparations.

Tablets contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable what ispolniteljami, which is suitable for the manufacture of tablets. These fillers can represent, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, dextrose, saccharose, cellulose, corn starch, potato starch, calcium phosphate or sodium phosphate; granulating and loosening substances, for example, maize starch, alginic acid, alginates or sodium starch glycolate; binders, for example starch, gelatin or the Arabian gum; lubricants, e.g. silica, magnesium stearate or calcium, stearic acid or talc; expanded onto a mixture; colorants, sweeteners, wetting agents such as lecithin, Polysorbate or valium. Tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a prolonged action over a longer period. For example, you can use the material to delay the destruction and absorption, such as glycerylmonostearate or glycerylmonostearate. Such preparations can be produced in a known manner, for example by means of mixing, granulating, tabletting, sugar coating or film.

Formulation for oral administration which may also be presented as hard gelatin capsules, where the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is represented by itself, or mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in a mixture with excipients suitable for the manufacture of aqueous suspensions. Such fillers are suspendresume means, for example, sodium carboxymethylcellulose, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone tragacanth gum and Arabic gum; dispersing or wetting agents may be a naturally occurring phosphatides, for example lecithin, or condensation products of accelerated with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecafluorooctane, or condensation products of ethylene oxide with partial esters derived from fatty acids, and exit, such as monooleate of polyoxyethylenesorbitan, or condensation products of ethylene oxide with partial esters derived of fatty acids, and anhydrides of exit, for example, m is noleta of polyoxyethylenesorbitan.

These aqueous suspensions may also contain one or more preservatives, for example ethyl -, or p-hydroxybenzoate n-propyl, one or more coloring substances, such as sucrose or saccharin.

Oil suspensions can be included in formulations of suspendirovanie active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.

You can add sweeteners, such as those mentioned above, and fragrances, to provide an oral drug with a pleasant taste and aroma. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for obtaining aqueous suspension by the addition of water provide the active ingredient in a mixture with dispersing or wetting agent, suspenders substance and one or more preservatives. Suitable dispersing or wetting agents and suspendresume substances are illustrated by the substances already mentioned above. May also contain additional excipients, for example sweetening, flavoring and KRA is Asia substances.

The pharmaceutical compositions according to the invention can also be represented in the form of emulsions of oil-in-water. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying means may be a naturally occurring resin, for example, Arabian gum or tragacanth gum, naturally occurring phosphatides, for example lecithin soybeans, and esters or partial esters derived from fatty acids and exicurity, for example, monooleate sorbitan, and condensation products of these partial esters with ethylene oxide, for example, monooleate of polyoxyethylenesorbitan. The emulsions may also contain sweetening and flavouring substances. Syrups and elixirs may be included in the preparative form with sweetening agents, for example glycerol, sorbitol or sucrose. In particular, the syrup for patients with diabetes may contain as carriers only products, such as sorbitol, which is not metabolized into glucose or which are metabolized into glucose only in very small quantities.

Such formulation may also contain a softening agent, a preservative and flavoring and coloring agents;

p> B) parenterally or subcutaneously, or intravenously, or intramuscularly, or vnutriserdechno, or by infusion techniques, in the form of a sterile injectable aqueous or oil suspensions. This suspension can be included in the preparative form, in accordance with known methods using those suitable dispersing or wetting agents and suspendresume substances which have been described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic, acceptable diluent or solvent, for example, such as a solution of 1,3-butanediol.

Among the acceptable vehicles and solvents that can be used are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile liquid oils are commonly used as a solvent or suspendida environment. For this purpose you can use any non-irritating, liquid oils, including synthetic mono - or diglycerides. In addition, when receiving injectable drugs are used fatty acids such as oleic acid;

(C) by inhalation in the form of aerosols or solutions for nebulizers;

D) rectally in the form of suppositories, obtained by mixing the drug with a suitable not irritating excipient which is solid fuel is smoke at ordinary temperature, but liquid at rectal temperature and therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols;

E) locally in the form of creams, ointments, gels, lotions, solutions or suspensions.

Hereinafter the invention will be described in the following examples:

Reference example 1

2,4-dichlorethene[3,2-d]pyrimidine (64)

A mixture of methyl 3-amino-2-thiophenecarboxylate (13,48 g, 85,85 mmol) and urea (29,75 g, 5 EQ.) heated at 190°C for 2 hours. The hot reaction mixture is then poured into a solution of sodium hydroxide and any insoluble material removed by filtration. The mixture is then acidified (HCl, 2N) to obtain 1H-thieno[3,2-d]pyrimidine-2,4-dione (63) in the form of a white precipitate, which is collected by filtration and dried in air (9,49 g, 66%).

1H NMR (400 MHz, d6-DMSO) of 6.90 (1H, d, J=5,2 Hz), 8,10 (1H, d, J=5,2 Hz), 11,60-11,10 (2H, users).

A mixture of 1H-thieno[3,2-d]pyrimidine-2,4-dione (9,49 g, 56,49 mmol) and phosphorus oxychloride (150 ml) heated to boiling under reflux for 6 hours. The reaction mixture was then cooled and poured into ice water with vigorous stirring, receiving sediment. The mixture is then filtered to obtain 2,4-dichlorethene[3,2-d]pyrimidine (64) as a white solid (8,68 g, 75%).

1H NMR (400 MHz, CDCl3) 7,56 (1H, d, J=5.5 Hz), 8,13(1H, d, J=5,5 Hz).

Reference example 2

2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine (65)

A mixture of 2,4-dichlorethene[3,2-d]pyrimidine (64) (8,68 g, 42,34 mmol), research (8,11 ml, 2.2 EQ.) and MeOH (150 ml) was stirred at room temperature for 1 hour. The reaction mixture was then filtered, washed with water and Meon obtaining specified in the title compounds as white solids (11,04 g, 100%).

1H NMR (400 MHz, d6-DMSO) 3,74 (4H, t, J=4.9 Hz), 3,90 (4H, t, J=4.9 Hz), 7,40 (1H, d, J=5.6 Hz), 8,30 (1H, d, J=5.6 Hz).

Reference example 3

2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-carbaldehyde (66)

To a suspension of 2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine (65) (1.75 g, 6,85 mmol) in dry THF (40 ml) at -78°C. add 2.5 M solution of n-BuLi in hexane (3.3 ml, 1.2 EQ.). After stirring for 1 hour add dry DMF (796 μl, 1.5 EQ.). The reaction mixture is stirred for 1 hour at -78°C. and then slowly allowed to warm to room temperature. After another 2 hours at room temperature the reaction mixture was poured into water with ice, getting a yellow precipitate. It is collected by filtration and air-dried to obtain specified in the title compound (1.50 g, 77%).

1H NMR (400 MHz, d6-DMSO) 3,76 (4H, t, J=4.9 Hz), of 3.95 (4H, t, J=4.9 Hz), of 8.28 (1H, c), and 10.20 (1H, c).

Reference example 4

2-chloro-6-(4-IU reparacin-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine (72)

To a mixture of 2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-carbaldehyde (66) (147 mg, 0.52 mmol), 1-methylpiperazine (1.5 EQ., 87 μl) and acetic acid (of 1.05 EQ., 32 μl) in 1,2-dichloroethane (3 ml) add triacetoxyborohydride sodium (1.1 EQ., 121 mg) and then stirred at room temperature overnight. The reaction mixture was diluted with DCM, washed with a saturated solution of sodium bicarbonate, saline solution is separated and dried (MgSO4). The crude product is evaporated in vacuo and purify by chromatography to obtain specified in the connection header 72 in the form of not-quite-white crystalline solid (51 mg, 45%).

Reference example 5

Ester indazol-4-boronate (70):

Scheme 1

To a solution of 2-methyl-3-nitroaniline (2,27 g, 14,91 mmol) in acetic acid (60 ml) add a solution of sodium nitrite (1.13 g, 1.1 EQ.) in water (5 ml). After 2 hour deep-red solution is poured into ice water and the precipitate collected by filtration to obtain 4-nitro-1H-indazole (67) (1.98 g, 81%).

A mixture of 4-nitro-1H-indazole (760 mg, and 4.68 mmol), palladium-on-charcoal (10%, cat.) and ethanol (30 ml) is stirred under hydrogen atmosphere for 4 hours. Then the reaction mixture was filtered through celite and the solvent is removed in vacuum with recip is of 1H-indazol-4-ylamine (68) (631 mg, 100%).

An aqueous solution of sodium nitrite (337 mg, 4,89 mmol) in water (2 ml) is added dropwise to a suspension of 1H-indazol-4-ylamine (631 mg, 4,74 mmol) in 6M hydrochloric acid (7.2 ml) at a temperature below 0°C. After stirring for 30 min to the reaction mixture add tetrafluoroborate sodium (724 mg). The obtained viscous solution is filtered and briefly washed with water to obtain tetrafluoroborate 1H-indazol-4-page (69) (218 mg, 20%) as a dark red solid.

Dry Meon (4 ml), rinsed with argon for 5 minutes added tetrafluoroborate 1H-indazol-4-page (218 mg, of 0.94 mmol), bis-pinacolato Debora (239 mg, 1.0 EQ.) and chloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (20 mg). The reaction mixture is stirred for 5 hours and then filtered through celite. The residue is purified using flash chromatography, to obtain the desired specified in the title compound (70) (117 mg).

Reference example 6

Ester indazol-4-boronate (70):

Scheme 2

To a solution of 3-bromo-2-methylaniline (5.0 g, 26.9 mmol) in chloroform (50 ml) is added potassium acetate (of 1.05 EQ., of 28.2 mmol, 2,77 g). Add acetic anhydride (2.0 EQ., of 53.7 mmol, 5,07 ml) while cooling in ice water. The mixture is then stirred at room temperature for 10 min, after which the formed white STU is eniste substance. Then add 18-crown-6 (0.2 EQ., 5.37 mmol, 1.42 g) followed by the addition of isoamylamine (2.2 EQ., the 59.1 mmol, 7,94 ml) and the mixture heated to boiling under reflux for 18 hours. The reaction mixture allow to cool, divide between chloroform (3×100 ml) and saturated aqueous sodium bicarbonate (100 ml). The combined organic extracts washed with brine (100 ml), separated and dried (MgSO4).

The crude product is evaporated with silica and purified by chromatography, elwira 20%→40% EtOAc-petrol to obtain N-acetylimidazole (73) (3,14 g, 49%) as an orange solid substance with the subsequent receipt of indazole (74) (2,13 g, 40%) as a pale orange solid.

73:1H NMR (400 MHz, CDCl3) 2,80 (3H, c), 7,41 (1H, t, J=7.8 Hz), to 7.50 (1H, d, J=7.8 Hz), 8,15 (1H, c), 8,40 (1H, d, J=7,8 Hz).

74:1H NMR (400 MHz, CDCl3) to 7.25 (1H, t, J=7,3 Hz), 7,33 (1H, d, J=7,3 Hz), 7,46 (1H, d, J=7,3 Hz), 8,11 (1H, c), and 10.20 (1H, users).

To a solution of N-acetylimidazole (3,09 g, 12.9 mmol) in Meon (50 ml) was added 6N aqueous HCl (30 ml) and the mixture is stirred at room temperature for 7 hours. Meon is evaporated and the mixture was separated between EtOAc (2×50 ml) and water (50 ml). The combined organic layers washed with brine (50 ml), separated and dried (MgSO4). The solvent is removed by evaporation under reduced pressure to obtain an orange solid (2,36 g, 93%).

It races the thief 4-brominate (500 mg, 2.54 mmol) and bis(pinacolato)Debora (1.5 EQ., 3,81 mmol) in DMSO (20 ml) is added potassium acetate (3.0 EQ., to 7.61 mmol, 747 mg; dried in a drying pistol) and PdCl2(dppf)2(3 mol.%, 0,076 mmol, 62 mg). The reaction mixture allow to cool and divide between water (50 ml) and simple ether (3×50 ml). The combined organic layers washed with brine (50 ml), separated and dried (MgSO4). The crude material is purified by chromatography, elwira 30%→40% EtOAc-petrol obtaining an inseparable mixture of 3:1 complex ester of boronate (369 mg, 60%) and indazole (60 mg, 20%); it is isolated in the form of a yellow resin, which hardens after settling with obtaining compound (70) in the form of not-quite-white solid.

1H NMR (400 MHz, d6-DMSO) (70) of 1.41 (12H, c), 7,40 (1H, DD, J=8,4 Hz and 6.9 Hz), to 7.59 (1H, d, J=8,4 Hz), to 7.67 (1H, d, J=6.9 Hz), 10,00 (1H, users), to 8.45 (1H, c) and indazole: 7,40 (1H, t), 7,18 (1H, t, J=7.9 Hz), to 7.50 (1H, d, J=9.1 Hz), to 7.77 (1H, d, J=7.9 Hz), of 8.09 (1H, c). The admixture at 1.25.

Reference example 7

Ester 6-Florinda-4-boronate (75)

To a solution of 4-fluoro-2-nitrotoluene (3,44 g) in triperoxonane acid (13 ml) is added concentrated sulfuric acid (4 ml) followed by addition of N-bromosuccinimide (of 5.92 g). The reaction mixture was stirred for 16 h and then quenched with brine, extracted into ethyl acetate and dried (MgSO4). The solvent is removed in vacuum to obtain crude 1-br the m-5-fluoro-2-methyl-3-nitrobenzene (5,96 g).

To a solution of crude 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (5,96 g) in the Meon (90 ml) is added concentrated hydrochloric acid (11.7 ml) and iron (6,1 g)and the reaction mixture is heated to boiling under reflux. After 16 hours the mixture is cooled, diluted with DCM, washed with sodium carbonate solution, dried (MgSO4) and the solvent is removed in vacuum. The residue is purified using flash chromatography to obtain 3-bromo-5-fluoro-2-methylphenylamine (1,46 g).

To a solution of 3-bromo-5-fluoro-2-methylphenylamine (470 mg) in dioxane (6 ml), add triethylamine (1,28 ml), palladium acetate (25 mg), 2-dicyclohexylphosphino (161 mg) and pinacolborane (1,001 ml) and the mixture is heated to 80°C for 4 hours. The reaction mixture is cooled, diluted with chloroform, washed with brine, dried (MgSO4) and the solvent is removed in vacuum. The residue is purified using flash chromatography, to obtain the desired, specified in the title compound (466 mg).

Reference example 8

Getting 2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-carbaldehyde (71)

A mixture of 2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-carbaldehyde (66) (100 mg, 0.35 mmol), 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-indazole (70) (95 mg, 0,39 mmol) and sodium carbonate (112 mg) suspended in toluene (2.5 ml), ethanol (1.5 ml) and water (0.7 ml). To it add the chloride bis(triphenylphosphine)palladium (II) (13.5 mg) and the reaction vessel is rinsed with argon. The reaction mixture is subjected to microwave exposure at 120°C for 1 hour and then separated between DCM and water, the organic layer washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuum. The resulting residue is purified using flash chromatography, obtaining specified in the title compound 71 (97 mg).

Example 1

Getting 2-(1H-indazol-4-yl)-6-(4-methylpiperazin-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine (59) according to scheme 1

To a mixture of 2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-carbaldehyde (91 mg, 0.26 mmol), 1-methylpiperazine (34 mg, 0.36 mmol) and acetic acid (16 μl) in 1,2-dichloroethane (2 ml) add triacetoxyborohydride sodium (60 mg, 0.28 mmol). The reaction mixture was stirred at room temperature overnight and then transformed into the basis (saturated NaHCO3), diluted with DCM and washed with brine. The organic layer is separated, dried (MgSO4), filtered and evaporated in vacuum. The residue is purified using flash chromatography, obtaining specified in the title compound (33 mg).

1H NMR (400 MHz, d6-DMSO) to 2.18 (c, 3H), 2,30-2,45 (osirm, 4H), 2,48-2,55 (osirm, 4H), 3,82-a-3.84 (m, 4H), 3,86 (c, 2H), 3,98-4,00 (m, 4H), 7,44-7,47 (m, 2H), 7,65 (d, 1H, J=8,2 Hz), 8,21 (d, 1H, J=7,2 Hz), 8,87 (c, 1H), 13,16 (users, 1H); MS (ESI+) of 450.1 (MN+).

Example 2

Getting 2-(1H-indazol-4-the l)-6-(4-methylpiperazin-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine (59) according to scheme 2

Ester indazol-4-boronate (2.0 EQ., 0.82 mmol), 2-chloro-6-(4-methylpiperazin-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine (compound 72, obtained in reference example 4: 150 mg, 0.41 mmol) and sodium carbonate (3.0 EQ., 130 mg) are combined in a mixture of toluene (2 ml), ethanol (1 ml) and water (0.5 ml). Add PdCl2(PPh3)2(0.1 EQ.) and the reaction mixture is blown with argon and then heated in a microwave reactor at 130°C for 2 hours. After extraction (DCM/brine) and column flash chromatography, the product separated as a white solid (149 mg, 81%).

Example 2A

Other compounds according to the invention

The following compounds according to the invention receive by analogy with the method of example 2. The connection 72 substitute in each case the corresponding chlorine-containing compound is a precursor obtained by the method of reference example 4, using the relevant amine instead of 1-methylpiperazine. Getting amine, if necessary, as described below. Data of NMR are presented for each of the above in the header of the compounds according to the invention.

2-{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-yl}ethanol (60)

Get on the basis of 2-[4-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)piperazine-1-yl]ethanol.

1H NMR (400 MHz, d6-DMSO) 2,40 (osirm, 2H), 2,422,52 (user, 8H, under DMSO peak), of 3.48 (q, 2H, J=6.0 Hz), 3,82-3,86 (m, 6H), 3,98-4,01 (m, 4H), 4,34 (users, 1H), 7,44-of 7.48 (m, 2H), 7,65 (d, 1H, J=8,3 Hz), 8,21 (d, 1H, 6.8 Hz), 8,87 (c, 1H), 13,15 (users, 1H); MS (ESI+) 480,1 (MN+).

Dimethylamide 4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-sulfonic acid (62)

Get on the basis of dimethylamine 4-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)piperazine-1-sulfonic acid.

1H NMR (400 MHz, CDCl3) 2,63-of 2.66 (m, 4H), 2,84 (c, 6H), 3,31-to 3.34 (m, 4H), 3,89 (c, 2H), 3,92-of 3.94 (m, 4H), 4,08-4,11 (m, 4H), 7,39 (c, 1H), 7,51 (t, 1H, J=8.1 Hz), 7,60 (d, 1H, J=8.1 Hz), of 8.28 (d, 1H, J=6,7 Hz), 9,02 (c, 1H), 10,12 (users, 1H); MS (ESI+) 543,1 (MN+).

{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-yl}morpholine-4-ylmethanol (76)

Get on the basis of [4-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)piperazine-1-yl]morpholine-4-ylmethanone derived from morpholine-4-reparation-1 ylmethanone.

Getting amine: a mixture of 4-morpholinylcarbonyl (0,38 ml), 1-BOC-piperazine (552 mg) and potassium carbonate (439 mg) in MeCN (7 ml) was stirred at room temperature for 3 hours. Then the reaction mixture was diluted with DCM, washed with brine, dried (MgSO4) and the solvent is removed in vacuum to obtain complex tert-butyl ester 4-(morpholine-4-carbonyl)piperazine-1-carboxylic acid (865 mg). Treatment of this compound with HCl in DCM/MeOH gives the desired compound, which is the second release in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) 2,55-of 2.58 (4H, m), 3,28-of 3.32 (4H, m), 3,35-3,39 (4H, m), 3,67-3,71 (4H, m), 3,88 (2H, c), 3,92-of 3.96 (4H, m), 4,08-4,12 (4H, m), 7,39 (1H, c), 7,52 (1H, t, J=8.0 Hz), 7,60 (1H, d, J=6.3 Hz), 8,30 (1H, d, J=7,0 Hz), of 9.02 (1H, c), 10,10 (1H, user.); MS (ESI+) 549 (MN+).

(2-methoxyethyl)methylamide {4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-carboxylic acid (77)

Get from (2-methoxyethyl)methylamine 4-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)piperazine-1-carboxylic acid, obtained from (2-methoxyethyl)methylamine piperazine-1-carboxylic acid.

Getting amine: N-BOC-piperazine (500 mg) in DCM (5 ml) and triethylamine (0,41 ml) is added 4-nitrophenylphosphate (541 mg). After 1 hour the reaction mixture was diluted with DCM, washed with brine, dried (MgSO4) and the solvent is removed in vacuum to obtain complex tert-butyl and 4-nitrophenylamino esters piperazine-1,4-dicarboxylic acid (940 mg).

To complex tert-butyl and 4-nitrophenylamino esters piperazine-1,4-dicarboxylic acid (500 mg) in THF (5 ml) is added N-(2-methoxyethyl)methylamine (254 mg) and the reaction mixture is heated to boiling under reflux for 24 hours. The reaction mixture was concentrated in vacuo and purified flash column-chromatography with getting complicated tert-butyl ester 4-[(2-methoxyethyl)methylcarbamyl]piperazine-1-carboxylic acid (304 mg). Processing is as of this compound with HCl in DCM/MeOH gives the desired connection, which emit in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) at 2.59 2.63 in (4H, m), 2,90 (3H, c), 3.27 to 3.30 levels (4H, m), and 3.31 (3H, c), of 3.48 (2H, t), of 3.57 (2H, t), 3,90 (2H, c), 3,92-of 3.96 (4H, m), 4,08-4,12 (4H, m), 7,39 (1H, c), 7,52 (1H, t), 7,60 (1H, d, J=6.3 Hz), 8,30 (1H, d, J=7,0 Hz), of 9.02 (1H, c), 10,10 (1H, user.); MS (ESI+) 551 (MN+).

2-{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-yl}-N,N-dimethylacetamide (78)

Get on the basis of 2-[4-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)piperazine-1-yl]-N,N-dimethylacetamide, obtained from N,N-dimethyl-2-piperazine-1-ylacetamide.

Getting amine: a mixture of 1-BOC-piperazine (387 mg), 2-chloro-N,N-dimethylacetamide (0,43 ml) and triethylamine (of 0.58 ml) in chloroform was stirred at room temperature. After stirring over night the reaction mixture was diluted with DCM, washed with brine, dried (MgSO4) and the solvent is removed in vacuum to obtain complex tert-butyl ester 4-dimethylcarbamodithioato-1-carboxylic acid (558 mg). Treatment of this compound with HCl in DCM/MeOH gives the desired compound, which is isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) 2,63 (users, 8H, 4×CH2), 2,95 (c, 3H, CH3), of 3.07 (c, 3H, CH3), 3,20 (c, 2H, CH2), 3,85 (c, 2H, CH2), 3,90-3,93 (m, 4H, 2×CH2), 4,07-4,10 (m, 4H, 2×CH2), 4,36 (c, H, ArH), 7,49 (t, H, ArH, J=7,74 Hz), EUR 7.57 (d, H, ArH, J=compared to 8.26 Hz), compared to 8.26 (d, H, ArH, J=7.23 percent Hz), 9,00 (c, H, ArH), of 10.25 (users, H, NH) MS (ESI +) 521,29 (MN+).

Dimethylamide 4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-carboxylic acid (79)

Get on the basis of dimethylamine 4-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)piperazine-1-carboxylic acid, obtained from dimethylamide piperazine-1-carboxylic acid.

Getting amine: to a solution of 1-BOC-piperazine (867 mg) in dry THF (8 ml), add triethylamine (0,97 ml) followed by the addition of dimethylcarbamodithioato (0.51 ml). After stirring for 24 h the reaction mixture was diluted with DCM, washed with brine, dried (MgSO4) and the solvent is removed in vacuum to obtain complex tert-butyl ester 4-dimethylcarbamoyl-1-carboxylic acid (940 mg). Treatment of this compound with HCl in DCM/MeOH gives the desired compound, which is isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) to 2.57-2,61 (4H, m), 2,87 (6H, c), 3,30-to 3.35 (4H, m)to 3.89 (2H, c), 3,92-of 3.96 (4H, m), 4,08-4,12 (4H, m), 7,39 (1H, c), 7,52 (1H, t, J=8.0 Hz), 7,60 (1H, d, J=6.3 Hz), 8,30 (1H, d, J=7,0 Hz), of 9.02 (1H, c), 10,10 (1H, user.); (ESI+) MS (ESI+) 507 (MN+).

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-[4-(3-morpholine-4-improper-1-sulfonyl)piperazine-1-ylmethyl)thieno[3,2-d]pyrimidine (80)

Get on the basis of 2-chloro-4-morpholine-4-yl-6-[4-(3-morpholine-4-improper-1-sulfonyl)piperazine-1-ylmethyl]thieno[3,2-d]pyrimidine was obtained from 4-[3-(piperazine-1-sulfonyl)the filing]of the research.

Getting amine: a mixture of 1-BOC-piperazine (3,26 g), 3-chloropropanesulfonyl (2,63 g) and triethylamine (2,68 ml) was stirred at room temperature in DCM (25 ml). After 2 h the reaction mixture was diluted with DCM, washed with brine, dried (MgSO4) and the solvent is removed in vacuum to obtain complex tert-butyl ester 4-(3-chloropropane-1-sulfonyl)piperazine-1-carboxylic acid (4.65 in). The complex mixture of tert-butyl ester 4-(3-chloropropane-1-sulfonyl)piperazine-1-carboxylic acid (4,65 g), potassium iodide (1.1 g), potassium carbonate and research (1.6 ml) is heated to boiling under reflux in MeCN (100 ml). After 16 h, the reaction mixture was cooled, diluted with DCM, washed with brine, dried (MgSO4) and the solvent is removed in vacuum to obtain complex tert-butyl ester 4-(3-morpholine-4-improper-1-sulfonyl)piperazine-1-carboxylic acid (4.8 g). Treatment of this compound with HCl in DCM/MeOH gives the desired compound, which is isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) 1,98-2,02 (m, 2H), 2,44-2,47 (m, 6H), 2,67-2,69 (m, 4H), 2,99-3,03 (m, 2H), 3,36-to 3.38 (m, 4H), 3,69-3,71 (m, 4H), 3,90 (c, 2H), 3,91-3,93 (m, 4H), 4,08-4,10 (m, 4H), 7,39 (c, H, ArH), 7.50 for (t, H, ArH, J=7,7 Hz), 7,58 (d, H, ArH, J=8,32 Hz), of 8.27 (d, H, ArH, J=7,44 Hz), 9,00 (c, H, ArH), 10,10 (users, H, NH); MS (ESI+) 627,29 (MN+).

{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}-(2-methoxyethyl)methylamine (81)

Poluchaetsja of [1-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)piperidine-4-yl]-(2-methoxyethyl)methylamine, obtained from (2-methoxyethyl)methylpiperazin-4-ylamine.

Getting amine: a mixture of N-BOC-4-piperidine (500 mg), N-(2-methoxyethyl)methylamine (335 mg), acetic acid (0.15 ml) and triacetoxyborohydride sodium (797 mg) was stirred at room temperature in 1,2-dichloroethane (5 ml). After stirring over night the reaction mixture was diluted with chloroform, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent is removed in vacuum. The residue is purified using flash column chromatography, obtaining complex tert-butyl ester 4-[(2-methoxyethyl)methylamino]piperidine-1-carboxylic acid. Treatment of this compound with HCl in DCM/MeOH gives the desired compound, which is isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) 1,62-1,72 (2H, m), 1,76-of 1.84 (2H, m), 2,10-to 2.18 (2H, m), a 2.36 (3H, c), 2,40-2,48 (1H, m), 2,68 (2H, t, J=6.0 Hz), 3.04 from-3,11 (2H, m)to 3.38 (3H, c), a 3.50 (2H, t, J=6.3 Hz), 3,85 (2H, c), 3,92-of 3.97 (4H, m), 4,08-4,12 (4H, m), 7,39 (1H, c), 7,52 (1H, t, J=8.0 Hz), 7,60 (1H, d, J=6.3 Hz), 8,30 (1H, d, J=7,0 Hz), of 9.02 (1H, c), 10,10 (1H, user.); MS (ESI+) 522 (MN+).

3-{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-sulfonyl}propyl)dimethylamine (82)

Get on the basis of 3-{4-[2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)piperazine-1-sulfonyl)propyl}dimethylamine obtained from dimethyl[3-(piperazine-1-sulfonyl)propyl]amine. A step for Amina conduct as to connect the means 80.

1H NMR (400 MHz, CDCl3) 2,00-of 2.08 (2H, m), and 2.26 (6H, c), 2,42 (2H, t, J=6,7 Hz), 2,68-of 2.72 (4H, m), 3.00 and was 3.05 (2H, m), 3,37-to 3.41 (4H, m), 3,90 (2H, c), 3,92-of 3.96 (4H, m), 4,08-4,12 (4H, m), 7,39 (1H, c), 7,52 (1H, t, J=8.0 Hz), of 7.60 (1H, d, J=6.3 Hz), 8,30 (1H, d, J=7,0 Hz), of 9.02 (1H, c), 10,10 (1H, user.); MS (ESI+) 585 (MN+).

2-{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-yl}-2-methylpropan-1-ol (83)

Get on the basis of 2-[4-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)piperazine-1-yl]-2-methylpropan-1-ol, obtained from 2-methyl-2-piperazine-1-improper-1-ol.

Getting amine: a mixture of BOC-piperazine (1,87 g), ethyl-2-bromoisobutyrate (5,90 g) and potassium carbonate (1,53 g) in MeCN (20 ml) is heated in a sealed tube at 80°C for 3 days. The reaction mixture is cooled, diluted with chloroform, washed with brine, dried (MgSO4) and the solvent is removed in vacuum. The residue is purified column flash chromatography with getting complicated tert-butyl ester 4-(1-etoxycarbonyl-1-methylethyl)piperazine-1-carboxylic acid (2,97 g).

Processing complex tert-butyl ester 4-(1-etoxycarbonyl-1-methylethyl)piperazine-1-carboxylic acid sociallyengaged in a simple ester gives the corresponding alcohol, complex tert-butyl ester 4-(2-hydroxy-1,1-dimethylethyl)piperazine-1-carboxylic acid. Treatment of this compound with HCl in DCM/MeOH gives the desired compound, which is isolated in the form of chlorotoluron the salt.

1H NMR (400 MHz, CDCl3) of 9.02 (1H, c), of 8.25 (1H, d), 7,60 (1H, d), 7,51-7,49 (1H, m), 7,39 (1H, c), 4,08-4,06 (4H, m), 3,90-3,88 (4H, m), 3,85 (2H, c), of 3.46 (2H, c), 2,70-of 2.50 (8H, m)of 1.05 (6H, c); MS (ESI+) 508 (MN+).

1'-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-[1,4']bipyridinyl (84)

Get on the basis of 1'-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-[1,4']bipiperidine obtained from 4-piperidinylidene.

1H NMR (400 MHz, CDCl3) of 1.40-1.50 (2H, usher.), 1,50-1,75 (6H, usher.), 1,80-1,90 (2H, usher.), of 2.21 (2H, t, J=10,7 Hz), 2,35 is 2.43 (1H, usher.), 2,50-2,60 (4H, usher.), 3.04 from-3,10 (2H, user., d, J=11.4 in Hz)of 3.84 (2H, c), 3,92-of 3.96 (4H, m), 4,08-4,12 (4H, m), 7,39 (1H, c), 7,52 (1H, t, J=8.0 Hz), 7,60 (1H, d, J=6.3 Hz), 8,30 (1H, d, J=7,0 Hz), of 9.02 (1H, c), 10,10 (1H, user.); MS (ESI+) 518 (MN+).

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-(morpholine-4-reparacin-1-ylmethyl)thieno[3,2-d]pyrimidine (85)

Get on the basis of 2-chloro-4-morpholine-4-yl-6-(4-(morpholine-4-reparacin-1-ylmethyl)thieno[3,2-d]pyrimidine was obtained from 4-morpholinopropan.

1H NMR (400 MHz, CDCl3) 1,55 by 1.68 (2H, m), 1,83-1,90 (2H, m), 2,11-to 2.18 (2H, m), 2,18 was 2.25 (1H, m), 2,54-2,60 (4H, m), 3,05-3,11 (2H, m), 3,70 is 3.76 (4H, m), a-3.84 (2H, c), 3,92-of 3.96 (4H, m), 4,08-4,12 (4H, m), 7,39 (1H, c), 7,52 (1H, t, J=8.0 Hz), 7,60 (1H, d, J=6.3 Hz), 8,30 (1H, d, J=7,0 Hz), of 9.02 (1H, c), 10,10 (1H, user.); MS (ESI+) 520 (MN+).

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-(pyrimidine-2-reparation-1-ylmethyl)thieno[3,2-d]pyrimidine (86)

Get on the basis of 2-chloro-4-morpholine-4-yl-6-(4-(pyrimidine-2-reparation-1-ylmethyl)is ieno[3,2-d]pyrimidine, obtained from 1-(2-pyrimidyl)piperazine.

1H NMR (400 MHz, CDCl3) 2,64-2,70 (4H, m), a 3.87-3.96 points (10H, m), 4,10-to 4.14 (4H, m), 6,50 (1H, t, J=4,8 Hz), 7,40 (1H, c), 7,52 (1H, t, J=7.8 Hz), 7,60 (1H, d, J=8,3 Hz), 8,29-8,33 (3H, m), of 9.02 (1H, c), 10,10 (1H, user.); MS (ESI+) 514 (MN+).

1-(2-hydroxyethyl)-4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-2-he (87)

Get on the basis of 4-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)-1-(2-hydroxyethyl)piperazine-2-it is obtained from 1-(2-hydroxyethyl)piperazine-2-it.

Getting amine: 4-CBZ-piperazine-2-ONU (1,95 g) in DMF (5 ml) at 0°C. add sodium hydride (60% dispersion in mineral oil, 660 mg) in multiple aliquot quantities. After stirring for 1 hour add 2-Bromeliaceae (1,38 ml). The reaction mixture was stirred at room temperature overnight; then it is diluted with ethyl acetate, washed with brine, dried (MgSO4) and the solvent is removed in vacuum. The resulting residue is purified using flash chromatography, to obtain the complex benzyl ester 4-(2-acetoxyethyl)-3-oxopiperidin-1-carboxylic acid (925 mg).

1H NMR (400 MHz, d6-DMSO) 2,77 (2H, d, J=5.5 Hz), and 3.16 (2H, c), 3,32-to 3.36 (2H, m), 3,38-of 3.42 (2H, m), 3,51-3,55 (2H, m), 3,80-of 3.85 (4H, m), of 3.97 (2H, c), 4,00-Android 4.04 (4H, m), 4,70 (1H, t, J=5.4 Hz, HE), was 7.45 (1H, t, J=7,7 Hz), to 7.50 (1H, c), 7,66 (1H, d, J=8,2 Hz), by 8.22 (1H, d, J=7,3 Hz), 8,89 (1H, c), 13,15 (1H, user., NH); MS (ESI+) 494 (MN+).

6-(4-cyclopropyl ethylpiperazin-1-ylmethyl)-2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine (88)

Get on the basis of 2-chloro-6-(4-cyclopropylamines-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine was obtained from 1-cyclopropylalanine.

Getting amine: a mixture of BOC-piperazine (887 mg), (methyl bromide)cyclopropane (0.5 ml) and potassium carbonate (779 mg) in MeCN (10 ml) is heated to boiling under reflux for 16 hours. The reaction mixture is cooled, diluted with chloroform, washed with brine, dried (MgSO4) and the solvent is removed in vacuum. The residue is purified using flash chromatography, to obtain the complex tert-butyl ester 4-cyclopropylamines-1-carboxylic acid (1,05 g). Treatment of this compound with HCl in DCM/MeOH gives the desired compound, which is isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) 0,07-0,14 (m, 2H, 2×CH2), 0,48-of 0.51 (m, 2H, 2×CH), 0,8-0,95 (m, H, CH), 2,28 of-2.32 (m, 2H, CH2), to 2.5-2.7 (m, 8H, 4×CH2), 3,86 (c, 2H, CH2), 3,90-3,93 (m, 4H, 2×CH2), 4,07-4,11 (m, 4H, 2×CH2), 7,38 (c, H, ArH), 7.50 for (t, H, ArH, J=7,79 Hz), 7,58 (d, H, ArH, J=8,28 Hz), of 8.28 (d, H, ArH, J=EUR 7.57 Hz), 9,02 (c, H, ArH), 10,15 (users, H, NH); MS (ESI+) 490,19 (MN+).

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-pyridine-2-reparation-1-ylmethyl)thieno[3,2-d]pyrimidine (89)

Get on the basis of 2-(chloro-4-morpholine-4-yl-6-(4-pyridine-2-reparation-1-ylmethyl)thieno[3,2-d]pyrimidine was obtained from 1-pyridin-2-reperusing (commercially available).

1H NMR (400 MHz, CDCl3the 10.1 (1H, users), of 9.02 (1H, c), of 8.25 (1H, d), by 8.22-to 8.20 (1H, m), 7,60 (1H, d), 7,51-the 7.43 (2H, m), 7,39 (1H, c), 6,61-6,60 (1H, m), 4,08-4,06 (4H, m), 3,90-3,88 (6H, m), 3,60-to 3.58 (4H, m), 2,72-2,70 (4H, m); MS (ESI+) 513 (MN+).

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-[4-(2,2,2-triptorelin)piperazine-1-ylmethyl]thieno[3,2-d]pyrimidine (90)

Is obtained from 2-chloro-4-morpholine-4-yl-6-[4-(2,2,2-triptorelin)piperazine-1-ylmethyl]thieno[3,2-d]pyrimidine was obtained from 1-(2,2,2-triptorelin)piperazine.

Getting amine: to a BOC-piperazine (4 g) in DCM (40 ml) add triperoxonane anhydride (6,06 ml) and triethylamine (3,29 ml). After stirring over night the reaction mixture was diluted with DCM, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent is removed in vacuum to obtain complex tert-butyl ester 4-(2,2,2-TRIFLUOROACETYL)piperazine-1-carboxylic acid (6,06 g).

To complex tert-butyl ether 4-(2,2,2-TRIFLUOROACETYL)piperazine-1-carboxylic acid (6,06 g) in dry THF (60 ml) is added porandamaterjalides complex (4,5 ml) and the reaction mixture is heated to boiling under reflux. After 2 h the reaction mixture was cooled to 0°C and carefully add Meon and then adding water. Organic matter extracted into ethyl acetate, dried (MgSO4) and the solvent is removed in vacuum to obtain complex tert-butyl ester 4-(2,2,2-triptorelin)piperazine-1-carboxylic acid (4,46 g). Treatment with HCl in DCM/MeOH Yes the t desired connection, which emit in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) of 2.56 (4H, m), 2,69 (4H, m), with 2.93 (2H, q), with 3.79 (2H, c), 3,85 (4H, m), was 4.02 (4H, m), 7.23 percent (1H, c), 7,44 (1H, d), 7,52 (1H, d), 8,21 (1H, d), to 8.94 (1H, c).

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-thiazol-2-reparation-1-ylmethyl)thieno[3,2-d]pyrimidine (91)

Is obtained from 2-chloro-4-morpholine-4-yl-6-(4-thiazol-2-reparation-1-ylmethyl)thieno[3,2-d]pyrimidine 1-thiazol-2-reperusing (commercially available).

1H NMR (400 MHz, CDCl3) a 10.1 (1H, users), of 9.02 (1H, c), of 8.25 (1H, d), 7,60 (1H, d), 7,51-7,49 (2H, m), 7,39 (1H, c), 7,20 (1H, d), 6,60 (1H, d), 4,08-4,06 (4H, m), 3,90-3,88 (6H, m), 3,55-to 3.50 (4H, m), 2,72-2,70 (4H, m); MS (ESI+) 519 (MN+).

2-(6-fluoro-1H-indazol-4-yl)-6-(4-methylpiperazin-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine (92)

Receive processing 5-fluoro-2-methyl-3-[6-methylpiperazin-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine-2-yl] - phenylamine solidities in chloroform and acetic acid.

1H NMR (400 MHz, CDCl3) a 10.1 (1H, users), of 9.02 (1H, c), 8,10 (1H, DD), 7,39 (1H, c), 7,22 (1H, DD), 4,08-4,06 (4H, m), 3,90-3,88 (4H, m), 3,85 (2H, c), 2,70-of 2.50 (8H, m), is 2.30 (3H, c); MS (ESI+) 468 (MN+).

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-pyridine-2-iletileri-1-ylmethyl)thieno[3,2-d]pyrimidine (93)

Get on the basis of 2-chloro-4-morpholine-4-yl-6-(4-pyridine-2-iletileri-1-ylmethyl)thieno[3,2-d]pyrimidine. Amin receive as described for compound 95.

1H NMR (400 MHz, CDCl3) 2,61 (m, 8H, 4×CH2), 3,70 (c, 2H, With the 2), 3,86 (c, 2H, CH2), 3,90-3,93 (m, 4H, 2×CH2), 4,07-4,10 (m, 4H, 2×CH2), 7,14-7,17 (m, H, ArH), was 7.36 (c, H, ArH), 7,40 (d, H, ArH, J=7,78 Hz), 7,49 (t, H, ArH, J=to 7.77 Hz), EUR 7.57 (d, H, ArH, J=8 Hz), to 7.64 (t, H, ArH, J=of 7.64 Hz), of 8.27 (d, H, ArH, J=6,64 Hz), 8,56 (d, H, ArH, J=a 4.83 Hz), 9,0 (c, H, ArH), 10,12 (users, H, NH); MS (ESI+) 527,28 (MN+).

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-thiazol-2-iletileri-1-ylmethyl)thieno[3,2-d]pyrimidine (94)

Get on the basis of 2-chloro-4-morpholine-4-yl-6-(4-thiazol-2-iletileri-1-ylmethyl)thieno[3,2-d]pyrimidine was obtained from 1-thiazol-2-iletilerini. Amin receive, as described below for compound 95.

1H NMR (400 MHz, CDCl3) to 2.67 (m, 8H, 4×CH2), a 3.87 (c, 2H, CH2), 3,91-3,93 (m, 6H, 3×CH2), 4,07-4,10 (m, 4H, 2×CH2), 7,28 (d, H, ArH, J=3,23 Hz), 7,37 (c, H, ArH), 7,49 (t, H, ArH, J=7,73 Hz), 7,58 (d, H, ArH, J=8,31 Hz), of 7.70 (d, H, ArH, J=3,32 Hz), of 8.27 (d, H, ArH, J=6,79 Hz), 9,0 (c, H, ArH), 10,1 (users, H, NH).

2-(1H-indazol-4-yl)-6-[4-(5-methylfuran-2-ylmethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine (95)

Is obtained from 2-chloro-6-[4-(5-methylfuran-2-ylmethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine was obtained from 1-(5-methylfuran-2-ylmethyl)piperazine.

Getting amine: a mixture of 1-BOC-piperazine (1.63 g), 5-methylpyrrole (964 mg) and acetic acid (0,50 ml) was stirred in 1,2-dichloroethane (10 ml) at room temperature. To it add triacetoxyborohydride sodium (2,04 g) and the reaction mixture was stirred over night. Reactio the ing mixture is diluted with chloroform, washed with brine, dried (MgSO4) and the solvent is removed in vacuum to release the complex tert-butyl ester 4-(5-methylfuran-2-ylmethyl)piperazine-1-carboxylic acid as an orange oil. Treatment of this compound with HCl in DCM/MeOH gives the desired compound, which is isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) a 10.1 (1H, users), of 9.02 (1H, c), of 8.28 (1H, d), 7,60 (1H, d), 7,51-of 7.48 (1H, m), 6,10 (1H, d), 5,88 (1H, d), 4,08-4,06 (4H, m), 3,90-3,88 (4H, m), 3,83 (2H, c), 3,51 (2H, c), 2,70-of 2.50 (8H, m), and 2.26 (3H, c); MS (ESI+) 530 (MN+).

Amide 1-[2-(1H-indazol-4-yl)4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-carboxylic acid (96)

Get on the basis of amide 1-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-carboxylic acid, obtained using isonipecotamide (commercially available).

1H NMR (400 MHz, d6-DMSO) 1,52-of 1.74 (4H, m), 2.00 in of 2.16 (3H, m), 2,90 are 2.98 (2H, m), 3,80-are 3.90 (6H, m), (4H, t, J=4,7 Hz), 6,70 (1H, c), 7,20 (1H, c), of 7.48 (2H, t, J=7,7 Hz), the 7.65 (1H, d, J=8,2 Hz), by 8.22 (1H, d, J=7,3 Hz), 8,88 (1H, c), 13,15 (1H, c); MS (ESI+) 478 (MN+).

2-(1H-indazol-4-yl)-6-[4-(2-methoxy-1,1-dimethylethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine (97)

Get on the basis of 2-chloro-6-[4-(2-methoxy-1,1-dimethylethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine was obtained from 1-(2-methoxy-1,1-dimethylethyl)piperazine.

Getting amine: a mixture of benzylpiperazine, metaxia is inflorida triethylamine is stirred in DCM for 2 h to obtain 1-(4-benzylpiperazine-1-yl)-2-methoxyethanol in accordance with the standard design.

To a solution of 1-(4-benzylpiperazine-1-yl)-2-methoxyethanol (6,14 g) in dry THF (80 ml) at -10°C. add the chloride of zirconium (USD 5.76 g). After 30 min added dropwise methylmagnesium (3,03 M solution in simple ether, 49,6 ml). The reaction mixture is heated to room temperature. After stirring for 1 day, the reaction mixture was cooled, diluted with chloroform, washed with brine, dried (MgSO4) and the solvent is removed in vacuum. The resulting residue is purified using flash chromatography to obtain 1-benzyl-4-(2-methoxy-1,1-dimethylethyl)piperazine. Subsequent transfer hydrogenation using ammonium formate and 10% palladium-on-carbon in the Meon gives the desired connection.

1H NMR (400 MHz, CDCl3) 1,07 (c, 6H, 2×CH3), 2,61 (m, 4H, 2×CH2), 2,69 (m, 4H, 2×CH2), 3,26 (c, 2H, CH2), 3,33 (c, 3H, CH3), 3,83 (c, 2H, CH2), 3,90-3,93 (m, 4H, 2×CH2), 4,07-4,10 (m, 4H, 2×CH2), was 7.36 (c, H, AGN), 7,49 (t, H, ArH, J=7,72 Hz), EUR 7.57 (d, H, ArH, J=of 8.25 Hz), compared to 8.26 (d, H, ArH, J=7,13 Hz), 9,0 (c, H, ArH), 10,1 (users, H, NH); MS (ESI+) 522 (MN+).

2-(1H-indazol-4-yl)-6-[(3R,5S)-4-(2-methoxyethyl)for 3,5-dimethylpiperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine (98)

Get on the basis of 2-chloro-6-[(3R,5S)-4-(2-methoxyethyl)for 3,5-dimethylpiperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine was obtained from (2R,6S)-1-(2-methoxyethyl)-2,6-dimethylpiperazine.

Getting amine: to a solution of 2,6-dimethyl perazine (mainly CIS-) (250 mg), tert-butanol (2.5 ml), sodium hydroxide (88 mg) and water (0.5 ml) add a solution of di-tert-BUTYLCARBAMATE (478 mg) in tert-butanol (0.5 ml). After stirring over night the reaction mixture was diluted with ethyl acetate, washed with brine, dried (MgSO4) and the solvent is removed in vacuum to obtain complex tert-butyl ether (3R,5S) - for 3,5-dimethylpiperazine-1-carboxylic acid (400 mg).

The complex mixture of tert-butyl methyl ether (3R,5S) - for 3,5-dimethylpiperazine-1-carboxylic acid (1.5 g), a simple 2-pomatoleios ether (1,32 ml) and potassium carbonate (1.06 g) was heated to 120°C. in DMF (15 ml) for 2 days. The reaction mixture is cooled, diluted with ethyl acetate, washed with brine, dried (MgSO4) and the solvent is removed in vacuum to release the complex tert-butyl ether (3R,5S)-4-(2-methoxyethyl)for 3,5-dimethylpiperazine-1-carboxylic acid (1.4 g) after column chromatography.

Removal of the BOC-group by the action of HCl gives the desired compound, which is isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) a 1.01 (6H, d), 1,9 (2H, m), 2,61 (4H, m), 2,82 (2H, t), with 3.27 (3H, c), 3,37 (2H, t), 3,71 (2H, c), 3,85 (4H, m), was 4.02 (4H, m), and 7.3 (1H, c), the 7.43 (1H, t), 7,51 (1H, d), 8,21 (1H, d), of 8.95 (1H, c), 10,10 (1H, m); MS (ESI+) 522,35 (MN+).

(2-methoxyethyl)methylamide 1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-carboxylic acid (99)

Get on the C (2-methoxyethyl)methylamine 1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-carboxylic acid, obtained from (2-methoxyethyl)methylamine piperidine-4-carboxylic acid. Amin receive, as described for compounds 100.

1H NMR (400 MHz, CDCl3) 1,71 (2H, m)to 1.98 (2H, t), to 2.18 (2H, m), 2,46-2,70 (1H, m), 2,99+3,12 (3H, s, 2×rotamer), is 3.08 (2H, m)to 3.34 (3H, c), 3,42-3,62 (4H, m), 3,86 (2H, c), of 3.95 (4H, m), 4,10 (4H, m), of 7.36 (1H, c), to 7.50 (1H, t), 7,58 (1H, d), of 8.28 (1H, d), 9,01 (1H, c), 10,07 (1H, users); MS (ESI+) 550 (MN+).

Dimethylamide 1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-carboxylic acid (100)

Get on the basis of dimethylamide 1-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)piperidine-4-carboxylic acid, obtained from dimethylamide piperidine-4-carboxylic acid.

Getting amine: to a stirred solution of the BOC-isonipecotic acid (400 mg) in DMF (4 ml) is added 1,1'-carbonyldiimidazole (560 mg). The reaction mixture was stirred over night and then add dimethylaminohydrolase (280 mg) and triethylamine (0,48 ml). After 5 h the reaction mixture was diluted with ethyl acetate, washed with water, dried (MgSO4) and the solvent is removed in vacuum to obtain complex tert-butyl ester 4-dimethylcarbamoyl-1-carboxylic acid. Removal of the BOC-group by the action of HCl gives the desired compound, which is isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) 1,72 (2H, m)to 1.98 (2H, m), of 2.20 (2H, t), to 2.55 (1H, m), of 2.97 (3H, c), 3,00-3,10 (5H, m), 3,86 (2H, c), of 3.94 (4H, is), 4,10 (4H, m), of 7.36 (1H, c), to 7.50 (1H, t, J=7,7 Hz), 7,60 (1H, d, J=8,2 Hz), of 8.28 (1H, d, J=7,3 Hz); of 9.02 (1H, c); 10,15 (1H, users); MS (ESI+) 506 (MN+).

2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-pyridine-3-iletileri-1-ylmethyl)thieno[3,2-d]pyrimidine (101)

Get on the basis of 2-chloro-4-morpholine-4-yl-6-(4-pyridine-3-iletileri-1-ylmethyl)thieno[3,2-d]pyrimidine was obtained from 1-pyridin-3-iletilerini. Amin receive as described for compound 95.

1H NMR (400 MHz, CDCl3) 2,50-to 2.65 (m, 8H), 3,55 (c, 2H), 3,85 (c, 2H), 3,90-3,93 (m, 4H), 4,07-4,10 (m, 4H), from 7.24 (m, 1H), was 7.36 (c, 1H), 7,49 (t, 1H), EUR 7.57 (d, 1H), 7,66 (d, 1H), 8,27 (d, 1H,), and 8.50 (d, 1H), 8,54 (c, 1H), 9,0 (c, 1H), 10,1 (users, H, NH); MS (ESI+) 527,25 (MN+).

Methylamide 1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-carboxylic acid (102)

Receive from methylamide 1-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)piperidine-4-carboxylic acid, obtained from methylamide piperidine-4-carboxylic acid. Amin receive, as described for compounds 100.

1H NMR (400 MHz, d6-DMSO) 1,58 is 1.70 (4H, m), 2.00 in to 2.15 (3H, m), to 2.57 (3H, d, J=4.5 Hz), to 2.94 (2H, m), a-3.84 (6H, m)4,00 (4H, m), 7,46 (2H, t), the 7.65 (2H, d), to 8.20 (1H, d), 8,87 (1H, c); 13,14 (1H, c); MS (ESI+) 492 (MN+).

2-{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-yl}-N-methylisoleucine (103)

Get on the basis of 2-[4-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-yl]-N-methyl who isobutyramide, obtained from N-methyl-2-piperazine-1-isobutyramide.

Getting amine: to a mixture of DCM (10 ml), aqueous bicarbonate solution (2M, 10 ml) and aqueous sodium carbonate (2M, 10 ml) add methylaminopropane (300 mg) at 0°C. To it was added 2-bromoisobutyrate (0,50 ml) with vigorous stirring. After 2 h stirring the standard development gives 2-bromo-2,N-dimethylpropanamide (548 mg) in the form of not-quite-white solid.

A mixture of 2-bromo-2,N-dimethylpropanamide (312 mg), 1-BOC-piperazine (323 mg) and silver oxide (800 mg) was stirred in toluene (5 ml) by boiling under reflux. After 24 hours the reaction mixture is cooled, filtered through celite, diluted with chloroform, washed with brine, dried (MgSO4) and the solvent is removed in vacuum to obtain complex tert-butyl ester 4-(1-methyl-1-methylcarbamoylmethyl)piperazine-1-carboxylic acid (461 mg). Removal of the BOC-group by the action of HCl gives the desired compound, which is isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) a 10.1 (1H, users), of 9.02 (1H, c), 8,30 (1H, d), 7,60 (1H, d), 7,51-7,49 (1H, m), 7,39 (1H, c), 7,20 (1H, HF), 4,12-4.09 to (4H, m), 3.95 to 3,90 (4H, m), a 3.87 (2H, c), 2,80 (3H, d), 2,65-of 2.50 (8H, m)to 1.21 (6H, c); MS (ESI+) 535 (MN+).

2-{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-yl}-2-methyl-1-pyrrolidin-1-improper-1-he (104)

Get on the basis of 2-[4-(2-chloro-4-morpholine-4-yl is ieno[3,2-d]pyrimidine-6-ylmethyl)piperazine-1-yl]-2-methyl-1-pyrrolidin-1-improper-1-it, obtained from 2-methyl-2-piperazine-1-yl-1-pyrrolidin-1-improper-1-it.

Getting Amin: pyrrolidine (390 μl) in dry THF (4 ml) at 0°C. add n-BuLi (1,86 ml). The reaction mixture was stirred for 5 min and then add complex tert-butyl ester 4-(1-etoxycarbonyl-1-methylethyl)piperazine-1-carboxylic acid (700 mg) in THF (5 ml). The reaction mixture was stirred at room temperature for 24 hours and then quenched with aqueous ammonium chloride, extracted into DCM, washed with water, dried (MgSO4) and the solvent is removed in vacuum to obtain complex tert-butyl ester 4-(1,1-dimethyl-2-oxo-2-pyrrolidin-1-retil)piperazine-1-carboxylic acid (745 mg). Removal of the BOC-group by the action of HCl gives the desired compound, which is isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) to 1.24 (6H, c), 1,79-of 1.92 (4H, m), 2,52-2,66 (8H, usher.), to 3.49 (2H, t), 3,82 (2H, c)to 3.92 (4H, t), of 4.00 (2H, t), of 4.05 (4H, t), 7,35 (1H, c), 7,51 (1H, t), to 7.59 (1H, d), 8,29 (1H, d), 9,03 (1H, c), 10,10 (1H, user.); MS (ESI+) 575 (MN+).

2-(1H-indazol-4-yl)-6-[4-(1-methyl-1H-imidazol-2-ylmethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine (105)

Get on the basis of 2-chloro-6-[4-(1-methyl-1H-imidazol-2-ylmethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine was obtained from 1-(1-methyl-1H-imidazol-2-ylmethyl)piperazine. Amin receive as described for compound 95.

1H NMR (400 MHz, CDCl3) 2,50-to 2.65 (8H of usher.), 3,63 (2N, c), 3,71 (3H, c), 3,85 (2H, c)to 3.92 (4H, t), of 4.05 (4H, t), 6,85 (1H, c), 6,92 (1H, c), 7,38 (1H, c), 7,51 (1H, t), 7,60 (1H, d), 8,29 (1H, d), of 9.02 (1H, c); MS (ESI+) 530 (MN+).

2-(1H-indazol-4-yl)-6-[4-(5-methylisoxazol-3-ylmethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine (106)

Get on the basis of 2-chloro-6-[4-(5-methylisoxazol-3-ylmethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine was obtained from 1-(5-methylisoxazol-3-ylmethyl)piperazine.

Getting amine: to a suspension of sociallyengaged (1.04 g) in THF (10 ml) is added methyl 5-methylisoxazol-3-carboxylate (1,00 g) in solution in THF (10 ml). After 24 hours the reaction mixture was quenched with aqueous ammonium chloride, extracted into ethyl acetate, dried (MgSO4) and the solvent is removed in vacuum to obtain (5-methylisoxazol-3-yl)-Meon (579 mg).

To a solution of (5-methylisoxazol-3-yl)-Meon (570 mg) in DCM (15 ml), add triethylamine (0,98 ml) followed by the addition of methanesulfonanilide (0.51 ml). After 1 hour the reaction mixture was diluted with DCM, washed with water, dried (MgSO4) and the solvent is removed in vacuum to obtain a complex 5-methylisoxazol-3-Eletropaulo ether methanesulfonate acid (887 mg).

To a solution of N-BOC-piperazine (300 mg) in MeCN (5 ml) is added potassium carbonate (289 mg) followed by the addition of complex 5-methylisoxazol-3-Eletropaulo ether methanesulfonate acid (369 mg). The reaction mixture is heated to the boil with bratim the refrigerator for 24 hours. After cooling, the reaction mixture is diluted with water, extracted into ethyl acetate, dried (MgSO4) and the solvent is removed in vacuum to obtain complex tert-butyl ester 4-(5-methylisoxazol-3-ylmethyl)piperazine-1-carboxylic acid (404 mg).

Removal of the BOC-group by the action of HCl gives the desired compound, which is isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) 2,41 (c, 3H), 2,59 (users, 8H), 3,59 (c, 2H), 3,85 (c, 2H), 3,92 (t, 4H), 4.09 to (t, 4H), 5,99 (c, 1H), 7,37 (c, 1H), 7,50 (t, 1H), 7,58 (d, 1H), 8,28 (d, 1H), 9,02 (c, 1H), 10,15 (users, 1H); MS (ESI+) 531 (MN+).

1-{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-yl}-2-methylpropan-2-ol (107)

Get on the basis of 1-[4-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-yl}-2-methylpropan-2-ol, obtained from 2-methyl-1-piperazine-1-improper-2-ol.

Getting amine: a mixture of 1-benzylpiperazine (5 g), ethylbromoacetate (3.15 ml) and potassium carbonate (or 4.31 g) was stirred at room temperature in MeCN (50 ml). After stirring over night the reaction mixture was diluted with chloroform, washed with brine, dried (MgSO4) and the solvent is removed in vacuum to obtain complex tert-butyl ester 4-ethoxycarbonylmethylene-1-carboxylic acid (5,86 g).

To complex tert-butyl ether 4-ethoxycarbonylmethylene-1-carboxylic acid (1.0 g) in dry THF (10 ml) pri°C add methylanisole (3.0m solution in simple diethyl ether, 8.6 ml). Then the reaction mixture is heated to boiling under reflux for 24 hours. The reaction mixture was poured into ice/water/brine and then extracted into ethyl acetate, dried (MgSO4) and the solvent is removed in vacuum to obtain complex tert-butyl ester 4-(2-hydroxy-2-methylpropyl " piperazine-1-carboxylic acid. Transfer hydrogenation with ammonium formate and 10% palladium-on-carbon in the Meon gives the desired connection.

1H NMR (400 MHz, CDCl3) of 1.17 (6H, c), a 2.36 (2H, c), 2,62 (4H, m), 2,73 (4H, m), 3,86 (2H, c)to 3.92 (4H, m), 4,1 (4H, m), 7,38 (1H, c), to 7.50 (1H, t), 7,58 (1H, d), of 8.28 (1H, d), of 9.02 (1H, c); MS (ESI+) 508 (MN+).

Cyclopropylmethyl-{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}-(2-methoxyethyl)Amin 108)

Get on the basis of [1-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl]cyclopropylmethyl-(2-methoxyethyl)amine obtained from cyclopropylmethyl-(2-methoxyethyl)piperidine-4-ylamine.

Getting amine: 1-BOC-4-piperidone (500 mg) and 2-methoxyethylamine (218 μl) is stirred Meon at room temperature. After 16 hours carefully add sodium borohydride (190 mg). After 3 h the reaction mixture was diluted with DCM, washed with water, dried (MgSO4) and the solvent is removed in vacuum to obtain complex tert-butyl ester 4-(2-methoxyethylamine)piperidine-1-carboxylic acid (560 mg).

Mixture with whom you tert-butyl ester 4-(2-methoxyethylamine)piperidine-1-carboxylic acid (525 mg), cyclopropanemethylamine (218 μl) and potassium carbonate (340 mg) is heated to boiling under reflux in MeCN for 16 hours. After cooling, the reaction mixture is diluted with chloroform, washed with brine, dried (MgSO4) and the solvent is removed in vacuum to obtain complex tert-butyl ester 4-[cyclopropylmethyl-(2-methoxyethyl)amino]piperidine-1-carboxylic acid (475 mg). Removal of the BOC-group by the action of HCl gives the desired compound, which is isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3): -0,01-0,01 (2H, m), 0,40-of 0.48 (2H, m), 1,45-to 1.60 (3H, m), 1,62 is 1.70 (2H, m), 1,97-2,04 (2H, m), 2,33 (2H, d), 2,52-2,61 (1H, m)to 2.67 (2H, t), 2,92-of 3.00 (2H, m)of 3.25 (3H, c)to 3.34 (2H, t), 3,71 (2H, c), is 3.82 (4H, t), of 4.00 (4H, t), 7,22 (1H, c), 7,49 (1H, t), of 7.48 (1H, d), of 8.28 (1H, d), of 8.90 (1H, c), 10,00 (1H, user.); MS (ESI+) 562 (MN+).

6-[4-(1-ethyl-1-methoxymethyl)piperazine-1-ylmethyl]-2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine (109)

Get on the basis of 2-chloro-6-[4-(1-ethyl-1-methoxymethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine was obtained from 1-(1-ethyl-1-methoxymethyl)piperazine.

To a solution of 1-(4-benzylpiperazine-1-yl)-2-methoxyethanol (2,60 g) in dry THF (30 ml) at -10°C. add isopropoxide titanium (3,22 ml) followed by the addition of ethylmagnesium (1.0m solution in THF, 22,05 ml). The reaction mixture is heated to boiling under reflux for 2 days. After cooling the reaction mixture is cooled, diluted with chloroform, washed with brine, dried (MgSO4) and the solvent is removed in vacuum. The residue is purified using flash chromatography to obtain 1-benzyl-4-(1-methoxyoestradiol)piperazine (452 mg) and 1-benzyl-4-(1-ethyl-1-methoxymethyl)piperazine (248 mg). Conditions of transfer hydrogenation using ammonium formate and 10% Pd/C in the Meon gives the desired connection.

1H NMR (400 MHz, CDCl3): 0,85 (6N, t), 1,58-of 1.33 (4H, m), 2,55-of 2.50 (4H, m), of 2,75 2,70 (4H, m), 3,30 (5H, c), 3,85 (2H, c), 3.95 to 3,91 (4H, m), 4,12-4.09 to (4H, m), 7,39 (1H, c), 7,51-7,49 (1H, m), 7,60 (1H, d), 8,30 (1H, d), 9,02 (1H, c), 10,2 (1H, users); MS (ESI+) 550 (MN+).

2-(1H-indazol-4-yl)-6-[4-(1-methoxyoestradiol)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine (110).

Get on the basis of 2-chloro-6-[4-(1-methoxyoestradiol)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine was obtained from 1-(1-methoxyoestradiol)piperazine. Amin receive as described for compound 109.

1H NMR (400 MHz, CDCl3) 0,65-0,52 (4H, m), 2,55-of 2.50 (4H, m), 2,85 is 2.80 (4H, m), 3,32 (3H, c), 3,40 (2H, c), 3,85 (2H, c), 3.95 to 3,91 (4H, m), 4,12-4.09 to (4H, m), 7,39 (1H, c), 7,51-7,49 (1H, m), 7,60 (1H, d), 8,30 (1H, d), of 9.02 (1H c), 10,2 (1H, users); MS (ESI+) 520 (MN+).

111. {1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}-(2-methoxyethyl)-(2,2,2-triptorelin)Amin

Get on the basis of [1-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)piperidine-4-is]-(2-methoxyethyl)-(2,2,2-triptorelin)amine, obtained from (2-methoxyethyl)piperidine-4-yl-(2,2,2-triptorelin)amine.

Getting amine: 1-BOC-4-piperidine (2.00 g) and 2-methoxyethylamine (872 μl) are mixed together in the Meon (20 ml) at room temperature over night. Then added in several portions sodium borohydride (760 mg) and the reaction mixture is allowed the opportunity to mix at ambient temperature. After 16 hours the solvent is removed in vacuo, the residue was diluted in DCM, washed with brine, dried (MgSO4) and the solvent is removed in vacuum. The residue is purified using flash chromatography, to obtain the complex tert-butyl ester 4-(2-methoxyethylamine)piperidine-1-carboxylic acid as a colourless oil (1,69 g).

To a solution of tert-butyl ester 4-(2-methoxyethylamine)piperidine-1-carboxylic acid (500 mg) in DCM (5 ml) and triethylamine (540 μl) add triperoxonane anhydride (548 μl). The reaction mixture was stirred at room temperature overnight, diluted with DCM, washed with brine, dried (MgSO4) and the solvent is removed in vacuum. The residue is purified using flash chromatography, to obtain the complex tert-butyl ester 4-[(2-methoxyethyl)-(2,2,2-TRIFLUOROACETYL)amino)piperidine-1-carboxylic acid as a colourless oil (685 mg).

To a solution of complex tert-butyl ester 4-[(2-methoxyethyl)-(2,2,2-TRIFLUOROACETYL)amino)piperidine-1-carboxylic to the slots (685 mg) in dry THF (7 ml) was added borane-methylsulfinyl complex (405 μl) at 0°C in an inert atmosphere. The reaction mixture is refluxed for 3 hours and then stirred at room temperature overnight, quenched Meon, diluted with DCM, washed with brine, dried (MgSO4) and the solvent is removed in vacuum. The residue is purified using flash chromatography, to obtain the complex tert-butyl ester 4-[(2-methoxyethyl)-(2,2,2-triptorelin)amino]piperidine-1-carboxylic acid in the form of oil (635 mg). Treatment of this compound with HCl in DCM/MeOH gives the desired amine selected in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) 1,55-of 1.64 (2H, m), 1,76-to 1.82 (2H, m), 2,12-to 2.18 (2H, m), 2,58-2,62 (1H, m), of 2.86 (2H, t, J=6.3 Hz), 3,03-is 3.08 (2H, m), 3,20 (2H, q, J=9.4 Hz), to 3.33 (3H, c), of 3.45 (2H, t, J=6.4 Hz), a-3.84 (2H, c), of 4.00 (4H, t, J=5,1 Hz), 7,22 (1H, c), 7,49 (1H, t, J=7.2 Hz), of 7.48 (1H, d, J=8,3 Hz), of 8.28 (1H, d, J=7,1 Hz), of 8.90 (1H, c), 10,00 (1H, user.); MS (ESI+) 590 (MN+).

121. 2-(1H-indazol-4-yl)-6-[4-(2-methoxyethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine

Get on the basis of 2-chloro-6-[4-(2-methoxyethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine was obtained from 1-(2-methoxyethyl)piperazine.

1H NMR (400 MHz, CDCl3) 2,55-2,70 (m, 10H, 5×CH2), to 3.35 (s, 2H, CH2), 3,50-of 3.53 (m, 2H, CH2), 3,85 (c, 2H, CH2), 3,90-3,93 (m, 4H, 2×CH2), 4,07-4,11 (m, 4H, 2×CH2), 7,37 (c, H, ArH), 7,49 (t, H, ArH, J=7,76 Hz), EUR 7.57 (d, H, AGN, J=8,3 Hz), of 8.27 (d, H, ArH, J=of 6.71 Hz), 9,0 (c, H, ArH), 10,15 (users, H, NH). MS (ESI+) 494,18 (MN+).

122. 2-{4-[2-(1H-indaz the l-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-yl}isobutyramide

Get on the basis of 2-[4-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)piperazine-1-yl]isobutyramide obtained from 2-piperazine-1-isobutyramide.

Getting amine: a mixture of 1-BOC-piperazine (1,063 g), DCM/MeOH (20 ml) and 0.2m HCl in simple ether (3,14 ml) stirred at 0°C. After 1 hour the solvent is removed in vacuum to obtain a white solid. It is dissolved in water and add sodium cyanide (280 mg). To it was added a solution of acetone (420 ml) in water (2 ml). After stirring for 48 h the reaction mixture was dissolved in ethyl acetate, washed with brine, dried (MgSO4) and the solvent is removed in vacuum to obtain complex tert-butyl ester 4-(centimetres)piperazine-1-carboxylic acid (1,11 g).

To a cooled (bath with ice water) to the solution of complex tert-butyl ester 4-(centimetres)piperazine-1-carboxylic acid (102,9 mg) in dry DMSO is added To2CO3(9.8 mg) followed by the addition dropwise of a solution of hydrogen peroxide (200 μl). The resulting solution was heated at 40°C during the night. Add water and the white solid is collected, washed with water and dried in air to obtain a complex tert-butyl ester 4-(1-carbarnoyl-1-methylethyl)piperazine-1-carboxylic acid (to 59.6 mg) (see Tetrahedron 2002, 58, 3217). Treatment of this compound with HCl in DCM/MeOH gives the desired amine, which was isolated in the form of aristolochiaceae salt.

1H NMR (400 MHz, CDCl3) 1,24 (c, 6H, 2×CH2), 2,55-to 2.65 (m, 8H, 4×CH2), 3,85 (c, 2H, CH2), 3,90-to 3.92 (m, 4H, 2×CH2), 4,07-4.09 to (m, 4H, 2×CH2), to 5.35 (m, H, NH), to 7.09 (m, H, NH), 7,37 (c, H, ArH), of 7.48 (t, H, ArH, J=7,72 Hz), EUR 7.57 (d, H, ArH, J=by 8.22 Hz), compared to 8.26 (d, H, ArH, J=7,14 Hz), 9,0 (c, H, ArH), 10,4 (users, H, NH). MS (ESI+) 521,27 (MN+).

123. {1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}methanol

Get on the basis of [1-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}methanol derived from pyridine-4-ylmethanol.

Getting amine: to a solution of complex ethyl ester piperidine-4-carboxylic acid (5.0 g), stirring in dry MeCN (70 ml), add triethylamine (5.3 ml) followed by addition of di-tertiary BUTYLCARBAMATE (of 7.64 g). The reaction mixture was stirred at room temperature for 24 hours, then diluted with water (150 ml), extracted into ethyl acetate, dried (MgSO4) and the solvent is removed in vacuum. The residue is purified using flash chromatography, to obtain the complex 1-BOC-piperidine-4-ethyl ester (6.8 g) as a colourless oil. To a suspension of powder sociallyengaged (300 mg), stir in dry THF (10 ml) under nitrogen atmosphere, add complex 1-BOC-piperidine-4-ethyl ester in dry THF (5 ml). The reaction mixture was stirred at room temperature. After 2 h the reaction mixture was quenched with a saturated p is the target of ammonium chloride (10 ml), filtered through a layer of celite and the solvent is removed in vacuum to obtain complex tert-butyl ester 4-hydroxyethylpiperazine-1-carboxylic acid (0.793 g) as a pale yellow solid. Processing TFA gives the desired amine, which was isolated in the form of the TFA salt.

1H NMR (400 MHz, d6-DMSO) of 1.18 (m, 2H), 1,37 (m, 1H), 1,64 (m, 2H), 2,04 (t, 2H), 2,92 (m, 2H), 3.27 to (m, 2H), 3,82 (m, 4H & CH2), to 3.99 (m, 4H), 4,39 (t, 1H), 7,45 (t, 2H), 7,65 (d, 1H, J=8,2 Hz), 8,21 (d, 1H, J=7,3 Hz), 8,87 (c, 1H), 13,16 (users, 1H); MS (ESI+) 465,17 (MN+).

124. 2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-pyridin-4-iletileri-1-ylmethyl)thieno[3,2-d]pyrimidine

Get on the basis of 2-chloro-4-morpholine-4-yl-6-(4-pyridin-4-iletileri-1-ylmethyl)thieno[3,2-d]pyrimidine was obtained from 1-pyridin-4-iletilerini.

Getting amine: a mixture of 1-BOC-piperazine (2 g), 4-pyridinecarboxamide (1.26 g), triacetoxyborohydride sodium (2,96 g) and acetic acid (0.6 ml) is stirred in dry 1,2-dichlorethane (15 ml) at room temperature. After 4 h the reaction is quenched with saturated solution of NaHCO3and extracted with DCM, dried (MgSO4), filtered and concentrated in vacuo to obtain complex tert-butyl ester 4-pyridin-4-iletileri-1-carboxylic acid (3 g). Treatment of this compound with HCl in DCM/MeOH gives the desired amine, which was isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) ,40-2,60 (m, 8H, 4×CH2), 3,45 (c, 2H, CH2), 3,78 (c, 2H, CH2), 3,82-a-3.84 (m, 4H, 2×CH2), 3,99-4,01 (m, 4H, 2×CH2), 7,18-7,19 (m, 2H, 2×ArH), 7,30 (c, H, ArH), 7,39 (t, H, ArH, J=7,7 Hz), 7,47 (d, H, ArH, J=8,55 Hz), 8,18 (d, H, ArH, J=7,17 Hz), 8,46 (d, H, ArH, J=5,34 Hz), 8,93 (c, H, ArH), of 10.25 (users, H, NH); MS (ESI+) 527,29 (MN+).

125. 2-(1H-indazol-4-yl)-6-[4-(6-methylpyridin-2-ylmethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine

Get on the basis of 2-chloro-6-[4-(6-methylpyridin-2-ylmethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine was obtained from 1-(6-methylpyridin-2-ylmethyl)piperazine. Amine, 1-(6-methylpyridin-2-ylmethyl)piperazine, get, using 6-methyl-2-pyridinecarboxamide similar connection 124.

1H NMR (400 MHz, CDCl3) 2,54 (c, 3H, CH3), 2,60-2,70 (m, 8H, 4×CH2), 3,67 (c, 2H, CH2), 3,86 (c, 2H, CH2), 3,90-3,93 (m, 4H, 2×CH2), 4,07-4,10 (m, 4H, 2×CH2), 7,00 (d, H, ArH, J=7,6 Hz), 7,22-7,25 (m, H, ArH partially under CDCl3), was 7.36 (c, H, ArH), 7,47-EUR 7.57 (m, 3H, 3×ArH), of 8.27 (d, H, ArH, J=7,2 Hz), 9,00 (c, H, ArH), 10,2 (users, H, NH); MS (ESI+) 541,24 (MN+).

126. 2-(1H-indazol-4-yl)-6-[4-(4-methylthiazole-2-ylmethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine

Get on the basis of 2-chloro-6-[4-(4-methylthiazole-2-ylmethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine was obtained from 1-(4-methylthiazole-2-ylmethyl)piperazine. Amine, 1-(4-methylthiazole-2-ylmethyl)piperazine, get, using 4-methylthiazole-2-carboxaldehyde is, a similar connection 125.

1H NMR (400 MHz, CDCl3) 2,43 (c, 3H), (users, 8H), 3,85 (m, 4H), 3,92 (m, 4H), 4.09 to (m, 4H), 6,83 (c, 1H), 7,38 (c, 1H), 7,51 (m, 1H), 7,60 (d, J=8,3 Hz, 1H), 8,28 (d, J=6,8 Hz, 1H), 9,02 (c, 1H); MS (ESI+) 547 (MN+).

127. {1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}pyridine-2-ylamine

Get on the basis of [1-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)piperidine-4-yl]pyridine-2-ylamine derived from piperidine-4-espiridion-2-ylamine.

Getting amine: a mixture of 1-BOC-4-piperidone (496 mg), 2-aminopyridine (234 mg), triacetoxyborohydride sodium (580 mg) and acetic acid (0,14 ml) is stirred together in dry 1,2-dichloroethane (10 ml) at room temperature. After 24 hours the reaction is quenched with saturated solution of NaHCO3and extracted with DCM, dried (MgSO4), filtered and concentrated in vacuo to obtain complex tert-butyl ester 4-(pyridine-2-ylamino)piperidine-1-carboxylic acid (135 mg) after flash chromatography. Treatment of this compound with HCl in DCM/MeOH gives the desired amine, which was isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) 1,65-of 1.55 (2H, m), 2,10-of 2.08 (2H, m), 2.40 a-2,30 (2H, m), 3,01 (2H, d), of 3.73-to 3.67 (1H, m), 3,85 (2N, c), 3.95 to 3,91 (4H, m), 4,12-4.09 to (4H, m), and 4.40 (1H, userd), to 6.39 (1H, d), 6,56-6,521 (1H, m), of 7.48-7,40 (2H, m), 7,51-7,49 (1H, m), 7,60 (1H, d), of 8.09 (1H, d), 8,30 (1H, d), of 9.02 (1H, c), 10,2 (1H, users); MS (ESI+) 527 (MN+).

128. N-{1-[2-(1H-indazol-4-yl)-4-morphol is n-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}-2-methoxy-N-methylacetamide

Get on the basis of N-[1-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)piperidine-4-yl]-2-methoxy-N-methylacetamide obtained from 2-methoxy-N-methyl-N-piperidine-4-ylacetamide.

Getting amine: To a solution of 1-BOC-4-piperidone (1.0 g) in Meon (10 ml) is added a freshly prepared solution of methylamine in the Meon (1.0 ml). The reaction mixture is stirred for 1 hour and then add cyanoborohydride sodium (0,315 g). After stirring for 24 h the reaction mixture was then diluted with DCM, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent is removed in vacuum. The residue is purified with flash chromatography to obtain complex tert-butyl ester 4-methylaminopropyl-1-carboxylic acid (0.85 grams).

To a solution of complex tert-butyl ester 4-methylaminopropyl-1-carboxylic acid (0,42 g) in DCM (10 ml), add triethylamine (0,30 ml) followed by the addition of methoxyacetanilide (0,20 ml). After stirring for 3 h the reaction mixture was then diluted with DCM, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent is removed in vacuum. The residue is purified with flash chromatography to obtain complex tert-butyl ester 4-[(2-methoxyacetyl)methylamino]piperidine-1-carboxylic acid (0,293 g). Treatment of this compound with HCl in DCM/MeOH gives the desired amine, which was isolated in the form of hydrochloric with the Lee.

1H NMR (400 MHz, CDCl3) of 1.66 (2H, m), 1,80+1,97 (2H, m, 2 rotamer), a 2.36 (2H, m), 2,90 (3H, c), is 3.08 (2H, m), 3.43 points (3H, c), 3,65+4,50 (1H, m, 2 rotamer), 3,86 (2H, c), of 3.94 (4H, m), 4,10 (4H, m), 7,40 (1H, c), 7,51 (1H, t, J=7,7 Hz), rate of 7.54 (1H, d, J=8,2 Hz), of 8.28 (1H, d, J=7,2 Hz), of 9.02 (1H, c), 10,18 (1H, users); MS (ESI+) 536 (MN+).

129. N-{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}-N-methylmethanesulfonamide

Obtained from N-[1-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}-N-methylmethanesulfonamide obtained from N-methyl-N-piperidine-4-ylmethanesulfonamide. Amine, N-methyl-N-piperidine-4-ylmethanone receive processing complex tert-butyl ester 4-methylaminopropyl-1-carboxylic acid methanesulfonamido similar connection 128.

1H NMR (400 MHz, CDCl3) 1,72 (2H, m), 1,90 (2H, m), of 2.23 (2H,t, J=11,0 Hz), 2,85 (6H, c), is 3.08 (2H, userd, J=11,4 Hz), 3,80 (1H, m), 3,86 (2H, c), of 3.94 (4H, m), 4,10 (4H, m), 7,39 (1H, c), 7,52 (1H, t, J=7,7 Hz), 7,60 (1H, d, J=8.0 Hz), 8,29 (1H, d, J=7,1 Hz), 9,03 (1H, c), 10,15 (1H, users); MS (ESI+) 542 (MN+).

130. {1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}-(3-methoxypropyl)methylamine

Get on the basis of [1-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)piperidine-4-yl}-(3-methoxypropyl)methylamine obtained from (3-methoxypropyl)methylpiperidin-4-ylamine. Amine, (3-methoxypropyl)methylpiperidin-4-ylamine, obtained from complex tert-BU is silt ether 4-methylaminopropyl-1-carboxylic acid and complex 3-methoxypropyl ester toluene-4-sulfonic acid (obtained from 3-methoxy-1-propanol using standard conditions) similar to the connection 128.

1H NMR (400 MHz, CDCl3) 1,55-of 1.85 (6H, 3×CH2), 2,11 (m, 2H, CH2), 2,31 (s, 3H, CH3), 2,44 (m, H, CH), to 2.57 (m, 2H, CH2), was 3.05 (m, 2H, CH2), 3,33 (c, 3H, CH3), 3,42 (m, 2H, CH2), 3,83 (c, 2H, CH2), 3,91-3,93 (m, 4H, 2×CH2), 4,08-4,10 (m, 4H, 2×CH2), 7,35 (c, H, ArH), 7.50 for (t, H, ArH, J=to 7.77 Hz), 7,58 (d, H, AGN, J=8,27 Hz), compared to 8.26 (d, H, ArH, J=6,77 Hz), 9,00 (c, H, ArH), 10,23 (users, H, NH); MS (ESI+) 536,46 (MN+).

131. 6-((3S,5R) - for 3,5-dimethyl-4-pyridin-2-iletileri-1-ylmethyl)-2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine

Get on the basis of 2-chloro-6-((3S,5R) - for 3,5-dimethyl-4-pyridin-2-iletileri-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine was obtained from (2S,6R)-2,6-dimethyl-1-pyridin-2-iletilerini. Getting Amin: complex tert-butyl ether (3R,5S) - for 3,5-dimethylpiperazine-1-carboxylic acid (845 mg), the hydrobromide of 2-(methyl bromide)pyridine (1 g) and potassium carbonate (1,15 g) is heated to boiling under reflux in MeCN (10 ml). After heating for 24 hours, the reaction mixture was diluted with DCM, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent is removed in vacuum. The residue is purified with flash chromatography to obtain complex tert-butyl ether (3R,5S) - for 3,5-dimethyl-4-pyridin-2-iletileri-1-carboxylic acid (867 mg). Treatment of this compound with HCl in DCM/MeOH gives the desired amine, which was isolated in the form of a hydrochloric salt.

1H NMR 400 MHz, CDCl3) to 1.00 (d, J=6.0 Hz, 6H), and 1.54 (c, 2H), 2.05 is (m, 2H), 2,84 (m, 4H), 3,81 (c, 2H), 3,92 (m, 4H), 4,10 (m, 4H), 7,11 (m, 1H), 7,38 (c, 1H), 7,51 (m, 1H), to 7.61 (m, 3H), 8,29 (d, J=7,4 Hz, 1H), 8,51 (d, J=4.5 Hz, 1H), 9,03 (c, 1H); MS (ESI+) 555 (MN+).

132. 2-(1H-indazol-4-yl)-6-(4-methoxypiperidine-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine

Get on the basis of 2-chloro-6-(4-methoxypiperidine-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine was obtained from 4-methoxypiperidine. Getting amine: to a solution of complex tert-butyl ester 4-hydroxyethylpiperazine-1-carboxylic acid (212 mg), stir in dry THF (10 ml) under nitrogen atmosphere, add sodium hydride (60% in paraffin oil; 45 mg) followed by the addition over 20 min methyliodide and the reaction mixture is heated to 70°C. After 4 hours the mixture is cooled and quenched with water (10 ml), extracted into ethyl acetate and dried (MgSO4). The residue is purified using flash chromatography, to obtain the complex tert-butyl ester 4-methoxypiperidine-1-carboxylic acid (158 mg) as a colorless oil. Processing TFA gives the desired amine, which was isolated in the form of the TFA salt.

1H NMR (400 MHz, CDCl3) of 1.23 (m, 2H), and 1.54 (m, 1H), and 1.63 (m, 2H), 2.05 is (m, 2H), 2.91 in (m, 2H), 3,18 (d, 2H, J=6.2 Hz), 3,22 (c, 3H), 3,82 (m, 4H, + CH2), to 3.99 (m, 4H), 7,45 (t, 2H, J=7.0 Hz), the 7.65 (d, 1H, J=8,2 Hz), 8,21 (d, 1H, J=7,1 Hz), 8,87 (c, 1H), 13,16 (users, 1H); MS (ESI+) 479,2 (MN+).

133. {1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimi the Jn-6-ylmethyl]piperidine-4-yl}-(2-methoxyethyl)thiazol-2-ylmethylamino

Get on the basis of [1-[2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl]-(2-methoxyethyl)thiazol-2-ylmethylamino obtained from (2-methoxyethyl)piperidine-4-iltiazem-2-ylmethylamino.

Getting Amin: complex tert-butyl ester 4-(2-methoxyethylamine)piperidine-1-carboxylic acid (465 mg) and 2-thiazolecarboxamide (190 μl) is stirred in dry 1,2-dichloroethane (5 ml) for 1 hour. Then add acetic acid (1 EQ.) and triacetoxyborohydride sodium (458 mg). The reaction mixture was stirred at room temperature overnight, diluted with DCM, washed with brine, dried (MgSO4) and the solvent is removed in vacuum. The residue is purified with flash chromatography to obtain complex tert-butyl ester 4-[(2-methoxyethyl)thiazol-2-ylmethylamino]piperidine-1-carboxylic acid (574 mg). Treatment of this compound with HCl in DCM/MeOH and the main washing with sodium bicarbonate gives the desired amine.

1H NMR (400 MHz, CDCl3) 1,62-of 1.73 (2H, m), 1,81-of 1.88 (2H, m), 2.06 to and 2.14 (2H, m), 2,60 of 2.68 (1H, m), is 2.88 (2H, t, J=6.4 Hz), 3,02-is 3.08 (2H, m), 3,30 (3H, c)to 3.49 (2H, t, J=6.4 Hz), 3,82 (2H, c), 3,92-of 3.96 (4H, m), 4,10 (2H, c), 4,10-to 4.14 (4H, m), 7,22 (1H, d, J=3.2 Hz), 7,35 (1H, c), 7,51 (1H, t, J=8.0 Hz), to 7.59 (1H, d, J=8,3 Hz), 7,72 (1H, d, J=3.2 Hz), 8,29 (1H, d, J=6.6 Hz), 9,03 (1H, c), 10,10 (1H, user.); MS (ESI+) 605 (MN+).

134. 1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-4-pyridine-2-iletilerini-4-ol.

Get on the basis of 1-(2-the ENT-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-4-pyridine-2-iletilerini-4-ol, obtained from 4-pyridine-2-iletilerini-4-ol.

Getting amine: to a solution of 2-picoline (333 mg) in dry THF (5 ml) at -78°C. add n-BuLi (2.5m solution in hexano, 1,50 ml). The reaction mixture was warmed to room temperature for 30 min and then cooled to -78°C. Then was added 1-BOC-4-piperidone (713 mg) and the temperature of the reaction mixture was raised to 0°C for 20 minutes the Reaction mixture is stirred overnight and then quenched with water. Organic matter extracted into ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo to obtain the crude product. The residue is purified using flash chromatography, to obtain the complex tert-butyl ester 4-hydroxy-4-pyridine-2-iletilerini-1-carboxylic acid (290 mg). Treatment of this compound with HCl in DCM/MeOH gives the desired amine, which was isolated in the form of hydrochloride.

1H NMR (400 MHz, CDCl3) 1,55-1,75 (4H, m), 2,55-2,61 (2H, m), 2,68-of 2.72 (2H, m), 2.91 in (2H, c), 3,88 (2H, c), 3,91-of 3.94 (4H, m), 4,05-4,10 (4H, m), 5,80 (1H, c), 7,05-7,11 (2H, m), 7,37 (1H, c), 7,46-7,51 (1H, c), 7,55 to 7.62 (2H, m), 8,29 (1H, d), and 8.50 (1H, d), 9,03 (1H, c), 10,10 (1H, users); MS (ESI+) 542 (MN+).

135. {1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}isopropyl-(2-methoxyethyl)Amin

Get on the basis of [1-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl]isopropyl-(2-methoxyethyl)amine obtained from isopropyl-(2-methods Sitel)piperidine-4-ylamine.

Getting amine: a mixture of complex tert-butyl ester 4-(2-methoxyethylamine)piperidine-1-carboxylic acid (see connection 121) and 2-bromopropane (1.20 ml) in MeCN (3 ml) with potassium carbonate (192 mg) is heated at 60°C in a sealed tube for 7 days. The reaction mixture is cooled, diluted with DCM, washed with brine, dried (MgSO4) and the solvent is removed in vacuum. The residue is purified with flash chromatography to obtain complex tert-butyl ester 4-[isopropyl-(2-methoxyethyl)amino]piperidine-1-carboxylic acid in the form of oil (131 mg). Treatment of this compound with HCl in DCM/MeOH and the main irrigation water sodium bicarbonate gives the desired amine.

1H NMR (400 MHz, CDCl3) of 1.03 (6H, d, J=6.6 Hz), 1,62-1,72 (4H, m), 2,08 with 2.14 (2H, m), 2,52-2,60 (1H, m), 2,69 (2H, t, J=7.4 Hz), 3,03-of 3.12 (4H, m)to 3.33 (2H, t, J=7,3 Hz), the 3.35 (3H, c), 3,82 (2H, c)to 3.92 (4H, t, J=4.5 Hz), 4,05 (4H, t, J=4.5 Hz), 7,35 (1H, c), 7,51 (1H, t, J=8.0 Hz), to 7.59 (1H, d, J=8,3 Hz), 8,29 (1H, d, J=6.6 Hz), 9,03 (1H, c), 10,10 (1H, user.); MS (ESI+) 550 (MN+).

136. 2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-[4-(pyridine-2-yloxy)piperidine-1-ylmethyl]thieno[3,2-d]pyrimidine

Get on the basis of 2-chloro-4-morpholine-4-yl-6-[4-(pyridine-2-yloxy)piperidine-1-ylmethyl]thieno[3,2-d]pyrimidine was obtained from 2-(piperidine-4-yloxy)pyridine.

Getting amine: a mixture of 1-benzylpiperidine-4-ol (1 g), 2-chloropyridine (0.5 ml), 18-crown-6 (72 mg) and KOH (290 mg) is refluxed in dry toluene. After 1 hour the reaction mixture is diluted with water, extracted with DCM, dried (Na2SO4), filtered and concentrated in vacuo, then purified flash chromatography with getting complicated tert-butyl ester 4-(pyridine-2-yloxy)piperidine-1-carboxylic acid (789 mg). Treatment of this compound with hydrogen and 10% palladium-on-carbon and ammonium formate in the Meon give the desired amine.

1H NMR (400 MHz, CDCl3) 1,88-1,90 (m, 2H, 2×CH), 2,04-of 2.08 (m, 2H, 2×CH), 3,48-2,52 (m, 2H, 2×CH), 2,85-2,90 (m, 2H, 2×CH), 3,88 (c, 2H, CH2), 3,91-3,93 (m, 4H, 2×CH2), 4,08-4,11 (m, 4H, 2×CH2), 5,10-by 5.18 (m, H, CH), of 6.71 (d, H, ArH, J=8.34 per Hz), PC 6.82 (t, H, ArH, J=6,11 Hz), 7,37 (c, H, ArH), 7,47-7,58 (m, 3H, 3×ArH), to 8.12 (d, H, ArH, J=5,01 Hz), of 8.27 (d, H, ArH, J=6,8 Hz), 9,01 (c, H, ArH), to 10.09 (users, H, NH); MS (ESI+) 528,31 (MN+).

137. N-{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}-N-(2-methoxyethyl)methanesulfonamide

Get on the basis of N-[1-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl]-N-(2-methoxyethyl)methanesulfonamide obtained from N-(2-methoxyethyl)-N-piperidine-4-ylmethanesulfonamide.

Getting amine: to a solution of complex tert-butyl ester 4-(2-methoxyethylamine)piperidine-1-carboxylic acid (see connection 121) (0.50 g) in DCM (10 ml), add triethylamine (0,30 ml) followed by the addition of methanesulfonanilide (0.16 ml). After stirring for 4 h the reaction mixture was then diluted with DCM, washed with a solution of bicarbon is the sodium, dried (MgSO4) and the solvent is removed in vacuum. The residue is purified with flash chromatography to obtain complex tert-butyl ester 4-[methanesulfonyl-(2-methoxyethyl)amino]piperidine-1-carboxylic acid (0,474 g). Treatment of this compound with HCl in DCM/MeOH and the main irrigation water sodium bicarbonate gives the desired amine, which was isolated in the form of hydrochloride.

1H NMR (400 MHz, CDCl3) of 1.78 (2H, m), with 1.92 (2H, m), of 2.21 (2H, t, J=10,9 Hz), 2,90 (3H, c), of 3.07 (2H, userd, J=11,6 Hz)to 3.38 (5H, m), of 3.54 (2H, t, J=6.3 Hz), 3,68 (1H, m), 8,83 (2H, c), of 3.94 (4H, m), 4,10 (4H, m), 7,38 (1H, c), to 7.50 (1H, t, J=7,7 Hz), 7,60 (1H, d, J=8,2 Hz), 8,29 (1H, d, J=7,1 Hz), of 9.02 (1H, c), 10,10 (1H, users); MS (ESI+) 586 (MN+).

138. 2-{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}propan-2-ol

Get on the basis of 2-[1-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}propan-2-ol, obtained from 2-piperidine-4-improper-2-ol.

Getting amine: to a solution of complex ethyl ester piperidine-4-carboxylic acid (3.0 g), stir in dry MeCN (30 ml), add potassium carbonate (2,90 g) followed by the addition of benzylbromide (2.5 ml). The mixture is heated to 78°C. After 3 hours the mixture is cooled, poured into water (100 ml) and extracted into ethyl acetate, dried (MgSO4) and the solvent is removed in vacuum. The residue is purified using flash chromatography, to obtain the complex ethyl ester 1-benzylpiperidine-carboxylic acid (2.17 g) as a pale yellow oil.

To a solution of complex ethyl ester 1-benzylpiperidine-4-carboxylic acid (1.0 g), stir in dry THF (15 ml) under nitrogen atmosphere at 0°C, add methylanisole (3.0m solution in simple diethyl ether (8,10 ml) and stirred for 2 hours at 0°C. the Reaction mixture was quenched with a saturated solution of ammonium chloride and extracted into ethyl acetate, dried (MgSO4) and the solvent is removed in vacuum to obtain 2-(1-benzylpiperidine-4-yl)propan-2-ol (1,11 g) as a white solid.

To a suspension of 10% palladium-on-charcoal (40 mg), stir in the dry Meon (10 ml) under nitrogen atmosphere, is added 2-(1-benzylpiperidine-4-yl)propan-2-ol (0.25 g) and the mixture heated to 60°C. After 3 hours the mixture is cooled, filtered through a layer of celite and the solvents removed in vacuo to give the desired amine (153 mg) as a colourless oil.

1H NMR (400 MHz, d6-DMSO) 1,03 (c, 6H), of 1.09 (m, 1H), 1,23 (m, 2H), of 1.66 (m, 2H), up to 1.98 (m, 2H), 2,97 (m, 2H), 3,83 (m, CH2×2+CH2), of 4.00 (m, 4H), 7,46 (t, 2H, J=7,3 Hz), the 7.65 (d, 1H, J=8,2 Hz), 8,21 (d, 1H, J=7,1 Hz), 8,87 (c, 1H), 13,15 (users, 1H); MS (ESI+) 493,2 (MN+).

139. 2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-[4-(1-oxypyridine-3-ylmethyl)piperazine-1-ylmethyl]thieno[3,2-d]pyrimidine

Get on the basis of 2-chloro-4-morpholine-4-yl-6-[4-(1-oxypyridine-3-ylmethyl)piperazine-1-ylmethyl]thieno[3,2-d]pyrimidine was obtained from 1-(1-oxypyridine-3-ylmethyl)piperazine.

<> Getting amine: a mixture of 3-pyridylcarbinol-N-oxide (2,09 g) and thionyl chloride (1.65 ml) in dry chloroform (20 ml) is heated at 60°C. After 3 hours, the excess thionyl chloride destroy the addition of ethanol (0.5 ml). The resulting mixture was concentrated in vacuo. Kneading the powder with simple ether/acetone to give 1-oxide chloromethylpyridine of 2.27 g). A mixture of 1-oxide-3-chloromethylpyridine (1,25 g), 1-BOC-piperazine (1.47 g), K2CO3(1.23 g) heated to boiling under reflux in dry MeCN (25 ml). After 18 h, the reaction mixture was cooled, diluted with water, extracted with DCM, dried (Na2SO4), filtered and concentrated in vacuo, then purified flash chromatography (4% MeOH/DCM) to obtain the complex tert-butyl ester 4-(1-oxypyridine-3-ylmethyl)piperazine-1-carboxylic acid (1.18 g). Treatment of this compound with HCl in DCM/MeOH gives the desired amine, which was isolated in the form of hydrochloride.

1H NMR (400 MHz, CDCl3) to 2.54 (m, 4H, 2×CH2), 2,61 (m, 4H, 2×CH2), 3,49 (c, 2H, CH2), 3,85 (c, 2H, CH2), 3,90-3,93 (m, 4H, 2×CH2), 4,07-4,10 (m, 4H, 2×CH2), 7,18-7,22 (m, 2H, 2×ArH), 7,37 (c, H, ArH), 7,49 (t, H, AGN, J=7,75 Hz), 8,11 (d, H, ArH, J=5,2 Hz), of 8.27 (m, 2H, 2×ArH), of 9.30 (c, H, ArH), 10,27 (users, H, NH); MS (ESI+) 543,3 (MN+).

140. 2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-(morpholine-4-iletilerini-1-ylmethyl)thieno[3,2-d]pyrimidine

Get on the basis of 2-chloro-4-morpholine-4-yl-6-(4-(morpholine-4-ylmethyl is peridin-1-ylmethyl)thieno[3,2-d]pyrimidine, obtained from 4-piperidine-4-iletilmeyen.

Getting amine: to a solution of complex 1-BOC-piperidine-4-ethyl ester (2.0 g) under stirring in dry DCM (30 ml) at -78°C under nitrogen atmosphere add a solution diisobutylaluminum hydride (1.0 M in hexane; 8,0 ml), the mixture was stirred at -78°C for 2 h, then warmed to room temperature and the reaction quenched Meon (1 ml). The mixture was extracted into DCM and dried (MgSO4) and the solvents removed in vacuo to obtain a residue, which was purified using flash chromatography to obtain 1-BOC-4-formylpiperidine (457 mg).

To a solution of 1-BOC-4-formylpiperidine (210 mg) in dry 1,2-dichloroethane (10 ml) is added morpholine (86 mg) and glacial acetic acid (60 μl) and stirred for 1 hour at room temperature. To the mixture add triacetoxyborohydride sodium (272 mg) and the mixture is stirred for 12 hours. The reaction mixture was extracted in DCM (25 ml), washed with 50% solution of sodium bicarbonate (10 ml), brine (10 ml) and dried (MgSO4). The solvents are removed in vacuo to obtain a residue, which was purified using flash chromatography, to obtain the complex tert-butyl ester 4-morpholine-4-iletilerini-1-carboxylic acid (120 mg). Processing TFA gives the desired amine, which was isolated in the form of the TFA salt.

1H NMR (400 MHz, d6-DMSO) of 1.13 (m, 2H), 1,50 (m, 1H), 1,67 (m, 2H), 2,04 (m, 2H), 2,10 (d, 2H, J=7.2 Hz, 2,28 (users, 4H), 2,89 (m, 2H), 3,53 (m, 4H), of 3.77 (m, 4H+CH2), to 3.99 (m, 4H), 7,45 (t, 2H, J=9.8 Hz), the 7.65 (d, 1H, J=8,2 Hz), 8,21 (d, 1H, J=6,8 Hz), 8,87 (c, 1H), 13,15 (users, 1H); MS (ESI+) 534,3 (MN+).

141. {1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-ylmethyl}-(2-methoxyethyl)methylamine

Get on the basis of [1-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)piperidine-4-ylmethyl]-(2-methoxyethyl)methylamine obtained from (2-methoxyethyl)methylpiperidin-4-ylmethylamino. Amine, (2-methoxyethyl)methylpiperidin-4-ylmethylamino, get the same connection 140, using N-(2-methoxyethyl)methylamine.

1H NMR (400 MHz, d6-DMSO) of 1.09 (m, CH2), the 1.44 (m, CH2) to 1.67 (m, CH2), 2,04 (t, CH2, J=11.5 Hz), of 2.15 (m, 3H+CH2), 2,43 (t, CH2, J=6.0 Hz), 2,90 (m, CH2), 3,21 (c, 3H), 3,39 (m, CH2), 3,83 (m, 4H+CH2), to 3.99 (m, 4H), 7,46 (t, 1H, J=6.2 Hz), 7,66 (d, 1H, J=8,3 Hz), 8,21 (d, 1H, J=7.4 Hz), 8,87 (c, 1H), 13,25 (users, 1H); MS (ESI+) 536,4 (MN+).

142. {1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-ylmethyl}dimethylamine

Get on the basis of [1-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)piperidine-4-ylmethyl]dimethylamine obtained from dimethylpiperidin-4-ylmethylamino. Amin, dimethylpiperidin-4-ylmethylamino, get the same connection 140, using dimethylamine.

1H NMR (400 MHz, d6-DMSO) to 1.11 (m, CH2, of 1.42 (m, CH), of 1.66 (m, CH2), 2,03 (m, CH2×2), 2,08 (c, 6H), 2,89 (m, 2H), 3,82 (m, 4H,+CH2), to 3.99 (m, 4H), 7,45 (t, 2H, J=7,3 Hz), the 7.65 (d, 1H, J=8,3 Hz), 8,21 (d, 1H, J=7,3 Hz), 8,87 (c, 1H), 13,2 (users, 1H); MS (ESI+) 492,3 (MN+).

143. {1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-3-yl}-(2-methoxyethyl)methylamine

Get on the basis of [1-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-3-yl]-(2-methoxyethyl)methylamine obtained from (2-methoxyethyl)methylpiperidin-3-ylamine.

Obtain amine: a mixture of 1-BOC-3-piperidone (0.50 g), N-(2-methoxyethyl)methylamine (0.29 grams), triacetoxyborohydride sodium (0.74 g) and acetic acid (0,14 ml) in 1,2-dichloroethane (30 ml) was stirred at room temperature for 6 hours. Then the reaction mixture was diluted with DCM, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent is removed in vacuum. The residue is purified with flash chromatography to obtain complex tert-butyl ester 3-[(2-methoxyethyl)methylamino]piperidine-1-carboxylic acid (0,556 g). Treatment of this compound with HCl in DCM/MeOH gives the desired amine, which was isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) of 1.27 (1H, m), 1,60 (1H, m), 1.77 in (1H, m)to 1.98 (3H, m)to 2.35 (3H, c), 2,68 (3H, m), 2,92 (1H, d, J=10.5 Hz), 3,10 (1H, m)to 3.34 (3H, c), 3,44 (2H, m), 3,86 (2H, c)to 3.92 (4H, m), 4,08 (4H, m), 7,37 (1H c), to 7.50 (1H, t, J=7,7 Hz), 7,60 (1H, d, J=8,3 Hz), of 8.27 (1H, d, J=7,3 Hz), 9,01 (1H, c), and 10.20 (1H, users); MS (ESI+) 522 (MN+).

144. Methylamide 1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-3-carboxylic acid

Receive from methylamide 1-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)piperidine-3-carboxylic acid, obtained from methylamide piperidine-3-carboxylic acid.

Getting amine: to a solution of 1-(tert-butoxycarbonyl)-3-piperidinecarboxylic acid (0.50 g) in DMF (3 ml) is added 1,1'-carbonyldiimidazole (0,70 g). The reaction mixture is stirred for 4 hours and then add triethylamine (0,60 ml) followed by the addition of methylaminopropane (0.29 grams). After stirring for 24 h the reaction mixture was diluted with ethyl acetate, washed with water, brine, dried (MgSO4) and the solvent is removed in vacuum. The residue is purified with flash chromatography to obtain complex tert-butyl ester 3-methylcarbamoylmethyl-1-carboxylic acid (0,41 g). Treatment of this compound with HCl in DCM/MeOH gives the desired amine, which was isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) 1,58-of 1.94 (4H, m)of 2.50 (2H, m), 2,65 (2H, m), 2,84 (3H, d), 2,80 (1H, m), 3,85 (2H, m)to 3.92 (4H, m), 4,10 (4H, m), 7,00 (1H, users), 7,40 (1H, c), to 7.50 (1H, t, J=7,7 Hz), 7,60 (1H, d, J=8,2 Hz), 8,29 (1H, d, J=7,1 Hz), 9,03 (1H, c), 10,10 (1H, users); MS (ESI+) 492 (MN+).

145. 2-(1H-indazol-4-yl)-6-(3-methoxypiperidine-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine

Receive based on 2-chlor-(3-methoxypiperidine-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine, obtained from 3-methoxypiperidine.

Getting amine: to a solution of 1-BOC-3-piperidinecarboxylic acid (3.0 g) in DMF (25 ml) is added potassium carbonate (3.62 in) followed by the addition of iodomethane (4,07 ml). After 2.5 h the reaction mixture was diluted with water and extracted in a simple diethyl ether. The organic layer was washed with brine, separated and dried (MgSO4). The solvent is evaporated to obtain a complex 1-tert-butyl 3-methyl ester piperidine-1,3-dicarboxylic acid (2,98 g).

To a suspension of sociallyengaged (1,41 g) in THF (15 ml) at 0°C. add complex 1-tert-butyl 3-methyl ester piperidine-1,3-dicarboxylic acid in the form of a solution in THF (10 ml) and the mixture is stirred at room temperature for 3 hours. The reaction mixture was cooled to 0°C and quenched by addition of aqueous ammonium chloride, and the mixture filtered through celite. The filtrate is diluted with ethyl acetate, washed with water, separated and dried (Na2SO4). The solvent is evaporated to obtain a complex tert-butyl ester 3-hydroxyethylpiperazine-1-carboxylic acid (1.25 g). To a solution of this alcohol (422 mg) in THF (8 ml) is added sodium hydride (94 mg; 60% dispersion in mineral oil). After 15 minutes add logmean (0,49 ml) and the reaction mixture stirred for 18 hours. The mixture is then diluted with ethyl acetate and washed successively with water, brine is m, separated and dried (MgSO4). The solvent is evaporated and the residue purified flash chromatography with getting complicated tert-butyl ester 3-methoxypiperidine-1-carboxylic acid (414 mg). To a solution of complex tert-butyl ester 3-methoxypiperidine-1-carboxylic acid (204 mg) in DCM (3 ml) is added 2M hydrochloride in simple diethyl ether and the mixture is stirred for 18 hours. The solvent is evaporated to obtain the desired amine (168 mg).

1H NMR (400 MHz, CDCl3) 1,06 (c, 1H), 1,63 is 1.75 (m, 2H), 1,90-1,95 (m, 3H), 2,12 (m, 1H), 2,88 (m, 1H), 2,99 (m, 1H), 3,25 (m, 2H), 3,31 (c, 3H), 3,83 (c, 2H), 3,92 (t, J=4.8 Hz, 4H), 4.09 to (t, J=4.8 Hz, 4H), 7,35 (c, 1H), 7,50 (t, J=7.8 Hz, 1H), EUR 7.57 (d, J=8,2 Hz, 1H), 8,28 (d, J=7,4 Hz, 1H), 9,02 (c, 1H), 10,10 (users, 1H); MS (ESI+) 479,26 (MN+).

146. 2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-pyridine-2-iletilerini-1-ylmethyl)thieno[3,2-d]pyrimidine

Get on the basis of 2-chloro-4-morpholine-4-yl-6-(4-pyridine-2-iletilerini-1-ylmethyl)thieno[3,2-d]pyrimidine was obtained from 2-piperidine-4-iletilmedigini.

Getting Amin: complex tert-butyl ester 4-pyridin-2-iletilerini-1-carboxylic acid synthesized in accordance with the procedure described in J. Org. Chem. 2001, 66, 2487. Next, it is treated with HCl in DCM/MeOH to give the desired amine.

1H NMR (400 MHz, CDCl3) of 1.40-1.50 (2H, m), 1,64 is 1.70 (2H, m), 1,81-of 1.92 (1H, m), 2.06 to a 2.13 (2H, m), is 2.74 (2H, d, J=7,2 Hz), 2,96-3,03 (2H, m), 3,83 (2H, c), 3,90-of 3.96 (4H, m), of 4.05 (4H, m), 7,10-7,13 (2H, is), to 7.32 (1H, c), 7,50-7,53 (1H, m), 7,56 to 7.62 (2H, m), compared to 8.26 (1H, d, J=6.8 Hz), charged 8.52-8,54 (1H, m), 9,01 (1H, c), and 10.20 (1H, user.); MS (ESI+) 526 (MN+).

147. 2-(1H-indazol-4-yl)-6-[4-(2-methoxyethoxy)piperidine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine

Get on the basis of 2-chloro-6-[4-(2-methoxyethoxy)piperidine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine was obtained from 4-(2-methoxyethoxy)piperidine.

Getting amine: to a complex tert-butyl ether 4-hydroxypiperidine-1-carboxylic acid (1.5 g) in dry DMF (15 ml) is added sodium hydride (447 mg). After stirring for 2 hours at room temperature add a simple 2-bromatology ether (0.7 ml). The reaction mixture is heated to 40°C. overnight and then diluted with ethyl acetate, washed with water and dried (MgSO4). The solvent is evaporated and the residue purified flash chromatography with getting complicated tert-butyl ester 4-(2-methoxyethoxy)piperidine-1-carboxylic acid (447 mg). Treatment of this compound with HCl in DCM/MeOH gives the desired amine, which was isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) 1,72 (m, 2H), was 1.94 (m, 2H), 2,30 (m, 2H), 2,85 (m, 2H), 3,40 (c, 4H), 3,55 (m, 2H), 3,61 (m, 2H), 3,84 (c, 2H), 3,92 (m, 4H), 4.09 to (m, 4H), 7,35 (c, 1H), 7,52 (m, 1H), to 7.59 (d, J=8,2 Hz, 1H), 8,28 (d, J=6,8 Hz, 1H), 9,02 (c, 1H); MS (ESI+) 509 (MN+).

148. 6-((3R,5S) - for 3,5-dimethyl-4-thiazol-2-iletileri-1-ylmethyl)-2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine

Get on the basis of 2-chloro-6-((3R,5S) - for 3,5-dimethyl-4-thiazol-2-iletileri-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine was obtained from (2R,6S)-2,6-dimethyl-1-thiazol-2-iletilerini.

Getting amine: 2-thiazolecarboxamide converted into the corresponding alcohol by treatment with sodium borohydride. Interaction with methanesulfonamido gives complex thiazol-2-ymetray ether methanesulfonate acid. A mixture of complex thiazol-2-Eletropaulo ether methanesulfonate acid (393 mg), complex tert-butyl ether (3R,5S) - for 3,5-dimethylpiperazine-1-carboxylic acid (described earlier, 435 mg), potassium carbonate (309 mg) and tetrabutylammonium (827 mg) is heated to boiling under reflux in MeCN (10 ml). After 4 days the reaction mixture is cooled, diluted with ethyl acetate, washed with water and dried (MgSO4). The solvent is evaporated and the residue purified flash chromatography to obtain compound (S)-tert-butyl ether (R)for 3,5-dimethyl-4-thiazol-2-iletileri-1-carboxylic acid (314 mg). Treatment of this compound with HCl in DCM/MeOH gives the desired amine, which was isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) of 1.12 (d, J=6.0 Hz, 6H), to 2.06 (m, 2H), 2,85 (m, 4H), 3,80 (c, 2H), 3,92 (m, 4H), 4.09 to (m, 4H), 4,17 (c, 2H), 7,24 (d, J=3.2 Hz, 1H), 7,38 (c, 1H), 7,51 (m, 1H), to 7.59 (d, J=8,3 Hz, 1H), 7,74 (d, J=3.3V Hz, 1H), 8,29 (d, J=7,3 Hz, 1H), 9,03 (c, 1H), 10,1 (users, 1H); MS (ESI+) 561 (MN+).

149. 2-(1H-ind is evil-4-yl)-4-morpholine-4-yl-6-[4-(1-oxypyridine-2-ylmethyl)piperazine-1-ylmethyl]thieno[3,2-d]pyrimidine

Get on the basis of 2-chloro-4-morpholine-4-yl-6-[4-(1-oxypyridine-2-ylmethyl)piperazine-1-ylmethyl]thieno[3,2-d]pyrimidine was obtained from 1-(1-oxypyridine-2-ylmethyl)piperazine.

Getting amine: 2-pyridylcarbinol (of 2.26 g) in chloroform (20 ml) is added mCPBA (5,57 g) at 0°C. the Reaction mixture is stirred at this temperature for 1 hour, the solvent is removed in vacuo and the residue purified using flash chromatography, obtaining (1-oxypyridine-2-yl)methanol as a white solid (2,73 g). To pre-cooled (0°C.) solution of (1-oxypyridine-2-yl)methanol (2,73 g) in dry chloroform (25 ml) is added dropwise thionyl chloride (2,07 ml). The reaction mixture is heated at 60°C for 3 h, cooled to room temperature, quenched with ethanol (1 ml) and restore in a vacuum. The residue is collected in DCM, washed with aqueous sodium bicarbonate, dried (MgSO4) and the solvent is removed in vacuum to obtain 2-chloromethylpyridine-1-oxide in the form of oil (2,60 g), which solidified after settling. BOC-piperazine (500 mg) and 2-chloromethylpyridine-1-oxide (385 mg) is refluxed in MeCN (10 ml) with potassium carbonate (550 mg). After 4 hours the reaction mixture restore in vacuum, the residue is collected in DCM, washed with brine, dried (MgSO4) and the solvent is removed in vacuum to obtain complex tert-butyl ester 4-(1-oxypyridine-2-metil)piperazine-1-carboxylic acid (788 mg). Treatment of this compound with HCl in DCM/MeOH gives the desired amine, which was isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) 2,65 was 2.76 (8H, m), 3,88 (2H, c), with 3.89 (2H, c), 3,90-to 3.92 (4H, m), a 4.03-of 4.05 (4H, m), 7,14-to 7.18 (1H, m), 7,26-7,29 (1H, m), 7,37 (1H, c), of 7.48-7,51 (1H, m), 7,55-to 7.59 (2H, m), 8,23-8,29 (2H, m), of 9.02 (1H, c); MS (ESI+) 543 (MN+).

150. 2-(1H-indazol-4-yl)-6-[4-(2-methoxyethyl)piperidine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine

Get on the basis of 2-chloro-6-[4-(2-methoxyethyl)piperidine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine was obtained from 4-(2-methoxyethyl)piperidine.

Getting amine: to a solution of 4-piperidinemethanol (540 mg) in MeCN (8 ml), add triethylamine (0,70 ml) followed by addition of tert-BUTYLCARBAMATE (1,00 g). The mixture is stirred at room temperature for 22 h and partitioned between 0.5 M hydrochloric acid and ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and the solvent is evaporated to obtain a complex tert-butyl ester 4-(2-hydroxyethyl)piperidine-1-carboxylic acid (897 mg). It is dissolved in THF (14 ml) and add sodium hydride (172 mg; 60% dispersion in mineral oil) at 0°C. After 30 minutes add logmean (0,97 ml) and the mixture is stirred for 22 hours. The mixture was diluted with ethyl acetate and washed with water, brine and dried (MgSO4). The solvent is evaporated and the residue purified flash chromatography with what rucenim complex tert-butyl ester 4-(2-methoxyethyl)piperidine-1-carboxylic acid (724 mg). To a solution of complex tert-butyl ester 4-(2-methoxyethyl)piperidine-1-carboxylic acid (284 mg) in DCM (5 ml) is added 2M hydrochloride in simple diethyl ether (5.0 ml) and the mixture is stirred for 21 hours. The solvent is evaporated to give the desired amine as a white solid.

1H NMR (400 MHz, CDCl3) 1,45-1,25 (m, 5H), 1,71 (m, 2H), 2,10 (m, 2H), 2,98 (m, 2H), 3.33 and (c, 3H), 3.42 points (t, J=6.5 Hz, 2H), 3,83 (c, 2H), 3,92 (t, J=4.8 Hz, 4H), 4.09 to (t, J=4.8 Hz, 4H), of 7.36 (c, 1H), 7,51 (t, J=7.7 Hz, 1H), to 7.59 (d, J=8,3 Hz, 1H), 8,28 (d, J=6,7 Hz, 1H), 9,02 (c, 1H), of 10.05 (users, 1H); MS (ESI+) 493,27 (MN+).

151. 2-(1H-indazol-4-yl)-6-(4-methanesulfonamido-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine.

Is obtained from 2-chloro-6-(4-methanesulfonamido-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine was obtained from 4-methanesulfonanilide.

Getting amine: a mixture of complex tert-butyl ester 4-methanesulfonylaminoethyl-1-carboxylic acid (1,015 g), timelocked sodium (635 mg) is heated to 80°C in DCF (10 ml). After 4 hours the reaction mixture is diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo and then purified flash chromatography with getting complicated tert-butyl ester 4-methylsulfinylphenyl-1-carboxylic acid (600 mg). To a solution of complex tert-butyl ester 4-methylsulfinylphenyl-1-carboxylic acid (600 mg) in chloroform (15 ml) to ablaut mCPBA (1,46 g). After stirring for 2 days the reaction mixture was diluted with DCM, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent is removed in vacuum to obtain complex tert-butyl ester 4-methanesulfonamido-1-carboxylic acid (505 mg) as a white solid. Treatment of this compound with HCl in DCM/MeOH gives the desired amine, which was isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) 1,90-of 2.05 (2H, m), 2,10-to 2.18 (4H, m), 2,90 (3H, c), 2,91-to 2.94 (1H, m), 3,21 (2H, d), 3,88 (2H, c), 3,91-3,93 (4H, m), 4,10-4,12 (4H, m), 7,40 (1H, c), of 7.48-7,52 (1H, m), 7,58 (1H, d), of 8.25 (1H, d), 9,05 (1H c), of 10.25 (users, 1H); MS (ESI+) 513 (MN+).

152. {1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}-(3-methanesulfonyl)methylamine

Get on the basis of [1-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)piperidine-4-yl]-(3-methanesulfonyl)methylamine obtained from (3-methanesulfonyl)methylpiperidin-4-ylamine.

Getting Amin: complex 3-methylsulfinylpropyl ester toluene-4-sulfonic acid obtained from 3-(methylthio)-1-propanol, using standard conditions. Processing mCPBA in DCM gives the complex 3-methanesulfonylaminoethyl ester toluene-4-sulfonic acid. The complex mixture of tert-butyl methyl ether 4-methylaminopropyl-1-carboxylic acid and complex 3-methanesulfonamido ester toluene-4-sulfonic sour the s heated in MeCN in the presence of potassium carbonate to obtain complex tert-butyl ester 4-[(3-methanesulfonyl)methylamino]piperidine-1-carboxylic acid. Treatment of this compound with HCl in DCM/MeOH gives the desired amine, which was isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) 1,50-1,70 (m, 4H, 2×CH2), 1,90-of 1.97 (m, 2H, CH2), 2,00-2,05 (m, 2H, CH2), 2,21 (c, 3H, CH3), of 2.38 (m, H, CH), to 2.55 (m, 2H, CH2), 2,74 (c, 3H, CH2), 2,96 totaling 3.04 (m, 4H, 2×CH2in ), 3.75 (c, 2H, CH2), 3,83-to 3.89 (m, 4H, 2×CH2), 4,00-was 4.02 (m, 4H, 2×CH2), 7,28 (c, H, CH), 7,41 (t, H, ArH, J=7,74 Hz), 7,50 (d, H, ArH, J=8,24 Hz), 8,18 (d, H, ArH, J=7,05 Hz), 8,93 (c, H, ArH); MS (ESI+) 584,39 (MN+).

153. 2-(1H-indazol-4-yl)-6-[4-(3-methoxypropan-1-sulfonyl)piperidine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine

Get on the basis of 2-chloro-6-[4-(3-methoxypropan-1-sulfonyl)piperidine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine was obtained from 4-(3-methoxypropan-1-sulfonyl)piperidine.

Getting amine: a mixture of complex tert-butyl ester 4-methanesulfonylaminoethyl-1-carboxylic acid (2,82 g) and thioacetate potassium (2,31 g) heated to 60°C. in DMF (10 ml). After 4 hours the reaction mixture is diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo and then purified flash chromatography with getting complicated tert-butyl ester 4-acetylsulfapyridine-1-carboxylic acid (1.80 g). To a solution of complex tert-butyl ester 4-acetylsulfapyridine-1-carboxylic acid (607 mg) in dry Meon (5 ml) add a solution m is toxid sodium in the Meon (25 wt.%, 0,59 ml). After stirring for 15 min add complex 3-methoxypropylamine ether toluensulfonate acid (571 mg) in the Meon. After 24 hours the reaction mixture is diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo to obtain complex tert-butyl ester 4-(3-methoxypropionitrile)piperidine-1-carboxylic acid. Processing mCPBA (as described above) gives a complex tert-butyl ester 4-(3-methoxypropan-1-sulfonyl)piperidine-1-carboxylic acid. Treatment of this compound with HCl in DCM/MeOH gives the desired amine, which was isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) 1,95-of 2.20 (8H, m), 2,85-only 2.91 (1H, m), 3,02-of 3.06 (2H, t), 3,13-3,20 (2H, d), and 3.31 (3H, c), 3,52 (2H, t), 3,88 (2H, c), 3,94-3,99 (4H, m), 4.09 to-4,13 (4H, m), 7,35 (1H, c), 7,45-7,52 (1H, m), 7,55 (1H, d), 8,29 (1H, d), 9,05 (1H, c), 10,30 (1H, users); MS (ESI+) 571 (MN+).

154. Methylamide (R)-1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-3-carboxylic acid

Receive from methylamide (R)-1-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-3-carboxylic acid, obtained from methylamide (R)-piperidine-3-carboxylic acid.

Getting amine: to a suspension of the hydrochloride of (S)-(-)-nipecotate acid (1.0 g) in MeCN (10 ml), add triethylamine (1,85 ml) followed by addition of di-tert-BUTYLCARBAMATE (1.45 g). After stirring for 24 h the reaction is ionic mixture is diluted with DCM, washed with brine, dried (MgSO4) and the solvent is removed in vacuum. The residue is purified with flash chromatography to obtain complex 1-tert-butyl ether piperidine-1,3-dicarboxylic acid (0.54 g). The procedure continues similarly to the connection 144.

1H NMR (400 MHz, CDCl3) 1,58-of 1.94 (4H, m)of 2.50 (2H, m), 2,65 (2H, m), 2,84 (3H, d), 2,80 (1H, m), 3,85 (2H, m)to 3.92 (4H, m), 4,10 (4H, m), 7,00 (1H, users), 7,40 (1H, c), to 7.50 (1H, t, J=7,7 Hz), 7,60 (1H, d, J=8,2 Hz), 8,29 (1H, d, J=7,1 Hz), 9,03 (1H, c), 10,10 (1H, users); MS (ESI+) 492 (MN+).

155. Methylamide (S)-1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-3-carboxylic acid

Receive from methylamide (S)-1-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)piperidine-3-carboxylic acid, obtained from methylamide (S)-piperidine-3-carboxylic acid. Getting amine spend for connection 154 using the hydrochloride of (R)-(+)-nipecotate acid as the starting material.

1H NMR (400 MHz, CDCl3) 1,58-of 1.94 (4H, m)of 2.50 (2H, m), 2,65 (2H, m), 2,84 (3H, d), 2,80 (1H, m), 3,85 (2H, m)to 3.92 (4H, m), 4,10 (4H, m), 7,00 (1H, users), 7,40 (1H, c), to 7.50 (1H, t, J=7,7 Hz), 7,60 (1H, d, J=8,2 Hz), 8,29 (1H, d, J=7,1 Hz), 9,03 (1H, c), 10,10 (1H, users); MS (ESI+) 492 (MN+).

156. 6-(4-imidazol-1-iletilerini-1-ylmethyl)-2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine

Get on the basis of 2-chloro-6-(4-imidazol-1-iletilerini-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimi the ina, obtained from 4-imidazol-1-iletilmedigini.

Getting amine: to a solution of complex tert-butyl ester 4-hydroxyethylpiperazine-1-carboxylic acid (250 mg) in dry THF (15 ml) add tetrabromide carbon (769 mg) and teenyporn (609 mg). The reaction mixture was stirred at room temperature for 24 hours and then the solvent is evaporated in vacuum to obtain a residue, which was purified flash chromatography with getting complicated tert-butyl ester 4-bromomethylbiphenyl-1-carboxylic acid (279 mg) as a colorless oil. To a solution of complex tert-butyl ester 4-bromomethylbiphenyl-1-carboxylic acid (240 mg) in dry DMF (5.0 ml) is added imidazole (129 mg). The reaction mixture is heated in a sealed reaction vial at 100°C for 24 h, then cooled and the contents evaporated on the silicon dioxide for cleaning. Treatment of this compound with HCl in DCM/MeOH gives the desired amine, which was isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, d6-DMSO) of 1.23 (m, 2H), 1,47 (m, 2H), 1.69 in (m, CH), a 2.01 (m, 2H), 2,92 (m, 2H), 3,83 (m, 4H+CH2×2), 3,99 (m, 4H), 6.87 in (c, 1H), 7,13 (c, 1H), 7,46 (t, 1H, J=7,6 Hz), 7,58 (c, 1H), 7,65 (d, 1H, J=8,2 Hz), 8,21 (d, 1H, J=7,3 Hz), 8,87 (c, 1H), 13,2 (users, 1H); MS (ESI+) 515,2 (MN+).

157. 2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-morpholine-4-ilmatieteen[3,2-d]pyrimidine

Get on the basis of 2-chloro-4-morpholine-4-yl-6-morpholine-4-ilmatieteen[3,2-d]is rimidine, derived from the research.

1H NMR (400 MHz, CDCl3) of 2.58 2.63 in (4H, m), 3.72 points-of 3.78 (4H, m), 3,82 (2H, c), 3,88-3,93 (4H, m), 4,05-4,11 (4H, m), 7,38 (1H, c), 7,50-of 7.55 (2H, m), 7,60 (1H, d, J=8,3 Hz), of 8.28 (1H, d, J=7,2 Hz), of 9.00 (1H, c), 10,10 (1H, user.); MS (ESI+) 437 (MN+).

158. 2-(1H-indazol-4-yl)-6-(3-methylpiperidin-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine

Get on the basis of 2-chloro-6-(3-methylpiperidin-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine was obtained from 3-methylpiperidine.

1H NMR (400 MHz, CDCl3) to 0.88 (4H, m)to 1.70 (5H, m), 2,04 (1H, m), 2,90 (2H, m), 3,80 (2H, c), 3,90 (4H, m), 4,10 (4H, m), of 7.36 (1H, c), to 7.50 (1H, t, J=7,7 Hz), 7,58 (1H, d, J=8,2 Hz), 8,29 (1H, d, J=7,1 Hz), of 9.02 (1H, c), 10,10 (1H, users); MS (ESI+) 490 (MN+).

159. {1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-3-yl}methanol

Get on the basis of [1-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)piperidine-3-yl]methanol obtained from piperidine-3-ylmethanol.

1H NMR (400 MHz, CDCl3) of 1.18 (m, 1H), 1,58-of 1.88 (m, 4H), 2,12 (m, 1H), and 2.27 (m, 1H), 2,77 (m, 1H), 2,93 (m, 1H), of 3.56 (DD, J=10,6 Hz, 6.4 Hz, 1H), 3,64 (DD, J=10,6 Hz, 5.5 Hz, 1H), 3,84 (c, 2H), 3,92 (t, J=4.8 Hz, 4H), 4.09 to (t, J=a 4.8 Hz, 4H), of 7.36 (c, 1H), 7,51 (t, J=7.7 Hz, 1H), to 7.59 (d, J=8,3 Hz, 1H), 8,27 (d, J=7,3 Hz, 1H), 9,01 (c, 1H), 10,10 (users, 1H); MS (ESI+) 465,20 (MN+).

160. 2-{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}ethanol

Get on the basis of 2-[1-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}ethane is La, obtained from 2-piperidine-4-retinol.

1H NMR (400 MHz, d6-DMSO) of 1.18 (m, 2H), 1,36 (m, 3H), and 1.63 (m, 2H), 2,02 (m, 2H), 2.91 in (m, 2H), 3,30 is-3.45 (m, 2H), 3,84 (m, 6N), to 3.99 (t, J=4.8 Hz, 4H), 4,35 (t, J=4.8 Hz, 4H), 7,46 (m, 2H), 7,65 (d, J=8,3 Hz, 1H), 8,21 (d, J=7.8 Hz, 1H), 8,87 (s, 1H); MS (ESI+) 479,25 (MH+).

161. 1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-4-thiazole-2-reparacin-4-ol

Get on the basis of 1-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)-4-thiazole-2-reparacin-4-ol, obtained from 4-thiazol-2-reparacin-4-ol.

1H NMR (400 MHz, d6-DMSO) of 1.73 (m, 2H), and 2.14 (m, 2H), 2,53 (m, 2H), 2,78 (m, 2H), 3,83 (m, 4H), 3,91 (c, 2H), 4,01 (m, 4H), 5,95 (c, 1H), 7,46 (t, 1H, J=7,6 Hz), 7,49 (c, 1H), EUR 7.57 (d, 1H, J=3.1 Hz), the 7.65 (d, 1H, J=8,3 Hz), 7,72 (d, 1H, J=3.3 Hz), 8,21 (d, 1H, J=7,3 Hz), 8,88 (c, 1H), of 13.18 (users, 1H); MS (ESI+) 534,3 (MN+).

Getting monomers of ester of boronate for the synthesis of compounds 162 and 163

A solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole (400 mg) in dry DHF (4 ml), cooled to 0°C, added to a suspension of sodium hydride (80 mg) in dry THF (5 ml) at -78°C in an inert atmosphere. After 30 min, to the mixture add logmean (112 μl) at -78°C. the Reaction mixture is slowly warmed to room temperature overnight and then diluted with DCM, washed with brine, dried (MgSO4) and the solvent is removed in vacuum. The residue is purified using flash chromatography to obtain 1-methyl-4-(4,4,5,5-tetrameth the l-[1,3,2]dioxaborolan-2-yl)-1H-indazole (143 mg) and 2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole (160 mg).

162. 2-(1-methyl-1H-indazol-4-yl)-6-(4-methylpiperazin-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine

Get a similar connection 59.

1H NMR (400 MHz, CDCl3) 2,32 (3H, s), 2,45 is 2.55 (4H, osirm), 2,55-2,70 (4H, osirm), 3,83 (2H, s), 3,90-3,93 (4H, m), a 4.03-4,06 (4H, m), of 4.12 (3H, s), 7,40 (1H, s), 7,49-7,52 (2H, m), 8,25-of 8.27 (1H, m), of 8.90 (1H, s); MS (ESI+) 464 (MN+).

163. 2- (2-methyl-2H-indazol-4-yl)-6-(4-methylpiperazin-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine

Get a similar connection 59.

1H NMR (400 MHz, CDCl3) 2,32 (3H, s), 2,45 is 2.55 (4H, osirm), 2,55-2,70 (4H, osirm), 3,83 (2H, s), 3,90-3,93 (4H, m), a 4.03-4,06 (4H, m), 4,30 (3H, s)of 7.48 (2H, m), 7,81 (1H, d, J=8,4 Hz), of 8.28 (1H, d, J=6.8 Hz), of 8.90 (1H, s); MS (SI+) 464 (MN+).

Alternative methods of synthesis

164. 2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-thiazole-4-iletileri-1-ylmethyl)thieno[3,2-d]pyrimidine

Get on the basis of 2-chloro-4-morpholine-4-yl-6-(4-thiazole-4-iletileri-1-ylmethyl)thieno[3,2-d]pyrimidine was obtained from 1-thiazole-4-iletilerini on the basis of 2-chloro-4-morpholine-4-yl-6- (4-thiazole-4-iletileri-1-ylmethyl)thieno[3,2-d]pyrimidine obtained in accordance with the following procedure: to a suspension of 4-thiazolecarboxamide acid (500 mg) in THF (10 ml) is added a complex of borane-dimethyl sulfide (0,73 ml). After 24 hours the mixture is cooled to 0°C and quenched by addition of 2M hydrochloric acid and extracted into ethyl acetate. The organic layers washed the Ute brine and dried (MgSO 4). The solution is evaporated and the residue is stirred in DCM/MeOH overnight. The mixture is concentrated and the residue purified flash chromatography to obtain thiazole-4-ylmethanol (173 mg). To a solution of thiazole-4-ylmethanol (168 mg) in DCM (5 ml) was added triethylamine (0.33 ml) followed by the addition of methanesulfonanilide (0.17 ml) at 0°C. the Mixture is stirred at room temperature for 10 min and diluted with DCM, washed with brine and dried (MgSO4). The crude product is purified flash chromatography with obtaining a complicated thiazole-4-Eletropaulo ether methanesulfonate acid (263 mg). To a solution of 2-chloro-4-morpholine-4-yl-6-piperazine-1-ilmatieteen[3,2-d]pyrimidine (300 mg) and complex thiazole-4-Eletropaulo ether methanesulfonate acid (213 mg) in MeCN (10 ml) is added potassium carbonate (164 mg) and the mixture is heated at 80°C for 8 hours. The cooled mixture is filtered, the solvent is evaporated and the residue separated between DCM and water. The organic layer was washed with brine and dried (MgSO4) and the solvent is evaporated. The residue is purified with flash chromatography to give the desired product (249 mg).

1H NMR (400 MHz, CDCl3) to 2.57 (users, 4H), 3,71 (c, 2H), 3,79 (c, 2H), 3,85 (t, J=4.8 Hz, 4H), was 4.02 (t, J=4.8 Hz, 4H), 7,13 (c, 1H), 7,30 (c, 1H), 7,43 (t, J=7.8 Hz, 1H), 7,51 (d, J=8,3 Hz, 1H), 8,21 (d, J=6,9 Hz,1H), 8,71 (d, J=2.0 Hz, 1H), 8,95 (c, 1H), 10,10 (users, 1H); MS (ESI+) 533,25 (MN+).

165. 1-{4-[2-(1H-indazol-4-yl)-4-morpholine-4-elteen the[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-yl}-3-phenoxypropan-2-ol

Get on the basis of complex tert-butyl ester 4-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)piperazine-1-carboxylic acid, obtained from 1-BOC-piperazine.

Processing complex tert-butyl ester 4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)piperazine-1-carboxylic acid HCl in DCM/MeOH gives 2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-piperazine-1-ilmatieteen[3,2-d]pyrimidine. A mixture of 2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-piperazine-1-ilmatieteen[3,2-d]pyrimidine (150 mg) and 1,2-epoxy-3-phenoxypropane (40 mg) is suspended in 50% DMF/0,1M phosphate buffer sodium (2 ml) and shaken at 55°C over night. After stirring for 24 h the reaction mixture was diluted with DCM, washed with brine and dried (MgSO4) and the solvent is removed in vacuum. The residue is purified with flash chromatography.

1H NMR (400 MHz, CDCl3) 2,50-2,70 (8H, usher.), 2,70-2,82 (2H, usher.), of 3.85 (2H, c), 3,90-3,93 (4H, m), 3,99-4,01 (2H, m), 4,07-4,14 (5H, m), 6.90 to-6,98 (3H, m), 7,26-7,30 (2H, m), 7,40 (1H, c), 7,50-7,53 (1H, m), to 7.59 (1H, d, J=8,3 Hz), 8,29 (1H, d, J=7,0 Hz), of 9.02 (1H, c); MS (ESI+) 568 (MN+).

166. 6-{4-(1H-imidazol-2-ylmethyl)piperazine-1-ylmethyl]-2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine

Get on the basis of 2-chloro-4-morpholine-4-yl-6-piperazine-1-ilmatieteen[3,2-d]pyrimidine was obtained from 1-BOC-piperazine followed by treatment with HCl and subsequent interaction with the imidazole-2-carboxaldehyde using with undertie conditions reductive amination. In subsequent allocate amine, 2-chloro-6-[4-(1H-imidazol-2-ylmethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine.

1H NMR (400 MHz, CDCl3) 2,55-of 2.72 (8H, osirm), 3,71 (2H, c), with 3.89 (2H, c), 3,92-of 3.96 (4H, m), a 4.03-4,11 (4H, m), 7,02 (2H, c), 7,32 (1H, c), 7,51 (1H, t, J=8.0 Hz), to 7.59 (1H, d, J=8,3 Hz), 8,29 (1H, d, J=6.6 Hz), 9,03 (1H, s), 10,10 (1H, osirm); MC (ESI+) 516 (MN+).

167. 6-{4-(3H-imidazol-4-ylmethyl)piperazine-1-ylmethyl]-2-(1H-indazol-4-yl) -4-morpholine-4-illiano [3, 2-d] pyrimidine

Similarly, the connection 167 (PI1343) get 2-chloro-6-[4-(3H-imidazol-4-ylmethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine by reductive amination complex tert-butyl ester 5-formylindole-1-carboxylic acid with the subsequent removal of the group VOS using Hcl.

1H NMR (400 MHz, d6-DMSO) 2,45 (users, 4H), 3,29 (s, 2H), 3,42 (users, 4H), of 3.84 (m, 6N), to 3.99 (t, 4H), 7,46 (m, 3H), 7,47 (s, 1H), 7,65 (d, J=7,4 Hz, 1H), 8,21 (d, J=7,4 Hz, 1H), 8,86 (s, 1H), 13,20 (s, 1H). MC (ESI+) 516 (MN+).

Synthesis based on allylbromide (scheme 3)

173. 2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-((2S,6R)-2,4,6-trimethylpyrazine-1-ylmethyl)thieno[3,2-d]pyrimidine

To the compound (66) (1.5 g) in ethanol (30 ml) is added sodium borohydride (1 g). After 4 hours the reaction mixture was quenched with brine and the resulting solid is collected by filtration and air-dried to obtain compound 168 (2-chloro-4-morpholine-4-illiano[3,2-d]pyrimi the in-6-yl)methanol (1.42 g).

To a solution of compound 168 (1.42 g) in toluene (14 ml), heated to 40°C, add tribromide phosphorus (0.16 ml). The resulting mixture was then heated to 100°C for 6 hours, cooled, diluted with chloroform, washed with brine and dried (MgSO4). The solvent is removed in vacuo to obtain 6-methyl bromide-2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine, compound 169 (1.40 g).

The complex mixture of tert-butyl methyl ether (3R,5S) - for 3,5-dimethylpiperazine-1-carboxylic acid (0,92 g), 6-methyl bromide-2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine (1 g) and potassium carbonate (1,59 g) in MeCN (10 ml) is heated to boiling for 5 days. The reaction mixture is subsequently cooled, diluted with chloroform, washed with brine and dried (MgSO4) and the solvent is removed in vacuum. The residue is purified column flash chromatography with getting complicated tert-butyl ether (3S,5R)-4-(2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl)for 3,5-dimethylpiperazine-1-carboxylic acid, compound 170 (1.2 g). Treatment of this compound with HCl in DCM/MeOH gives 2-chloro-6-(2S,6R)-2,6-dimethylpiperazine-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine, compound 171, which then was identified in using 37% solution of formaldehyde and sodium borohydride in the Meon, receiving the connection 172.

1H NMR (400 MHz, CDCl3) of 1.17 (6H, d), with 1.92 (2H, t), and 2.3 (3H, c), 2,73 (2H, d), and 2.83 (2H, m), of 3.95 (4H, m), a 4.03 (4H, m), 4,18 (2H, c), of 7.36 (1H, c), of 7.48 (1H, t), 7,56 (1H, d), compared to 8.26 (1H, d), of 9.00 (1H, c), the 10.40 (1H, ears the mkm); MS (ESI+) 478 (MN+).

174. {4-[2-1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-1-methanesulfonylaminoethyl-2-yl]methanol

Get on the basis of [4-[2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-1-methanesulfonylaminoethyl-2-yl]methanol obtained from (1-methanesulfonylaminoethyl-2-yl)methanol.

Getting amine: To a suspension dihydrochloride piperazine-2-carboxylic acid (10.0 g) in 1,4-dioxane (100 ml) and water (50 ml), cooled to 0°C, slowly add 17M solution of sodium hydroxide (8.6 ml) followed by addition of di-tert-BUTYLCARBAMATE (11.8 g). The reaction mixture is heated to room temperature and stirred for 5 hours. Then add triethylamine (13,7 ml) followed by the addition of methanesulfonanilide (3.8 ml). After stirring for 24 h the reaction mixture was concentrated, the residue diluted with ethyl acetate, washed with 2M hydrochloric acid, brine, dried (MgSO4) and the solvent is removed in vacuo to obtain the crude complex 1-tert-butyl ester 4-methanesulfonylaminoethyl-1,3-dicarboxylic acid (8,46 g). It subsequently dissolved in DMF (50 ml) and treated with potassium carbonate (7.5 g) and iodomethane (8.5 ml). After stirring for 24 h the reaction mixture was diluted with ethyl acetate, washed with water, brine, dried (MgSO4) and the solvent is removed in HAC is the mind. The residue is purified with flash chromatography to obtain complex 3-methyl and 1-tert-butyl ester 4-methanesulfonylaminoethyl-1,3-dicarboxylic acid (3,27 g).

To a suspension of sociallyengaged (0.75 g) in THF (30 ml) add a solution of complex 3-methyl and 1-tert-butyl ester 4-methanesulfonylaminoethyl-1,3-carboxylic acid (3.2 g) in THF (20 ml) at 0°C. Then the reaction mixture is heated to room temperature. After stirring for 2.5 hours to the reaction mixture add a solution of ammonium chloride (5 ml), then filtered through celite, washed with brine, dried (MgSO4) and the solvent is removed in vacuum. The residue is purified with flash chromatography to obtain complex tert-butyl ester 3-hydroxymethyl-4-methanesulfonylaminoethyl-1-carboxylic acid (1.13 g). Treatment of this compound with HCl in DCM/MeOH gives the desired amine, which was isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) of 2.38 (1H, m), 2,50 (1H, DD, J=3,9 Hz, 7.7 Hz), 2,70 (1H, users), of 2.97 (1H, m)of 3.00 (3H, c), 3,06 (1H, d, J=11,6 Hz), 3,52 (1H, m), and 3.72 (1H, d, J=12,8 Hz), 3,86 (2H, m), of 3.94 (5H, m)to 4.01 (1H, m), 4,10 (5H, m), 7,40 (1H, c), 7,51 (1H, t, J=7.8 Hz), 7,60 (1H, d, J=8,2 Hz); of 8.27 (1H, d, J=7.2 Hz); of 9.02 (1H, c); for 10.16 (1H, users). MS (ESI+) 544 (MN+).

175. 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-3-methoxypiperidine-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine

Get on the basis of 2-chloro-6-(4-methanesulfonyl-3-methoxypiperidine-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine, obtained from 1-methanesulfonyl-2-methoxypiperidine.

Getting amine: to a solution in THF (5 ml) of a compound tert-butyl ester 3-hydroxymethyl-4-methanesulfonylaminoethyl-1-carboxylic acid (0,30 g described with getting 174) add sodium hydride (0,043 g). The reaction mixture was stirred for 20 min and then add logmean (0,19 ml). After stirring for 24 h the reaction mixture was diluted with DCM, washed with brine, dried (MgSO4) and the solvent is removed in vacuum. The residue is purified with flash chromatography to obtain complex tert-butyl ester 4-methanesulfonyl-3-methoxypiperidine-1-carboxylic acid (0,254 g). Treatment of this compound with HCl in DCM/MeOH gives the desired amine, which was isolated in the form of a hydrochloric salt.

1H NMR (400 MHz, CDCl3) was 2.34 (1H, m), 2,42 (1H, DD, J=3,9 Hz and 7.6 Hz), to 2.94 (2H, m), of 3.07 (3H, c), or 3.28 (1H, m), 3,40 (3H, c), 3,74 (1H, d, J=12.9 Hz), a-3.84 (2H, m), of 3.94 (4H, m)4,00 (1H, t, J=5,1 Hz), 4,10 (4H, m), 4,20 (1H, m), 7,40 (1H, c), 7,52 (1H, t, J=7.8 Hz), 7,60 (1H, d, J=8,3 Hz), of 8.28 (1H, d, J=7,1 Hz), of 9.00 (1H, c), 10,15 (1H, users); MS (ESI+) 558 (MN+).

Example 3

Biological test

Compounds according to the invention, obtained as described in the previous examples, were subjected to the following series of biological tests:

(i) Biochemical screening PI3K

Inhibition of PI3K compounds was determined in a radiometric analysis using cleaned up the th recombinant enzyme and ATP in a concentration of 1 μm. All compounds were serially diluted in 100% DMSO. The reaction mixture kinase were incubated for 1 hour at room temperature and the reaction was stopped by adding PBS (saline phosphate buffer). The value of the IC50(concentration inhibiting 50%) was then determined using the definition of conformity of the sigmoid curve dose-response (variable slope). All illustrated connection had IC50against PI3K 510 μm or less. In particular, all of the compounds tested against the isoforms 110δ PI3K, had IC50of 0.1 μm or less.

(ii) Inhibition of cell proliferation

Cells were sown at the optimum density in 96-well plates and incubated for 4 days in the presence of the test compound. To the analytical environment then add Alamar BlueTMand cells were incubated for 6 h before reading at excitation 544 nm, emission 590 nm. Size EU50calculated using the definition of conformity of the sigmoid curve dose-response. Size EU50all the tested compounds was 50 μm or less in the range of the used cell lines.

(iii) the Permeability of SASO-2

Cells SASO-2 were sown on tablets Millipore Multiscreen at 1×105cells/cm2and were cultured for 20 days. Subsequently conducted assessment of the permeability for the connection. Compounds were applied to the apical surface (A) cell monolayers and measured the penetration of top-side connections (In) compartment. This is performed in the reverse direction (B-A) for studies of active transport. Expected value of the permeability coefficient, Parrfor each connection, measure the speed of penetration of compounds through the membrane. Compounds were grouped on low (Rarr≤1,0×106cm/s) or high (Parr≥1,0×106cm/s) potential acquisitions on the basis of comparison with a control connection established by absorption in humans.

To assess the ability of the compound to be active outflow was determined by the ratio of the top-side (In) to apollinea (A) transport, in comparison with a Century to Value In-And/a-b≥1,0 pointed to the emergence of active cell outflow. All compounds tested by screening permeability of SASO-2, the values of Rarr≥1,0×106cm/sec. a single connection, assessed by bi-directional analysis, R, had an index of asymmetry-a/a Is less than 1.0, indicating that the compound does not undergo active cell outflow.

(iv) Clearance of hepatocyte

Used suspension cryopreserved human hepatocytes. Incubation was performed at concentrations of compounds 1 mm or 3 MK is at a density of cells in 0.5×10 6viable cells/ml Final concentration of DMSO in the incubation was 0.25%. Also performed a control incubation in the absence of cells to identify any not enzymatic destruction. 2 sample (50 μl) were removed from the incubation mixture after 0, 5, 10, 20, 40 and 60 min (control sample only after 60 min) and added to the internal standard (100 μl)containing Meon, to stop communicating. Tolbutamide, 7-hydroxycoumarin and testosterone were used as control compounds. The samples were centrifuged and the supernatant at each time point were pooled for analysis of LC-MSMS (liquid chromatography - mass spectrometry-mass spectroscopy). Our schedule was determined by the changing attitudes of ln peak area (peak area parent compound/peak area of internal standard) over time, the inner clearance (CLint) was calculated as follows: CLint(ál/min/million cells) = V×k, where k represents the rate constant of excretion obtained by concentration gradient ln, plotted on a graph it changes over time; V is the volume, derived from the incubation volume and expressed as µl of 106cells-1.

Compounds classified low (CL≤4,6 µl/min/106cells), medium (CL≥4,6; ≤25,2 µl/min/106cells) and high ≥25,2 µl/min/10 6cells) clearance. It was determined that most of the tested compounds according to the invention had a low clearance hepatocytes.

(v) Inhibition of cytochrome P450

Organized the screening of compounds according to the invention against five targets CYP450 (1A2, 2C9, 2C19, 2D6, 3A4) in 10 concentrations in two repetitions, using the highest concentration of 100 μm. As controls used standard inhibitors (furafylline, sulfaphenazole, tranilcipromin, quinidine, ketoconazole). Tablets read using device BMG Lab Technologies PolarStar in fluorescence mode. Most of the tested compounds evaluated in this analysis, showed weak activity (IC50≥5 nm) against all isoforms of CYP450.

(vi) Induction of cytochrome P450

Freshly isolated the human hepatocytes from a single donor were cultured for 48 h before addition of the test compounds at three concentrations and incubated for 72 hours. Probe substrates for CYP3A4 and CYP1A2 was added within 30 min and 1 hour before the end of incubation. After 72 hours the cells and medium were removed and using LC-MS/MS quantify the degree of metabolism of each probe substrate. The experiment was controlled by inducers of individual P450, incubated in the same concentration in three repetitions. Compounds according to the invention is evaluated in this Ana is ize, showed effects on the induction of cytochrome P450 enzymes, which can be neglected.

(vii) plasma protein Binding

Received solutions of the test compounds (5 μm, and 0.5% final concentration of DMSO in buffer and 10% plasma (about./about. in the buffer). 96-well plate for hemagglutinating dialysis collected so that each hole was divided into 2 semi-permeable cellulose membrane. Buffer solution was added to one side of the membrane; then incubation was performed at 37°C for 2 h in three repetitions. Cells subsequently drained and solutions for each batch, the compounds were combined into 2 groups (without plasma, and contents of the plasma), and then were analyzed by LC-MSMS using 2 set of calibration standards for deprived plasma (6 points) and containing the plasma (7 points) solutions. For each compound was calculated the value of the unbound fraction: compounds with a high relationship with the squirrels (related to ≥90%) had Fu≤0,1. Compounds according to the invention, estimated in this analysis, had a magnitude Fu≥0,1.

(viii) the Blockade of hERG channels

Compounds according to the invention were evaluated to determine their ability to modulate the outflow of rubidium cell SOME 294, stably expressing the hERG potassium channel, using the methodology established flow. The cells were obtained in the medium containing RbCl, and were sown in 96-well plates, and grow and during the night for the formation of monolayers. Experiment outflow began aspirate medium and wash each well 3×100 μl of pre-incubated in buffer containing a low concentration of potassium [K+]) at room temperature. After the final aspiration in each well was added 50 μl of the working uterine (2 ×) compounds, and incubated at room temperature for 10 minutes Then to each well was added 50 μl of stimulating buffer (containing high [K+]), providing the final concentration of the test compounds. Then the cell plates were incubated at room temperature for a further 10 minutes and Then 80 μl of supernatant from each well was transferred into equivalent wells of 96-well plates and analyzed by atomic emission spectroscopy. Screening of the compounds was performed in a 10-point curves IC50in two repetitions, n=2, the maximum concentration of 100 ám.

Example 4

Composition for tablets

Tablets, each weighing 0.15 g and containing 25 mg of the compounds according to the invention is made as follows:

Composition for 10,000 tablets

The active compound (250 g)

Lactose (800 g)

Corn starch (415 g)

The talc powder (30 g)

Magnesium stearate (5 g)

Mix the active compound, lactose and half the corn starch. The mixture is then forced across the sieve with the mesh size, mesh., 0.5 mm Corn starch (10 g) is suspended in warm water (90 ml). The resulting paste is used for granulation of powder. Granulated mass is dried and break it down into small fragments on the sieve mesh. 1,4 mm Add the remaining quantity of starch, talc and magnesium, thoroughly mixed and produced tablets.

Example 5

Injectable preparative form

The composition And

Active connection200 mg
Hydrochloric acid solution 0.1m or
the sodium hydroxide solution 0.1m
As required
to pH 4,0-7,0
Sterile waterAs required
to 10 ml

The connection according to the invention is dissolved in a larger amount of water (35-40°C) and pH adjusted to a level of 4.0-7.0 depending on the feasibility of hydrochloric acid or sodium hydroxide. Then the batch is brought to the desired volume with water and filtered through a sterile micropore filter into a sterile vial with a capacity of 10 ml amber glass (type 1) and sealed with sterile tubes and additional sealing means.

Composition

Active connection125 mg
Sterile pyrogen-free phosphate buffer with pH 7As needed up to 25 ml
Active connection200 mg
Benzyl alcohol : 0.10 g
Glucotrol 751.45 g
Water for injectionHow much you want to 3.00 ml

The active compound is dissolved in glucotrole. Then add benzyl alcohol, dissolve and add water to 3 ml of the mixture is Then filtered through a sterile Millipore filter and sealed in sterile glass bottles with a capacity of 3 ml (type 1).

Example 6

Preparative form syrup

Active connection250 mg
The solution of sorbitol1.50 g
Glycerin2,00 g
Sodium benzoate0.005 g
Perfumeof 0.0125 ml
Purified waterHow much you want to 5.00 ml

The connection according to the invention is dissolved in a mixture of glycerin and more purified water. Then to the solution was added an aqueous solution of sodium benzoate followed by the addition of sorbitol solution and, finally, the odorant. The volume was adjusted with purified water and thoroughly mixed.

1. The connection, which is a condensed pyrimidine of the formula (I)

where a represents a thiophene ring;
n=1;
R1represents a group of the formula:

where m=1;
R30represents hydrogen;
R4and R5form together with the N atom to which they are attached, a 5 - or 6-membered saturated N-containing heterocyclic group which includes 0 or 1 additional heteroatom selected from N and O, which is unsubstituted or substituted by one or more substituents selected from C1-6of alkyl, which is unsubstituted or substituted C1-6alkoxy, which is unsubstituted or substituted, -N(R'")-ALK-OR-ALK-OR, -O-ALK-OR-ALK-C(O)NR2, -C(O)NR2, -ALK-Het, -N(R)-Het, -O-Het, -N(R)-C(O)-ALK-OR, -NR-S(O)2R, -N(R)-ALK-S(O)2R, -N(R)-ALK-OR-ALK-R NR'r", -N(R'")-S(O)2R, S(O)2R'",-S(O)2-ALK-OR 5 - or 6-membered saturated N-containing heterocyclics the Oh group, as defined above, which is substituted or unsubstituted, 5 - or 6-membered N-containing heteroaryl group which includes 0 or 1 additional heteroatom selected from N, O or S, which is unsubstituted or substituted, oxo(=O), -SO2NR2, -SO2-ALK-NR2where ALK represents a C1-6alkylenes chain; Het represents a 5 - or 6-membered N-containing heteroaryl group, as defined above, which is unsubstituted or substituted or furan optionally substituted C1-6by alkyl; R represents H or C1-6alkyl, which is unsubstituted or substituted, or when 2 groups R are associated with N, they may form, together with the N atom, a saturated 5 - or 6-membered N-containing heterocyclic group as defined above which is unsubstituted or substituted; each of R' and R" is independently H, C1-6alkyl or C1-6alkoxy; and R'" represents a C1-6alkyl, which is unsubstituted or substituted CF3, NR2OR 5 - or 6-membered saturated N-containing heterocyclic group as defined above, or a 5-or 6-membered N-containing heteroaryl group, as defined above, and the specified heterocyclic and heteroaryl groups are unsubstituted or substituted;
R2represents a

where R6and R7form together with the nitrogen atom to which they are attached, morpholino group, which is unsubstituted;
R3represents indazol group, which is unsubstituted or substituted by one or more substituents selected from a halogen atom and C1-6of alkyl;
and where in the above definitions:
(i) substituted C1-6alkyl represents a C1-6alkyl group which carries one or more substituents R20selected from halogen, C1-6alkoxy, C3-10carbocycle, 5 - or 6-membered saturated N-containing heterocyclic group as defined above, HE or phenoxy;
(ii) substituted C1-6alkoxygroup represents a C1-6alkoxygroup, which carries one or more substituents R20as defined above;
(iii) a 5 - or 6-membered heteroaryl group, as defined above, which is substituted, represents a 5 - or 6-membered heteroaryl group, substituted by actigraphy or C1-6by alkyl;
(iv) substituted 5 - or 6-membered saturated N-containing heterocyclic group as defined above, represents a 5 - or 6-membered saturated N-containing heterocyclic group, substituted C1-6by alkyl;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where the condensed Piri which one has the formula (Ia):

where X represents S and R1, R2, R3and n have the meanings given in claim 1.

3. The compound according to claim 1, which is selected from
2-(1H-indazol-4-yl)-6-(4-methylpiperazin-1-ylmethyl)-4-morpholine-4-yl-thieno[3,2-d]pyrimidine;
dimethylamide 4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-sulfonic acid;
{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-piperazine-1-yl} morpholine-4-ylmethanone;
(2-methoxyethyl)methylamine 4-[2-(1H-indazol-4-yl)-4-morpholine-4-yl-thieno[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-carboxylic acid;
2-{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano [3,2-d]pyrimidine-6-ylmethyl]-piperazine-1-yl}-N,N-dimethylacetamide;
dimethylamide 4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-carboxylic acid;
2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-[4-(3-morpholine-4-improper-1-sulfonyl)-piperazine-1-ylmethyl]thieno[3,2-d]pyrimidine;
{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano [3,2-d]pyrimidine-6-ylmethyl]-piperidine-4-yl}-(2-methoxyethyl)methylamine;
(3-{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-piperazine-1-sulfonyl}propyl)dimethylamine;
2-{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano [3,2-d]pyrimidine-6-ylmethyl]-piperazine-1-yl}-2-methylpropan-1-ol;
1'-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-[1,4']bipiperidine;
2-(1H-in the azole-4-yl)-4-morpholine-4-yl-6-(4-(morpholine-4-reparacin-1-ylmethyl)thieno[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-(pyrimidine-2-reparation-1-ylmethyl)thieno[3,2-d]pyrimidine;
1-(2-hydroxyethyl)-4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-2-it;
6-(4-cyclopropylamines-1-ylmethyl)-2-(1H-indazol-4-yl)-4-morpholine-4-yl-thieno[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-pyridine-2-reparation-1-ylmethyl)thieno[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-[4-(2,2,2-triptorelin)piperazine-1-ylmethyl]thieno[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-thiazol-2-reparation-1-ylmethyl)thieno[3,2-d]pyrimidine;
2-(6-fluoro-1H-indazol-4-yl)-6-(4-methylpiperazin-1-ylmethyl)-4-morpholine-4-yl-thieno[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-pyridine-2-iletileri-1-ylmethyl)thieno[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-thiazol-2-iletileri-1-ylmethyl)thieno[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-[4-(5-methylfuran-2-ylmethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine;
amide 1-[2-(1H-indazol-4-yl)4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-carboxylic acid;
2-(1H-indazol-4-yl)-6-[4-(2-methoxy-1,1-dimethylethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-[(3R,53)-4-(2-methoxyethyl)for 3,5-dimethylpiperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine;
(2-methoxyethyl)methylamine 1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiana-[3,2-d]PI is kidin-6-ylmethyl]piperidine-4-carboxylic acid;
dimethylamide 1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-(1]pyrimidine-6-yl-methyl]piperidine-4-carboxylic acid;
2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-pyridine-3-iletileri-1-ylmethyl)thieno[3,2-d]pyrimidine;
methylamide 1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-carboxylic acid;
2-{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-yl}-N-methylisourea;
2-{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano [3,2-d]pyrimidine-6-ylmethyl]piperazine-1-yl}-2-methyl-1-pyrrolidin-1-improper-1-it;
2-(1H-indazol-4-yl)-6-[4-(1-methyl-1H-imidazol-2-ylmethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-[4-(5-methylisoxazol-3-ylmethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano [3,2-d] pyrimidine;
1-{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperazine-1-yl}-2-methylpropan-2-ol;
cyclopropylmethyl-{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-4-yl}-(2-methoxyethyl)amine;
6-[4-(1-ethyl-1-methoxymethyl)piperazine-1-ylmethyl]-2-(1H-indazol-4-yl)-4-morpholine-4-illiano [3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-[4-(1-methoxyoestradiol)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine;
{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-piperidine-4-yl}-(2-methoxyethyl)-(2,2,2-triptorelin)amine;
2-(1H-indazol-4-yl)-6-[4-(2-marks ITIL)piperazine-1-ylmethyl]-4-morpholine-4-yl-thieno[3,2-d]pyrimidine;
{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-piperidine-4-yl}methanol;
2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-pyridin-4-iletileri-1-ylmethyl)thieno[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-[4-(6-methylpyridin-2-ylmethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-[4-(4-methylthiazole-2-ylmethyl)piperazine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine;
{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-piperidine-4-yl}pyridine-2-ylamine;
N-{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-piperidine-4-yl}-2-methoxy-N-methylacetamide;
N-{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-piperidine-4-yl}-N-methylmethanesulfonamide;
{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-piperidine-4-yl}-(3-methoxypropyl)methylamine;
6-((3S,5R) - for 3,5-dimethyl-4-pyridin-2-iletileri-1-ylmethyl)-2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-(4-methoxypiperidine-1-ylmethyl)-4-morpholine-4-yl-thieno[3,2-d]pyrimidine;
{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-piperidine-4-yl}-(2-methoxyethyl)thiazol-2-ylmethylamino;
1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-4-pyridine-2-iletilerini-4-ol;
{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]pyridine-4-yl}isopropyl-(2-methoxyethyl)amine;
2-(1H-indazol-4-yl)-4-morph the Lin-4-yl-6-[4-(pyridine-2-yloxy)piperidine-1-ylmethyl]thieno[3,2-d]pyrimidine;
N-{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano [3,2-d]pyrimidine-6-ylmethyl]-piperidine-4-yl}-N-(2-methoxyethyl)methanesulfonamide;
2-{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano [3,2-d]pyrimidine-6-ylmethyl]-piperidine-4-yl}propan-2-ol;
2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-[4-(1-oxypyridine-3-ylmethyl)piperazine-1-ylmethyl]thieno[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-(morpholine-4-iletilerini-1-yl-methyl)thieno[3,2-d]pyrimidine;
{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano [3,2-d] pyrimidine-6-ylmethyl]-piperidine-4-ylmethyl}-(2-methoxyethyl)methylamine;
{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano [3,2-d]pyrimidine-6-ylmethyl]piperidine-4-ylmethyl}dimethylamine;
{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-piperidine-3-yl}-(2-methoxyethyl)methylamine;
methylamide 1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano [3,2-d]pyrimidine-6-ylmethyl]piperidine-3-carboxylic acid;
2-(1H-indazol-4-yl)-6-(3-methoxypiperidine-1-ylmethyl)-4-morpholine-4-yl-thieno [3,2-d] pyrimidine;
2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-(4-pyridine-2-iletilerini-1-ylmethyl)thieno[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-[4-(2-methoxyethoxy)piperidine-1-ylmethyl]-4-morpholine-4-yl-thieno[3,2-d]pyrimidine;
6-((3R,5S) - for 3,5-dimethyl-4-thiazol-2-iletileri-1-ylmethyl)-2-(1H-indazol-4-yl)-4-morpholine-4-illiano [3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-[4-(1-oxypyridine-2-ylmethyl)piperazine-1-ylmethyl]thieno[3,2-d]pyrimidine;br/> 2-(1H-indazol-4-yl)-6-[4-(2-methoxyethyl)piperidine-1-ylmethyl]-4-morpholine-4-yl-thieno[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-6-(4-methanesulfonamido-1-ylmethyl]-4-morpholine-4-yl-thieno[3,2-d]pyrimidine;
{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-piperidine-4-yl}-(3-methanesulfonyl)methylamine;
2-(1H-indazol-4-yl)-6-[4-(3-methoxypropan-1-sulfonyl)piperidine-1-ylmethyl]-4-morpholine-4-illiano[3,2-d]pyrimidine;
methylamide (R)-1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano [3,2-d] pyrimidine-6-ylmethyl]piperidine-3-carboxylic acid;
methylamide (S)-1-[2-(1H-indazol-4-yl)-4-morpholine-illiano[3,2-d]pyrimidine-6-ylmethyl]piperidine-3-carboxylic acid;
6-(4-imidazol-1-iletilerini-1-ylmethyl)-2-(1H-indazol-4-yl)-4-morpholine-4-yl-thieno[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-morpholine-4-ilmatieteen[3,2-d] pyrimidine;
2-(1H-indazol-4-yl)-6-(3-methylpiperidin-1-ylmethyl)-4-morpholine-4-yl-thieno[3,2-d]pyrimidine;
{1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-piperidine-3-yl}methanol;
2-{1[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-piperidine-4-yl}ethanol;
1-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-4-thiazole-2-reparacin-4-ol;
2-(1-methyl-1H-indazol-4-yl)-6-(4-methylpiperazin-1-ylmethyl)-4-morpholine-4-yl-thieno[3,2-d]pyrimidine;
2-(2-methyl-2H-indazol-4-yl)-6-(4-methylpiperazin-1-ylmethyl)-4-morpholine-4-yl-thieno[3,2-d]pyrimidine;
2-(1H-in the azole-4-yl)-4-morpholine-4-yl-6-(4-thiazole-4-iletileri-1-ylmethyl)thieno[3,2-d]pyrimidine;
1-{4-[2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-piperazine-1-yl}-3-phenoxypropan-2-ol;
6-[4-(1H-imidazol-2-ylmethyl)piperazine-1-ylmethyl]-2-(1H-indazol-4-yl)-4-morpholine-4-illiano [3,2-d]pyrimidine;
6-[4-(3H-imidazol-4-ylmethyl)piperazine-1-ylmethyl]-2-(1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine;
2-(1H-indazol-4-yl)-4-morpholine-4-yl-6-((2S,6R)-2,4,6-trimethylpyrazine-1-ylmethyl)thieno [3,2-d] pyrimidine;
{4-[2-1H-indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-ylmethyl]-1-methane-sulfonylureas-2-yl}methanol; and
2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-3-methoxypiperidine-1-ylmethyl)-4-morpholine-4-illiano[3,2-d] pyrimidine;
and pharmaceutically acceptable salts of the above free connections.

4. A method of obtaining a compound according to claim 1, comprising processing the compounds of formula (II):

where a and R2have the meanings defined in claim 1, Bronevoy acid or a complex ester of the formula R3B(OR15)2in which R3has the values defined above, and each R15represents N or C1-C6alkyl or 2 groups OR15together with the boron atom to which they are attached, form the group of ester of pinacolborane, in the presence of a palladium catalyst; and processing the obtained compound of the formula (III):

where A, R2The R 3have the meanings defined above, an amine of the formula with other4R5in which R4and R5have the meanings given above, in the presence of a suitable reducing agent; and, if necessary, converting the resulting compounds of formula (I) and its pharmaceutically acceptable salt.

5. A method of obtaining a compound according to claim 1, comprising processing the compounds of formula (II):

where a and R2have the meanings defined in claim 1, the amine of the formula with other4R5where R4and R5have the meanings defined in claim 1, in the presence of a suitable reducing agent; and processing the obtained compound of the formula (IV):

where A, R2, R4and R5have the meanings given above, Bronevoy acid or a complex ester of the formula R3B(OR15)2in which R3has the values defined above, and each R15represents N or C1-C6alkyl or 2 groups OR15together with the boron atom to which they are attached, form the group of ester of penatration in the presence of a palladium catalyst; and, if necessary, converting the resulting compounds of formula (I) and its pharmaceutically acceptable salt.

6. The method according to claim 4 or 5, further comprising transforming the received connection of the texts of the formula (I) into its pharmaceutically acceptable salt.

7. Pharmaceutical composition having inhibitory activity against PI3 kinase, which comprises a pharmaceutically acceptable carrier or diluent and, as active ingredient an effective amount of a compound according to any one of claims 1 to 3.

8. The compound according to claim 1, having inhibitory activity against PI3 kinase.

9. The use of compounds according to claim 1 in getting medicines for the treatment of diseases or disorders caused by pathological growth, function or behavior of cells associated with PI3 kinase.

10. Method of inhibiting PI3 kinase, comprising introducing an effective amount of a compound according to claim 1.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the new fused pyrimidines of formula (I) and to their pharmaceutically acceptable salts exhibiting P13 kinase inhibitor properties; in formula (I), A represents a thiophen ring; n=1; R1 represents a group of formula , where m=1; R30 represents hydrogen; R4 and R5 together with N atom whereto attached form a 5- or 6-members saturated N-containing heterocyclic group which includes 1 additional heteroatom selected from N which is unsubstituted or substituted by C1-C3alkyl which can be substituted by OH; S(O)2C1-3alkyl; C(O)N(diC1-C3alkyl); N(CH3)2; CON(CH3)-CH2CH2OCH3; N(CH3)-CH2CH2OCH3; -C(O)morpholine or morpholine; R2 is selected from where R6 and R7 together with nitrogen atom whereto attached form a morpholine group which is unsubstituted; and R3 represents an indole group which is unsubstituted.

EFFECT: production of the compounds of formula (I), a pharmaceutical composition, their application for preparing a drug and a method of inhibition.

9 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to condensed heterocyclic derivative, represented by formula (I): where ring A represents 5-member monocyclic heteroaryl, containing 1 or 2 heteroatoms, selected from N or S; RA represents lower alkyl group, optionally substituted with hydroxyl group, COW1, COOW1 or CONW2W3, in which W1-W3 independently represent a hydrogen atom or lower alkyl group; m represents integer 0 or 2; ring B represents benzene ring or thiophene ring; RB represents halogen atom, cyano group, lower alkyl group or OW4, in which W4 represents a hydrogen atom or lower alkyl group; n represents integer 0-2; E1 represents an oxygen atom; E2 represents an oxygen atom; U represents a single bond or lower alkelene group; X represents group, represented by Y, -CO-Y, -SO2-Y, -S-L-Y, -O-L-Y, -CO-L-Y, -SO-L-Y, -SO2-L-Y, -S-Z or -O-Z, in which L represents a lower alkylene group optionally substituted with halogen or hydroxy group; Y represents group, represented by Z or -NW7W8, where W7 and W8 independently represent a hydrogen atom, lower alkyl group or Z on condition that W7 and W8 are not simultaneously hydrogen atoms, or W7 and W8 can bind together with adjacent nitrogen atom with formation of cyclic amino group; Z represents cycloalkyl group, optionally condensed with phenyl and optionally substituted with phenyl group, optionally substituted with halogen or alkoxy group; 6-8-member heterocycoalkyl group, which has 1 heteroatom, selected from nitrogen atom or oxygen atom, optionally condensed with phenyl and optionally substituted with phenyl; phenyl group optionally substituted with a substituent, selected from group, consisting of a halogen atom, cyano group, alkyl group, optionally substituted with halogen atom, hydroxy group or alkoxy group, alkoxy group, optionally substituted with halogen atom, hydroxy group, alkoxy group, alkoxy-carbonyl-oxy group or acyloxy group, alkylthio group, carboxy group and alkoxy-carbonyl group; pyridyl; or its pharmaceutically acceptable salt. Invention also relates to pharmaceutical composition possessing antagonistic activity with respect to gonatotropin-releasing hormone, based on the claimed compound.

EFFECT: obtained are novel compounds and based on them pharmaceutical composition, which can be applied in medicine for prevention or treatment of a disease depending on sex hormones, which is selected from group, consisting of benign prostatic hypertrophy, hysteromyoma, endometriosis, premature puberty, prostate cancer, ovarian cancer and breast cancer.

29 cl, 112 tbl, 428 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to application of thienopyridone derivatives of formula (I), in which B represents CH, represents , or , R represents H, R1 and R2, independently on each other, represent H, linear or branched (C1-C4)alkyl, (C1-C4)cycloalkyl, halogen or together form group -(CH2)n-, where n=1- 4, R3 and R4, independently on each other, represent H, R6 represents H, X represents -O-, or their pharmaceutically acceptable salts for preparation of pharmaceutical composition.

EFFECT: obtaining pharmaceutical composition, suitable for treatment of diabetes, metabolic syndrome and obesity.

8 cl, 1 tbl, 210 ex

Thienopyridines // 2415859

FIELD: chemistry.

SUBSTANCE: invention relates to pharmaceutically suitable salts which are given in claim 1. The invention also relates to medicinal agents based on the said compounds, which are HSP90 inhibitors.

EFFECT: novel compounds and medicinal agents based on said compounds are obtained, which can be used to treat diseases influenced by inhibition, regulation or modulation of HSP90.

3 cl, 1 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel pyrazole derivatives of formula (I) or pharmaceutically acceptable salts thereof, having tyrosine kinase Trk inhibiting properties and used for treating or preventing malignant growths accompanied by high level of Trk, to a method of producing said derivatives, use thereof to prepare a medicinal agent, pharmaceutical compositions based on said derivatives, a method of inhibiting Trk activity and a method of obtaining antiproliferative action. where A denotes a single bond or C1-2alkylene; where the said C1-2alkylene can be optionally substituted with one R22; ring C is a phenyl or a 5-6-member heterocyclic ring with 1-2 heteroatoms selected from N or S. Values of R1-R7, R22 and n are given in the formula of invention.

EFFECT: obtaining pharmaceutically acceptable salts having tyrosine kinase Trk inhibiting properties and used for treating or preventing malignant growths.

20 cl, 5 dwg, 193 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of tetrahydrobenzo[4,5]thiophene[2,3-d]pyrimidine derivatives, including groups of known compounds, having formula (I), for preparing a medicinal agent for treating and/or preventing diseases and disorders which require inhibition of the 17β-hydroxysteroid-dehydrogenase (17β-HSD) enzyme, more preferably which require inhbition of type 1 17β-HSD enzyme, type 2 17β-HSD enzyme or type 3 17β-HSD enzyme. In formula X denotes S or SO2, R1 and R2 are separately selected from a group which includes -C1-C12alkyl, where the alkyl can be straight, cyclic, branched or partially unsaturated, and can be optionally substituted with up to three substitutes, independently selected from a group consisting of hydroxyl, C1-C12alkoxy group, thiol, C1-C12alkylthio-, aryloxy group, -CO-aryl, -CO-OR, -O-COR, -O-CO-heteroaryl and a -N(R)2 group; where the said aryl group is phenyl or naphthyl and can be optionally substituted with up to 3 halogen atoms; where the said heteroaryl group is thienyl, furyl or pyridyl; -aryl and arylC1-C12alkyl, where the aryl is selected from a group consisting of phenyl, biphenyl, naphthyl, indanyl, indenyl and fluorenyl. Other values of substitutes are given in the formula of invention.

EFFECT: high efficiency of using novel compounds in therapy.

32 cl, 3 tbl, 7 dwg, 151 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel compounds of formula where values of radicals are given in the formula of invention, and a pharmaceutically acceptable salt thereof. Said compounds have 17β-hydroxysteroid dehydrogenase enzyme (17β-HSD) inhibiting activity. The invention describes use of the formula (I) compound in treating or preventing diseases or disorders which require inhibition of 17β- hydroxysteroid dehydrogenase enzyme, use of the formula (I) compound to prepare a medicinal agent for treating or preventing diseases or disorders which require inhibition of 17β- hydroxysteroid dehydrogenase enzyme, and a pharmaceutical composition based on the formula (I) compound.

EFFECT: derivatives are highly effective.

18 cl, 7 tbl

FIELD: chemistry.

SUBSTANCE: use of compounds of formula (I): where: X denotes >CR1R2 or, when R6 denotes H, X denotes >SO2; Y denotes >CR1R2; Z denotes >C=O, >CH2, single bond; R1 denotes H, R2 denotes H, -COOH, -OH; or R1 and R2 together denote =O, ethylenedioxy or hydroxyimino group; R3 denotes H, lower alkyl group; R4 denotes two H, =O, hydroxyimino group; R5 denotes H, lower alkyl group, halogen; R6 denotes H, lower alkoxy, COOH; R7 and R8 are identical or different from each other and each denotes H, lower alkyl, halogen; and pharmaceutically acceptable salts thereof and esters for preparing a medicinal agent.

EFFECT: agent having neuroprotective action against hypoxia.

2 tbl, 24 ex, 13 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) and formula (II), their tautomers and pharmaceutically acceptable salts. In formula (I) and in formula (II), X - S; R1 - H; R2 - NR5R6; R3 - 5-6-member heteroaryl with 1 heteroatom, selected from N and S, or phenyl, optionally substituted with one or two substituents, selected from halogen, amino, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-halogenalkyl and C1-C6-halogenalkoxy; R4 - H, C1-C6 alkyl, C1-C6 alkoxy or XR3, where X and R3 are determined above; R5 - H; R6 - H; L - N or CR7, where R7 - H; M - S. Invention also relates to pharmaceutical composition, containing as active component invention compound, to method of inhibiting activity of caseinkinase lε and to method of obtaining compounds of formula (I) or formula (II).

EFFECT: compounds of claimed invention possess properties of casein kinase lε inhibitors.

13 cl, 5 tbl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention describes a neutral semiconductor organic compound of formula (I) , where R1 and R2 denote a hydrogen atom, n is the number links in formula (I) and is an integer between 2 and 1000, terminal groups of the compound R3 and R4 denote a hydrogen atom or a linear or branched alkyl group with 1-20 carbon atoms. The invention also describes use of the said compound as a semiconductor in electronic functional elements.

EFFECT: higher oxidation resistance, which enables use of the compound in transistors and other electronic functional elements.

5 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the new fused pyrimidines of formula (I) and to their pharmaceutically acceptable salts exhibiting P13 kinase inhibitor properties; in formula (I), A represents a thiophen ring; n=1; R1 represents a group of formula , where m=1; R30 represents hydrogen; R4 and R5 together with N atom whereto attached form a 5- or 6-members saturated N-containing heterocyclic group which includes 1 additional heteroatom selected from N which is unsubstituted or substituted by C1-C3alkyl which can be substituted by OH; S(O)2C1-3alkyl; C(O)N(diC1-C3alkyl); N(CH3)2; CON(CH3)-CH2CH2OCH3; N(CH3)-CH2CH2OCH3; -C(O)morpholine or morpholine; R2 is selected from where R6 and R7 together with nitrogen atom whereto attached form a morpholine group which is unsubstituted; and R3 represents an indole group which is unsubstituted.

EFFECT: production of the compounds of formula (I), a pharmaceutical composition, their application for preparing a drug and a method of inhibition.

9 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula formula (1) formula (2) or to their hydrate, solvate, salt or tautomer form where R1 independently represents H or halogen; R2 represents H or --R10-NR11R12 where R10 represents C1-C6 alkylene; R11 and R12 independently represent H, C1-C4 alkyl; and R3 independently represents H or halogen. Besides, the invention covers methods of preparing the compounds of the present invention.

EFFECT: new compounds which can find application for preparing the compounds applicable for treatment or prevention of cardiac arrhythmia.

6 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to cardiology and angiology, and deals with normalisation of functional activity of vessel wall in patients with arterial hypertension of I-II degree with metabolic syndrome, after thrombosis of eye vessels. For this purpose, indices of anti-aggregation, anti-coagulation and fibrinolytic activity of vascular wall are determined. On the basis of said indices general anti-thrombotic potential of vessels is calculated and if its value is 0.069 and lower, administered is complex treatment, including application of individually selected hupocaloric diet, dosed physical load, introduction of pioglitazone in dose 30 mg 1 time per day and lisinopril in dose 20 mg 1 time per day for 4 months.

EFFECT: complex of drug and non-drug therapy in combination with empirically selected treatment duration ensures complete normalisation of functional activity of vascular wall and, thus, reduction of risk of thrombotic complications in said group of patients due to potentiation of therapeutic effect of separate components of medicinal complex.

2 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to cardiology, and deals with complex immunomodulating treatment of patients with chronic heart failure with reduced left ventricular heart ejection fraction. For this purpose in commonly accepted complex of drug therapy, which includes β-adrenoblockers, ACE inhibitors, diuretics, cardiomagnyl, additionally introduced is recombinant human interleukin 2 (IL-2). IL-2 is introduced in dose 500 IU/ml, in 200 ml of physiological solution, which containf for stabilisation 10 ml of 5% albumin solution, intravenously drop-by-drop daily 1 time for 10 days; treatment course is repeated 1 time per 3 months during 12 months.

EFFECT: complex treatment ensures suppression of chronic immune inflammation due to ability of IL-2 in elaborated mode of introduction to reduce level of endogenic cytokins and activate T- and B- lymphocytes efficiently in said group of patients.

2 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to cardiology and balneophysiotherapy. Method includes balneotherapy, walks in the park, physiotherapy. Balneotherapy is performed by carrying out carbonate mineral baths with concentration of carbon dioxide 0.8-1.1 g/l. Course includes 10 baths. Walks in the park are carried out on therapeutic routes of health path with length in both directions 6800 metres. Physiotherapy is performed by impact of continuous and pulsed electric current of low frequency, current intensity 0.1 mA from apparatus "МДМК"-4. Impact is performed in contact way by application of cathode in region of forehead, anode - in region of occiput. Impact is realised by pulses of rectangular shape with 4 ms duration, with ratio by amplitude of continuous and pulse current 1:1 or 0.5:1; frequency from 70 to 90 Hz, changing cyclically for 1 minute. Time of impact is from 8 to 16 minutes, with increase of exposure by 2 minutes every 2 days. Course includes daily performed 6-10 procedures. Additionally drinking mineral waters of Kislovodsk Narzan of medium mineralisation are taken in.

EFFECT: method increases treatment efficiency due to increase of adaptive abilities of hypothalamic stem regulatory centres, produces inhibitory effect on cerebral cortex (CC) and underlying structures of brain stemm reduces frequency of stenocardia recurrences, improves physical exercise tolerance, increases patients' life quality.

2 ex, 12 tbl

FIELD: medicine.

SUBSTANCE: endothelial dysfunction correction is ensured by simulating endothelial dysfunction by the intraperitoneal introduction to laboratory male rats Wistar of N-nitro-L-arginine methyl ether 25 mg/kg daily for 7 days. A development degree of endothelial dysfunction is estimated by the relation of endothelium-independent and endothelium-dependent vasodilation indicators. The endothelial dysfunction correction is ensured by the intragastric introduction of trimetazidine 6 mg/kg and the intraperitoneal introduction of L-arginine 200 mg/kg.

EFFECT: method provides activation of the L-NAME-induced endothelial dysfunction correction ensured by the introduction of a specific combination of the pharmacological preparations promoting the improvement of endothelial vasorelaxation properties.

2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: endothelial dysfunction correction is ensured by simulating endothelial dysfunction by the intraperitoneal introduction to laboratory male rats Wistar of N-nitro-L-arginine methyl ether 25 mg/kg daily for 7 days. A development degree of endothelial dysfunction is estimated by the relation of endothelium-independent and endothelium-dependent vasodilation indicators. The endothelial dysfunction correction is ensured by the intragastric introduction of trimetazidine 6 mg/kg and the intraperitoneal introduction of L-arginine 200 mg/kg.

EFFECT: method provides activation of the L-NAME-induced endothelial dysfunction correction ensured by the introduction of a specific combination of the pharmacological preparations promoting the improvement of endothelial vasorelaxation properties.

2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), where each R1, R2 and R3 is independently selected from a group comprising H, OH, F, Cl, Br, a methoxy group and an ethoxy group; or R1 and R2 together form -OCH2O-, and R3 is selected from a group comprising H, OH, methoxy group, ethoxy group and halogens; R4 denotes OH or o-acetoxybenzoyloxy nicotinoyloxy or iso-nicotinoyloxy; R5 denotes or , and at least one of R1, R2 and R3 is not hydrogen.

EFFECT: method for synthesis of a compound of formula (I) and use of the compound of formula (I) in preparing medicinal agents for preventing or treating cerebrovascular diseases.

17 cl, 14 tbl, 5 dwg, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely to a composition for prevention and treatment of chronic cardiovascular insufficiency. The composition for prevention and treatment of chronic cardiovascular insufficiency represents mixed powders of blossom and fruit of blood-red hawthorn and hypoxene taken in certain proportions.

EFFECT: composition is effective for prevention and treatment of chronic cardiovascular insufficiency, promotes reducing myocardial excitability, intensifies cardiovascular circulation, provides sedative action on the central nervous system, improves body resistance to adverse factors, reduces dyspnea, undue rest and exercise fatigability.

2 cl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to surgery, and concerns treating the patients with critical ischemia of lower extremities of various geneses. That is ensured by a complex background therapy of lower extremities involving intravenous drop introduction of SEROTONIN ADIPINATE 10 mg/day for 10 days with Mexicor added. For the first five days, Mexicor is administered once a day intra-arterially through a femoral catheter on an affected side in a daily dose 800 mg at rate 200 mg/hour. For the following five days, the intravenous drop introduction of Mexicor is performed by the schedule: at 6 o'clock - 200 mg; at 1400 - 300 mg; at 2200 - 300 mg dissolved in physiologic saline 100 ml at introduction rate 200-300 mg/hour.

EFFECT: method provides effective treatment and reduced number of failures in the form of amputation of the extremity due to improvement of microcirculation and elimination of reperfusion disorders in ischemic tissues.

2 ex, 4 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the new fused pyrimidines of formula (I) and to their pharmaceutically acceptable salts exhibiting P13 kinase inhibitor properties; in formula (I), A represents a thiophen ring; n=1; R1 represents a group of formula , where m=1; R30 represents hydrogen; R4 and R5 together with N atom whereto attached form a 5- or 6-members saturated N-containing heterocyclic group which includes 1 additional heteroatom selected from N which is unsubstituted or substituted by C1-C3alkyl which can be substituted by OH; S(O)2C1-3alkyl; C(O)N(diC1-C3alkyl); N(CH3)2; CON(CH3)-CH2CH2OCH3; N(CH3)-CH2CH2OCH3; -C(O)morpholine or morpholine; R2 is selected from where R6 and R7 together with nitrogen atom whereto attached form a morpholine group which is unsubstituted; and R3 represents an indole group which is unsubstituted.

EFFECT: production of the compounds of formula (I), a pharmaceutical composition, their application for preparing a drug and a method of inhibition.

9 cl, 6 ex

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