Iap inhibitors


FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

 

The text descriptions are given in facsimile form.

1. The compound of formula IVa

where R1means N or C1-C4alkyl;
R2means N or C1-C4alkyl;
R3means1-C4alkyl;
R4means cyclohexyl, cyclopentyl or1-C4alkyl;
R5means N;
U represents a group of formula V

where n is 0;
X represents N;
Rc denotes H;
Rd means Ar1-D-Ar2where D is-CH2-, -CF2-, -O-, -C(O)-, -S-, -S(O)-, -S(O)2, 1,3-dioxolane, or-N(Rh), where Rh denotes H, C1-C7alkyl, -CF3, -CH2CH2HE, -C(O)H or-SO2CH3and Ar1and AG2mean substituted or unsubstituted aryl or het, where specified het, which may be substituted stands selected from pyridinyl, pyrimidinyl, tetrazolyl, triazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,4-oxadiazolyl, pyrrolyl, imidazolyl, pyrazinyl or triazinyl, as specified aryl means phenyl which may be substituted by one or two halogen;
R6, R7, R6' and R7' each denotes H;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where Ar1means pyridinyl or thiazolyl and AG3means phenyl which may be substituted by one or two halogen; or its pharmaceutically acceptable salt.

3. The compound according to claim 1 or 2, where D denotes-CH2-, -CF2-, -O - or-C(O)-, or its pharmaceutically acceptable salt.

4. The compound according to claim 1, selected from the group including:

N-[(1S)]-1-cyclohexyl-2-[(2S)-2[6-[(2-forfinal)methylamino]-2-pyridinyl]-1-pyrrolidinyl]-2-oxoethyl]-2(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-[2-(phenylmethyl)-2H-tetrazol-5-yl]-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-butanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-(3-phenoxyphenyl)-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]-1-pyrrolidinyl]et the l]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-[1-(phenylmethyl)-1H-imidazol-4-yl]-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-[6-(phenylmethyl)pyrazinyl]-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-[4-(phenylmethyl)-1,3,5-triazine-2-yl]-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-[(2S)-2-[2-[(4-forfinal)methylamino]-4-pyridinyl]-1-pyrrolidinyl]-2-oxoethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-[1-(phenylmethyl)-1H-pyrrol-3-yl]-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-[2-(phenylamino)-5-oxazolyl]-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-2-[(2S)-2-(5-benzoyl-1,2,4-oxadiazol-3-yl)-1-pyrrolidinyl]-1-cyclohexyl-2-oxoethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-2-[(2S)-2-(4-benzoyl-2-thiazolyl)-1-pyrrolidinyl]-1-cyclohexyl-2-oxoethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-[4-(2-phenyl-1,3-dioxolane-2-yl)-2-oxazolyl]-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohex the l-2-oxo-2-[(2S)-2-[4-(phenylmethyl)-2-oxazolyl]-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-2-[(2S)-2-(4-benzoyl-5-methyl-2-oxazolyl)-1-pyrrolidinyl]-1-cyclohexyl-2-oxoethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-2-[(2S)-2-(4-benzoyl-2-oxazolyl)-1-pyrrolidinyl]-1-cyclohexyl-2-oxoethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-[1-(phenylmethyl)-1H-pyrazole-4-yl]-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-[1-(phenylmethyl)-1H-1,2,3-triazole-4-yl]-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-[(2S)-2-[2-fluoro-5-(methyl-2-pyridinylamino)phenyl]-1-pyrrolidinyl]-2-oxoethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-[(2S)-2-[3-(methyl-2-pyrimidinamine)phenyl]-1-pyrrolidinyl]-2-oxoethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-[(2S)-2-[3-(methyl-2-pyridinylamino)phenyl]-1-pyrrolidinyl]-2-oxoethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-[(2S)-2-[6-(methyl-2-pyridinylamino)-2-pyridinyl]-1-pyrrolidinyl]-2-oxoethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-[(2S)-2-[6-[(2,4-differenl)methylamino]-2-pyridinyl]-1-pyrrolidinyl]-2-oxoethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-2-[(2S)-2-[6-[(3-chlorophenyl)methylamino]-2-pyridinyl]-1-pyrrolidinyl]-1-cyclohexyl-2-oxoethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-[(2S)-2-[6-[(4-forfinal)methylamino]-2-pyridinyl]-1-pyrrolidinyl]-2-oxoethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-[(2S)-2-[6-(methylpentylamino)-2-pyridinyl]-1-pyrrolidinyl]-2-oxoethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-[(2S)-2-[2-[(2-forfinal)methylamino]-4-pyridinyl]-1-pyrrolidinyl]-2-oxoethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-[(2S)-2-[2-[(2-forfinal)methylamino]-4-pyrimidinyl]-1-pyrrolidinyl]-2-oxoethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-[3-[phenyl(trifluoromethyl)amino]phenyl]-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-[(2S)-2-[3-[(2-hydroxyethyl)phenylamino]phenyl]-1-pyrrolidinyl]-2-oxoethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-[(2S)-2-[3-(formylpyridine)phenyl]-1-pyrrolidinyl]-2-oxoethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-[(2S)-2-[3-[(methylsulphonyl)phenylamino]phenyl]-1-pyrrolidinyl]-2-oxoethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclopentyl-2-[(2S)-2-[3-(methylpentylamino)phenyl]-1-pyrrolidinyl]-2-oxoethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-2,2-dimethyl-1-[[(2S)-2-[3-(methylpentylamino)phenyl]-1-pyrrolidinyl]carbonyl]propyl]-2-(methylamino)-(2S)-propanamide;

2-(methylamino)-N-[(1S)-3-methyl-1-[[(2S)-2-[3-(methylpentylamino)phenyl]-1-pyrrolidinyl]carbonyl]butyl]-(2S)-propanamide,

2-(methylamino)-N-[(1S)-1-[[(2S)-2-[3-(methylpentylamino)phenyl]-1-pyrrolidinyl]carbonyl]propyl]-(2S)-propanamide;

2-(methylamino)-N-[(1S)-1-methyl-2-[(2S)-2-[3-(methylpentylamino)phenyl]-1-pyrrolidinyl]-2-oxoethyl]-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-[3-(phenylamino)phenyl]-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-[3-(3-pyridyloxy)phenyl]-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-(2-phenoxy-4-pyrimidinyl)-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-(2-phenoxy-4-pyridinyl)-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-(5-phenoxy-3-pyridinyl)-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-(6-phenoxy-2-pyridinyl)-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-2,2-dimethyl-1-[[(2S)-2-(3-phenoxyphenyl)-1-pyrrolidinyl]carbonyl]propyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclopentyl-2-oxo-2-[(2S)-2-(3-phenoxyphenyl)-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;

2-(methylamino)-N-[(1S)-3-methyl-1-[[(2S)-2-(3-phenoxyphenyl)-1-pyrrolidinyl]carbonyl]butyl]-(2S)-propanamide;

2-(methylamino)-N-[(1S)-1-[[(2S)-2-(3-phenoxyphenyl)-1-pyrrolidinyl]carbonyl]propyl]-(2S)-propanamide;

2-(methylamino)-N-[(1S)-1-methyl-2-oxo-2-[(2S)-2-(3-phenoxyphenyl)-1-pyrrolidinyl]ethyl]-(2S)-propanamide;

2-(methylamino)-N-[(1S)-2-methyl-1-[[(2S)-2-(3-phenoxyphenyl)-1-pyrrolidinyl]carbonyl]propyl]-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-(2-phenoxyphenyl)-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-(4-phenoxyphenyl)-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-[3-(2-phenyl-1,3-dioxolane-2-yl)phenyl]-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;
< / br> N-[(1S)-2-[(2S)-2-(3-benzoylphenyl)-1-pyrrolidinyl]-1-cyclohexyl-2-oxoethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-[(2S)-2-[3-(differenlty)phenyl]-1-pyrrolidinyl]-2-oxoethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-[3-(phenylsulfinyl)phenyl]-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-[3-(phenylsulfonyl)phenyl]-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-[1-(phenylmethyl)-1H-tetrazol-5-yl]-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-butanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-[1-(phenylmethyl)-1H-tetrazol-5-yl]-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-[2-(phenylmethyl)-2H-tetrazol-5-yl]-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-butanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-[2-(phenylmethyl)-2H-tetrazol-5-yl]-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-[3-(phenylthio)phenyl]-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-(3-phenoxyphenyl)-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2)-propanamide;

N-[(1S)-1-cyclohexyl-2-[(2S)-2-[3-(methylpentylamino)phenyl]-1-pyrrolidinyl]-2-oxoethyl]-2-(methylamino)-(2S)-propanamide;

2-(methylamino)-N-[(1S)-2-methyl-1-[[(2S)-2-[3-(methylpentylamino)phenyl]-1-pyrrolidinyl]carbonyl]propyl]-(2S)-propanamide; and

N-[(1S)-1-cyclohexyl-2-oxo-2-[(2S)-2-[3-(phenylmethyl)phenyl]-1-pyrrolidinyl]ethyl]-2-(methylamino)-(2S)-propanamide;
or its pharmaceutically acceptable salt.



 

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9 cl, 1 tbl, 95 ex

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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: chemistry.

SUBSTANCE: invention relates to a novel crystalline form of a compound of formula (I), which has P2T antagonist properties and can be used to prevent arterial thrombotic complications in patients suffering from coronary artery disease, cerebrovascular and peripheral vascular diseases. The crystalline form of compound (I) is essentially a pure polymorph II, which is essentially in anhydrous form and which is characterised by X-ray powder diffraction pattern, having characteristic base peaks of high intensity at 5.5°(±0.1°), 13.5°(+0.1°), 18.3°(±0.1°), 22.7°(±0.1°) and 24.3°(±0.1°) 2θ, and has characteristic peaks at 5.5°(±0.1°), 6.8°(±0.1°), 10.6°(±0.1o), 13.5°(±0.1°), 14.9°(±0.1°), 18.3°(±0.1°), 19.2°(±0.1°), 22.7°(+0.1°), 24.3°(±0.1°) and 27.1°(±0.1°) 2θ. The differential scanning calorimetry curve of the said crystalline polymorph has melting onset point in the range of 136-139°C.

EFFECT: invention also relates to a method of producing the disclosed polymorph, according to which a compound of formula (I) is crystallised from chloroform.

9 cl, 6 dwg, 2 ex

Heterocompound // 2425832

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or pharmaceutically acceptable salt thereof, where symbols assume the following values; ring denotes

or , X denotes a single bond, -CH2-, -NR3-, -O-, -S-, R1 denotes a halogen; phenyl; pyridyl; (C3-C8)cycloalkyl; or (C1-C6) alkyl or (C2-C6) alkenyl, each of which can contain a halogen, -CONH2, phenyl or (C3-C8)cycloalkyl as a substitute, R2 denotes CN, -O-(C1-C6)alkyl, -C(=O)H, halogen; or (C1-C6)alkyl, which can be substituted with a halogen or -OH, R3 can form morpholino or 1-pyrrolidinyl together with R1 and nitrogen, and when X denotes a single bond, R1 and R2 can jointly form a 5-member ring and additionally contain -(C1-C6)alkyl as a substitute, R4 denotes the following ring: , , , , , , , , , , or , where any one of the bonds in the ring is linked to an oxazole ring, R5 denotes -H, (C1-C6)alkyl, which can be substituted by not less than one group selected from: -C(=O)NRXRY, -NHRX and -ORX- (C2-C6)alkenyl-; -C(=O)H; -C(=O)NRXRY, RX and RY can be identical or different and denote -H; or (C1-C6)alkyl. The invention also relates to a pharmaceutical composition based on said compounds, having SlP1 agonist activity.

EFFECT: compounds and compositions can be used in medicine for preventing and treating rejection during organ transplant, bone marrow or tissue transplant and autoimmune diseases.

16 cl, 84 tbl, 198 ex

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