Novel cyp17 inhibitors/antiandrogens

Patent metadata

Field	Value
Publication number	US-2016130254-A1
Application number	US-201414897326-A
Country	US
Kind code	A1
Filing date	Jun 10, 2014
Priority date	Jun 11, 2013
Publication date	May 12, 2016
Grant date	—

Abstract

Compounds of formula (I)

wherein R 1 to R 8 , A, B, Z 1 , and Z 2 are as defined in the claims and pharmaceutically acceptable salts and esters thereof are disclosed. The compounds of formula (I) possess utility as androgen receptor antagonists (inhibitors) and/or cytochrome P450 monooxygenase 17α-hydroxylase/17,20-lyase (CYP17) inhibitors. The compounds are useful as medicaments in the treatment of cancer, particularly prostate cancer, and other androgen dependent conditions and diseases where androgen antagonism is desired.

First claim

1 . A compound of formula (I)

wherein
Z 1 and Z 2 are, independently, C or N, wherein at least one of Z 1 and Z 2 is C;
ring A is a non-aromatic 3-7 membered carbocyclic or a non-aromatic 5-6 membered heterocyclic ring;
ring B is a 5-6 membered heterocyclic ring, or
ring B is a 5-6 membered heterocyclic ring or a 7-12 membered heterocyclic ring, when ring A is a non-aromatic 3-7 membered carbocyclic ring;
R 1 is halogen, CHF 2 , CF 3 , C 1-7 alkyl, or C 1-7 alkoxy;
R 2 is cyano or nitro;
R 3 is H, halogen, or C 1-7 alkyl;
R 4 is C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-7 alkyl, hydroxy C 1-7 alkyl, halo C 1-7 alkyl, C 1-7 alkoxy C 1-7 alkyl, C 1-7 alkylcarbonyl, or phenyl C 1-7 alkyl,
or R 4 is C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-7 alkyl, hydroxy C 1-7 alkyl, halo C 1-7 alkyl, C 1-7 alkoxy C 1-7 alkyl, C 1-7 alkylcarbonyl, phenyl C 1-7 alkyl, or hydrogen, when ring A is a non-aromatic 3-7 membered carbocyclic ring and ring B is an aromatic 5-6 membered heterocyclic ring;
R 5 is H, OH, C 1-7 alkyl, C 1-7 alkoxy, or hydroxy C 1-7 alkyl;
R 5 ′, R 6 ′ and R 6 are, independently, H, OH, C 1-7 alkyl, or halogen;
or, when R 6 ′ and R 6 are attached to the same carbon atom of ring A, R 6 ′ and R 6 may, together with the carbon atom to which they are attached, form a C 3-7 cycloalkyl ring;
R 7 is H, OH, cyano, halogen, C 1-7 alkyl, C 3-7 cycloalkyl, C 1-7 alkoxy, hydroxy C 1-7 alkyl, halo C 1-7 alkyl, cyano C 1-7 alkyl, halo C 1-7 alkoxy, C 1-7 alkoxy C 1-7 alkyl, hydroxy C 1-7 alkoxy C 1-7 alkyl, C 1-7 alkyl carbonyl C 1-7 alkyl or —C 1-7 alkyl-X—(CH 2 ) n —R 9 , or R 9 ;
R 8 is H or C 1-7 alkyl;
R 9 is an optionally substituted 3-7 membered carbocyclic ring, an optionally substituted 4-6 membered heterocyclic ring, or —NR 10 R 11 ;
X is a bond, oxygen, or —NH—;
n is 0, 1, 2, or 3;
R 10 and R 11 are, independently, H, C 1-7 alkyl, or C 1-7 alkyl carbonyl;
or a pharmaceutically acceptable salt thereof.

2 . The compound according to claim 1 , wherein Z 2 is C.

3 . The compound according to claim 1 , wherein Z 1 is C.

4 . The compound according to claim 1 , wherein ring A is a non-aromatic 3-7 membered carbocyclic ring.

5 . The compound according to claim 1 , wherein ring A is a non-aromatic 5-6 membered heterocyclic ring.

6 . The compound according to claim 1 , wherein ring A is a cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, piperidinyl, pyrrolidinyl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridazinyl, dihydrothiopyranyl, or azabicyclo[2.2.1]heptanyl ring, and wherein the ring is substituted by R 5 , R 5 ′, R 6 , and R 6 ′.

7 . The compound according to claim 1 , wherein ring A is selected from the following groups wherein an asterisk denotes the point of attachment to the non-cyclic nitrogen atom of formula (I)

and wherein the ring is substituted by R 5 , R 5 ′, R 6 , R 6 ′.

8 . The compound according to claim 1 wherein ring A is a cyclopentyl, cyclohexyl, cyclopentenyl, or cyclohexenyl ring, and wherein the ring is substituted by R 5 , R 5 ′, R 6 , and R 6 ′.

9 . The compound according to claim 1 , wherein ring B is a imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, pyridinyl, tetrazolyl, pyrimidinyl, 1,3,4-oxadiazolyl, pyrazolyl, benzo[d]imidazolyl, pyrazinyl, 1,3,4-thiadiazolyl, oxazolyl, thiazolyl, or isoxazolyl ring, and wherein the ring is substituted by R 7 and R 8 .

10 . The compound according to claim 1 , wherein ring B is selected from the following groups or tautomers thereof wherein an asterisk denotes the point of attachment to ring A

and wherein the ring is substituted by R 7 and R 8 .

11 . The compound according to claim 1 , wherein ring B is a imidazolyl, pyridinyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiazolyl, or oxazolyl ring, and wherein the ring is substituted by R 7 and R 8 .

12 . The compound according to claim 1 , wherein R 1 is CF 3 or chloro; R 2 is cyano; and R 3 is H, methyl, or fluoro.

13 . The compound according to claim 1 , wherein R 4 is C 1-7 alkyl, C 2-7 alkenyl, C 3-7 cycloalkyl, or C 3-7 cycloalkyl C 1-7 alkyl.

14 . The compound according to claim 13 , wherein R 4 is C 1-7 alkyl.

15 . The compound according to claim 14 , wherein R 4 is methyl or ethyl.

16 . The compound according to claim 1 , wherein R 5 and R 5 ′ are, independently, H or C 1-7 alkyl, and R 6 and R 6 ′ are, independently, H or OH.

17 . The compound according to claim 16 , wherein R 5 and R 5 ′ are, independently, H or methyl, and R 6 and R 6 ′ are, independently, H or OH.

18 . The compound according to claim 17 , wherein R 5 and R 5 ′ are methyl, and R 6 and R 6 ′ are, independently, H or OH.

19 . The compound according to claim 18 , wherein R 5 and R 5 ′ are attached to a same carbon atom of ring A.

20 . The compound according to claim 1 , wherein R 7 is H, halogen, C 1-7 alkyl, C 1-7 alkoxy, hydroxy C 1-7 alkyl, or C 1-7 alkoxy C 1-7 alkyl.

21 . The compound according to claim 1 , wherein R 9 is a imidazolyl, pyrazolyl, oxetanyl, thiazolyl, pyridinyl, phenyl, or morpholinyl ring, which may be substituted with -one C 1-7 alkyl or -one C 1-7 alkoxy group.

22 . The compound according to claim 1 , wherein the compound is
4-(Ethyl(3-(2-methyl-2H-tetrazol-5-yl)cyclohexyl)amino)-2-(trifluoromethyl)benzonitrile; 4-(Ethyl(3-(2-methyl-2H-tetrazol-5-yl)cyclohexyl)amino)-2-(trifluoromethyl)benzonitrile cis-diastereomer; 4-((3-(1H-imidazol-1-yl)-6,6-dimethylcyclohex-2-en-1-yl)(ethyl)amino)-2-(trifluoromethyl)benzonitrile; 4-((3-(1H-imidazol-1-yl)-6,6-dimethylcyclohex-2-en-1-yl)(ethyl)amino)-2-(trifluoromethyl)benzonitrile enantiomer 1; 4-((3-(1H-imidazol-1-yl)-6,6-dimethylcyclohex-2-en-1-yl)(ethyl)amino)-2-(trifluoromethyl)benzonitrile enantiomer 2; 4-((3-(1H-imidazol-1-yl)cyclohexyl)(ethyl)amino)-2-chloro-3-methylbenzonitrile; 4-((3-(1H-imidazol-1-yl)cyclohexyl)(ethyl)amino)-2-chloro-3-methylbenzonitrile cis-diastereomer; 4-((3-(1H-imidazol-1-yl)cyclohexyl)(ethyl)amino)-2-chloro-3-methylbenzonitrile cis-diastereomer enantiomer 1; 4-((3-(1,3,4-Oxadiazol-2-yl)cyclohexyl)(ethyl)amino)-2-(trifluoromethyl)benzonitrile; 4-((3-(1,3,4-Oxadiazol-2-yl)cyclohexyl)(ethyl)amino)-2-(trifluoromethyl)benzonitrile cis-diastereomer; 4-((3-(1H-imidazol-1-yl)-6,6-dimethylcyclohex-2-enyl)(ethyl)amino)-2-chlorobenzonitrile; 4-((3-(1H-imidazol-1-yl)-6,6-dimethylcyclohex-2-enyl)(ethyl)amino)-2-(difluoromethyl)benzonitrile; 4-((3-(1H-imidazol-1-yl)-6,6-dimethylcyclohex-2-enyl)(ethyl)amino)-2-(difluoromethyl)benzonitrile enantiomer 1; 4-((5-(1H-Imidazol-1-yl)-2,2-dimethylcyclohexyl)(ethyl)amino)-2-(trifluoromethyl)benzonitrile; 4-((5-(

Assignees

• Orion Corp

Inventors

• Wohlfahrt Gerd
• Rummakko Petteri
• Karjalainen Arja
• Passiniemi Mikko
• Pietikäinen Pekka
• Haikarainen Anssi
• Väisänen Emilia
• Tiainen Eija

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P13/08

  of the prostate · CPC title

• C07D257/04

  Five-membered rings · CPC title

• C07D231/12

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title