Tetrahydro-pyrido[3,4-b]indole estrogen receptor modulators and uses thereof

Patent metadata

Field	Value
Publication number	US-9980947-B2
Application number	US-201514972326-A
Country	US
Kind code	B2
Filing date	Dec 17, 2015
Priority date	Dec 18, 2014
Publication date	May 29, 2018
Grant date	May 29, 2018

Abstract

Described herein are tetrahydro-pyrido[3,4-b]indol-1-yl compounds with estrogen receptor modulation activity or function having the Formula I structure:

and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula I compounds, as well as methods of using such estrogen receptor modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.

First claim

We claim:

1. A compound having formula (Ih):

or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
Y 2 is —(CH 2 );
R a is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 8 alkenyl, propargyl, C 3 -C 6 cycloalkyl, and C 3 -C 6 heterocyclyl, each optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br, I, CN, OH, OCH 3 , and SO 2 CH 3 ;
R b is independently selected from the group consisting of H, —O(C 1 -C 3 alkyl), C 1 -C 6 alkyl, C 2 -C 8 alkenyl, and propargyl, each optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br, I, CN, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, OH, OCH 3 , and SO 2 CH 3 ,
R c is H;
R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of H, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —CH(OH)CH(CH 3 ) 2 , —C(CH 3 ) 2 CH 2 OH, —CH 2 CH 2 SO 2 CH 3 , —CH 2 OP(O)(OH) 2 , —CH 2 F, —CHF 2 , —CH 2 NH 2 , —CH 2 NHSO 2 CH 3 , —CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH(CH 3 )CN, —C(CH 3 ) 2 CN, and —CH 2 CN;
R 5 is selected from the group consisting of C 1 -C 9 alkyl, C 3 -C 9 cycloalkyl, C 3 -C 9 heterocycle, C 6 -C 9 aryl, C 6 -C 9 heteroaryl, —(C 1 -C 6 alkyldiyl)-(C 3 -C 9 cycloalkyl), —(C 1 -C 6 alkyldiyl)-(C 3 -C 9 heterocycle), C(O)NR a , SO 2 R a , and SO 2 NR a , each optionally substituted with one or more of halogen, CN, OR a , N(R a ) 2 , C 1 -C 9 alkyl, C 3 -C 9 cycloalkyl, C 3 -C 9 heterocycle, C 6 -C 9 aryl, C 6 -C 9 heteroaryl, C(O)R b , C(O)NR a , SO 2 R a , and SO 2 NR a ;
R 6 is independently F or Cl;
m is 0, 1, 2, 3, or 4;
R 7 is independently halogen; and
n is 0, 1 or 2.

2. The compound of claim 1 having Formula Ii:

3. The compound of claim 2 having Formula Ij:

4. The compound of claim 3 having Formula Ik:

5. The compound of claim 1 wherein R 7 is F.

6. The compound of claim 1 wherein R 1 and R 2 are H.

7. The compound of claim 1 wherein R 3 is H, and R 4 is —CH 3 .

8. The compound of claim 1 wherein R 5 is C 1 -C 6 fluoroalkyl.

9. The compound of claim 1 wherein m is 0.

10. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of claim 1 and at least one pharmaceutically acceptable excipient.

11. The pharmaceutical composition according to claim 10 , further comprising an additional therapeutic agent.

12. A method of treating breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer in a patient having said cancer, the method comprising administering to said patient a therapeutically effective amount of a compound of formula (Ih) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof

wherein:
Y 2 is —(CH 2 );
R a is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 8 alkenyl, propargyl, C 3 -C 6 cycloalkyl, and C 3 -C 6 heterocyclyl, each optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br, I, CN, OH, OCH 3 , and SO 2 CH 3 ;
R b is selected from the group consisting of H, —O(C 1 -C 3 alkyl), C 1 -C 6 alkyl, C 2 -C 8 alkenyl, and propargyl, each optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br, I, CN, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, OH, OCH 3 and SO 2 CH 3 ;
R c is H;
R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of H, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —CH(OH)CH(CH 3 ) 2 , —C(CH 3 ) 2 CH 2 OH, —CH 2 CH 2 SO 2 CH 3 , —CH 2 OP(O)(OH) 2 , —CH 2 F, —CHF 2 , —CH 2 NH 2 , —CH 2 NHSO 2 CH 3 , —CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH(CH 3 )CN, —C(CH 3 ) 2 CN, and —CH 2 CN;
R 5 is selected from the group consisting of C 1 -C 9 alkyl, C 3 -C 9 cycloalkyl, C 3 -C 9 heterocycle, C 6 -C 9 aryl, C 6 -C 9 heteroaryl, —(C 1 -C 6 alkyldiyl)-(C 3 -C 9 cycloalkyl), —(C 1 -C 6 alkyldiyl)-(C 3 -C 9 heterocycle), C(O)NR a , SO 2 R a , and SO 2 NR a , each optionally substituted with one or more of halogen, CN, OR a , N(R a ) 2 , C 1 -C 9 alkyl, C 3 -C 9 cycloalkyl, C 3 -C 9 heterocycle, C 6 -C 9 aryl, C 6 -C 9 heteroaryl, C(O)R b , C(O)NR a , SO 2 R a , and SO 2 NR a ;
R 6 is independently F or Cl;
m is 0, 1, 2, 3, or 4;
R 7 is independently halogen; and
n is 0, 1 or 2.

13. The method of claim 12 , wherein the cancer is breast cancer.

14. The method of claim 12 , further comprising administering to the patient an additional therapeutic agent selected from the group consisting of an anti-inflammatory agent, an immunomodulatory agent, chemotherapeutic agent, an apoptosis-enhancer, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, and an agent for treating immunodeficiency disorders, or a combination thereof.

15. The method of claim 12 , wherein the compound or a pharmaceutically acceptable salt thereof is administered in combination with a therapeutic agent selected from the group consisting of paclitaxel, anastrozole, exemestane, cyclophosphamide, epirubicin, fulvestrant, letrozole, gemcitabine, trastuzumab, trastuzumab emtansine, pegfilgrastim, filgrastim, tamoxifen, docetaxel, toremifene, vinorelbine, capecitabine, and ixabepilone, or a combination thereof.

16. The method of claim 12 , wherein the compound or pharmaceutically acceptable salt thereof is administered in combination with a CDK 4/6 inhibitor.

17. The method of claim 16 , wherein the CDK 4/6 inhibitor is selected from the group consisting of palbociclib, ribociclib and LY283519, or a pharmaceutically acceptable salt thereof.

18. A kit for treating breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer, the kit comprising:
a) a pharmaceutical composition of claim 10 ; and
b) instructions for use.

19. The compound of claim 1 comprising one or more deuterium.

20. The compound 3-[(1R,3R)-1-[2,6-difluoro-4-[[1-(3-fluoropropyl)azetidin-3-yl]amino]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoro-propan-1-ol, or a pharmaceutically acceptable salt thereof.

21. The compound 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol, or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1 having the formula:

Assignees

• Genentech Inc

Inventors

• Labadie Sharada
• Liang Jun
• Ortwine Daniel Fred
• Wang Xiaojing
• Zbieg Jason
• Zhang Birong
• Goodacre Simon Charles
• Ray Nicholas Charles
• Li Jun

Classifications

• A61K31/565

  not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol · CPC title

• A61K31/138

  Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine (atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377) · CPC title

• A61P5/30

  Oestrogens · CPC title

• A61K45/06 Primary

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P43/00

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