TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF

Patent metadata

Field	Value
Publication number	US-2016175289-A1
Application number	US-201514972326-A
Country	US
Kind code	A1
Filing date	Dec 17, 2015
Priority date	Dec 18, 2014
Publication date	Jun 23, 2016
Grant date	—

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 selected from Formula I:

and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein:
Y 1 is CR b or N;
Y 2 is —(CH 2 )—, —(CH 2 CH 2 )—, or NR a ;
Y 3 is NR a or C(Rb) 2 ;
where one of Y 1 , Y 2 and Y 3 is N or NR a ;
R a is selected from H, C 1 -C 6 alkyl, C 2 -C 8 alkenyl, propargyl, C 3 -C 6 cycloalkyl, and C 3 -C 6 heterocyclyl, optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, OH, OCH 3 , and SO 2 CH 3 ;
R b is independently selected from H, —O(C 1 -C 3 alkyl), C 1 -C 6 alkyl, C 2 -C 8 alkenyl, propargyl, —(C 1 -C 6 alkyldiyl)-(C 3 -C 6 cycloalkyl), C 3 -C 6 cycloalkyl, and C 3 -C 6 heterocyclyl, optionally substituted with one or more groups independently selected from 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 selected from H, C 1 -C 6 alkyl, allyl, propargyl, optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, OH, OCH 3 , and SO 2 CH 3 ;
Z 1 is selected from CR a R b , C(O), and a bond;
Cy is selected from C 6 -C 20 aryldiyl, C 3 -C 12 carbocyclyldiyl, C 2 -C 20 heterocyclyldiyl, and C 1 -C 20 heteroaryldiyl;
Z 2 is selected from O, S, NR a , C 1 -C 6 alkyldiyl, C 1 -C 6 fluoroalkyldiyl, O—(C 1 -C 6 alkyldiyl), O—(C 1 -C 6 fluoroalkyldiyl), C(O), and a bond;
R 1 , R 2 , R 3 and R 4 are independently selected from H, F, Cl, Br, I, —CN, —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, —CH 2 CN, —CO 2 H, —COCH 3 , —CO 2 CH 3 , —CO 2 C(CH 3 ) 3 , —COCH(OH)CH 3 , —CONH 2 , —CONHCH 3 , —CONHCH 2 CH 3 , —CONHCH(CH 3 ) 2 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 , —N(CH 3 )COCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , —NO 2 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 N(CH 3 ) 2 , —OP(O)(OH) 2 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , —S(O) 3 H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl, morpholino-methanone, and morpholino;
R 5 is selected from H, 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)R b , C(O)NR a , SO 2 R a , and SO 2 NR a , 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 selected from F, Cl, Br, I, —CN, —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 2 CH 2 F, —CH(CH 3 )CN, —C(CH 3 ) 2 CN, —CH 2 CN, —CO 2 H, —COCH 3 , —CO 2 CH 3 , —CO 2 C(CH 3 ) 3 , —COCH(OH)CH 3 , —CONH 2 , —CONHCH 3 , —CONHCH 2 CH 3 , —CONHCH(CH 3 ) 2 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 , —N(CH 3 )COCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , —NO 2 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 N(CH 3 ) 2 , —OP(O)(OH) 2 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , —S(O) 3 H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl, morpholino-methanone, and morpholino; and
m is selected from 0, 1, 2, 3, and 4;
where alkyldiyl, fluoroalkyldiyl, aryldiyl, carbocyclyldiyl, heterocyclyldiyl, and heteroaryldiyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CN, —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 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CH(CH 3 )CN, —C(CH 3 ) 2 CN, —CH 2 CN, —CH 2 NH 2 , —CH 2 NHSO 2 CH 3 , —CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , —CO 2 H, —COCH 3 , —CO 2 CH 3 , —CO 2 C(CH 3 ) 3 , —COCH(OH)CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 , —N(CH 3 )COCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , —NO 2 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 N(CH 3 ) 2 , —OP(O)(OH) 2 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , —S(O) 3 H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl, morpholino-methanone, and morpholino.

2 . The compound of claim 1 having Formula Ia:

3 . The compound of claim 2 having Formula Ib:

wherein R 7 is F, Cl, Br, I, —CN, —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, —CH 2 CN, —CO 2 H, —COCH 3 , —CO 2 CH 3 , —CO 2 C(CH 3 ) 3 , —COCH(OH)CH 3 , —CONH 2 , —CONHCH 3 , —CONHCH 2 CH 3 , —CONHCH(CH 3 ) 2 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 , —N(CH 3 )COCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , —NO 2 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 N(CH 3 ) 2 , —OP(O)(OH) 2 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , —S(O) 3 H, cyclopropyl, cyclopropylamide, oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl, morpholino-methanone, and morpholino; and
n is selected from 0, 1, 2, 3, and 4.

4 . The compound of claim 1 having Formula Ic:

5 . The compound of claim 4 having Formula Id:

6 . The compound of claim 5 having Formula Ie:

wherein R 8 is H or —CH 3 .

7 . T

Assignees

• Genentech Inc

Inventors

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

Classifications

• 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

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title