Tetrahydroquinoline compositions as bet bromodomain inhibitors

Patent metadata

Field	Value
Publication number	US-2016257692-A1
Application number	US-201615153692-A
Country	US
Kind code	A1
Filing date	May 12, 2016
Priority date	Nov 18, 2013
Publication date	Sep 8, 2016
Grant date	—

Abstract

The present invention relates to inhibitors of bromo and extra terminal (BET) bromodomains that are useful for the treatment of cancer, inflammatory diseases, diabetes, and obesity, having Formula I:

wherein W, X, Y, Z, R 1 , R 2 , R 5 , and R 8 are as described herein.

First claim

1 . A compound of Formula I:

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, prodrug, isomer, or tautomer thereof,
wherein:
W is O, S, C(O), or CHR 3 ;
X is N or CR 4 ;
Y is N or CR 6 ;
Z is N or CR 7 ;
R 1 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 2 is hydrogen or NR a R b ;
R 3 is hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 4 is hydrogen, —(CH 2 ) n R d , —O(CH 2 ) n R d , —N(CH 2 ) n R d , —O(CH 2 ) n C(O)R d , or —O(CH 2 ) n S(O) 2 R d ;
R 5 and R 6 are each independently hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, —(C 1 -C 6 )-alkylene-aryl, —(C 1 -C 6 )-alkylene-heteroaryl, —(C 1 -C 6 )-alkylene-heterocycloalkyl, —(CR a R b ) n OR c , —(CR a R b ) n R c , —O(CR a R b ) n NR a R b , —NR a R b , —NR a C(O)R b , —NR a S(O) 2 R b , or R c , wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from R a , R b , and R c ;
R 7 is hydrogen or halogen;
R 8 is R a , —OR a , —NR a , or heterocycloalkyl;
R a and R b are each independently hydrogen, halogen, C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl, wherein C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R e ;
R c is —NH 2 , OH, —NH(C 1 -C 6 alkyl), —O(CH 2 ) n NR a R b , —NH(C 1 -C 6 alkoxy), —(CH 2 ) n R a , —(CH 2 ) n OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —(CH 2 ) n S(O) 2 CH 3 , —S(O) 2 R a , —S(O) 2 NR a R b , —NR a —S(O) 2 R b , —NHC(O)R a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, cyano, or oxo, wherein C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R e ;
or two adjacent R c can combine with the carbons to which they are attached to form a carbocycle or heterocycle;
R d is hydrogen, NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from R a , R b , and R c ;
R e is hydrogen, halogen, OH, C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, oxo, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkoxy, or S(O) 2 (C 1 -C 6 alkyl); and
n is 0, 1, or 2.

2 . The compound of claim 1 , wherein X is CR 4 and Y and Z are CH.

3 . The compound of claim 2 , wherein W is CHR 3 .

4 . The compound of claim 1 , having the Formula II

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, prodrug, isomer, or tautomer thereof,
wherein:
W is O, C(O), or CHR 3 ;
Ar is aryl or heteroaryl;
R 2 is hydrogen or NR a R b ;
R 3 is hydrogen, hydroxy, or halo;
R 4 hydrogen, —O(CH 2 ) n R d , —O(CH 2 ) n C(O)R d , or —O(CH 2 ) n S(O) 2 R d ;
R 7 is hydrogen or halo;
R 8 is R a , —OR a , or heterocycloalkyl;
R a and R b are independently hydrogen, C 1 -C 6 alkyl, heterocycloalkyl, or cycloalkyl;
R c is R a , —(CH 2 ) n OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b —S(O) 2 R a , halo, or oxo; and
n is 0, 1, or 2.

5 . The compound of claim 4 , wherein W is CHR 3 .

6 . The compound of claim 4 , wherein Ar is pyrazole or phenyl.

7 . The compound of claim 1 , having the Formula III

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, prodrug, isomer, or tautomer thereof,
wherein:
Ar is pyrazolyl or phenyl;
R 4 is hydrogen, —O(CH 2 ) n R d , —O(CH 2 ) n C(O)R d , or —O(CH 2 ) n S(O) 2 R d ;
R 8 is methyl, methoxy, or cyclopropyl;
R a and R b are independently hydrogen or C 1 -C 6 alkyl;
R c is —(CH 2 ) n R a , —(CH 2 ) n OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —(CH 2 ) n S(O) 2 CH 3 , —S(O) 2 R a , —S(O) 2 NR a R b , C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, cycloalkyl, heterocycloalkyl, halo, cyano, or oxo;
R d is hydrogen, NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from R a , R b , and R c ; and
n is 0, 1, or 2.

8 . The compound of claim 7 , wherein Ar is pyrazole and R c is cycloalkyl or heterocycloalkyl.

9 . The compound of claim 8 , wherein R c is cyclopropyl.

10 . The compound of claim 7 , wherein Ar is phenyl, R c is —(CH 2 ) n S(O) 2 CH 3 .

11 . The compound of claim 1 , having the Formula IV

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, prodrug, isomer, or tautomer thereof,
wherein:
R 4 is —O(CH 2 ) n R d , —O(CH 2 ) n C(O)R d , or —O(CH 2 ) n S(O) 2 R d ;
R 8 is alkyl, cycloalkyl, O-alkyl, or O-cycloalkyl
R a and R b are independently hydrogen or C 1 -C 6 alkyl;
R c is —(CH 2 ) n R a , —(CH 2 ) n OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b —S(O) 2 R a , —S(O) 2 NR a R b , C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, cyano, or oxo;
R d is hydrogen, NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from R a , R b , and R c ; and
n is 0, 1, or 2.

12 . The compound of claim 11 , wherein R c is cycloalkyl, or heterocycloalkyl.

13 . The compound of claim 12 , wherein R 4 is —O(CH 2 ) n R d .

14 . The compound of claim 13 , wherein R d is aryl, heteroaryl, or cycloalkyl.

15 . The compound of claim 1 selected from the group consisting of:
methyl (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;
methyl (2S)-5-(4-fluorophenoxy)-2-methyl-6-(1-{octahydrocyclopenta[c]pyrrol-5-yl}-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate;
methyl (2S)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(3,3-difluorocyclobutoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate;
(2S)-1-cyclopropanecarbonyl-2-methyl-5-phenoxy-6-(1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinoline;
methyl (2S)-5-(azetidin-3-ylmethoxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinoline-1-

Assignees

• Forma Therapeutics Inc

Inventors

• Bair Kenneth W
• Herbertz Torsten
• Kauffman Goss S
• Kayser-Bricker Katherine J
• Luke George P
• Martin Matthew W
• Millan David S
• Schiller Shawn E R
• Talbot Adam C

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title