Tetrahydroquinoline compositions as BET bromodomain inhibitors

Patent metadata

Field	Value
Publication number	US-9388161-B2
Application number	US-201414546775-A
Country	US
Kind code	B2
Filing date	Nov 18, 2014
Priority date	Nov 18, 2013
Publication date	Jul 12, 2016
Grant date	Jul 12, 2016

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

The invention claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, 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 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 )R d , —O(CH 2 )C(O)R d , or —O(CH 2 ) n S(O) 2 R d ;
R 5 is 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 6 is 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, —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, —(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 susbtitued 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, 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, 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, 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)ox

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

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P29/00

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

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title