Benzopiperazine compositions as bet bromodomain inhibitors

Patent metadata

Field	Value
Publication number	US-2016256458-A1
Application number	US-201615153698-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 X, Y, Z, R 1 , R 2 , R 4 and R 7 are defined herein.

First claim

1 . A method of treating or inhibiting a cancer associated with the activity of one or more BET-family bromodomains in a patient comprising administering to said patient in need thereof a therapeutically effective amount of the compound of Formulae (I), (II), (III), (IV), (V), or (VI):

wherein:
X is selected from N or CR 3 ;
Y is selected from N or CR 5 ;
Z is selected from N or CR 6 ;
R 1 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 2 is —C(O)(CR k R l ) n O(CR k R l ) m R d , —C(O)(CR k R l ) n R e , —S(O) 2 (CR k R l ) n R f , —(CR k R l ) n R g , —C(O)(CR k R l ) n NR a R g or —C(O)(CR k R l ) n S(CR k R l ) m R f ;
R 3 and R 6 are each independently selected from hydrogen or halogen;
R 4 is hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, heterocycloalkyl, heteroaryl, —NR a R b , —C(O)R h , C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —C 1 -C 4 alkyl(aryl), —C 1 -C 4 alkyl(heteroaryl), or —C 1 -C 4 alkyl(heterocycloalkyl), wherein the cycloalkyl, aryl, heterocycloalkyl, heteroaryl, and alkyl are optionally substituted with one or more R 10 ;
R 5 is hydrogen, halogen, C 1 -C 6 alkyl, nitro, —NH 2 , C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 aminoalkyl, C 1 -C 6 aminoalkoxy, CN, C 1 -C 6 alkoxy, —C(O)NR a R b , —NR a S(O) 2 R b , —NR a C(O)R b , —NR a C(O)OR b , —NR a C(O)NR b R c , C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —S(O) 2 NR a R b , or —S(O) 2 R a ;
R 7 is —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , or —S(O) 2 R 8 ;
R 8 and R 9 are each independently hydrogen, —(CR k R l ) m OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 10 is independently at each occurrence selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —OR i , —NR a R i , CN, oxo, —(CR k R l ) n S(O) 2 R i , —(CR k R l ) n NR a S(O) 2 R i , —(CR k R l ) n S(O) 2 NR a R i , —(CR k R l ) n NR a R i S(O) 2 NR a R i , —(CR k R l ) n C(O)OR a , —(CR k R l ) n C(O)R i , —(CR k R l ) n C(O)NR a R i , —(CR k R l ) n R i , —(CR k R l ) n NR a C(O)NR b , —(CR k R l ) n NR a C(O)OR b , and oxo, wherein each alkyl is substituted with one or more R 11 ; or
two R 10 together when on adjacent carbons form an aryl ring optionally substituted with one or more R 11 ; or two R 10 together when on adjacent carbons form a heteroaryl ring optionally substituted with one or more R 11 ; or two R 10 together when on adjacent carbons form a heterocycloalkyl ring optionally substituted with one or more R 11 ;
each R 11 is independently at each occurrence selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy, CN, C 1 -C 6 hydroxyalkyl, —(CR k R l ) m NH 2 , C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, —C(O)NR a R b , —C(O)OR a , —C(O)R a , —S(O) 2 R a , —C(O)H, —NR a C(O)OR a , —NR a C(O)C 1 -C 6 alkyl, or oxo;
or two R 11 together can form a heterocycloalkyl ring;
R a , R b , and R c are each independently at each occurrence hydrogen, C 1 -C 6 alkyl, —C 1 -C 4 alkyl(aryl), or aryl, wherein the alkyl and aryl are optionally substituted with one or more R 10 ;
R d is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, CN, —C(O)C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R 12 ;
R e is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkoxy, CN, C 3 -C 7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R 12 ;
R f is C 3 -C 7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein cycloalkyl, aryl, heteroaryl and heterocycloalkyl are optionally substituted with one or more R 12 ;
R 8 is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, —C 1 -C 4 alkyl(C 3 -C 7 cycloalkyl), aryl, —C 1 -C 4 alkyl(aryl), heteroaryl, —C 1 -C 4 alkyl(heteroaryl), heterocycloalkyl, or —C 1 -C 4 alkyl(heterocycloalkyl), wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R 12 ;
R h is C 3 -C 7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R 10 ;
R i is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, —(CH 2 ) q N(H)C 1 -C 6 alkyl, —(CH 2 ) q N(C 1 -C 6 alkyl) 2 , —(CR k R l ) m C 3 -C 7 cycloalkyl, —(CR k R l ) m aryl, —(CR k R l ) m heteroaryl, or —(CR k R l ) m heterocycloalkyl, wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are optionally substituted with one or more R 11 ;
each R 12 is independently at each occurrence selected from C 1 -C 6 alkyl, halogen, CN, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy, NO 2 , —NH 2 , CH 2 NH 2 , —(CH 2 ) q N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, —O(CH 2 ) q N(H)C 1 -C 6 alkyl, —O(CH 2 ) q N(C 1 -C 6 alkyl) 2 , aryl, heteroaryl, —NH-heteroaryl, —O-aryl, —S(O) p —C 1 -C 6 alkyl, —S(O) p —N(H)C 1 -C 6 alkyl, —S(O) p —N(C 1 -C 6 alkyl) 2 , —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, —NHC(O)(C 1 -C 6 alkyl), or oxo, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, halogen, CN, C 1 -C 6 alkoxy, hydroxy, NO 2 , —NH 2 , C 1 -C 6 alkylamino, or C 1 -C 6 dialkylamino; or
two R 12 together with the carbon to which they are attached can form a 4- to 6 membered heterospirocycle; or two R 12 together when on adjacent carbons form a C 4 -C 6 cycloalkyl optionally substituted with one or more R 13 ; or two R 12 together when on adjacent carbons form an aryl optionally substituted with one or more R 13 ; or two R 12 together when on adjacent carbons form a heteroaryl optionally substituted with one or more R 13 ; or two R 12 together when on adjacent carbons form a heterocycloalkyl optionally substituted with one or more R 13 ; or R 12 with the carbon to which it is attached and the adjacent carbon form a C 3 cycloalkyl optionally substituted with one or more R 13 ;
each R 13 is independently at each occurrence selected from C 1 -C 6 alkyl, halogen, CN, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy, NO 2 , —NH 2 , CH 2 NH 2 , —(CH 2 ) q N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, —O(CH 2 ) n N(H)C 1 -C 6 alkyl, —O(CH 2 ) q N(C 1 -C 6 alkyl) 2 , aryl, heteroaryl, —NH-heteroaryl, —O-aryl, —S(O) p —C 1 -C 6 alkyl, —S(O) p —N(H)C 1 -C 6 alkyl, —S(O) p —N(C 1 -C 6 alkyl) 2 , —C(O)C 1 -C 6 alkyl, —NHC(O)(C 1 -C 6 alkyl), or oxo, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, halogen, CN, C 1 -C 6 alkoxy, hydroxy, NO 2 , —NH 2 , C 1 -C 6 alkylamino, and C 1 -C 6 dialkylamino;
R k and R l are each independently at each occurrence selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, or halogen;
each m, n, and p is independently at each occurrence 0, 1, or 2; and
each q is independently at each occurrence 1, 2, 3 or 4;
provided that when m is 0, R d is not C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or CN;

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
• Tebbe Mark J

Classifications

• A61K31/517

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K45/06

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