Compounds for regulating fak and/or src pathways

Patent metadata

Field	Value
Publication number	US-2016222014-A1
Application number	US-201415021186-A
Country	US
Kind code	A1
Filing date	Sep 5, 2014
Priority date	Sep 10, 2013
Publication date	Aug 4, 2016
Grant date	—

Abstract

The present application provides novel optionally substituted fused pyridine and pyrimidine bicyclic compounds and pharmaceutically acceptable salts thereof. Also provided are methods for preparing these compounds. These compounds are useful in co-regulating FAK and/or Src activity by administering a therapeutically effective amount of one or more of the compounds to a subject. By doing so, these compounds are effective in treating conditions associated with the dysregulation of the FAK and/or Src pathway. Advantageously, these compounds perform as dual FAK and/or Src inhibitors. A variety of conditions can be treated using these compounds and include diseases which are characterized by inflammation or abnormal cellular proliferation. In one embodiment, the disease is cancer.

First claim

What is claimed is:

1 . A compound of formula IA or IB having the following structure:

wherein:
X and Y are, independently, N or CH;
W is CH 2 , —C═O, or NR 13 ;
Z is absent, CH 2 , —C═O or —SO 2 , with the proviso that:
(i) Z is not —C═O or —SO 2 when W is C═O; and
(ii) Z is not absent, when Y is CH;

Q is N or CR 3 ;
R 1 is optionally substituted C 6 -C 10 aryl or optionally substituted C 2 -C 10 heteroaryl;
R 3 is H, C 1 -C 6 alkyl, halogen, CN, or C 1 -C 6 trifluoroalkyl;
R 4 and R 5 are, independently, H, F or optionally substituted C 1 -C 6 alkyl; or
R 4 and R 5 are taken together to form a 3 to 6 membered cyclic ring having 0-1 heteroatom;
R 2 is optionally substituted C 6 -C 10 aryl, optionally substituted heteroaryl, C 3 -C 6 optionally substituted cycloalkyl or C 2 -C 6 heterocyclyl;
R 13 is H or optionally substituted alkyl;
or a pharmaceutically acceptable salt or prodrug thereof.

2 . The compound according to claim 1 , which is of formula IA:

3 . The compound according to claim 1 , which is of formula IB:

4 . The compound according to claim 1 , which is of formula IA-2 or IB-2:

5 . The compound according to claim 1 , which is of formula IA-3 or IB-3:

6 . The compound according to claim 1 , which is of formula IA-4 or IB-4:

7 . The compound according to claim 1 , which is of formula IA-5:

8 . The compound according to claim 1 , which is of formula IA-6:

9 . The compound according to claim 1 which is of formula IA-8:

10 . The compound according to claim 1 , wherein R 3 is H, CH 3 , or F.

11 . The compound according to claim 1 , wherein R 4 and R 5 are, independently, H or CH 3 .

12 . The compound according to claim 1 , wherein R 4 and R 5 are joined to form a cyclopropyl.

13 . The compound according to claim 1 , wherein R 2 is optionally substituted heteroaryl.

14 . The compound according to claim 13 , wherein R 2 is optionally substituted imidazole, pyridine, thiophene, quinoline, naphthalene, benzothiazole, or benzothiodiazole.

15 . The compound according to claim 14 , wherein R 2 is optionally substituted imidazole.

16 . The compound according to claim 15 , wherein R 2 is imidazole substituted with 1 or 2 C 1 -C 6 alkyl.

17 . The compound according to claim 16 , wherein R 2 is imidazole substituted with 1 or 2 CH 3 groups.

18 . The compound according to claim 14 , wherein R 2 is optionally substituted pyridine.

19 . The compound according to claim 18 , wherein R 2 is pyridine substituted with 1 or more C 1 -C 6 alkoxy, N(C 1 -C 6 alkyl)OSO 2 (C 1 -C 6 alkyl), N(C 1 -C 6 alkyl)(SO 2 (C 1 -C 6 alkyl), or N(C 1 -C 6 alkyl)SO 2 (C 3 -C 8 cycloalkyl).

20 . The compound according to claim 19 , wherein R 2 contains a SO 2 group in the backbone of ring.

21 . The compound according to claim 19 or 20 , wherein R 2 is 1-N(CH 3 )(OSO 2 CH 3 )-pyridin-2-yl, 1-N(CH 3 )SO 2 CH 3 -pyridin-2-yl, 2-N(CH 3 )SO 2 CH 3 -pyridin-3-yl, pyridine-2-yl, pyridine-3-yl, 2-OCH 3 -pyridin-4-yl, 2-N(CH 3 )SO 2 -cyclopropyl-pyridin-3-yl, or dioxidoisothiazolidin-2-yl.

22 . The compound according to claim 14 , wherein R 2 is optionally substituted quinoline.

23 . The compound according to claim 22 , wherein R 2 is quinoline substituted with 1 or more C 1 -C 6 alkyl.

24 . The compound according to claim 22 , wherein said quinoline contains a C(O) in the backbone of the ring.

25 . The compound according to claim 22 , wherein R 2 is quinolone, 4-CH 3 -quinolin-8-yl, 2-CH 3 -quinolin-8-yl, 6-CH 3 -quinolin-8-yl, or 8-isoquinoline.

26 . The compound according to claim 14 , wherein R 2 is thiophene.

27 . The compound according to claim 1 , wherein R 2 is optionally substituted aryl.

28 . The compound according to claim 27 , wherein R 2 is optionally substituted phenyl.

29 . The compound according to claim 27 , wherein R 2 is phenyl substituted with 1 or more of halogen, C 1 -C 6 alkoxy, C 1 -C 6 trifluoroalkyl, C 1 -C 6 alkyl, CN, NH 2 , C 1 -C 6 trifluoroalkoxy, SO 2 N(C 1 -C 6 alkyl) 2 , SO 2 NH(C 1 -C 6 alkyl), SO 2 (C 1 -C 6 alkyl), N(C 1 -C 6 alkyl)SO 2 (C 1 -C 6 alkyl), N(C 3 -C 8 cycloalkyl)SO 2 (C 1 -C 6 alkyl), NHC(O)(C 1 -C 6 alkyl), N(C 1 -C 6 hydroxyalkyl)SO 2 (C 1 -C 6 alkyl), N(alkylamino)SO 2 (C 1 -C 6 alkyl), N(C 1 -C 6 alkoxy)SO 2 (C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-C(O)NH(C 1 -C 6 alkyl), or N(C 1 -C 6 alkyl-morpholine)SO 2 (C 1 -C 6 alkyl).

30 . The compound according to claim 27 , wherein R 2 is phenyl, 2,3-di-Cl-phenyl, 2,5-di-Cl-phenyl, 2,5-di-OCH 3 -phenyl, 2-5-di-Cl-phenyl, 2-CF 3 -phenyl, 2-CH 3 -phenyl, 2-Cl-5-CH 3 -phenyl, 3-Cl-phenyl, 3-CN-phenyl, 2-Cl-phenyl, 2-F-phenyl, 2-OCF 3 -phenyl, 2-OCH 3 -phenyl, 2-NH 2 -phenyl, 4-tolyl, 3-OCH 3 -phenyl, 4-OCF 3 -phenyl, 3-OCF 3 -phenyl, 2-OCHF 2 -phenyl, 2-SO 2 N(CH 3 ) 2 -phenyl, 2-NHSO 2 CH 3 -phenyl, 2-SO 2 —NHCH 3 -phenyl, 3-SO 2 —NHCH 3 -phenyl, 3-SO 2 (CH 3 )-phenyl, 2-N(CH 3 )SO 2 CH 3 -phenyl,2-N(CH 3 )SO 2 CH 3 -3-OCH 3 -phenyl, 2-N(cyclopropyl)SO 2 CH 3 -phenyl, 3-N(CH 3 )SO 2 (CH 3 )-phenyl, 2-NH(CH 3 )—SO 2 CH 3 -phenyl, 4-NHC(O)CH 3 -phenyl, 2-N(CH 2 CH 2 OH)SO 2 CH 3 -phenyl, 2-N(CH 2 CH 2 NH 2 )SO 2 CH 3 -phenyl, 2-N(CH 2 CH 2 OCH 3 )SO 2 CH 3 -phenyl, 2-CH 2 —C(O)NHCH 3 -phenyl, 2-N(CH 2 CH 2 -morpholine)SO 2 CH 3 -phenyl.

31 . The compound according to claim 1 , wherein R 2 is optionally substituted C 3 -C 8 cycloalkyl.

32 . The compound according to claim 31 , wherein R 2 is cyclopentyl or cyclopropyl.

33 . The compound according to claim 1 , wherein:
R 2 is C 6 -C 10 aryl or heteroaryl substituted with one or more R 12 ; R 12 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, alkoxy, —S(O) n —C 1 -C 6 alkyl, —O(CH 2 ) a NR 8 R 9 , —O(CH 2 ) a OH, —O(CH 2 ) a O—C 1 -C 6 alkyl, CN, aryl, heteroaryl, optionally substituted monocyclic cycloalkyl, optionally substituted bicyclic cycloalkyl, optionally substituted monocyclic heterocyclyl, optionally substituted bicyclic heterocyclyl, (aryl)alkyl, COOH, NH 2 , NR 8 R 9 , —C(O)NH 2 , —C(O)NR 10 R 11 , —SO 2 NH 2 , —SO 2 NR 10 R 11 , aminoalkyl, (alkyl)amido, (alkyl)amino, arylalkyl, alkylcarboxyl, (alkyl)carboxyamido, heterocyclyl(alkyl), heteroaryl(alkyl) (aryl)oxy, (heteroaryl)oxy, halogen,

Assignees

• Asana Biosciences Llc

Inventors

• Venkatesan Aranapakam M
• Smith Roger A
• Thompson Scott K
• Laping Nicholas
• Kulkarni Bheemashankar
• Hallur Gurulingappa
• Viswanadhan Vellarkad N
• Pendyala Muralidhar
• Kethiri Raghava Reddy
• Tyagi Rajiv
• Sivanandhan Dhanalakshmi
• Bakthavatchalam Rajagopal

Classifications

• A61K31/5377

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

• C07D471/04

  Ortho-condensed systems · CPC title

• A61K31/538

  ortho- or peri-condensed with carbocyclic ring systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K45/06

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