Compounds and methods for kinase modulation, and indications therefor

Patent metadata

Field	Value
Publication number	US-9771369-B2
Application number	US-201514637303-A
Country	US
Kind code	B2
Filing date	Mar 3, 2015
Priority date	Mar 4, 2014
Publication date	Sep 26, 2017
Grant date	Sep 26, 2017

Abstract

Compounds active on c-kit protein kinases or mutant c-kit protein kinases having any mutations are described, wherein the compounds are of Formula (I):

Methods of making and using such compounds to treat diseases and conditions associated with aberrant activity of the c-kit protein kinases and/or mutant c-kit protein kinases are also described.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer or a deuterated analog thereof, wherein:
Z is CR 1 ;
Q 1 is CR 2 ;
Q 2 is N;
R 1 is optionally substituted aryl or optionally substituted heteroaryl;
R 2 is H, halogen, CH 3 , CH 3 O, or CN, wherein CH 3 or CH 3 O is optionally substituted with from 1 to 3 halogens;
R 3 is H, F, CH 3 , CH 3 O, CHF 2 , CH 2 F, CF 3 , CHF 2 O, CH 2 FO or CF 3 O;
R 4 , R 5 , R 6 and R 7 are each independently H, C 1-4 alkyl or C 1-4 haloalkyl;
R 8 is H, C 1-4 alkyl or C 1-4 haloalkyl;
Y 1 is N or CR 9 ;
Y 2 is N or CR 10 ;
R 9 is H, C 1-4 alkyl or C 1-4 haloalkyl; and
R 10 and R 11 are each independently optionally substituted C 1-4 alkyl, optionally substituted C 1-4 haloalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl, wherein two adjacent substituents on an aryl or heteroaryl ring are optionally taken together with the atoms to which they attach to form an optionally substituted fused 5- or 6-membered ring having from 0-2 heteroatoms selected from O, N or S.

2. The compound of claim 1 , having formula (IIa):

3. The compound of claim 1 , having formula (IIa-1):

4. The compound of claim 1 , having formula (IIa-1a):

5. The compound of claim 1 , wherein Q 1 is CH.

6. The compound of claim 1 , wherein Y 1 is N.

7. The compound of claim 1 , wherein Y 2 is CR 10 and one of R 10 or R 11 is C 1-4 alkyl or C 1-4 haloalkyl and the other is optionally substituted aryl or optionally substituted heteroaryl.

8. The compound of claim 1 , wherein R 1 is aryl or heteroaryl, each of which is optionally substituted with from 1-3 R a substituents independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, C 3-6 cycloalkenyl, CH 2 ═CH—, C 3-6 cycloalkyl-C 2-4 alkenyl, C 3-6 cycloalkyl-C 2-4 alkynyl, heterocycloalkyl, heterocycloalkyl-C 1-4 alkyl or R b ; or
two adjacent R a substituents on an aromatic ring are taken together with the atoms to which they are attached form a 5- or 6-membered ring having from 0-2 heteroatoms selected from O, N or S;
wherein each R b is independently selected from halogen, CN, —OH, —NH 2 , —NO 2 , —C(O)OH, —C(S)OH, —C(O)NH 2 , —C(S)NH 2 , —S(O) 2 NH 2 , —NHC(O)NH 2 , —NHC(S)NH 2 , —NHS(O) 2 NH 2 , —C(NH)NH 2 , —OR c , —SR c , —OC(O)R c , —OC(S)R c , —C(O)R c , —C(S)R c , —C(O)OR c , —C(S)OR c , —S(O)R c , —S(O) 2 R c , —C(O)NHR c , —C(S)NHR c , —C(O)NR c R c , —C(S)NR c R c , —S(O) 2 NHR c , —S(O) 2 NR c R c , —C(NH)NHR c , —C(NH)NR c R c , —NHC(O)R c , —NHC(S)R c , —NR c C(O)R c , —NR c C(S)R c , —NHS(O) 2 R c , —NR c S(O) 2 R c , —NHC(O)NHR c , —NHC(S)NHR c , —NR c C(O)NH 2 , —NR c C(S)NH 2 , —NR c C(O)NHR c , —NR c C(S)NHR c , —NHC(O)NR c R c , —NHC(S)NR c R c , —NR c C(O)NR c R c , —NR c C(S)NR c R c , —NHS(O) 2 NHR c , —NR c S(O) 2 NH 2 , —NR c S(O) 2 NHR c , —NHS(O) 2 NR c R c , —NR c S(O) 2 NR c R c , —NHR c , R c or —NR c R c ;
wherein each R c is independently selected from C 1-6 alkyl, aryl, aryl-C 1-2 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, heterocycloalkyl or heterocycloalkyl-C 1-4 alkyl; or
two R c groups when attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached form a 4-, 5- or 6-membered ring;
wherein the aliphatic or aromatic portion of each R a is further optionally substituted with from 1-3 R d groups independently selected from halogen, CN, —OH, —NH 2 , —NO 2 , —C(O)OH, —C(S)OH, —C(O)NH 2 , —C(S)NH 2 , —S(O) 2 NH 2 , —NHC(O)NH 2 , —NHC(S)NH 2 , —NHS(O) 2 NH 2 , —C(NH)NH 2 , —OR e , —SR e , —OC(O)R e , —OC(S)R e , —P(═O)HR e , —P(═O)R e R e , —PH(═O)OR e , —P(═O)(OR e ) 2 , —OP(═O)(OR e ) 2 , —C(O)R e , —C(S)R e , —C(O)OR e , —C(S)OR e , —S(O)R e , —S(O) 2 R e , —C(O)NHR e , —C(S)NHR e , —C(O)NR e R e , —C(S)NR e R e , —S(O) 2 NHR e , —S(O) 2 NR e R e , —C(NH)NHR e , —C(NH)NR e R e , —NHC(O)R e , —NHC(S)R e , —NR e C(O)R e , —NR e C(S)R e , —NHS(O) 2 R e , —NR e S(O) 2 R e , —NHC(O)NHR e , —NHC(S)NHR e , —NR e C(O)NH 2 , —NR e C(S)NH 2 , —NR e C(O)NHR e , —NR e C(S)NHR e , —NHC(O)NR e R e , —NHC(S)NR e R e , —NR e C(O)NR e R e , —NR e C(S)NR e R e , —NHS(O) 2 NHR e , —NR e S(O) 2 NH 2 , —NR e S(O) 2 NHR e , —NHS(O) 2 NR e R e , —NR e S(O) 2 NR e R e , —NHR e , —NR e R e or R e ;
wherein each R e is independently C 1-6 alkyl or aryl; or two R e groups when attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached form a 4-to 6-membered ring;
wherein each R c is further optionally substituted with from 1-3 R f substituents independently selected from halogen, CN, —OH, —NH 2 , —NO 2 , —C(O)OH, —C(S)OH, —C(O)NH 2 , —C(S)NH 2 , —S(O) 2 NH 2 , —NHC(O)NH 2 , —NHC(S)NH 2 , —NHS(O) 2 NH 2 , —C(NH)NH 2 , —OR g , —SR g , —OC(O)R g , —OC(S)R g , —C(O)R g , —C(S)R g , —C(O)OR g , —C(S)OR g , —S(O)R g , —S(O) 2 R g , —C(O)NHR g , —C(O)NR g R g , —S(O) 2 NHR g , —S(O) 2 NR g R g , —NHC(O)R g , —NR g C(O)R g , —NR g S(O) 2 R g , —NHC(O)NHR g , —NR g C(O)NH 2 , —NR g C(O)NHR g , —NHC(O)NR g R g , —NHC(S)NR g R g , —NR g C(O)NR g R g , —NHS(O) 2 NHR g , —NR g S(O) 2 NH 2 , —NR g S(O) 2 NHR g , —NHS(O) 2 NR g R g , —NR g S(O) 2 NR g R g , —NHR g , —NR g R g or R g , wherein each R g is independently C 1-6 alkyl.

9. The compound of claim 1 , wherein R 1 is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-pyrazolyl or 3-pyrazolyl, each of which is optionally substituted with from 1-3 R 12 substituents independently selected from halogen, CN, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkylalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, heterocycloalkyl, heterocycloalkylalkyl, —NHR g , —N(R g ) 2 , —C(O)NH 2 , —C(O)NHR g , —C(O)NR g R g , —COOH, —COOR g , —SO 2 NH 2 , —SO 2 NHR g , —SO 2 NR g R g , —NHSO 2 R g , —NHC(O)R g or —OC(O)R g , wherein each R g is independently C 1-6 alkyl.

10. The compound of claim 9 , wherein R 12 is selected from halogen, CN, C 1-6 alkyl, C 1-6 alkoxy, —CF 3 , —CHF 2 , CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, —NHR g , —N(R g ) 2 , 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C(O)NH 2 , —C(O)NHCH 3 , —C(O)N(CH 3 ) 2 , —COOH, —COOCH 3 , —SO 2 NH 2 , —SO 2 NHCH 3 , —SO 2 N(CH 3 ) 2 , —NHSO 2 CH 3 , —NHC(O)CH 3 or —OC(O)CH 3 .

11. The compound of claim 8 , wherein one of R 10 or R 11 is C 1-4 alkyl, aryl-C 1-4 alkyl, heteroaryl-C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl or C 1-4 haloalkyl and the other R 10 or R 11 is aryl or heteroaryl, each of which is optionally substituted with from 1-3 R c or 1-3 R d substituents; or two adjacent R c substituents or R d substituents on an aromatic ring are taken together with the atoms to which they are attached form an optionally substituted 5- or 6-membered ring having from 0-2 heteroatoms selected from O, N or S.

12. The compound of claim 9 , wherein one of R 10 or R 11 is —CH 3 , —CH 2 CH 3 , —CF 3 , or cyclopropyl, and the

Assignees

• Plexxikon Inc

Inventors

• Lin Jack
• Pham Phuongly
• Buell John
• Spevak Wayne

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K31/5377

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

• A61P35/00

  Antineoplastic agents · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title