Compounds and methods for kinase modulation, and indications therefor

Patent metadata

Field	Value
Publication number	US-9676748-B2
Application number	US-201314137438-A
Country	US
Kind code	B2
Filing date	Dec 20, 2013
Priority date	Dec 21, 2012
Publication date	Jun 13, 2017
Grant date	Jun 13, 2017

Abstract

Compounds active on c-kit protein kinases or mutant c-kit protein kinases having any mutations are described, as well as 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.

First claim

What is claimed is:

1. A compound of Formula (IV):

or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer, or a deuterated analog thereof, wherein:
ring A is a 5 membered fused heteroaryl ring having from 1-3 heteroatoms as ring members selected from O, N or S;
each R 7 is independently selected from C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, —X 1 -aryl, heteroaryl-X 1 —, heteroaryl-C 1-4 alkylene-X 1 —, C 3-6 cycloalkyl-X 1 —, C 3-6 cycloalkyl-C 1-4 alkylene-X 1 —, C 3-6 cycloalkenyl-X 1 —, CH 2 ═CH—X 1 , C 3-6 cycloalkyl-C 2-4 alkenylene-X 1 —, C 3-6 cycloalkyl-C 2-4 alkynylene-X 1 —, heterocyclyl-X 1 —, heterocyclyl-C 1-4 alkylene-X 1 — or R 8 , wherein R 8 is 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 a , —SR a , —OC(O)R a , —OC(S)R a , —C(O)R a , —C(S)R a , —C(S)OR a , —S(O)R a , —S(O) 2 R a , —C(O)NHR a , —C(S)NHR a , —C(O)NR a R a , —C(S)NR a R a , —S(O) 2 NHR a , —S(O) 2 NR a R a , —C(NH)NHR a , —C(NH)NR a R a , —NHC(O)R a , —NHC(S)R a , —NR a C(O)R a , —NR a C(S)R a , —NHS(O) 2 R a , —NR a S(O) 2 R a , —NHC(O)NHR a , —NHC(S)NHR a , —NR a C(O)NH 2 , —NR a C(S)NH 2 , —NR a C(O)NHR a , —NR a C(S)NHR a , —NHC(O)NR a R a , —NHC(S)NR a R a , —NR a C(O)NR a R a , —NR a C(S)NR a R a , —NHS(O) 2 NHR a , —NR a S(O) 2 NH 2 , —NR a S(O) 2 NHR a , —NHS(O) 2 NR a R a , —NR a S(O) 2 NR a R a , —NHR a or —NR a R a , wherein each R a 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, wherein each R a is further optionally substituted with 1-3 R b substituents independently selected from C 1-6 alkyl, C 1-6 alkoxy, halogen, C 1-6 haloalkyl or C 1-6 haloalkoxy; wherein X 1 is a bond or —C(O)— and
wherein R 7 is optionally substituted with from 1-5 R 9 members selected from halogen, —CH═CH 2 , —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 , —P(═O)HR c , —P(═O)R c R c , —PH(═O)OR c , —P(═O)(OR c ) 2 , —OP(═O)(OR c ) 2 , —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 ; or two adjacent R 9 substituents, 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 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, wherein each R c is further optionally substituted with from 1-3 R d groups independently selected from —CN, —OH, —N(R e )(R e ), —NO 2 , —C(O)OH, —C(O)NH 2 , —S(O) 2 NH 2 , —NHC(O)NH 2 , —C(NH)NH 2 , —OC(O)R e , —OC(S)R e , —C(O)R e , —C(S)R e , —C(O)OR 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 , —S(O) 2 R e , —C(O)NHR e , C 1-6 alkyl, C 1-6 alkoxy, halogen, C 1-6 haloalkyl or C 1-6 haloalkoxy, wherein each R e is independently C 1-6 alkyl;
or two adjacent R 7 substituents together with the atoms to which they are attached form a 4-, 5- or 6-membered carbocyclic ring or heterocyclic ring having from 1-2 heteroatoms as ring members selected from O, N or S;
Y 2 is C—R 10 , wherein R 10 is H, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, aryl-C 1-4 alkyl-, heteroaryl-C 1-4 alkyl-, C 3-6 cycloalkyl-C 1-4 alkyl-, C 3-6 cycloalkenyl-C 1-4 alkyl-, CH 2 ═CH—X 2 —, C 3-6 cycloalkyl-C 2-4 alkenylene-X 2 —, C 3-6 cycloalkyl-C 2-4 alkynylene-X 2 —, heterocyclyl-C 1-4 alkyl- or R 8 , each of which is optionally substituted with from 1-5 R 9 groups; wherein X 2 is C 1-4 alkylene, —O—, —S— or —NH—;
R 3 and R 4 are each independently selected from H, halogen, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, cyclopropyl, phenyl, —CN, CN—CH 2 —, C 1-6 alkoxy, or R g ; or R 3 and R 4 are taken together with the atoms to which they are attached form an optionally substituted 4 to 8-membered ring having from 0-2 heteroatoms as ring members selected from O, N or S;
wherein R g is —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 h , —SR h , —OC(O)R h , —OC(S)R h , —C(O)R h , —C(S)R h , —C(O)OR h , —C(S)OR h , —S(O)R h , —S(O) 2 R h , —C(O)NHR h , —C(S)NHR h , —C(O)NR h R h , —C(S)NR h R h , —S(O) 2 NHR h , —S(O) 2 NR h R h , —C(NH)NHR h , —C(NH)NR h R h , —NHC(O)R h , —NHC(S)R h , —NR h C(O)R h , —NR h C(S)R h , —NHS(O) 2 R h , —NR h S(O) 2 R h , —NHC(O)NHR h , —NHC(S)NHR h , —NR h C(O)NH 2 , —NR h C(S)NH 2 , —NR h C(O)NHR h , —NR h C(S)NHR h , —NHC(O)NR h R h , —NHC(S)NR h R h , —NR h C(O)NR h R h , —NR h C(S)NR h R h , —NHS(O) 2 NHR h , —NR h S(O) 2 NH 2 , —NR h S(O) 2 NHR h , —NHS(O) 2 NR h R h , —NR h S(O) 2 NR h R h , —NHR h or —NR h R h , wherein each R h is independently H or C 1-2 alkyl;
R 5 is H or C 1-4 alkyl;
Y 1 is N or C;
Y 3 is CH; and
the subscript m is 0, 1 or 2.

2. The compound of claim 1 , having Formulas (IVa), (IVb), (IVc), or (IVd):

3. The compound of claim 1 , having Formula (IVa-2):

4. The compound of claim 3 , wherein R 10 is H.

5. The compound of claim 3 , wherein R 3 and R 4 are each independently H, halogen, C 1-6 alkyl, C 1-6 alkoxy, cyclopropyl, —CN, C 1-4 haloalkyl or C 1-4 haloalkoxy; or R 3 and R 4 are taken together with the atoms to which they are attached form an optionally substituted fused 4 to 8-membered ring having from 0-2 heteroatoms selected from N or S.

6. The compound of claim 3 , wherein R 3 and R 4 are each independently selected from H, Br, Cl, methyl, ethyl, cyclopropyl, —CN, CF 3 , CHF 2 , CH 2 F, —OCH 3 , —OCF 3 , —OCHF 2 or OCH 2 F, CNCH 2 —, NH 2 C(O)—, CH 3 NHCO— or CH 3 C(O)NH—; or R 3 and R 4 are taken together with the atoms to which they are attached form a fused ring selected from benzene, pyridine, pyrimidine, pyrazine, pyridazine, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cyclooctane or cyclooctatriene, each of which is optionally substituted.

7. The compound of claim 3 , wherein R 7 is selected from halogen, —CN, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, heterocyclyl or heterocyclyl-C 1-4 alkyl, —C(O)—R a , —C(O)NHR a , —C(O)NR a R a , —NHC(O)R a , —NHC(O)NHR a , —NHC(O)NR a R a , —NR a R a , —NHR a , —OC(O)R a , —SO 2 R a , —NHSO 2 R a , —NHSO 2 NHR a , —NHSO 2 NR a R a , —SO 2 NHR a or —SO 2 NR a R a , wherein at each occurrence R 7 is optionally substituted w

Assignees

• Plexxikon Inc

Inventors

• Wu Guoxian
• Chan Katrina
• Ewing Todd
• Ibrahim Prabha N
• Lin Jack
• Nespi Marika
• Spevak Wayne
• Zhang Ying

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

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

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07F9/65616

  containing the ring system [IMAGE cpc-sch-C07F-1006.gif] having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs · CPC title