Compounds and methods for kinase modulation, and indications therefor

Patent metadata

Field	Value
Publication number	US-10160747-B2
Application number	US-201715460095-A
Country	US
Kind code	B2
Filing date	Mar 15, 2017
Priority date	Mar 16, 2016
Publication date	Dec 25, 2018
Grant date	Dec 25, 2018

Abstract

Disclosed are compounds of Formula I(b):

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof, wherein Ring A, Ring HD, J, each T, R 3 , R 4 , R 5 , each R 7 , and m are as described in any of the embodiments described in this disclosure; compositions thereof; and uses thereof.

First claim

What is claimed is:

1. A compound having Formula II(a) or II(b):

or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer or a deuterated analog thereof, wherein:
Ring A is phenyl, pyridyl, pyrimidinyl, or pyridazinyl;
Y is N or CR 9 ; R 9 is hydrogen, halo, amino, alkyl optionally substituted with alkoxy or hydroxy, haloalkyl, or alkoxy;
(i) is a single bond, wherein:
Z 1 is CH or N, Z 2 is C(R 12 )(R 12a ) and Z 3 is C(R 13 )(R 13a ); or
Z 1 is CH, Z 2 is N(R 12 ) and Z 3 is C(R 13 )(R 13a ); or
Z 1 is CH, Z 2 is C(R 12 )(R 12a ) and Z 3 is N(R 13 );

or
(ii) is a double bond, wherein:
Z 1 is CH or N, Z 2 is C(R 12 ) and Z 3 is C(R 13 ); or
Z 1 is CH, Z 2 is N and Z 3 is C(R 13 ); or
Z 1 is CH, Z 2 is C(R 12 ) and Z 3 is N;

R 2 is

wherein:
Ring B is a 5 or 6-membered saturated or unsaturated ring having 0-3 heteroatoms selected from O, N, and S;
each Q is independently hydrogen, alkyl, halo, cyano, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, oxo, —R 20 OR 21 , —R 20 OR 21 , —R 20 OC(O)R 21 , —R 20 C(O)N(R 24 )(R 25 ), —R 20 S(O) t R 22 , —R 20 N(R 24 )(R 25 ), or —R 20 N(R 24 )(R 25 ), or —R 20 N(R 24 )C(O)R 21 , wherein each alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl is independently optionally substituted with 1 to 3 groups each independently halo, oxo, amino, alkyl, haloalkyl or —R 20 OR 21 ,
Q 1 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, —R 23 OR 21 , —R 23 OR 23 OR 21 , —R 23 C(O)R 21 , —R 23 N(R 24 )(R 25 ), —R 23 OC(O)R 21 , —R 23 C(O)OR 21 , —R 23 C(O)N(R 24 )(R 25 ), or —R 23 S(O) t R 22 , wherein each alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl is independently optionally substituted with 1 to 3 groups each independently halo, oxo, amino, alkyl, haloalkyl or —R 20 OR 21 ;
each Q 3 is independently hydrogen, cyano, —S —C 1 -C 2 alkyl, halo, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 3 alkoxy, cyclopropyl, amino, —N(H)(C 1 -C 3 alkyl), —N(H)C(O)C(H)=CH 2 or C 1 -C 3 alkyl, wherein each Q 3 is optionally substituted with 1-3 substituents each independently halo, hydroxy or methoxy;
Q 4 is hydrogen, cyclopropyl, C 1 -C 4 alkoxy, or C 1 -C 4 alkyl optionally substituted with 1-3 substituents each independently halo, hydroxy or methoxy;
each R 20 is independently alkylene, alkenylene, alkynylene or a direct bond;
each R 21 is independently hydrogen, alkyl, haloalkyl, alkenyl, alkynyl or cycloalkyl;
each R 22 is independently alkyl, haloalkyl, alkenyl, alkynyl or cycloalkyl;
each R 23 is independently alkylene, alkenylene or alkynylene;
R 24 and R 25 are each independently hydrogen or alkyl;
a is an integer from 0 to 3;
each t is independently 0, 1 or 2;

R 3 is hydrogen or C 1 -C 6 alkyl;
each R 6 is independently hydrogen, halo, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy;
each R 7 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl, C 3 -C 6 cycloalkylalkyl, —S(O) 2 alkyl, or a 4-6 membered heterocycloalkyl-C 1 -C 6 alkyl, wherein each R 7 is optionally substituted with 1 to 3 groups each independently hydroxy, halo, C 1 -C 6 alkyl, cyano or C 1 -C 6 haloalkyl;
R 9a is hydrogen, halo, hydroxy-C 1 -C 6 alkyl, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy-C 1 -C 6 alkyl;
each R 11 is independently a 5-6 membered heterocycloalkyl, cyano, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —C(O)OCH 3 , or —C(O)OH;
R 10 is C 1 -C 6 alkyl, hydroxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, 5-membered heteroaryl optionally substituted with alkyl, C 3 -C 6 cycloalkyl, —C(O)OCH 3 , or —C(O)OH;
R 12 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —(CH 2 ) 0-2 —N(R 1b ) 2 , halo, C 3 -C 6 cycloalkyl, —C(O)—C 3 -C 6 cycloalkyl, phenyl optionally substituted with 1-2 R 11 groups, 5-6 membered heteroaryl optionally substituted with 1-2 R 11 groups, or alkynyl optionally substituted with R 10 ;
R 13 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —C(O)—C 1 -C 4 alkyl, halo, cyano, —(CH 2 ) 0-2 —N(R 1b ) 2 , —C(O)NHCH 3 , amino, —NHC(O)CF 3 , C 3 -C 6 cycloalkyl, —C(O)—C 3 -C 6 cycloalkyl, phenyl optionally substituted with 1-2 R 11 groups, 5-6 membered heteroaryl optionally substituted with 1-2 R 11 groups, or alkynyl optionally substituted with R 10 ;
each R 1b is independently hydrogen or alkyl;
R 12a is hydrogen; or
R 12 and R 12a , together with the carbon to which they are attached, join to form a C 3-6 spirocycloalkyl; or
R 12 and R 12a form an oxo group;
R 13a is hydrogen; or
R 13 and R 13a , together with the carbon to which they are attached, join to form a C 3-6 spirocycloalkyl; or
R 13 and R 13a form an oxo group; and
m is 0, 1 or 2.

2. The compound of claim 1 , wherein:
R 3 is hydrogen;
each R 6 is independently chloro, fluoro, methoxy, or methyl;
each R 7 is independently C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, hydroxy-C 1 -C 4 alkyl, C 1 -C 3 alkoxy-C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl, C 3 -C 6 cycloalkylalkyl, or a 4-6 membered heterocycloalkyl-C 1 -C 6 alkyl; and
m is 1 or 2.

3. The compound of claim 1 having Formula III(a):

or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer or a deuterated analog thereof, wherein each R 6a is independently hydrogen or fluoro.

4. The compound of claim 1 having Formula III(b) or III(c):

or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer or a deuterated analog thereof, wherein each R 6a is independently hydrogen or fluoro.

5. The compound of claim 1 , wherein:
Ring A is pyridyl or phenyl; and
each R 6 is hydrogen or one R 6 is halo, alkyl or alkoxy.

6. The compound of claim 1 , wherein:

is:

wherein:
R 7a is C 1 -C 4 alkoxy, C 1 -C 4 alkyl optionally substituted with cyano, C 1 -C 4 haloalkyl, cyclopropyl, halo, morpholinyl or cyano; and
R 7b is C 1 -C 4 alkoxy, C 1 -C 4 alkyl optionally substituted with cyano, C 1 -C 4 haloalkyl, halo or cyano.

7. The compound of claim 1 , wherein:

wherein:
R 7a is cyclopropyl, —OCH 3 , —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCF 3 , —C(CH 3 ) 3 , —C(CN)(CH 3 ) 2 , F, Cl, Br, or cyano; and
R 7b is cyclopropyl, —OCH 3 , —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —C(CH 3 ) 3 , —C(CN)(CH 3 ) 2 , —OCF 3 , F, Cl, Br or cyano.

8. The compound of claim 1 , wherein:

is:

Assignees

• Plexxikon Inc

Inventors

• Lin Jack
• Ibrahim Prabha N
• Albers Aaron
• Buell John
• Guo Zuojun
• Pham Phuongly
• Powers Hannah
• Shi Songyuan
• Spevak Wayne
• Wu Guoxian
• Zhang Jiazhong
• Zhang Ying
• Wu Jeffrey

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P43/00

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

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P35/02

  specific for leukemia · CPC title