Compounds and methods for kinase modulation, and indications therefor

Patent metadata

Field	Value
Publication number	US-9938273-B2
Application number	US-201615370631-A
Country	US
Kind code	B2
Filing date	Dec 6, 2016
Priority date	Dec 7, 2015
Publication date	Apr 10, 2018
Grant date	Apr 10, 2018

Abstract

Disclosed are compounds of Formula I:

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof, wherein Z 2 , Z 3 , and Z 5 are as described herein, compositions thereof, and uses thereof.

First claim

What is claimed is:

1. A compound having Formula I:

or a pharmaceutically acceptable salt or a solvate thereof, wherein:
Z 2 is alkynyl optionally substituted with R b , aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, or heteroaryl, wherein each aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, or heteroaryl is optionally substituted with 1-3 R 1 groups;
Z 3 is hydrogen or halo;
Z 5 is -Cy-L;
Cy is heterocycloalkylene, arylene, or heteroarylene, wherein Cy is optionally substituted with 1-2 R a groups;
L is:
—C(O)NR 3 R 4 , wherein:
R 3 is hydrogen or C 1-6 alkyl optionally substituted with 1-3 G groups, and
R 4 is alkoxy, hydroxyalkylene, cyano, cyanoalkylene, or aminocarbonylalkyl, wherein R 4 is optionally substituted with 1-3 G groups;
or R 3 and R 4 , together with the N atom to which they are attached, join to form a heterocycloalkyl or heteroaryl moiety, wherein 1-2 carbon atoms of the heterocycloalkyl or heteroaryl moiety is substituted with 1-2 G groups; or

—C 1-3 alkyl-heterocycloalkyl, —C(O)-heterocycloalkyl, —N(H)-heterocycloalkyl, —C(O)-cycloalkyl, or —O-heterocycloalkyl, each of which is optionally substituted with 1-3 G groups; or
—C(O)—N(H)—O—R 5 or —NH—C(O)—R c , wherein:
R 5 is hydrogen, C 1-6 alkyl, or cycloalkyl; and
R c is C 1-6 alkyl, cycloalkyl, or heterocycloalkyl; or

—SO 2 —NR 6 R 7 , —N(H)C(O)NR 6 R 7 , or —N(H)—SO 2 —NR 6 R 7 , wherein:
R 6 is hydrogen, C 1-6 alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkylamino, or cycloalkyl, wherein each of the C 1-6 alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkylamino, and cycloalkyl are optionally substituted with 1-3 G groups,
R 7 is hydrogen or C 1-6 alkyl optionally substituted with 1-3 G groups;
or R 6 and R 7 , together with the N atom to which they are attached, join to form a heterocycloalkyl or heteoraryl moiety, wherein 1-2 carbon atoms of the heterocycloalkyl or heteroaryl moiety is substituted with 1-2 G groups; or

heterocycloalkyl substituted with 1-3 G groups;

R 1 is hydrogen, C 1-6 alkyl, cycloalkyl, —C(O)-cycloalkyl, —C(O)alkyl, cyano, cyanoalkyl, cyanocycloalkyl, cyanocycloalkylalkyl, hydroxy, alkoxy, alkoxyalkyl, hydroxyalkyl, halo, haloalkyl, oxo, aryl, arylalkyl, cycloalkylsulfonyl, alkylsulfonyl, alkylsulfonylalkyl, alkylcarbonylaminoalkyl, alkylsulfonylaminoalkyl, heterocycloalkyl optionally substituted with 1-2 R a , heterocycloalkylalkyl, —NR 6 R 7 , —C 1-6 alkylene-NR 6 R 7 , —C(O)O-alkyl, heterocycloalkyl optionally substituted with 1-2 R d groups, or heteroaryl optionally substituted with 1-2 R e groups;
each G is independently C 1-6 alkyl, C 1-6 haloalkyl, halo, amino, alkylamino, dialkylamino, alkylaminoalkyl, —(C 1-6 alkylene)-amino, —CN, —C(O)—C 1-6 alkyl, —C(O)—O—C 1-6 alkyl, —CO 2 H, —C(O)—N(H)—C 1-6 alkyl, oxo, —N(H)—C(O)—C 1-6 alkyl, —C(═NH)—NH 2 , —OH, —N(H)—C(O)—O— C 1-6 alkyl, —N(H)—C(O)—N(H)—C 1-6 alkyl, —N(H)—S(O) 2 —C 1-6 alkyl, —S(O) 2 —C 1-6 alkyl, hydroxyalkyl, cycloalkyl, cycloalkylamino, alkoxy, heterocycloalkyl, or heteroaryl,
each R a is independently alkyl, oxo, halo, or hydroxy;
R b is halo, C 3-6 cycloalkyl, aryl, heteroaryl, —NR 6 R 7 , or hydroxy;
each R d is independently C 1-6 alkyl, halo, oxo, alkylaminosulfonyl, alkylsulfonyl, alkylcarbonyl, hydroxyalkyl, or hydroxy; and
each R e is independently C 1-6 alkyl, halo, or hydroxy;
provided that when G is cycloalkyl, Z 2 is alkynyl optionally substituted with C 3 -C 6 cycloalkyl, —NR 6 R 7 , or hydroxy;
and further provided that the compound is not

2. The compound according to claim 1 , wherein:
Z 2 is ethynyl optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, aryl, —C 1 -C 6 alkylene-NR 6 R 7 , or hydroxyalkyl; or
Z 2 is phenyl, cyclohexyl, cyclohexenyl, pyrazolyl, pyrimidinyl, thiazolyl, pyridyl, pyridazinyl, pyrrolyl, dihydropyrrolyl, dihydropyranyl, dihydropyradinyl, tetrahydropyridyl, dihydrothiopyranyl, dihydrothiopyranyl oxide, or dihydrothiopyranyl dioxide, wherein each Z 2 is optionally substituted with 1-2 R 1 groups;
Z 3 is hydrogen or halo;
Cy is phenyl, 1H-indazolyl, pyridyl, quinolinyl, isoindolinyl, or thiophenyl, wherein Cy is optionally substituted with 1-2 R a groups;
L is
—C(O)NR 3 R 4 , wherein:
R 3 is hydrogen or C 1-6 alkyl;
R 4 is cyano or cyano-C 1-6 alkylene optionally substituted with 1-3 G groups;
or R 3 and R 4 , together with the N atom to which they are attached, join to form a 4-6 membered heterocycloalkyl moiety substituted with 1-2 G groups; or

—C(O)—N(H)—O—R 5 , wherein
R 5 is hydrogen or C 1-6 alkyl; or

—SO 2 —NR 6 R 7 , —N(H)C(O)NR 6 R 7 , and —N(H)—SO 2 —NR 6 R 7 , wherein:
R 6 is hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl;
R 7 is hydrogen or C 1-6 alkyl;
or R 6 and R 7 , together with the N atom to which they are attached, join to form a heterocycloalkyl moiety substituted with 1-2 G groups;

heterocycloalkyl substituted with 1-2 G groups, C 1-3 alkyl-heterocycloalkyl, —C(O)-heterocycloalkyl, —N(H)-heterocycloalkyl, or —O-heterocycloalkyl;

R 1 is hydrogen, cycloalkyl, —C(O)-cycloalkyl, C 1-6 alkyl, cyano, hydroxy, alkoxy, halo, haloalkyl, oxo, phenyl, heterocycloalkyl, heterocycloalkylalkyl, —C 1-6 alkylene-NR 6 R 7 , —C(O)O— alkyl, or heteroaryl optionally substituted with 1-2 R e groups;
each G is independently C 1-6 alkyl, halo, amino, —NH—C 1-6 alkyl, —N(C 1-6 alkyl) 2 , —(C 1-6 alkylene)-N(H)—C 1-6 alkyl, —CN, —C(O)—C 1-6 alkyl, —C(O)—N(H)—C 1-6 alkyl, —N(H)—C(O)—C 1-6 alkyl, —C(═NH)—NH 2 , —N(H)—C(O)—O—C 1-6 alkyl, —N(H)—C(O)—N(H)—C 1-6 alkyl, —N(H)—S(O) 2 —C 1-6 alkyl, —S(O) 2 —C 1-6 alkyl, C 3-6 cycloalkyl, —N(H)—C 3-6 cycloalkyl, C 1 -C 6 alkoxy, 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl, provided that when G is C 3-6 cycloalkyl, Z 2 is alkynyl optionally substituted with C 3-6 cycloalkyl, —NR 6 R 7 , or hydroxy; and
each R a is independently oxo, halo or hydroxy.

3. The compound according to claim 1 , wherein L is —SO 2 —NR 6 R 7 , —C(O)NR 3 R 4 , —C(O)—N(H)—O—R 5 , —N(H)—SO 2 —NR 6 R 7 , or —N(H)C(O)NR 6 R 7 .

4. The compound according to claim 1 , wherein:
L is —C(O)NR 3 R 4 .

5. The compound according to claim 1 , wherein Z 5 is

6. The compound according to claim 1 , wherein Z 5 is:

7. The compound according to claim 1 , wherein Z 5 is:

8. The compound according to claim 1 , wherein Z 5 is:

wherein B is a bond, methylene, or ethylene.

9. The compound according to claim 1 , wherein Z 2 is:

wherein:
m is 0-2;
n is 0-3;
R 8 is hydrogen, C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 3-6 cycloalkyl, —C(O)C 3-6 cycloalkyl, aryl-C 1-6 alkyl, 5-6 membered heterocycloalkyl-C 1-6 alkyl, or C 1-6 haloalkyl; and
R 9 is C 1-6 alkyl,

Assignees

• Plexxikon Inc

Inventors

• Wu Guoxian
• Wu Jeffrey
• Chan Katrina
• Dong Ken
• Ewing Todd
• Ibrahim Prabha N
• Lin Jack
• Spevak Wayne
• Zhang Ying

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61P37/06

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

• A61P43/00

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

• A61P35/02

  specific for leukemia · CPC title