Aminoheteroaryl benzamides as kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9242996-B2
Application number	US-201414527328-A
Country	US
Kind code	B2
Filing date	Oct 29, 2014
Priority date	Nov 1, 2013
Publication date	Jan 26, 2016
Grant date	Jan 26, 2016

Abstract

The present invention provides a compound of Formula (I) or a salt thereof;

and therapeutic uses of these compounds. The present invention further provides pharmaceutical compositions comprising these compounds, and compositions comprising these compounds with a therapeutic co-agent.

First claim

The invention claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is an optionally substituted group selected from C 3-8 cycloalkyl, 5-8 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S as ring members, phenyl, —SO 2 -phenyl, —C(O)-phenyl, —C(R 8 ) 2 -phenyl, and 5-6 membered heteroaryl ring, wherein said heterocyclyl and heteroaryl contain 1-2 heteroatoms selected from N, O and S as ring members,
and wherein the optional substituents for R 1 are 1-3 groups independently selected from D, halo, hydroxy, amino, —N(R 8 ) 2 , CN, C 1-4 alkyl, C 1-4 alkoxy, —S(C 1-4 alkyl), C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S, oxo (except on aromatic rings), CN, COOR 9 , CON(R 8 ) 2 , —NR 8 —C(O)R 8 , —NR 8 —C(O)OR 8 —SO 2 R 8 , —NR 8 SO 2 R 8 , and SO 2 N(R 8 ) 2 , where each R 8 is independently H or C 1-4 alkyl;
L is a bond, or L is selected from C 1-4 alkylene, C 2-4 alkenylene, C 1-4 alkynylene, C 3-6 cycloalkyl or a 4-7 membered heterocycloyl containing 1-2 heteroatoms selected from N, 0 and S as ring members, wherein L is optionally substituted with 1-3 groups independently selected from R 11 , D, OH, NH 2 , —NHR 11 , —NHC(═O)R 11 , —NHC(═O)—OR 11 , —NHC(═O)—NH 2 , —NHC(═O)—NHR 11 , —N(R 11 ) 2 , CN, halo, N 3 , CON(R 7 ) 2 , and COOR 7 ; where each R 11 is independently C 1-4 alkyl, which may be substituted with up to three groups independently selected from D, halo, OH, NH 2 , —NHMe, —NMe 2 , —OP(O)(OH) 2 and O—C 1-4 alkyl;
X and Y are independently selected from H, D, halo, CN, amino, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;
R 2 is H, C 1-4 alkyl, or aryl-C 1-2 -alkyl-, wherein the aryl and C 1-4 alkyl are optionally substituted with halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, or C 1-4 alkylsulfonyl;
or R 2 can cyclize with X to form a 5-7 membered heterocyclic ring containing 1-2 heteroatoms selected from N, O and S fused to the phenyl ring to which X is attached,
or R 2 can cyclize with L to form a 5-7 membered heterocyclic ring containing 1-2 heteroatoms selected from N, O and S,
wherein the optional heterocyclic ring formed by R 2 cyclizing with X, or by R 2 cyclizing with L, can be optionally substituted with one or two groups independently selected from CN, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, oxo, CN, COOR 7 , CON(R 7 ) 2 , and —SO 2 R 7 ;

each R 7 is independently H or C 1-4 alkyl;
Z is N or CR 4 ;
R 4 is H, D, halo, C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 alkoxy;
R 5 is selected from —C(O)—R 5a and R 5a ; wherein R 5a is an optionally substituted C 3-8 cycloalkyl, C 3-8 cycloalkenyl, saturated or unsaturated 3-8 membered heterocyclic ring containing 1-2 heteroatoms selected from N, O and S, phenyl, or 5-6 membered heteroaryl ring containing 1-3 heteroatoms selected from N, O and S, wherein the optional substituents for R 5 are 1-4 groups independently selected from D, halo, hydroxy, amino, CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S, oxo (except on aromatic rings), CN, —COOR 9 , —C(O)R 9 , CON(R 9 ) 2 , —NR 9 C(O)R 9 , —NR 9 CO 2 R 9 , —SO 2 R 9 , —NR 9 SO 2 R 9 , and —SO 2 N(R 9 ) 2 , where each R 9 is independently H or C 1-4 alkyl optionally substituted with 1-3 groups independently selected from D, halo, OH, NH 2 , NHMe and NMe 2 ; and two substituents on the same or adjacent carbon atoms of R 5 can optionally be taken together to form a 5-6 membered ring that can be saturated or aromatic and contains 1-2 heteroatoms selected from N, O and S and can optionally be substituted with 1-2 groups independently selected from D, Me, halo, OH, oxo, O(C 1-4 alkyl), NH 2 , C 1-4 alkylamino, di(C 1-4 alkyl)amino; and
R 6 is H, D, halo, C 1-4 alkyl, or C 1-4 haloalkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Z is N or CH;
R 2 is H or Me;
R 5 is selected from —C(O)—R 5a and R 5a ; wherein R 5a is selected from C 3-8 cycloalkyl, 5-8 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S, phenyl, and 5-6 membered heteroaryl, and is optionally substituted with 1-3 groups independently selected from D, halo, CN, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, —SO 2 R′, —N(R′) 2 , —NR′—C(O)—R′, and —SO 2 NR′ 2 , where each R′ is independently H or C 1-4 alkyl; and
R 6 is H.

3. The compound of claim 2 , wherein R 5 is selected from —C(O)—R 5a and R 5a ; wherein R 5a is selected from phenyl, pyridine, pyridone, pyrazine, pyridazine, pyrazole, triazole, tetrazole, thiazole, oxazole, imidazole, isothiazole, isoxazole, furan, and thiophene, each of which is optionally substituted with one or two groups independently selected from halo, D, CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, CN, COOR 9 , CON(R 9 ) 2 , and —SO 2 R 9 , where each R 9 is independently H or C 1-4 alkyl.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from —C(O)—R 5a and R 5a ; wherein R 5a is pyrazole or triazole and is optionally substituted with 1-2 groups independently selected from halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy.

5. The compound of claim 2 , wherein R 5 is selected from —C(O)—R 5a and R 5a ; wherein R 5a is selected from cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, tetrahydropyran, dihydropyran, tetrahydrofuran, oxetane, azetidine, pyrrolidine, piperidine, piperazine, morpholine, tetrahydrothiopyran (thiacyclohexane), and tetrahydrothiofuran (thiacyclopentane), each of which is optionally substituted with 1-3 groups independently selected from halo, D, CN, N(R 9 ) 2 , hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, oxo, CN, COOR 9 , CON(R 9 ) 2 , —NHC(O)R 9 , —NHCOOR 9 , —NHSO 2 R 9 , and —SO 2 R 9 , where each R 9 is independently H or C 1-4 alkyl.

6. The compound of claim 2 , wherein R 1 is phenyl and is optionally substituted with one to three groups independently selected from halo, D, CN, C 1-4 alkoxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, SR′, —SO 2 R′, —N(R′) 2 , —NR′—C(O)—R′, and —SO 2 NR′ 2 , where each R′ is independently H, C 1-4 alkyl or C 1-4 haloalkyl.

7. The compound of claim 2 , wherein R 1 is thiophene, thiazole, pyridine, pyrimidine, pyrazine or pyridazine, and is optionally substituted with up to three groups independently selected from halo, CN, C 1-4 alkoxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, —SO 2 R′, —N(R′) 2 , —NR′—C(O)—R′, and —SO 2 NR′ 2 , where each R′ is independently H or C 1-4 alkyl.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of: cyclopropane-1,1-diyl; cyclopropane-1,2-diyl; and —CHR″—, wherein R″ is H, D, or C 1-2 alkyl optionally substituted with up to three groups independently selected from D, hydroxy, halo, amino, C 1-2 alkylamino, di(C 1-2 alkyl)amino, and C 1-2 alkoxy.

9. The compound of claim 8 , wherein L is

wherein R″ is methyl or ethyl, and is optionally substituted with fluoro, amino, hydroxy,

Assignees

• Bagdanoff Jeffrey T
• Ding Yu
• Han Wooseok
• Huang Zilin
• Jiang Qun
• Jin Jeff Xianming
• Kou Xiang
• Lee Patrick
• Lindvall Mika
• Min Zhongcheng
• Pan Yue
• Pecchi Sabina
• Pfister Keith Bruce
• Poon Daniel
• Rauniyar Vivek
• Wang Xiaojing Michael
• Zhang Qiong
• Zhou Jianguang
• Zhu Shejin
• Novartis Ag

Inventors

• Bagdanoff Jeffrey T
• Ding Yu
• Han Wooseok
• Huang Zilin
• Jiang Qun
• Jin Jeff Xianming
• Kou Xiang
• Lee Patrick
• Lindvall Mika
• Min Zhongcheng
• Pan Yue
• Pecchi Sabina
• Pfister Keith Bruce
• Poon Daniel
• Rauniyar Vivek
• Wang Xiaojing Michael
• Zhang Qiong
• Zhou Jianguang
• Zhu Shejin

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title