Compounds and methods for kinase modulation, and indications therefor

Patent metadata

Field	Value
Publication number	US-10160755-B2
Application number	US-201615093660-A
Country	US
Kind code	B2
Filing date	Apr 7, 2016
Priority date	Apr 8, 2015
Publication date	Dec 25, 2018
Grant date	Dec 25, 2018

Abstract

Compounds of Formula I:

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof, wherein R 1 , R 2 , Q 1 , Q 2 , and Q 3 , are described in this disclosure, compositions thereof, and methods and uses thereof.

First claim

What is claimed is:

1. A compound of Formula I(b) or I(c):

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof, wherein:
R 1 is

R 2 is:

each R 4 is independently H, C 1 -C 3 alkoxy, C 1 -C 4 alkyl, halo, hydroxy, cyano, cyclopropyl, 5-6 membered heterocycloalkyl, C(O)(R 7 ), pyrrolidinylsulfonyl, amino, dimethylamino, isopropylsulfonamide, n-propyl sulfonamide, ethylsulfonamide, methylsulfonamide, N-methylmethanesulfonamide, cyclopropylsulfonamide, cyclopropylcarbonyl, —N(H)—C(O)-methyl, cyclopropylaminocarbonyl, carboxyl-(C 1 -C 4 )alkyl, oxenatyl, or 3-methyloxenatyl, wherein each alkyl, alkoxy, cyclopropyl, or heterocycloalkyl moiety of R 4 is optionally substituted with 1-3 groups independently selected from C 1 -C 4 alkyl, methoxy, fluoro and chloro;
each R 7 is independently H, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocycloalkyl, alkyl, alkoxy, hydroxyalkyl, amino, hydroxy, arylalkyl, heteroarylalkyl, or alkylsulfonyl;
and
L is absent, ethynylene, —O-alkylene-, —N(H)—C(O)—, —C(O)—N(H)—, or —N(H)—S(O) 2 —.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof, wherein R 2 is:

wherein:
each R 4 is independently cyano, C 1 -C 2 alkyl optionally substituted with 1-3 fluoro or chloro, fluoro, chloro, C 1 -C 2 alkoxy optionally substituted with 1-3 fluoro or chloro, isopropylsulfonamide, n-propyl sulfonamide, ethyl sulfonamide, methylsulfonamide, N-methylmethanesulfonamide, pyrrolidinyl, 1,2-thiazinanyl 1,1-dioxide, 1,3-thiazinanyl 1,1-dioxide, isothiazolidinyl 1,1-dioxide, isothiazolidinyl, morpholinyl, oxetanyl, or 3-methyloxetanyl.

3. The compound according to claim 1 , a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof, wherein:
R 1 is:

R 2 is:

and
each R 4 is independently cyano, fluoro, chloro, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy, or trifluoroethoxy.

4. The compound according to claim 1 , having Formula II(b) or II(c):

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof, wherein:
R 1 is:

and
each R 4 is independently cyano, methyl, trifluoromethyl, fluoro, chloro, methoxy, trifluoromethoxy, isopropylsulfonamide, n-propyl sulfonamide, ethylsulfonamide, methylsulfonamide, N-methylmethanesulfonamide, pyrrolidinyl, 1,2-thiazinanyl 1,1-dioxide, 1,3-thiazinanyl 1,1-dioxide, isothiazolidinyl 1,1-dioxide, isothiazolidinyl, morpholinyl, oxetanyl, or 3-methyloxetanyl.

5. The compound according to claim 1 , having Formula II(b)(i) or II(c):

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.

6. The compound according to claim 1 , having formula II(e) or II(h):

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.

7. The compound according to claim 1 , or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof, wherein R 2 is phenyl substituted with 1-2 R 4 .

8. The compound according to claim 1 , a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof, wherein R 2 is

wherein each R 4 is independently selected from fluoro, chloro, methyl, trifluoromethyl, methoxy, and trifluoromethoxy.

9. The compound according to claim 1 , a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof, wherein L is absent.

10. The compound according to claim 1 , or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof, wherein each R 4 is independently fluoro, chloro, cyano, methyl, methoxy, trifluoromethyl, or trifluoromethoxy.

11. The compound according to claim 1 , a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof, wherein each R 4 is independently methylsulfonamide, ethylsulfonamide, n-propylsulfonamide, isopropylsulfonamide, or cyclopropylsulfonamide.

12. The compound according to claim 1 , or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof, wherein each R 4 is independently morpholinyl, isothiazolidinyl 1,1-dioxide, or 1,2-thiazinanyl 1,1-dioxide.

13. A compound selected from:
3-(1H-benzimidazol-5-yl)-5-methoxy-1H-pyrrolo[2,3-b]pyridine;
3-(1H-benzimidazol-5-yl)-1H-pyrrolo[2,3-b]pyridine;
3-(1H-benzimidazol-5-yl)-5-(cyclopropylmethoxy)-1H-pyrrolo[2,3-b]pyridine;
3-(1H-benzimidazol-5-yl)-5-[(3-methyloxetan-3-yl)methoxy]-1H-pyrrolo[2,3-b]pyridine;
1-methyl-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)benzimidazole;
5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-benzimidazol-2-amine;
N-[3-[7-(1H-benzimidazol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]phenyl]methanesulfonamide;
2-methyl-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-benzimidazole;
N-[3-[3-(1H-benzimidazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]methanesulfonamide;
5-methoxy-3-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrrolo[2,3-b]pyridine;
5-methoxy-3-(3-methylbenzimidazol-5-yl)-1H-pyrrolo[2,3-b]pyridine;
[4-[3-(1H-benzimidazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-3,6-dihydro-2H-pyridin-1-yl]-cyclopropyl-methanone;
1-methyl-6-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzimidazole;
5-chloro-3-(3-methylbenzimidazol-5-yl)-1H-pyrrolo[2,3-b]pyridine;
3-(3-methylbenzimidazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile;
3-(3H-benzimidazol-5-yl)-5-methyl-1H-pyrrolo[2,3-b]pyridine;
3-(3H-benzimidazol-5-yl)-5-fluoro-1H-pyrrolo[2,3-b]pyridine;
3-(3H-benzimidazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile;
3-(1H-benzimidazol-5-yl)-5-(6-methoxy-3-pyridyl)-1H-pyrrolo[2,3-b]pyridine;
6-methyl-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-benzimidazole;
5-methoxy-3-(6-methyl-1H-benzimidazol-5-yl)-1H-pyrrolo[2,3-b]pyridine;
3-(1H-benzimidazol-5-yl)-5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine;
5-fluoro-3-(3-methylbenzimidazol-5-yl)-1H-pyrrolo[2,3-b]pyridine;
3-(1H-benzimidazol-5-yl)-5-(1-cyclopropylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)-1H-pyrrolo[2,3-b]p

Assignees

• Plexxikon Inc

Inventors

• Lin Jack
• Pham Phuongly
• Buell John
• Dong Ken
• Ibrahim Prabha
• Spevak Wayne
• Tsang Garson
• Wu Guoxian
• Zhang Ying

Classifications

• A61K31/538

  ortho- or peri-condensed with carbocyclic ring systems · CPC title

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/5377

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

• C07D471/04 Primary

  Ortho-condensed systems · CPC title