Pyrazolo-pyridine derivatives as kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10087180-B2
Application number	US-201515318473-A
Country	US
Kind code	B2
Filing date	Jun 11, 2015
Priority date	Jun 17, 2014
Publication date	Oct 2, 2018
Grant date	Oct 2, 2018

Abstract

A series of pyrazolo[3,4-b]pyridine derivatives that are substituted at the 4-position by a diaza monocyclic, bridged bicyclic or spirocyclic moiety, being selective inhibitors of phosphatidylinositol-4-kinase IIIβ (PI4KIIIβ) activity, are beneficial in the treatment and/or prevention of various human ailments, including inflammatory, autoimmune and oncological disorders; viral diseases and malaria; and organ and cell transplant rejection.

First claim

The invention claimed is:

1. A compound represented by formula (IA), or a pharmaceutically acceptable salt or solvate thereof:

wherein
R 11 represents hydrogen or amino;
R 12 represents hydrogen, trifluoromethyl or C 1-6 alkyl;
R 13 represents hydrogen or C 1-6 alkyl,
Q represents a group of formula (Qa),

in which the asterisk (*) represents the point of attachment to the remainder of the molecule;
Y represents a linker group selected from —C(O)—, —C(O)N(R 4 )— and —C(O)C(O)—;
Z represents phenyl, imidazo[1,2-a]pyridinyl, pyridinyl or pyrazinyl, any of which groups is optionally substituted by one, two or three substituents independently selected from halogen, cyano, C 1-6 alkyl, trifluoromethyl, dihalo(C 3-7 )-heterocycloalkyl, C 1-6 alkoxy, difluoromethoxy, trifluoro-methoxy and di(C 1-6 )alkylamino;
A 1 represents C 1-6 alkyl, optionally substituted by —OR a ;
A 2 represents hydrogen or C 1-6 alkyl;
R 4 represents hydrogen or C 1-6 alkyl; and
R a represents hydrogen or C 1-6 alkyl.

2. The compound as claimed in claim 1 wherein Q represents a group of formula (Qa-1), (Qa-2) or (Qa-3):

in which the asterisk (*) represents the point of attachment to the remainder of the molecule.

3. The compound as claimed in claim 1 represented by formula (IIA), or a pharmaceutically acceptable salt or solvate thereof:

wherein
A 11 represents C 1-6 alkyl or —CH 2 CH 2 OR a ;
R 11 represents hydrogen or amino;
R 12 represents hydrogen, trifluoromethyl or C 1-6 alkyl; and
R 13 represents hydrogen or C 1-6 alkyl.

4. The compound as claimed in claim 1 represented by formula (IIB), or a pharmaceutically acceptable salt or solvate thereof:

R 11 represents hydrogen or amino;
R 12 represents hydrogen or amino;
R 13 represents hydrogen or C 1-6 alkyl; and
A 11 represents C 1-6 alkyl or —CH 2 CH 2 OR a .

5. The compound as claimed in claim 3 wherein A 11 represents methyl, ethyl or 2-hydroxyethyl.

6. The compound as claimed in claim 1 wherein Z represents (methoxy)(methyl)-phenyl, (isopropoxy)(methyl)phenyl, (difluoromethoxy)(methyl)phenyl, (methyl)-(trifluoromethoxy)phenyl, imidazo[1,2-a]pyridinyl, (difluoroazetidinyl)(methyl)pyridinyl, (chloro)(methoxy)pyridinyl, (bromo)(methoxy)pyridinyl, (cyano)(methoxy)pyridinyl, (methoxy)(methyl)pyridinyl, (methoxy)(trifluoromethyl)pyridinyl, dimethoxypyridinyl, (ethoxy)(methyl)pyridinyl, (isopropoxy)(methyl)pyridinyl, (difluoromethoxy)(methyl)-pyridinyl, (dimethylamino)(methyl)pyridinyl or (dimethylamino)(methyl)pyrazinyl.

7. The compound as claimed in claim 1 wherein R 12 represents hydrogen or methyl.

8. The compound as claimed in claim 1 wherein R 13 represents hydrogen or methyl.

9. The compound of formula (I), wherein the compound is
(3S)-4-(6-Amino-1-methylpyrazolo[3,4-b]pyridin-4-yl)-N-(4-methoxy-2-methylphenyl)-3-methylpiperazine-1-carboxamide,
(3S)-4-(6-Amino-1-methylpyrazolo[3,4-b]pyridin-4-yl)-N-(6-methoxy-2-methylpyridin-3-yl)-3-methylpiperazine-1-carboxamide,
(3S)-4-(6-Amino-1-methylpyrazolo[3,4-b]pyridin-4-yl)-N-[6-(3,3-difluoroazetidin-1-yl)-2-methylpyridin-3-yl]-3-methylpiperazine-1-carboxamide,
(3S)—N-(6-Methoxy-2-methylpyridin-3-yl)-3-methyl-4-(1-methylpyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxamide,
(3S)—N-[6-(3,3-Difluoroazetidin-1-yl)-2-methylpyridin-3-yl]-3-methyl-4-(1-methylpyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxamide,
(3S)—N-[6-(Difluoromethoxy)-2-methylpyridin-3-yl]-3-methyl-4-(1-methylpyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxamide,
(3S)-4-(6-Amino-1-methylpyrazolo[3,4-b]pyridin-4-yl)-N-[6-(difluoromethoxy)-2-methylpyridin-3-yl]-3-methylpiperazine-1-carboxamide,
(3S)-4-(6-Amino-1-methylpyrazolo[3,4-b]pyridin-4-yl)-N-(imidazo[1,2-a]pyridin-8-yl)-3-methylpiperazine-1-carboxamide,
(3S)-3-Ethyl-N-(6-methoxy-2-methylpyridin-3-yl)-4-(1-methylpyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxamide,
(3S)-3-(2-Hydroxyethyl)-N-(6-methoxy-2-methylpyridin-3-yl)-4-(1-methylpyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxamide,
(3S)—N-[4-(Difluoromethoxy)-2-methylphenyl]-3-ethyl-4-(1-methylpyrazolo[3,4-b]-pyridin-4-yl)piperazine-1-carboxamide,
(3S)—N-[4-(Difluoromethoxy)-2-methylphenyl]-3-(2-hydroxyethyl)-4-(1-methylpyrazolo-[3,4-b]pyridin-4-yl)piperazine-1-carboxamide,
(3S)-4-(6-Amino-1-methylpyrazolo[3,4-b]pyridin-4-yl)-3-ethyl-N-(6-methoxy-2-methyl-pyridin-3-yl)piperazine-1-carboxamide,
(3S)-4-(6-Amino-1-methylpyrazolo[3,4-b]pyridin-4-yl)-N-[4-(difluoromethoxy)-2-methylphenyl]-3-ethylpiperazine-1-carboxamide,
(3S)-4-(6-Amino-1-methylpyrazolo[3,4-b]pyridin-4-yl)-3-ethyl-N-(6-methoxy-5-methyl-pyridin-3-yl)piperazine-1-carboxamide,
(3S)—N-(6-Methoxy-5-methylpyridin-3-yl)-3-methyl-4-(1-methylpyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxamide,
(3S)—N-(6-Ethoxy-2-methylpyridin-3-yl)-3-methyl-4-(1-methylpyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxamide,
(3S)—N-(6-Ethoxy-2-methylpyridin-3-yl)-3-ethyl-4-(1-methylpyrazolo[3,4-b]pyridin-4-yl)-piperazine-1-carboxamide,
(3S)-3-Methyl-4-(1-methylpyrazolo[3,4-b]pyridin-4-yl)-N-[2-methyl-4-(trifluoro-methoxy)phenyl]piperazine-1-carboxamide,
(3S)-3-Ethyl-4-(1-methylpyrazolo[3,4-b]pyridin-4-yl)-N-[2-methyl-4-(trifluoromethoxy)-phenyl]piperazine-1-carboxamide,
(3S)—N-(6-Isopropoxy-2-methylpyridin-3-yl)-3-methyl-4-(1-methylpyrazolo[3,4-b]-pyridin-4-yl)piperazine-1-carboxamide,
(3S)-3-Ethyl-N-(6-isopropoxy-2-methylpyridin-3-yl)-4-(1-methylpyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxamide,
(3S)-4-(6-Amino-1-methylpyrazolo[3,4-b]pyridin-4-yl)-N-(4-methoxy-3-methylphenyl)-3-methylpiperazine-1-carboxamide,
(3S)-4-(6-Amino-1-methylpyrazolo[3,4-b]pyridin-4-yl)-N-[5-methoxy-6-(trifluoromethyl)pyridin-2-yl]-3-methylpiperazine-1-carboxamide,
(3S)-4-(6-Amino-1-methylpyrazolo[3,4-b]pyridin-4-yl)-3-methyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]piperazine-1-carboxamide,
(3S)-4-(6-Amino-1-methylpyrazolo[3,4-b]pyridin-4-yl)-N-[6-(dimethylamino)-2-methyl-pyridin-3-yl]-3-methylpiperazine-1-carboxamide,
(3S)-4-(6-Amino-1-methylpyrazolo[3,4-b]pyridin-4-yl)-3-ethyl-N-[5-methoxy-6-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide,
(3S)-4-(6-Amino-1-methylpyrazolo[3,4-b]pyridin-4-yl)-3-ethyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]piperazine-1-carboxamide,
(3S)-4-(6-Amino-1-methylpyrazolo[3,4-b]pyridin-4-yl)-3-ethyl-N-(4-methoxy-2-methyl-phenyl)piperazine-1-carboxamide,
(3S)-4-(6-Amino-1-methylpyrazolo[3,4-b]pyridin-4-yl)-N-[6-(dimethylamino)-2-methyl-pyridin-3-yl]-3-ethylpiperazine-1-carboxamide,
(3S)-3-Ethyl-N-(4-isopropoxy-2-methylphenyl)-4-(1-methylpyrazolo[3,4-b]pyridin-4-yl)-piperazine-1-carboxamide,
(3S)-3-Ethyl-N-[5-methoxy-6-(trifluoromethyl)pyridin-2-yl]-4-(1-methylpyrazolo[3,4-b]-pyridin-4-yl)piperazine-1-carboxamide,
(3S)-3-Ethyl-N-(4-methoxy-3-methylphenyl)-4-(1-methylpyrazolo[3,4-b]pyridin-4-yl)-piperazine-1-carboxamide,
(3S)-3-Ethyl-N-(4-methoxy-2-methylphenyl)-4-(1-methylpyrazolo[3,4-b]pyridin-4-yl)-piperazine-1-carboxamide,
(3S)—N-[5-(Dimethylamino)-3-methylpyrazin-2-yl]-3-ethyl-4-(1-methylpyrazolo[3,4-b]-pyridin-4-yl)piperazine-1-carboxamide,
(3S)—N-(2,6-Dim

Assignees

• Ucb Biopharma Sprl
• Univ Leuven Kath

Inventors

• Ford Daniel James
• Reuberson James Thomas

Classifications

• A61P37/06

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P33/06

  Antimalarials · CPC title

• A61P31/12

  Antivirals · CPC title