Fused bicyclic heteroaromatic derivatives as kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9969748-B2
Application number	US-201515318422-A
Country	US
Kind code	B2
Filing date	Jun 11, 2015
Priority date	Jun 17, 2014
Publication date	May 15, 2018
Grant date	May 15, 2018

Abstract

A series of fused bicyclic heteroaromatic derivatives of formula (IA) or (IB), as defined herein, 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 of formula ((IB) or a pharmaceutically acceptable salt or solvate thereof:

wherein
X represents N;
T represents N;
U represents oxygen or N—R 4 ;
Q represents a group of formula (Qa), (Qb), (Qc), (Qd) or (Qe):

in which the asterisk (*) represents the point of attachment to the remainder of the molecule;
V represents —CH 2 —, —C(CH 3 ) 2 —, —CH 2 CH 2 — or —CH 2 CH 2 CH 2 —;
W represents the residue of a C 3-7 cycloalkyl group;
Y represents —C(O)—, —C(O)N(R 5 )—, OR —C(O)C(O)—;
Z represents aryl or heteroaryl, either of which groups is optionally substituted by one, two, or three substituents independently selected from halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, cyano-
(C 1-6 )alkyl, (C 3-7 )heterocycloalkyl, halo(C 3-7 )heterocycloalkyl, (C 1-6 )alkyl(C 3-7 )heterocycloalkyl, (C 2-6 )alkoxycarbonyl(C 3-7 )heterocycloalkyl, dihalo(C 3-7 )heterocycloalkyl, (C 3-7 )heterocycloalkyl(C 1-6 )alkyl, (C 1-6 )alkyl(C 3-7 )heterocycloalkyl(C 1-6 )alkyl, heteroaryl, hydroxy, oxo, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy (C 3-7 )heterocycloalkoxy, (C 2-6 )alkoxycarbonyl(C 3-7 )heterocycloalkoxy, (C 3-7 )heterocycloalkyl(C 1-6 )alkoxy, aryloxy, haloaryloxy, (C 1-6 )alkoxyaryloxy, C 1-3 alkylenedioxy, dihalo(C 1-3 )alkylenedioxy, arylcarbonyloxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkyl sulfonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, di(C 1-6 )alkylamino(C 1-6 )alkyl, arylamino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, C 1-6 alkylsulfonylamino, formyl, C 2-6 alkylcarbonyl, C 3-6 cycloalkylcarbonyl, C 3-6 heterocycloalkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl and di(C 1-6 )alkylaminosulfonyl;
A 1 represents hydrogen, cyano or trifluoromethyl; or A 1 represents C 1-6 alkyl, optionally substituted by one or more substituents independently selected from fluoro, —OR a , trifluoromethoxy, —NR b R c , —CO 2 R d and —CONR b R c ; or A 1 represents C 3-7 cycloalkyl;
A 2 represents hydrogen or C 1-6 alkyl;
R 1 represents —NR b R c ;
R 3 represents hydrogen, halogen or C 1-6 alkyl;
R 4 represents hydrogen; or R 4 represents C 1-6 alkyl, aryl, aryl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents;
R 5 represents hydrogen; or R 5 represents C 1-6 alkyl, optionally substituted by one or more substituents independently selected from —OR a and —NR b R c ;
R a represents hydrogen; or R a represents C 1-6 alkyl, aryl, aryl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents;
R b and R c independently represent hydrogen or trifluoromethyl; or C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents; or
R b and R c , when taken together with the nitrogen atom to which they are both attached, represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents; and
R d represents hydrogen; or C 1-6 alkyl, C 3-7 cycloalkyl, aryl, C 3-7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.

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 (IIB-1), or a pharmaceutically acceptable salt or solvate thereof:

wherein
A 11 represents hydrogen, cyano, C 1-6 alkyl, —CH 2 OR a , —CH 2 CH 2 OR a , —CH 2 CO 2 R d , —CH 2 CONR b R c or C 3-7 cycloalkyl; and
R 11 represents amino.

4. The compound as claimed in claim 1 represented by formula (IIB-2), or a pharmaceutically acceptable salt or solvate thereof:

A 11 represents hydrogen, cyano, C 1-6 alkyl, —CH 2 OR a , —CH 2 CH 2 OR a , —CH 2 CO 2 R d , —CH 2 CONR b R c or C 3-7 cycloalkyl; and
R 11 represents amino.

5. The compound as claimed in claim 3 wherein A 11 represents hydrogen or C 1-6 alkyl.

6. The compound as claimed in claim 5 wherein A 11 represents hydrogen, methyl or ethyl.

7. The compound as claimed in claim 1 wherein Z represents aryl or heteroaryl, either of which groups may be optionally substituted by one, two or three substituents independently selected from C 1-6 alkyl, trifluoromethyl, (C 3-7 )heterocycloalkyl, dihalo(C 3-7 )heterocycloalkyl, C 1-6 alkoxy, trifluoromethoxy and di(C 1-6 )alkylamino.

8. The compound as claimed in claim 7 wherein Z represents methoxyphenyl, dimethylaminophenyl, (methoxy)(methyl)phenyl, (isopropoxy)(methyl)phenyl, (methyl)(trifluoromethoxy)phenyl, (azetidinyl)(methyl)pyridinyl, (difluoroazetidinyl)-(methyl)pyridinyl, (methoxy)(trifluoromethyl)pyridinyl, dimethoxypyridinyl, (ethoxy)-(methyl)pyridinyl or (dimethylamino)(methyl)pyridinyl.

9. The compound as claimed in claim 1 wherein R 3 represents hydrogen or methyl.

10. The compound of formula ((IB) as defined in claim 1 which is
(3S)-4-(5-Amino-3-methyl[1,2]oxazolo[4,5-d]pyrimidin-7-yl)-N-(6-ethoxy-2-methylpyridin-3-yl)-3-ethylpiperazine-1-carboxamide,
(3S)-4-(5-Amino-3-methyl[1,2]oxazolo[4,5-d]pyrimidin-7-yl)-3-ethyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]piperazine-1-carboxamide,
(3S)-4-(5-Amino-3-methyl[1,2]oxazolo[4,5-d]pyrimidin-7-yl)-N-(2,6-dimethoxypyridin-3-yl)-3-ethylpiperazine-1-carboxamide,
(3S)-4-(5-Amino-1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-N-[6-(3,3-difluoroazetidin-1-yl)-2-methylpyridin-3-yl]-3-methylpiperazine-1-carboxamide,
(3S)-4-(5-Amino-1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-N-(4-methoxy-2-methylphenyl)-3-methylpiperazine-1-carboxamide,
(3S)-4-(5-Amino-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-N-[6-(3,3-difluoroazetidin-1-yl)-2-methylpyridin-3-yl]-3-methylpiperazine-1-carboxamide,
(3S)-4-(5-Amino-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-N-(4-methoxy-2-methylphenyl)-3-methylpiperazine-1-carboxamide,
(3S)-4-(2-Amino-5-methylpyrrolo[3,2-d]pyrimidin-4-yl)-3-methyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]piperazine-1-carboxamide,
(3S)-4-(5-Amino-3-methylisoxazolo[4,5-d]pyrimidin-7-yl)-3-ethyl-N-(4-methoxy-2-methylphenyl)piperazine-1-carboxamide,
(3S)-4-(5-Amino-3-methylisoxazolo[4,5-d]pyrimidin-7-yl)-3-ethyl-N-(4-methoxy-3-methylphenyl)piperazine-1-carboxamide,
(3S)-4-(5-Amino-3-methylisoxazolo[4,5-d]pyrimidin-7-yl)-N-[6-(dimethylamino)-2-meth

Assignees

• Ucb Biopharma Sprl
• Univ Leuven Kath

Inventors

• Ford Daniel James
• Huang Qiuya
• Neuss Judi Charlotte
• Reuberson James Thomas
• Vanderhoydonck Bart

Classifications

• 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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/02

  Immunomodulators · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title