Fused bicyclic heteroaromatic derivatives as kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10000497-B2
Application number	US-201515318507-A
Country	US
Kind code	B2
Filing date	Jun 11, 2015
Priority date	Jun 17, 2014
Publication date	Jun 19, 2018
Grant date	Jun 19, 2018

Abstract

A series of fused bicyclic heteroaromatic derivatives of formula (I), 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 (I), or a pharmaceutically acceptable salt or solvate thereof:

wherein
X represents N;
T and U independently represent N or C—R 2 ;
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 4 )—, or —C(O)C(O)—;
Z represents aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents;
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 2 represents hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, —OR a , —SR a , —SOR a , —SO 2 R a , —NR b R c , —CH 2 NR b R c , —NR c COR d , —CH 2 NR c COR d , —NR c CO 2 R d , —NHCONR b R c , —NR c SO 2 R e , —N(SO 2 R e ) 2 , —NHSO 2 NR b R c , —COR d , —CO 2 R d , —CONR b R c , —CON(OR a )R b or —SO 2 NR b R c ; 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, C 3-7 heterocycloalkenyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents;
R 3 represents hydrogen, halogen or C 1-6 alkyl;
R 4 represents hydrogen; or R 4 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;
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; and
R e represents C 1-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.

2. The compound as claimed in claim 1 wherein T represents N and U represents C—R 2 .

3. 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.

4. The compound as claimed in claim 1 represented by formula (IIA), 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.

5. The compound as claimed in claim 1 represented by formula (IIB), 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 Ie or C 3-7 cycloalkyl; and
R 11 represents amino.

6. The compound as claimed in claim 4 wherein A 11 represents methyl or ethyl.

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

8. The compound as claimed in claim 7 wherein Z represents (methoxy)(methyl)-phenyl, (difluoromethoxy)(methyl)phenyl, (chloro)(trifluoromethoxy)phenyl, (methyl)-(trifluoromethoxy)phenyl, (azetidinyl)(methyl)pyridinyl, (difluoroazetidinyl)(methyl)-pyridinyl, (methoxy)(methyl)pyridinyl, (methoxy)(trifluoromethyl)pyridinyl, dimethoxy-pyridinyl or (ethoxy)(methyl)pyridinyl.

9. The compound as claimed in claim 1 wherein R 2 represents hydrogen or methyl.

10. The compound as claimed in claim 1 wherein R 3 represents hydrogen, chloro or methyl.

11. The compound of formula (I) as defined in claim 1 that is
(3S)-4-(2-Aminopyrazolo[1,5-a][1,3,5]triazin-4-yl)-N-(4-methoxy-2-methylphenyl)-3-methylpiperazine-1-carboxamide;
(3S)-4-(2-Aminopyrazolo[1,5-a][1,3,5]triazin-4-yl)-3-methyl-N-[2-methyl-4-(trifluoro-methoxy)phenyl]piperazine-1-carboxamide;
(3S)-4-(2-Aminopyrazolo[1,5-a][1,3,5]triazin-4-yl)-N-(6-ethoxy-2-methylpyridin-3-yl)-3-methylpiperazine-1-carboxamide;
(3S)-4-(2-Amino-8-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)-N-[6-(3,3-difluoroazetidin-1-yl)-2-methylpyridin-3-yl]-3-methylpiperazine-1-carboxamide;
(3S)-4-(2-Amino-8-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)-N-(4-methoxy-2-methyl-phenyl)-3-methylpiperazine-1-carboxamide;
(3S)-4-(2-Amino-8-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)-3-methyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]piperazine-1-carboxamide;
(3S)-4-(2-Amino-8-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)-N-(6-ethoxy-2-methyl-pyridin-3-yl)-3-methylpiperazine-1-carboxamide formate;
(3S)-4-(2-Amino-7-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl)-N-(4-methoxy-2-methyl-phenyl)-3-methylpiperazine-1-carboxamide;
(3S)-4-[2-Amino-7-(4-fluorophenyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]-N-(4-methoxy-2-methylphenyl)-3-methylpiperazine-1-carboxamide;
(3S)-4-[2-Amino-7-(4-fluorophenyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]-N-[6-(3,3-difluoroazetidin-1-yl)-2-methylpyridin-3-yl]-3-methylpiperazine-1-carboxamide;
(3S)-4-(2-Amino-8-chloropyrazolo[1,5-a][1,3,5]triazin-4-yl)-N-(4-methoxy-2-methyl-phenyl)-3-methylpiperazine-1-carboxamide;
(3S)-4-(2-Amino-8-chloropyrazolo[1,5-a][1,3,5]triazin-4-yl)-3-methyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]piperazine-1-carboxamide;
(3S)-4-(2-Amino-8-chloropyrazolo[1,5-a][1,3,5]triazin-4-yl)-N-(6-ethoxy-2-methyl-pyridin-3-yl)-3-methylpiperazine-1-carboxamide;
(3S)-4-(2-Amino-8-chloropyrazolo[1,5-a][1,3,5]triazin-4-yl)-N-(2,6-dimethoxypyridin-3-yl)-3-ethylpiperazine-1-carboxamide;
(3S)-4-(2-Amino-8-chloropyrazolo[1,5-a][1,3,5]triazin-4-yl)-3-ethyl-N-(4-methoxy-3-methylphenyl)piperazine-1-carboxamide;
(3S)-4-(2-Amino-8-chloropyrazolo[1,5-a][1,3,5]triazin-4-yl)-N-[2-chloro-4-(trifluoro-methoxy)phenyl]-3-ethylpiperazine-1-carbo

Assignees

• Ucb Biopharma Sprl
• Univ Leuven Kath

Inventors

• Horsley Helen Tracey
• Huang Qiuya
• Neuss Judi Charlotte
• Reuberson James Thomas
• Vanderhoydonck Bart

Classifications

• 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

• A61K31/53

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title

• A61K31/495

  having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53}) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title