Therapeutically Active Pyrazolo-Pyrimidine Derivatives

Patent metadata

Field	Value
Publication number	US-2016194329-A1
Application number	US-201314650771-A
Country	US
Kind code	A1
Filing date	Dec 20, 2013
Priority date	Dec 20, 2012
Publication date	Jul 7, 2016
Grant date	—

Abstract

A series of pyrazolo[3,4-d]pyrimidine derivatives that are substituted at the 4-position by a diaza monocyclic, bridged bicyclic or spirocyclic moiety, 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

1 . A compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof:

wherein
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 —, —CH 2 CH 2 CH 2 —, —CH 2 OCH 2 —, —CH 2 SCH 2 —, —CH 2 S(O)CH 2 —, —CH 2 S(O) 2 CH 2 — or —CH 2 N(R 4 )CH 2 —;

W represents the residue of a C 3-7 cycloalkyl or C 3-7 heterocycloalkyl group;
Y represents a covalent bond, or a linker group selected from —C(O)—, —S(O)—, —S(O) 2 —, —C(O)O—, —C(O)N(R 4 )—, —C(O)C(O)— and —S(O) 2 N(R 4 )—, or a linker group of formula (Ya):

in which the asterisk (*) represents the point of attachment to the remainder of the molecule;
Z represents hydrogen; or Z represents C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(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;
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 and R 2 independently represent hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, —OR a , —SR a , —SOR a , —SO 2 Ra, —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; or R 3 represents C 1-6 alkyl, optionally substituted by one or more halogen atoms;
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 . A compound as claimed in claim 1 wherein R 1 represents —NR b R c , in which R b and R c are as defined in claim 1 .

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

wherein
R 12 represents hydrogen, trifluoromethyl or C 1-6 alkyl; and
R 13 represents hydrogen or C 1-6 alkyl.

4 . A compound as claimed in any 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.

5 . A 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, trifluoromethyl, —CH 2 CF 3 , —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;
R 12 represents hydrogen, trifluoromethyl or C 1-6 alkyl; and
R 13 represents hydrogen or C 1-6 alkyl.

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

wherein
R 12 represents hydrogen, trifluoromethyl or C 1-6 alkyl;
R 3 represents hydrogen or C 1-6 alkyl; and
A 11 represents hydrogen, cyano, C 1-6 alkyl, trifluoromethyl, —CH 2 CF 3 , —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.

7 . A compound as claimed in claim 5 wherein A 11 represents methyl, ethyl, hydroxymethyl or hydroxyethyl.

8 . A compound as claimed in claim 1 wherein Z represents C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, aryl or heteroaryl, any of which groups is optionally substituted by one, two or three substituents independently selected from halogen, cyano, C 1-6 alkyl, trifluoromethyl, (C 3-7 )heterocycloalkyl, dihalo(C 3-7 )-heterocycloalkyl, hydroxy, oxo, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, C 1-6 alkylsulfonyl, C 1-6 alkylamino and di(C 1-6 )alkylamino.

9 . A compound as claimed in claim 8 wherein Z represents (methoxy)(methyl)-phenyl, (methyl)(trifluoromethoxy)phenyl, (methoxy)(methyl)pyridinyl, (ethyl)-(methoxy)pyridinyl, (ethoxy)(methyl)pyridinyl or dimethoxypyridinyl.

10 . A compound as claimed in claim 3 wherein R 12 represents hydrogen or methyl.

11 . A compound as claimed in claim 3 wherein R 13 represents hydrogen or methyl.

12 . A compound of formula (I) as claimed in claim 1 which is
6-Amino-4-{4-[(4-methoxy-2-methlphenyl)carbamyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine;
6-Amino-4-{4-[(4-methoxyphenyl)carbamyl]piperazin-1-yl}-1H-pyrazolo[3,4-d]-pyrimdine;
6-Amino-4-{4-[(4-methoxy-2-methylphenyl)carbamyl]-2-(S)-methylpiperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine;
6-Amino-4-{4-[(4-methoxyphenyl)carbamyl]-2-(S)-methylpiperazin-1-yl}-1H-pyrazolo[3,4-d]pyrimidine;
6-Amino-4-{4-[(4-methoxy-2-methylphenyl)carbamyl]-2-(S)-methylpiperazin-1-yl}-1-methylpyrazolo[3,4-d]pyrimidine;
6-Amino-4-{4-[(4-methoxyphenyl)carbamyl]-2-(S)-methylpiperazin-1-yl}-1-methylpyrazolo[3,4-d]pyrimidine;
6-Amino-4-[4-(indan-5-ylcarbamyl)-2-(S)-methylpiperazin-1-yl]-1-methylpyrazolo[3,4-d]pyrimidine;
6-Amino-4-(4-{[4-(dimethylamino)phenyl]carbam

Assignees

• Ucb Pharma Sa
• Univ Leuven Kath

Inventors

• Ford Daniel James
• Franklin Richard Jeremy
• Ghawalkar Anant Ramrao
• Horsley Helen Tracey
• Huang Qiuya
• 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

• A61P37/02

  Immunomodulators · CPC title

• A61P29/00

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

• A61P31/12

  Antivirals · CPC title