Therapeutically active oxazoline derivatives

Patent metadata

Field	Value
Publication number	US-9382263-B2
Application number	US-201314432842-A
Country	US
Kind code	B2
Filing date	Oct 2, 2013
Priority date	Oct 3, 2012
Publication date	Jul 5, 2016
Grant date	Jul 5, 2016

Abstract

Compounds of formula (I) i.e. monocyclic or bicyclic diamine-substituted thieno[2,3-d]pyrimidine and isothiazolo[5,4-d]pyrimidine derivatives substituted by an optionally substituted oxazolin-2-yl moiety, are beneficial in the treatment and/or prevention of various human ailments, including inflammatory, autoimmune and oncological disorders; viral diseases; and organ and cell transplant rejection.

First claim

The invention claimed is:

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) or (Qb):

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 —;
X represents C—R 6 or N;
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 7 )— and —S(O) 2 N(R 7 )—;
Z represents hydrogen; or Z represents 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;
A represents hydrogen or trifluoromethyl; or A represents C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, —OR a , —S(O)R a and —NR b R c ;
R 1 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 R 1 represents 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;
R 2 represents hydrogen or C 1-6 alkyl; and
R 3 represents hydrogen; or R 3 represents C 1-6 alkyl, C 1-6 alkoxy, 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 2 and R 3 , when taken together with the carbon atom to which they are both attached, represent C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents;
R 4 represents hydrogen or C 1-6 alkyl; and
R 5 represents hydrogen; or R 5 represents C 1-6 alkyl, C 1-6 alkoxy, 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 4 and R 5 , when taken together with the carbon atom to which they are both attached, represent C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents;
R 6 and R 7 independently represent hydrogen; or 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 the compound of formula (I) is a compound of formula (IA), or a pharmaceutically acceptable salt or solvate thereof:

3. The compound as claimed in claim 1 , wherein R 1 represents hydrogen or —NR b R c .

4. The compound as claimed in claim 1 , wherein
R 2 represents hydrogen or C 1-6 alkyl; and
R 3 represents hydrogen or C 1-6 alkyl; or
R 2 and R 3 , when taken together with the carbon atom to which they are both attached, represent C 3-7 cycloalkyl or C 3-7 heterocycloalkyl.

5. The compound as claimed in claim 1 , wherein
R 4 represents hydrogen or C 1-6 alkyl; and
R 5 represents hydrogen or C 1-6 alkyl; or
R 4 and R 5 , when taken together with the carbon atom to which they are both attached, represent C 3-7 cycloalkyl or C 3-7 heterocycloalkyl.

6. The compound as claimed in claim 1 , wherein the compound of formula (I) is a compound of formula (IIA), or a pharmaceutically acceptable salt or solvate thereof:

wherein
R 12 and R 13 independently represent hydrogen or C 1-6 alkyl.

7. The compound as claimed in claim 1 , wherein the compound of formula (I) is a compound of formula (IIB), or a pharmaceutically acceptable salt or solvate thereof:

wherein
R 14 and R 15 independently represent hydrogen or C 1-6 alkyl.

8. The compound as claimed in claim 1 , wherein the compound of formula (I) is a compound of formula (IIC), or a pharmaceutically acceptable salt or solvate thereof:

9. The compound as claimed in claim 1 , wherein Y represents —C(O)N(R 7 ).

10. The compound as claimed in claim 1 , wherein Z represents aryl, C 3-7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or two substituents independently selected from halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, difluoromethoxy, C 2-6 alkylcarbonyl and C 2-6 alkoxy-carbonyl.

11. The compound as claimed in claim 1 , wherein A represents hydrogen; or A represents C 1-6 alkyl, optionally substituted by —OR a .

12. A pharmaceutical composition comprising a compound according to claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable carrier.

13. A method for treating organ or cell transplant rejection, which comprises administering to a patient in need of such treatment an effective amount of a compound according to claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof.

14. The compound according to claim 1 that is
4-[2-Amino-5-(4,4-dimethyl-5H-oxazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]piperazine-1-carboxylic acid (4-methoxy-2-methylphenyl)amide;
4-[2-A

Assignees

• Ucb Biopharma Sprl
• Univ Leuven Kath

Inventors

• Kulisa Claire Louise
• Brookings Daniel Christopher
• Ford Daniel James
• Franklin Richard Jeremy
• Reuberson James Thomas
• Ghawalkar Anant Ramrao

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• 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

• C07D495/04 Primary

  Ortho-condensed systems · CPC title