Inhibitor compounds

Patent metadata

Field	Value
Publication number	US-9890157-B2
Application number	US-201615091887-A
Country	US
Kind code	B2
Filing date	Apr 6, 2016
Priority date	Sep 7, 2012
Publication date	Feb 13, 2018
Grant date	Feb 13, 2018

Abstract

The present invention relates to compounds of formula I

wherein R 1 , R 4 , Ar, W, X and Z are all as defined herein. The compounds of the present invention are known to inhibit the spindle checkpoint function of Monospindle 1 (Mps1—also known as TTK) kinases either directly or indirectly via interaction with the Mps1 kinase itself. In particular, the present invention relates to the use of these compounds as therapeutic agents for the treatment and/or prevention of proliferative diseases, such as cancer. The present invention also relates to processes for the preparation of these compounds, and to pharmaceutical compositions comprising them.

First claim

The invention claimed is:

1. A compound of formula Ic shown below:

wherein:
R 1 is chloro, (1-6C)alkyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, NR 7 R 8, OR 9, C(O)R 9, C(O)OR 9, OC(O)R 9, N(R 10 )OR 9, N(R 10 )C(O)OR 9, C(O)N(R 10 )R 9, N(R 10 )C(O)R 9, S(O) p R 9 (where p is 0, 1 or 2), SO 2 N(R 10 )R 9, N(R 10 )SO 2 R 9, N(R 10 )SOR 9 or SON(R 10 )R 9 ;
and wherein R 1 is optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, (1-4C)alkoxy, S(O) q CH3 (where q is 0, 1 or 2), methylamino, dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, and (3-8C)cycloalkyl(1-2C)alkyl,
and wherein any (1-4C)alkyl, (1-4C)alkoxy, aryl, heteroaryl, heterocyclyl, or (3-8C)cycloalkyl moiety present within a substituent group on R 1 is optionally further substituted by fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, NR a R b , OR a , C(O)R a , C(O)OR a , OC(O)R a , N(R b )OR a , C(O)N(R b )R a , N(R b )C(O)R a , S(O) p R a (where p is 0, 1 or 2), SO 2 N(R b )R a , or N(R b )SO 2 R a , wherein R a and R b are each independently H or (1-4C)alkyl;

R 3 is hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, halo, CF 3 , CN or (1-4C)alkoxy;
R 4 is hydrogen, (1-3C)alkyl, (1-3C)alkoxy, fluoro, chloro or CF 3 ;
Ar has the formula:

wherein:
(i) all of A 1 , A 2 and A 3 are CH; or
(ii) one of A 1 , A 2 and A 3 is N and the others are CH;
R 5 is hydrogen, cyano, (1-3C)alkyl, (1-3C)fluoroalkyl, (1-3C)alkoxy, (1-3C)fluoroalkoxy, or halo,
and wherein any alkyl or alkoxy moieties present within a R 5 substituent group are optionally further substituted by hydroxy or methoxy;
R 6 is halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, ureido, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, or a group of the formula:
-L 1 -L 2 -R 17
wherein
L 1 is absent;
L 2 is absent or is O, S, SO, SO 2, N(R 20 ), C(O), C(O)O, OC(O), CH(OR 20 ), C(O)N(R 20 ), N(R 20 )C(O), N(R 20 )C(O)N(R 21 ), S(O) 2 N(R 20 ), or N(R 21 )SO 2 , wherein R 20 and R 21 are each independently hydrogen or (1-2C)alkyl; and
R 17 is (1-6C)alkyl, aryl, aryl-(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-4C)alkyl, heteroaryl, heteroaryl-(1-4C)alkyl, heterocyclyl, heterocyclyl-(1-4C)alkyl,
and wherein R 17 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, hydroxy, NR 22 R 23 , (1-4C)alkoxy, (1-4C)alkyl, (3-8 C)cycloalkyl, (3-8C)cycloalkyl-(1-3 C)alkyl, (1-5 C)alkanoyl, (1-5C)alkylsulphonyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, CONR 22 R 23 , and SO 2 NR 22 R 23 ; wherein R 22 and R 23 are each independently hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl;
and wherein when said substituent group comprises an alkyl, cycloalkyl, heterocyclyl or heteroaryl moiety then said moiety is optionally further substituted by hydroxy, fluoro, chloro, cyano, CF 3 , OCF 3 , (1-2C)alkyl, (1-2C)alkoxy, SO 2 (1-2C)alkyl or NR e R f (where R e and R f are each independently hydrogen, (1-3C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl);

R 8 and R 9 are each independently hydrogen, (1-6C)alkyl, (1-6C)alkoxy, (3-9C)cycloalkyl, (3-9C)cycloalkyl-(1-2C)alkyl, aryl, aryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, heteroaryl, or heteroaryl-(1-2C)alkyl, and wherein R 8 and R 9 are optionally further substituted by one or more substituents selected from hydroxy, fluoro, chloro, cyano, CF 3 , OCF 3 (1-2C)alkyl and (1-2C)alkoxy;
R 7 and R 10 are independently hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl-(1-2C)alkyl, and wherein R 7 and R 10 are optionally further substituted by one or more substituents selected from hydroxy, fluoro, chloro, cyano, CF 3 , OCF 3 , (1-2C)alkyl and (1-2C)alkoxy;
subject to the proviso that:
R 6 is not methoxy when R 1 is S(O) 2 R 9 and R 9 is heterocyclyl;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein R 1 is (1-6C)alkyl, phenyl, phenyl(1-2C)alkyl, 5 or 6 membered heteroaryl, 5 or 6 membered heteroaryl(1-2C)alkyl, 3 to 9 membered heterocyclyl(1-2C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, NR 7 R 8 , OR 9 , C(O)R 9 , C(O)OR 9 , OC(O)R 9 , N(R 10 )OR 9 , N(R 10 )C(O)OR 9 , C(O)N(R 10 )R 9 , N(R 10 )C(O)R 9 , S(O) p R 9 (where p is 0, 1 or 2), SO 2 N(R 10 )R 9 , or N(R 10 )SO 2 R 9 ;
and wherein R 1 is optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, carbamoyl, sulphamoyl, (1-4C)alkyl, (1-4C)alkoxy, S(O) q CH 3 (where q is 0, 1 or 2), methylamino, dimethylamino, 5 or 6 membered heteroaryl, 5 or 6 membered heteroaryl(1-2C)alkyl, 3 to 6 membered heterocyclyl, 3 to 6 membered heterocyclyl(1-2C)alkyl, (3-6C)cycloalkyl, and (3-6C)cycloalkyl(1-2C)alkyl,
and wherein any (1-4C)alkyl, (1-4C)alkoxy, heteroaryl, heterocyclyl, or (3-6C)cycloalkyl moiety present within a substituent group on R 1 is optionally further substituted by fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, NR a R b , OR a , C(O)R a , C(O)OR a , OC(O)R a , N(R b )OR a , C(O)N(R b )R a , N(R b )C(O)R a , S(O) p R a (where p is 0, 1 or 2), SO 2 N(R b )R a , or N(R b )SO 2 R a , wherein R a and R b are each independently H or (1-4C)alkyl.

3. A compound according to claim 2 , wherein R 1 is (1-6C)alkyl, phenyl, phenyl(1-2C)alkyl, 5 or 6 membered heteroaryl, 5 or 6 membered heteroaryl(1-2C)alkyl, 3 to 9 membered heterocyclyl(1-2C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, NR 7 R 8 , OR 9 , C(O)R 9 , C(O)OR 9 , OC(O)R 9 , N(R 10 )OR 9 , N(R 10 )C(O)OR 9 , C(O)N(R 10 )R 9 , N(R 10 )C(O)R 9 , S(O) p R 9 (where p is 0, 1 or 2), SO 2 N(R 10 )R 9 , or N(R 10 )SO 2 R 9 ;
and wherein R 1 is optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, carbamoyl, sulphamoyl, (1-4C)alkyl, (1-4C)alkoxy, S(O) q CH 3 (where q is 0, 1 or 2), methylamino or dimethylamino, 5 or 6 membered heteroaryl, and 4 to 6 membered heterocyclyl, and wherein any (1-4C)alkyl, (1-4C)alkoxy, heteroaryl, or heterocyclyl moiety present within a substituent group on R 1 is optionally further substituted by fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, carbamoyl, sulphamoyl, (1-4C)alkyl, NR a R b , OR a , C(O)R a , C(O)OR a , OC(O)R a , C(O)N(R b )R a , N(R b )C(O)R a , S(O) p R a (where p is 0, 1 or 2), SO 2 N(R b )R a , or N(R b )SO 2 R a , wherein R a and R b are each independently H or (1-4C)alkyl.

4. A compound according to claim 1 , wherein R 3 is hydrogen, (1-2C)alkyl, or (3-6C)cycloalkyl.

5. A compound according to claim 1 , wherein R 4 is hydrogen, (1-2C)alkyl, (1-2C)alkoxy, fluoro, chloro or CF 3 .

6. A compound according to claim 1 , wherein Ar has the formula:

wherein:
(i

Assignees

• Cancer Research Tech Ltd

Inventors

• Hoelder Swen
• Blagg Julian
• Solanki Savade
• Woodward Hannah
• Naud Sebastien
• Bavetsias Vassilios
• Sheldrake Peter
• Innocenti Paolo
• Cheung Kwai Ming J
• Atrash Butrus

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K31/4375 Primary

  the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title