Compounds that inhibit MPS1 kinase

Patent metadata

Field	Value
Publication number	US-10479788-B2
Application number	US-201815864499-A
Country	US
Kind code	B2
Filing date	Jan 8, 2018
Priority date	Sep 7, 2012
Publication date	Nov 19, 2019
Grant date	Nov 19, 2019

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 method of treating a proliferative disorder in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound according to formula Ic, or a pharmaceutically acceptable salt or solvate thereof:

wherein:
R 1 is selected from chloro, (1-6C)alkyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl, 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 and 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 CH 3 (where q is 0, 1 or 2), methylamino or 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 selected from H and (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;
(ii) one of A 1 , A 2 and A 3 is N and the others are CH; or
(iii) two of A 1 , A 2 and A 3 are N and the other is CH;
R 5 is selected from hydrogen, cyano, (1-3C)alkyl, (1-3C)fluoroalkyl, (1-3C)alkoxy, (1-3C)fluoroalkoxy, halo, (1-3C)alkanoyl, C(O)NR 15 R 16 or S(O) 2 NR 15 R 16 , and wherein R 15 and R 16 are each independently selected from H and (1-3C)alkyl,
and wherein any alkyl or alkoxy moities present within a R 5 substituent group are optionally further substituted by hydroxy or methoxy;
R 6 is selected from halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, ureido, (1-6C)alkyl, (2-6C)alkenyl, and (2-6C)alkynyl,
or R 6 is a group of the formula:
-L 1 -L 2 -R 17
wherein
L 1 is absent or a linker group of the formula —[CR 18 R 19 ] n — in which n is an integer selected from 1, 2, 3 and 4, and R 18 and R 19 are each independently selected from hydrogen and (1-2C)alkyl;
L 2 is absent or is selected from 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 ), and N(R 21 )SO 2 , wherein R 20 and R 21 are each independently selected from hydrogen and (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, or 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, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-3C)alkyl, (1-5C)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 selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl and (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 selected from hydrogen, (1-3C)alkyl, (3-6C)cycloalkyl, and (3-6C)cycloalkyl(1-2C)alkyl);
or R 17 is a group having the formula:
-L 3 -L 4 -R 24

wherein L 3 is absent or a linker group of the formula —[CR 25 R 26 ] n — in which n is an integer selected from 1, 2, 3 and 4, and R 25 and R 26 are each independently selected from hydrogen and (1-2C)alkyl;
L 4 is absent or is selected from O, S, SO, SO 2 , N(R 27 ), C(O), C(O)O, OC(O), CH(OR 27 ), C(O)N(R 27 ), N(R 27 )C(O), N(R 27 )C(O)N(R 28 ), S(O) 2 N(R 27 ), and N(R 28 )SO 2 , wherein R 27 and R 28 are each independently selected from hydrogen and (1-2C)alkyl; and
R 24 is (1-6C)alkyl, aryl, aryl-(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-4C)alkyl, heteroaryl, heteroaryl-(1-4C)alkyl, heterocyclyl, or heterocyclyl-(1-4C)alkyl;

R 8 and R 9 are each independently selected from 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, and 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 selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, and (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; and

wherein the proliferative disorder is a cancer selected from lung, colon, breast, ovarian, prostate, liver, pancreas, brain or skin cancer.

2. The method according to claim 1 , wherein R 1 is selected from (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, 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 , and 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 selected from H and (1-4C)alkyl.

3. The method according to claim 1

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

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · 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

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title