Inhibitor compounds

Patent metadata

Field	Value
Publication number	US-11046688-B2
Application number	US-201916598717-A
Country	US
Kind code	B2
Filing date	Oct 10, 2019
Priority date	Sep 7, 2012
Publication date	Jun 29, 2021
Grant date	Jun 29, 2021

Abstract

The present invention relates to compounds of formula Iwherein R1, R4, 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 combination comprising a compound according to formula Ic, or a pharmaceutically acceptable salt or solvate thereof, and a taxane;
where formula Ic is:

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; or
(ii) one of A 1 , A 2 and A 3 is N and the others are CH;
R 5 is selected from hydrogen, cyano, (1-3C)alkyl, (1-3C)fluoroalkyl, (1-3C)alkoxy, (1-3C)fluoroalkoxy, and halo,
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:
wherein L 1 is absent;
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)alkyl sulphonyl, 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);
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; and
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.

2. The combination of 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 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(0) p R a (where p is 0, 1 or 2), SO 2 N(R b )R a , and 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 combination of claim 1 , wherein R 3 is hydrogen, (1-2C)alkyl, or (3-6C)cycloalkyl.

4. The combination of claim 1 , wherein R 4 is hydrogen, (1-2C)alkyl, (1-2C)alkoxy, fluoro, chloro or CF 3 .

5. The combination of claim 1 , wherein Ar has the formula:

wherein
all of A 1 , A 2 and A 3 are CH;
and R 5 and R 6 are each as defined in claim 1 .

6. The combination of claim 1 , wherein R 5 is (1-2C)alkyl, CF 3 , (1-2C)alkoxy, —OCF 3 , —OCF 2 H or Cl.

7. The combination of claim 1 , wherein 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 or 2, and R 18 and R 19 are both hydrogen;
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 ), or N(R 20 )SO 2 , wherein R 20 and R 21 are each independently selected from hydrogen or (1-2C)alkyl; and
R 17 is (1-6C)alkyl, aryl, (3-6C)cycloalkyl, 5 or 6 membered heteroaryl, or 3 to 8 membered heterocyclyl,
and wherein R 17 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, hydroxy, NR 22 R 23 , (1-4C)alkoxy, (1-4C)alkyl, (1-5C)alkylsulphonyl, 3 to 6 membered heterocyclyl, 3 to 6 membered heterocyclyl-(1-2C)a

Assignees

• Cancer Research Tech Ltd

Inventors

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

Classifications

• 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

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title