Pharmacologically active compounds

Patent metadata

Field	Value
Publication number	US-10188642-B2
Application number	US-201715852639-A
Country	US
Kind code	B2
Filing date	Dec 22, 2017
Priority date	Sep 7, 2012
Publication date	Jan 29, 2019
Grant date	Jan 29, 2019

Abstract

The present invention relates to compounds of formula II

wherein X, Y, R 2 , R 3 , R 4 and Ar 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 having the structural formula II shown below:

wherein:
X is CH or N;
Y is N or C—H;
R 2 is (1-6C)alkyl, (1-8C)heteroalkyl, aryl, aryl(1-2C)alkyl, a 5 or 6 membered heteroaryl, a 5 or 6 membered heteroaryl(1-2C)alkyl, a 3 to 6 membered heterocyclyl, a 3 to 6 membered heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, C(O)R 13 , C(O)OR 13 , OC(O)R 13 , C(O)N(R 14 )R 13 , S(O) x R 13 (where x is 0, 1 or 2), or SO 2 N(R 14 )R 13 ;
and wherein R 2 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) x CH 3 (where x 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 2 is optionally further substituted by fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , N(R d )OR c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) y R c (where y is 0, 1 or 2), SO 2 N(R d )R c , or N(R d )SO 2 R c , wherein R c and R d 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, fluoro, chloro or CF 3 ;
Ar has the formula:

wherein:
(i) all of A 1 , A 2 and A 3 are CH; or
(ii) A 3 is CH and A 1 or A 2 are N or CH;
R 5 is 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 H or (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 halo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, ureido, (1-6C)alkyl, (2-6C)alkenyl, (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 hydrogen or (1-2C)alkyl;
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 selected from 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, 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 or (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; or R 22 and R 23 can be linked such that, together with the nitrogen atom to which they are attached, they form a 4-6 membered heterocyclic ring ring;
 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);

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 or 4, and R 25 and R 26 are each independently hydrogen or (1-2C)alkyl;
L 4 is absent or is 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 ), or N(R 28 )SO 2 , wherein R 27 and R 28 are each independently hydrogen or (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 13 is hydrogen, (1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-2C)alkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, or heteroaryl-(1-2C)alkyl, and wherein R 13 is 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 14 is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl-(1-2C)alkyl, and wherein R 14 is 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:
X can only be N when Y is N;
when X and Y are both N, R 3 is H or fluoro;

or a pharmaceutically acceptable salt or solvate thereof.

2. A compound according to claim 1 , wherein said compound has one of the structures IIa, IIb or IIc shown below:

and wherein Ar, R 2 , R 3 and R 4 are as defined in claim 1 .

3. A compound according to claim 1 , wherein R 2 is (1-6C)alkyl, phenyl, phenyl(1-2C)alkyl, a 5 or 6 membered heteroaryl, a 5 or 6 membered heteroaryl(1-2C)alkyl, a 3 to 6 membered heterocyclyl, a 3 to 6 membered heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, C(O)R 13 , C(O)OR 13 , OC(O)R 13 , C(O)N(R 14 )R 13 , S(O) x R 13 (where x is 0, 1 or 2), or SO 2 N(R 14 )R 13 ;
and wherein R 2 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) x CH 3 (where x is 0, 1 or 2), methylamino, dimethylamino, phenyl, phenyl(1-2C)alkyl, a 5 or 6 membered heteroaryl, a 5 or 6 membered heteroaryl(1-2C)alkyl, a 3 to 6 membered heterocyclyl, a 3 to 6 membered heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, and (3-8C)cycloalkyl(1-2C)alkyl,
and wherein any (1-4C)alkyl, (1-4C)alkoxy, phenyl, heteroaryl, heterocyclyl, or (3-8C)cycloalkyl moiety present within a substituent group on R 2 is optionally further substituted by fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , N(R d )OR c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) y R c (where y is 0, 1 or 2), SO 2 N(R d )R c , or N(R d )SO 2 R c , wherein R c and R d are each independently H or (1-4C)alkyl.

4. A compound according to claim 1 , wherein R 2 is (1-6C)alkyl, a 5 or 6 membered heteroaryl, a 3 to 6 membered heterocyclyl, a 3 to 6 membered heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, C(O)N(R 14 )R 13 , S(O) x R 13 (where x is 0, 1 or 2), or SO 2 N(R 14 )R 13 ;
and wherein R 2 is optionally substituted by one or more substituent groups fluoro, chloro, trifluoromethyl, trifluorom

Assignees

• Cancer Research Tech Ltd

Inventors

• Hoelder Swen
• Blagg Julian
• Cheung Kwai-Ming Jack
• Atrash Butrus
• Sheldrake Peter

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

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

• A61K31/541

  Non-condensed thiazines containing further heterocyclic rings · CPC title