Therapeutic compounds as inhibitors of the orexin-1 receptor

1. A compound of formula IA:

wherein:

R b is selected from:

i. (1-4C)alkyl which is optionally substituted by one or more fluor;

ii. (3-6C)cycloalkyl which is optionally substituted by one or more fluoro; or

iii. (3-6C)cycloalkyl(1-2C)alkyl which is optionally substituted by one or more fluoro;

Ar is aryl or heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, cyano, nitro or a group of the formula:

-L 1 -X 1 —R 6

wherein

L 1 is absent or a linker group of the formula —[CR 7 R 8 ] r — in which r is an integer selected from 1, 2, 3 or 4, and R 7 and R 8 are each independently selected from hydrogen, halo, hydroxy or a (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl group which is optionally substituted by one or more fluoro substituents; or R 7 and R 8 are optionally linked such that, together with the carbon atom to which they are attached, they form a (3-6C)cycloalkyl ring which is optionally substituted by one or more fluoro substituents;

X 1 is absent or selected from —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R 9 )—, —N(R 9 )—C(O)—, —C(O)—N(R 9 )—, —N(R 9 )—C(O)O—, —OC(O)—N(R 9 )—, —N(R 9 ) C(O)N(R 10 )—, —S—, —SO—, —SO 2 —, —S(O) 2 N(R 9 )—, —N(R 9 )SO 2 — or —S(O)(═NR 10 )—, wherein R 9 and R 10 are selected from hydrogen, (1-4C)alkyl, (1-4C)fluoroalkyl or (3-6C)cycloalkyl, and

R 6 is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, aryl(1-2C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, heteroaryl, or heteroaryl-(1-2C)alkyl,

and wherein R 6 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, or a group of the formula:

-L 2 -X 2 —R 11

wherein

L 2 is absent or a linker group of the formula —[CR 12 R 13 ] s — in which s is an integer selected from 1, 2, 3 or 4, and R 12 and R 13 are each independently selected from hydrogen or a (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl group which is optionally substituted by one or more fluoro substituents, or R 12 and R 13 are optionally linked such that, together with the carbon atom to which they are attached, they form a (3-6C)cycloalkyl ring which is optionally substituted by one or more fluoro substituents;

X 2 is absent or selected from —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R 14 )—, —N(R 14 )—C(O)—, —C(O)—N(R 14 )—, —N(R 14 )—C(O)O—, —OC(O)—N(R 14 )—, —N(R 14 )C(O)N(R 15 )—, —S—, —SO—, —SO 2 —, —S(O) 2 N(R 14 )—, —N(R 14 )SO 2 —or —S(O)(═NR 14 )—, wherein R 14 and R 15 are selected from hydrogen, (1-4C)alkyl, (1-4C)fluoroalkyl or (3-6C)cycloalkyl; and

R 11 is hydrogen or a (1-6C)alkyl (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl group which is optionally substituted by one or more fluoro substituents; and

R z2 is selected from halo, cyano, nitro, or a group of the formula:

-L 3 -X 3 —R 30

wherein

L 3 is absent;

X 3 is absent, or selected from —O—, —N(R 33 )—, —N(R 33 )—C(O)—, —C(O)—N(R 33 )—, —S—, —SO—, or —SO 2 —, wherein R 33 is selected from hydrogen or (1-2C)alkyl; and

R 30 is hydrogen, (1-4C)alkyl, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-2C)alkyl, 3-6-membered heterocyclyl, 3-6-membered heterocyclyl-(1-2C)alkyl, 5-6-membered heteroaryl, or 5-6-membered heteroaryl-(1-2C)alkyl,

and wherein R 30 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, or a group of the formula:

-L 4 -X 4 —R 35

wherein

L 4 is absent or a linker group of the formula —[CR 36 R 37 ] u — in which u is an integer selected from 1, 2 or 3, and R 36 and R 37 are each independently selected from hydrogen or a (1-4C)alkyl group which is optionally substituted by one or more fluoro substituents; or R 36 and R 37 are optionally linked such that, together with the carbon atom to which they are attached, they form a (3-4C)cycloalkyl ring which is optionally substituted by one or more fluoro substituents;

X 4 is absent or selected from —O—, —C(O)—, —N(R 38 )—, —N(R 38 )—C(O)—, —C(O)—N(R 38 )—, —N(R 38 )C(O)N(R 39 )—, —S—, —SO—, —SO 2 —, —S(O) 2 N(R 38 )—, —N(R 38 )SO 2 — or —S(O)(═NR 38 )—, wherein R 38 and R 39 are selected from hydrogen, (1-4C)alkyl, (1-4C)fluoroalkyl or (3-6C)cycloalkyl; and

R 35 is hydrogen or a (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl group which is optionally substituted by one or more fluoro substituents;

or a pharmaceutically acceptable salt or solvate thereof.

2. A compound according to claim 1 , wherein

R b is (1-4C)alkyl optionally substituted by one or more fluoro;

R z2 is selected from halo, cyano, nitro, and a group of the formula:

-L 3 -X 3 —R 30

wherein

L 3 is absent;

X 3 is absent, or selected from —O—, —N(R 33 )—, —N(R 33 )—C(O)—, —C(O)—N(R 33 )—, —S—, —SO—, or —SO 2 —, wherein R 33 is hydrogen or (1-2C)alkyl; and

R 30 is hydrogen or (1-4C)alkyl; and wherein R 30 is optionally further substituted by one or more fluoro atoms.

3. A compound according to claim 2 , wherein

R b is methyl optionally substituted by one or more fluoro;

R z2 is halo, methyl, methoxy, CF 3 or OCF 3 ; and

Ar is pyridyl, pyrmidinyl, pyrazinyl, which is optionally substituted by one or more substituent groups selected from halo, cyano, hydroxyl, mercapto, amino, carbamoyl, sulphamoyl, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy, (1-2C)alkylamino, di-[(1-2C)alkyl]amino, (1-2C)alkylthio, (1-2C)alkylsulphinyl, (1-2C)alkylsulphonyl, (1-2C)alkoxycarbonyl, N-(1-2C)alkylcarbamoyl, N,N-di-[(1-2C)alkyl]carbamoyl, (2C)alkanoyl, (2C)alkanoyloxy, (2C)alkanoylamino, N-(1-2C)alkylsulphamoyl and N,N-di-[(1-2C)alkyl]sulphamoyl.

4. A compound which is selected from:

(S)—N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N,5-dimethyl-2-(2H-1,2,3-triazol-2-yl)benzamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-[1,1′-biphenyl]-2-carboxamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)-4-methylpentan-2-yl)-[1,1′-biphenyl]-2-carboxamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-2-methyl-4-phenylthiazole-5-carboxamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)-4-methylpentan-2-yl)-2-methyl-4-phenylthiazole-5-carboxamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)-4-methylpentan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)-4-methylpentan-2-yl)-N,2-dimethyl-4-phenylthiazole-5-carboxamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N,2-dimethyl-4-phenylthiazole-5-carboxamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)-3,3-dimethylbutan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide;

(S)—N-(2-((5-chloropyridin-2-yl)amino)-1-cyclopropylethyl)-N-methyl-[1,1′-biphenyl]-2-carboxamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)propan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N-cyclopropyl-[1,1′-biphenyl]-2-carboxamide;

(S)-5-chloro-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N-methyl-2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)benzamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-5-fluoro-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide;

(S)-5-bromo-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N-methyl-2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethoxy)benzamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N,5-dimethyl-2-morpholinobenzamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-5-(dimethylamino)-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N-methyl-2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)nicotinamide;

(S)-5-chloro-N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-2-(2H-1,2,3-triazol-2-yl)benzamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N,2-dimethyl-5-phenylthiazole-4-carboxamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N-methyl-2-phenyl-1H-indole-3-carboxamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide;

(S)—N-(1-((4-fluorobenzyl)oxy)-3-methylbutan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide;

(S)—N-(1-((4,6-dimethylpyrimidin-2-yl)oxy)-3-methylbutan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide;

(S)—N-methyl-N-(3-methyl-1-(quinazolin-2-yloxy)butan-2-yl)-[1,1′-biphenyl]-2-carboxamide;

(S)—N-methyl-N-(3-methyl-1-((4-phenylpyrimidin-2-yl)oxy)butan-2-yl)-[1,1′-biphenyl]-2-carboxamide;

(S)—N-methyl-N-(3-methyl-1-((1-methyl-1H-benzo[d]imidazol-2-yl)oxy)butan-2-yl)-[1,1′-biphenyl]-2-carboxamide;

(S)—N -(1 -((5-chloropyridin-2-yl)oxy)-3-methylbutan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide;

(S)—N-methyl-N-(3-methyl-1 4(4-phenylpyrimidin-2-yl)amino)butan-2-yl)-[1,1′-biphenyl]-2-carboxamide;

(S)—N-methyl-N-(3-methyl-1-(quinazolin-2-ylamino)butan-2-yl) -[1,1′-biphenyl]-2-carboxamide;

(S)—N-(1-((4,6-dimethylpyrimidin-2-yl)amino)-3-methylbutan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide;

(S)—N-methyl-N-(3-methyl-1 4(1-methyl-1H-benzo[d]imidazol-2-yl)amino)butan-2-yl)1,1′-biphenyl]-2-carboxamide;

(S)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)benzamide;

(S)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)-N-(1-((5- (trifluoromethyl)pyrazin-2-yl)amino)butan-2-yl)benzamide;

(S)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)-N-(1-((6-(trifluoromethyl)pyridazin-3-yl)amino)butan-2-yl)benzamide;

(S)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyridin-2-yl)amino)butan-2-yl)benzamide;

(S)—N-(1-(benzo[d]oxazol-2-ylamino)butan-2-yl)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide;

(S)—N-(1-(benzo[d]thiazol-2-ylamino)butan-2-yl)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide;

(S)-5-chloro-N-(1-((5-chloro-3-nitropyridin-2-yl)amino)butan-2-yl)-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide;

(S)—N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-(1(5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)picolinamide;

(S)—N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrazin-2-yl)amino)butan-2-yl)picolinamide;

(S)—N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-(1 4(5-(trifluoromethyl)pyridin-2-yl)amino)butan-2-yl)picolinamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N,5-dimethyl-2-(2H-1,2,3-triazol-2-yl)benzamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N,1-dimethyl-1H-indole-3-carboxamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N,2-dimethylquinoline-4-carboxamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)-3-methylbutan-2-yl)-N-methyl-2-(trifluoromethoxy)benzamide;

(S)-5-chloro-N-methyl-N-(1 4(6-methylpyridin-2-yl)amino)butan-2-yl)-2-(2H-1,2,3-triazol -2-yl)benzamide;

(S)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)-N-(1-((6-(trifluoromethyl)pyridin-3-yl)amino)butan-2-yl)benzamide;

(S)—N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((6-(trifluoromethyl)pyridin-3-yl)amino)butan-2-yl)picolinamide;

(S)—N-(1-(4-fluorobenzamido)-3-methylbutan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide;

(S)—N-(1-((4-fluorobenzyl)amino)-3-methylbutan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide;

(S)—N-methyl-N-(3-methyl-1-(3-phenylureido)butan-2-yl) -N-methyl-[1,1′-biphenyl]-2-carboxamide;

(S)—N-(1-((4-chlorophenyl)amino)-3-methylbutan-2-yl)-N-methyl-[1,1′-biphenyl]-2-carboxamide;

(S)—N-(1-((3-amino-5-chloropyridin-2-yl)amino)butan-2-yl)-5-chloro-N-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide;

(S)—N,6-dimethyl-N-(1-(quinazolin-2-ylamino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide;

(S)—N-(1-(benzo[d]oxazol-2-ylamino)butan-2-yl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide;

(S)—N-(1-(benzo[d]thiazol-2-ylamino)butan-2-yl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide;

(S)—N-(1-((5-chlorobenzo[d]oxazol-2-yl)amino)butan-2-yl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide;

(S)—N,6-dimethyl-N-(1-(quinoxalin-2-ylamino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide;

(S)—N,6-dimethyl-N-(3-methyl-1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide;

(S)—N,6-dimethyl-N-(3-methyl-1-((5-(trifluoromethyl)pyrazin-2-yl)amino)butan-2-yl)-3-(2H -1,2,3-triazol-2-yl)picolinamide;

(S)—N,6-dimethyl-N-(3-methyl-1-(quinazolin-2-ylamino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide;

(S)—N,6-dimethyl-N-(3-methyl-1-((5-(trifluoromethyl)pyridin-2-yl)amino)butan-2-yl)-3-(2H -1,2,3-triazol-2-yl)picolinamide;

(S)—N-ethyl-6-methyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5(trifluoromethyl)pyrazin-2-yl)amino)butan-2-yl)picolinamide;

(S)—N-ethyl-6-methyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5(trifluoromethyl)pyridin-2-yl)amino)butan-2-yl)picolinamide;

(S)—N-ethyl-6-methyl-N-(1-(quinazolin-2-ylamino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide;

(S)—N-ethyl-6-methyl-3-(2H-1,2,3-triazol-2-yl)-N-(1-((5(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)picolinamide;

(S)—N-(1-cyclopropyl-2-((5 -(trifluoromethyl)pyrimidin-2-yl)amino)ethyl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide;

(S)—N,6-dimethyl-N-(1-(quinolin-2-ylamino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide;

(S)—N-(1 -((1,5-naphthyridin-2-yl)amino)butan-2-yl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide;

(S)-5-chloro-N-methyl-N-(1-(quinolin-2-ylamino)butan-2-yl)-2-(2H-1,2,3-triazol-2-yl)benzamide;

(S)—N,3-dimethyl-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)isoquinoline-1-carboxamide;

(S)—N-methyl-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)quinoline-8-carboxamide;

(S)-6-chloro-N-methyl-N-(1 4(5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)quinoline-8-carboxamide;

(S)-3-(dimethylamino)-N-methyl-N-(1 4(5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)isoquinoline-1-carboxamide;

(S)—N,6-dimethyl-N-(1-(methyl(5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)-3-(2H-1,2,3-triazol-2-yl)picolinamide;

(S)—N-(1-((2-methoxyethyl)(5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)picolinamide;

(S)—N,6-dimethyl-3-(pyrimidin-2-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)picolinamide formic acid salt;

(S)—N-methyl-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)isoquinoline-1-carboxamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-N,4,5-trimethyl-2-(2H-1,2,3-triazol-2-yl)benzamide;

(S)—N-(1-((5-chloropyridin-2-yl)amino)butan-2-yl)-5-methoxy-N,4-dimethyl-2-(2H-1,2,3-triazol-2-yl)benzamide;

(S)—N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-(4,4,4-trifluoro-1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)picolinamide;

(S)—N,6-dimethyl-3-(1H-1,2,4-triazol-1-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)picolinamide formic acid salt;

(S)—N,6-dimethyl-3-(1H-pyrazol-1-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)picolinamide formic acid salt;

(S)-2-fluoro-N-methyl-6-(2H-1,2,3-triazol-2-yl)-N-(1-((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)benzamide; and

(S)-6-methoxy-N-methyl-3-(2H-1,2,3-triazol-2-yl)-N-(1((5-(trifluoromethyl)pyrimidin-2-yl)amino)butan-2-yl)picolinamide;

or a pharmaceutically acceptable salt or solvate thereof.

5. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.