Therapeutic compounds as inhibitors of the orexin-1 receptor

A method of alleviating a disease or condition selected from anxiety disorders;

• panic disorders;
• mood disorders;
• addiction including substance dependence, alcohol dependence, nicotine dependence or gambling disorder;
• and eating disorders, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof:
• wherein:
• Ra is ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, or cyclopropylmethyl, each of which is optionally substituted by one or more fluoro;
• Rb is:
• (i) hydrogen;
• (ii) a (1-4C)alkyl which is optionally substituted by one or more fluoro;
• (iii) a (3-6C)cycloalkyl which is optionally substituted by one or more fluoro;
• or
• (iv) a (3-6C)cycloalkyl(1-2C)alkyl which is optionally substituted by one or more fluoro;
• X is a group:
• —X0—(CH2)n—
• wherein
• X0 is —O—, —N(R1)—, —C(O)—N(R1)—, —N(R1)C(O)N(R1)— or —S—;
• n is 0 or 1;
• R1 is hydrogen or a (1-2C)alkyl group which is optionally substituted by one or more substituents selected from fluoro, hydroxyl, NR1aR1b, (1-2C)alkoxy and (1-2C)haloalkoxy;
• R1a and R1b are each independently hydrogen or (1-2C)alkyl;
• or R1a and R1b are linked such that, together with the nitrogen atom to which they are attached, they form a 4, 5 or 6 membered heterocyclic ring;
• Ar is aryl or heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, cyano, nitro and a group of the formula:
• -L1-X1—R6
• wherein
• L1 is absent or a linker group of the formula —[CR7R8]r— in which r is an integer selected from 1, 2, 3 and 4, and R7 and R8 are each independently selected from hydrogen, halo, hydroxy and 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 R7 and R8 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;
• X1 is absent or selected from —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R9)—, —N(R9)—C(O)—, —C(O)—N(R9)—, —N(R9)—C(O)O—, —OC(O)—N(R9)—, —N(R9)C(O)N(R10)—, —S—, —SO—, —SO2—, —S(O)2N(R9)—, —N(R9)SO2— and —S(O)(═NR10)—, wherein R9 and R10 are hydrogen, (1-4C)alkyl, (1-4C)fluoroalkyl or (3-6C)cycloalkyl;
• and
• R6 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 R6 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, and a group of the formula:
• -L2-X2—R11
• wherein
• L2 is absent or a linker group of the formula —[CR12R13]s— in which s is an integer selected from 1, 2, 3 and 4, and R12 and R13 are each independently 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 R12 and R13 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;
• X2 is absent or selected from —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R14)—, —N(R14)—C(O)—, —C(O)—N(R14)—, —N(R14)—C(O)O—, —OC(O)—N(R14)—, —N(R14)C(O)N(R15)—, —S—, —SO—, —SO2—, —S(O)2N(R14)—, —N(R14)SO2— and —S(O)(═NR14)—, wherein R14 and R15 are hydrogen, (1-4C)alkyl, (1-4C)fluoroalkyl or (3-6C)cycloalkyl;
• and
• R11 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;
• Q is aryl or heteroaryl, each of which is optionally substituted with one or more Rz substituents, wherein Rz is halo, cyano, nitro, or a group of the formula:
• -L3-X3—R30
• wherein
• L3 is absent or a linker group of the formula —[CR31R32]t— in which t is an integer selected from 1, 2, 3 and 4, and R31 and R32 are each independently 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 R31 and R32 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;
• X3 is absent, —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R33)—, —N(R33)—C(O)—, —C(O)—N(R33)—, —N(R33)—C(O)O—, —OC(O)—N(R33)—, —N(R33)C(O)N(R34)—, —S—, —SO—, —SO2—, —S(O)2N(R33)—, —N(R33)SO2— or —S(O)(═NR33)—, wherein R33 and R34 are selected from hydrogen, (1-4C)alkyl, (1-4C)fluoroalkyl and (3-6C)cycloalkyl;
• and
• R30 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 R30 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, and a group of the formula:
• -L4-X4—R35
• wherein
• L4 is absent or a linker group of the formula —[CR36R37]u— in which u is an integer selected from 1, 2, 3 and 4, and R36 and R37 are each independently 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 R36 and R37 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;
• X4 is absent or selected from —O—, —C(O)—, —C(O)O—, —OC(O)—, —N(R38)—, —N(R38)—C(O)—, —C(O)—N(R38)—, —N(R38)—C(O)O—, —OC(O)—N(R38)—, —N(R38)C(O)N(R39)—, —S—, —SO—, —SO2—, —S(O)2N(R38)—, —N(R38)SO2— and —S(O)(═NR38)—, wherein R38 and R39 are hydrogen, (1-4C)alkyl, (1-4C)fluoroalkyl or (3-6C)cycloalkyl;
• and
• R35 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.