Autotaxin inhibitory compounds

A compound, or a pharmaceutically acceptable salt or solvate thereof, having the structural formula Ic shown below:

• wherein:
• R1 and R2 are independently selected from H, (1-2C)alkyl, halo, cyano, nitro, hydroxyl, amino, mercapto, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)fluoroalkoxy,
• A1 is C—Rd, wherein Rd is selected from H, halo, (1-2C)alkyl, cyano, nitro, hydroxyl, amino, (1-2C)haloalkyl, (1-2C)alkoxy, or (1-2C)haloalkoxy;
• A2 is N;
• A3 is N;
• L is a methylene optionally substituted by (1-2C)alkyl or oxo;
• Ar is either a 5 or 6 membered heteroaryl optionally substituted by H, halo, (1-4C)alkyl, (1-4C)haloalkyl, OCF3, (1-4C)alkoxy, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl or a group of the formula:
• wherein:
• Ra and Ra′ are independently selected from H, fluoro, (1-2C)alkyl (1-2C)alkoxy or (1-2C)fluoroalkoxy;
• Rb and Rb′ are independently selected from H, fluoro, chloro, (1-2C)alkyl, (1-2Cfluoroalkoxy or (1-2C)alkoxy;
• Rc is selected from is H, (1-4C)alkyl, halo, hydroxyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, NRiRj, ORi, C(O)Ri, C(O)ORi, OC(O)Ri, C(O)N(Rj)Ri, N(Rj)C(O)Ri, S(O)yRi (where y is 0, 1 or 2), SO2N(Rj)Ri, N(Rj)SO2Ri or (CH2)zNRjRi (where z is 1, 2 or 3), wherein Ri and Rj are each independently selected from H or (1-2C)alkyl;
• or
• Rc is a group of the formula:
• -L1-B
• wherein:
• L1 is (1-2C)alkylene or —O-(1-2C)alkylene, each of which is optionally substituted by (1-2C)alkyl or oxo;
• B is phenyl or 5 or 6 membered heteroaryl optionally substituted with halo or (1-2C)alkyl;
• Q is either a group of the formula:
• —CHRx—Rk—
• wherein:
• Rk is CH2, NRl or O, wherein Rl is selected from H or (1-2C)alkyl;
• and
• Rx is H or (1-2C)alkyl;
• or Q is a group of the formula:
• —Rm—CHRy—
• wherein:
• Rm is O, S, SO, SO2 or SO(NH);
• and
• Ry is H or (1-2C)alkyl;
• R3 is H;
• R4 is H, (1-4C)alkyl, carboxyl, carbamoyl, sulphamoyl, amido, ureido, (3-4C)cycloalkyl, (3-4C)cycloalkyl(1-4C)alkyl, wherein said (1-4C)alkyl, (3-4C)cycloalkyl or (3-4C)cycloalkyl(1-4C)alkyl is optionally substituted with one or more substituents selected from halo, amino, mercapto, cyano, hydroxyl, carboxyl, carbamoyl, sulphamoyl, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, NRpRq, ORp, C(O)Rp, C(O)ORp, OC(O)Rp, C(O)N(Rq)Rp, N(Rq)C(O)Rp, S(O)yRp (where y is 0, 1 or 2), SO2N(Rq)Rp, N(Rq)SO2Rp or (CH2)zNRqRp (where z is 1, 2 or 3), wherein Rp and Rq are each independently selected from H or (1-4C)alkyl;
• R5 is a group of formula Z, wherein:
• Z is phenyl, heteroaryl, heterocyclyl or (3-6C)carbocyclyl, optionally substituted with one or more substituents selected from halo, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, (2-4C)alkenyl, (2-4C)alkynyl, amino, mercapto, cyano, hydroxyl, carboxyl, carbamoyl, sulphamoyl, (1-4C)alkyl, NRsRt, ORs, C(O)Rs, C(O)ORs, OC(O)Rs, C(O)N(Rt)Rs, N(Rt)C(O)Rs, S(O)yRs (where y is 0, 1 or 2), SO2N(Rt)Rs, N(Rt)SO2Rs or (CH2)zNRsRt (where z is 1, 2 or 3), wherein Rs and Rt are each independently selected from H or (1-4C)alkyl;
• or
• Z is optionally substituted by a group of formula:
• —V-L6-Y
• wherein
• V is absent or selected from O, S, SO, SO2, N(Ru), C(O), C(O)O or OC(O), wherein Ru is hydrogen or (1-2C)alkyl;
• L6 is absent or a (1-4C)alkylene optionally substituted by (1-2C)alkyl or oxo;
• Y is selected from amino, (1-6C)alkyl, phenyl, 5 or 6 membered heteroaryl, (3-7C)heterocyclyl or amino, optionally substituted with one or more substituents selected from halo, (1-2C)alkyl, cyano, nitro, hydroxyl, (1-2C)hydroxyalkyl, amino, (1-2C)haloalkyl, NRaaRbb, OCF3 or (1-2C)alkoxy, wherein Raa and Rbb are each independently selected from H or (1-2C)alkyl;
• or R4 and R5 are linked such that, together with the carbon atom to which they are attached, they form a 5 or 6 membered cycloalkyl ring which is fused with a phenyl, 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclyl or (3-6C)carbocyclyl ring;
• each of which is optionally substituted with one or more substituents selected from halo, amino, mercapto, cyano, hydroxyl, carboxyl, carbamoyl, sulphamoyl, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, (2-4C)alkenyl, (2-4C)alkynyl, NRvRw, C(O)Rv, C(O)ORv, OC(O)Rv, C(O)N(Rw)Rv, N(Rw)C(O)Rv, S(O)yRv (where y is 0, 1 or 2), SO2N(Rw)Rv, N(Rw)SO2Rv or (CH2)zNRvRw (where z is 1, 2 or 3), wherein Rv and Rw are each independently selected from H or (1-4C)alkyl;
• with the proviso that:
• (i) when R1 and R2 are H, A1 is CH, Q is ethylene, R3 is H, R4 is H, L is methylene, R5 is:
• phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 2,5-dimethoxyphenyl, 4-methylsulfanyl-phenyl, 4-fluorophenyl, 2-furanyl, 5-(4-morpholinylmethyl)-2-furanyl, 2-pyridyl, 3-pyridyl, 1,3-benzodioxyl-5-yl, or 1-[(3-chlorophenyl)methyl]-4-piperidinyl;
• then Ar is not phenyl, furanyl, thiophenyl or paramethoxyphenyl;
• and
• (ii) when R4 is H, R5 is furanyl and Ar is phenyl, Rm is not S.