Heterocyclic GPCR Agonists

A compound of formula (I), or a pharmaceutically acceptable salt thereof:

• wherein Z is phenyl or a 6-membered N containing heteroaryl group which phenyl or heteroaryl group is substituted by —(CH2)j—C(O)NR1R11, -E1-CO2H, —CH(CH3)—C(O)NR1R11, a 5- or 6-membered N containing heterocyclyl ring, which ring is substituted with oxo and optionally substituted by methyl, or a 5- or 6-membered N containing heteroaryl ring optionally containing up to 3 additional heteroatoms selected from N, O and S, which ring is substituted by C1-3 alkyl or —NH2;
• or Z is 1H-quinazoline-4-one, 2,3-dihydroisoindol-1-one, 1,3-dihydroindol-2-one, 3,4-dihydro-1H-quinolin-2-one, or 3,4-dihydro-2H-isoquinolin-1-one, which is attached to W through an aromatic carbon atom;
• and wherein Z is further optionally substituted by one or more C1-2 alkyl, C1-2alkoxy, CH2NH2, or fluoro groups;
• j is 0, 1 or 2;
• E1 is —CH2—, —CH2CH2—, or —CH(CH3)—;
• W and Y are independently a bond, an unbranched or a branched C1-4alkylene optionally substituted by hydroxy or C1-3 alkoxy, or an unbranched or a branched C2-4 alkenylene;
• X is selected from CH2, O, S. CH(OH), CH(halogen), CF2, C(O), C(O)O, C(O)S, SC(O), C(O)CH2S, C(O)CH2C(OH), C(OH)CH2C(O), C(O)CH2C(O), OC(O), NR5, CH(NR5R55), C(O)NR2, NR2C(O), S(O) and S(O)2;
• Rx is hydrogen or hydroxy;
• G is CHR3, N—C(O)OR4, N—C(O)NR4R5, N—C1-4 alkylene-C(O)OR4, N—C(O)C(O)OR4, N—S(O)2R4, N—C(O)R4 or N—P(O)(O—Ph)2;
• or N-heterocyclyl or N-heteroaryl, either of which may optionally be substituted by one or two groups selected from C1-4 alkyl, C1-4 alkoxy or halogen;
• provided that U is not optionally substituted N-pyridazinyl;
• R1 and R11 together with the N atom to which they are attached form a 4- to 6-membered ring substituted by —N(R2)2 or —CH2NH2 and optionally further substituted with methyl;
• or R1 is hydrogen and R11 is C5-6 alkyl substituted by amino or
• in addition, when Z is —CH(CH3)—C(O)NR1R11, R1 may be hydrogen and R11 may be hydrogen, C1-3 alkyl, or C2-3 alkyl substituted by one or two hydroxy groups;
• L is a γ- or δ-lactam optionally substituted with methyl;
• k is 0, 1 or 2;
• R2 are independently hydrogen or C1-4 alkyl;
• R3 is C3-6 alkyl;
• R4 is C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl, any of which may be optionally substituted by one or more substituents selected from halo, NR5R55, OR5, C(O)OR5, OC(O)R5 and CN, and may contain a CH2 group that is replaced by O or S;
• or a C3-7 cycloalkyl, aryl, heterocyclyl, heteroaryl, C1-4 alkyleneC3-7 cycloalkyl, C1-4 alkylenearyl, C1-4 alkyleneheterocyclyl or C1-4 alkyleneheteroaryl, any of which may be substituted with one or more substituents selected from. halo, C1-4 alkyl, C1-4fluoroalkyl, OR5, CN, NR5R55, SO2Me, NO2 and C(O)OR5;
• R5 and R55 are independently hydrogen or or taken together R5 and R55 may form a 5- or 6-membered heterocyclic ring;
• or a group NR5 may represent NS(O)2-(2-NO2—C6R4);
• d is 0, 1, 2 or 3;
• and
• e is 1, 2, 3, 4 or 5, provided that d+e is 2, 3, 4 or 5.