Heterocyclic spiro-compounds as am2 receptor inhibitors

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

• wherein
• HET is a 4 to 9 membered saturated or partially saturated heterocyclyl containing 1 ring nitrogen heteroatom and optionally 1 additional ring heteroatom selected from O, S and N;
• L is absent or is —C(RA)2—;
• each RA is independently selected from H and C1-3 alkyl;
• X1 is N or CRB;
• X2 and X3 are each independently N or CH, provided that no more than one of X1, X2 and X3 is N;
• L1 is absent or is selected from:
• —O— and —N(R7)—
• R1 is selected from:
• H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl and Q1-L2-, wherein said C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl is optionally substituted by one or more R8;
• Q1 is selected from:
• C3-12 cycloalkyl, C3-12 cycloalkenyl, 4 to 12 membered heterocyclyl, C6-10 aryl and 5 to 10 membered heteroaryl,
• wherein said cycloalkyl, cycloalkenyl and heterocyclyl is optionally substituted by one or more R9, and
• wherein said aryl and heteroaryl is optionally substituted by one or more R10;
• L2 is absent or is selected from:
• C1-6 alkylene, C2-6 alkenylene and C2-6 alkynylene, wherein L2 is optionally substituted by one or more R11
• R2 is at each occurrence independently selected from:
• halo, ═O, C1-4 alkyl, C1-4 haloalkyl and —ORA12, or
• an R2 group forms a C1-6 alkylene bridge between the ring atom to which the R2 group is attached and another available ring atom in HET;
• R3 is selected from:
• H and C1-4 alkyl;
• R4 and R5 are independently selected from:
• H, C1-4 alkyl and C1-4 haloalkyl, or
• R4 and R5 together with the carbon to which they are attached form a C3-6 cycloalkyl;
• R6 is selected from:
• H, halo, C1-6 alkyl and C1-6 haloalkyl;
• R7 is selected from:
• H, C1-6 alkyl, C1-6 haloalkyl and —ORA1;
• R8, R9 and R11 are at each occurrence independently selected from:
• halo, ═O, ═NRA2, ═NORA2, —CN, —NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -L3-Q2, —OR16, —S(O)xR16 (wherein x is 0, 1, or 2), —NR16RB2, —C(O)R16, —OC(O)R16, —C(O)OR16, —NRB2C(O)R16, —NRB2C(O)OR16, —C(O)NR16RB2, —OC(O)NR16RB2, —NRB2SO2R16, —SO2NR16RB2, —NRA2C(O)NR16RB2, —NRA2C(═NRA2)RB2, —C(═NRA2)RB2, —C(═NRA2)NRA2RB2, —NRA2C(═NRA2)NRA2RB2, —NRA2C(═NCN)NRA2RB2, —ONRA2RB2 and —NRA2ORB2,
• wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by 1 or more R12, and
• wherein R16 is selected from:
• H, C1-6 alkyl and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted by one or more R18;
• R10 is at each occurrence independently selected from:
• halo, —CN, —NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, -L4-Q3, —OR17, —S(O)xR17 (wherein x is 0, 1, or 2), —NR17RB3, —C(O)R17, —OC(O)R17, —C(O)OR17, —NRB3C(O)R17, —NRB3C(O)OR17, —C(O)NR17RB3, —OC(O)NR17RB3, —NRB3SO2R17, —SO2NR17RB3, —NRA3C(O)NR17RB3, —NRA3C(═NRA3)RA3, —C(═NRA3)RB3, —C(═NRA3)NRA3RB3, —NRA3C(═NRA3)NRA3RB3, —NRA3C(═NCN)NRA3RB3, —ONRA3RB3 and —NRA3ORB3,
• wherein said C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by 1 or more R13, and
• wherein R17 is selected from:
• H, C1-6 alkyl and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted by one or more R19;
• Q2 and Q3 are at each occurrence independently selected from:
• C3-12 cycloalkyl, C3-12 cycloalkyl-C1-3 alkyl, C3-12 cycloalkenyl, C3-12 cycloalkenyl-C1-3 alkyl, 4 to 12 membered heterocyclyl, 4 to 12 membered heterocyclyl-C1-3 alkyl, C6-10 aryl, C6-10 aryl-C1-3 alkyl, 5 to 10 membered heteroaryl and 5 to 10 membered heteroaryl-C1-3 alkyl,
• wherein said C3-12 cycloalkyl, C3-12 cycloalkyl-C1-3 alkyl, C3-12 cycloalkenyl, C3-12 cycloalkenyl-C1-3 alkyl, 4 to 12 membered heterocyclyl and 4 to 12 membered heterocyclyl-C1-3 alkyl is optionally substituted by one or more R14, and
• wherein said C6-10 aryl, C6-10 aryl-C1-3 alkyl, 5 to 10 membered heteroaryl and 5 to 10 membered heteroaryl-C1-3 alkyl is optionally substituted by one or more R15;
• L3 and L4 are independently absent or independently selected from:
• —O—, —CH2O—, —NRA4—, —CH2NRA4—, —S(O)x—, —CH2S(O), (wherein x is 0, 1 or 2), —C(═O)—, —CH2C(═O)—, —NRA4C(═O)—, —CH2NRA4C(═O)—, —C(═O)NRA4—, —CH2C(═O)NRA4—, —S(O)2NRA4—, —CH2S(O)2NRA4—, —NRA4S(O)2—, CH2NRA4S(O)2—, —OC(═O)—, —CH2OC(═O)—, —C(═O)O— and —CH2—C(═O)O—;
• R12, R13, R14, R18 and R19 are at each occurrence independently selected from:
• halo, ═O, —CN, —NO2, C1-4 alkyl, C1-4 haloalkyl, -L5-Q4, —ORA5, —S(O)2RA5, —NRA5RB5, —C(O)RA5, —OC(O)RA5, —C(O)ORA5, —NRB5C(O)RA5, —NRB5C(O)ORA5, —C(O)NRA5RB5, —NRB5SO2RA5 and —SO2NRA5RB5;
• wherein said C1-4alkyl is optionally substituted by 1 or 2 substituents selected from:
• halo, ═O, —CN, —ORA6, —NRA6RB6 and —SO2RA6;
• R15 is at each occurrence independently selected from:
• halo, —CN, —NO2, C1-4 alkyl, C1-4 haloalkyl, -L6-Q5, —ORA7, —S(O)2RA7, —NRA7RB7, —C(O)RA7, —OC(O)RA7, —C(O)ORA7, —NRB7C(O)RA7, —NRB7C(O)ORA7, —C(O)NRA7RB7, —NRB7SO2RA7 and —SO2NRA7RB7—;
• wherein said C1-4alkyl is optionally substituted by 1 or 2 substituents selected from:
• halo, —CN, —ORA8, —NRA8RB8 and —SO2RA8;
• Q4 and Q5 are at each occurrence independently selected from:
• phenyl, phenyl-C1-3 alkyl, 5- or 6-membered heteroaryl, 5- or 6-membered heteroaryl-C1-3 alkyl-, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-3 alkyl-, 4 to 6-membered heterocyclyl and 4 to 6-membered heterocyclyl-C1-3 alkyl,
• wherein said C3-6 cycloalkyl, C3-6 cycloalkyl-C1-3 alkyl-, 4 to 6-membered heterocyclyl and 4 to 6-membered heterocyclyl-C1-3 alkyl of Q4 and Q5 are each independently optionally substituted by 1 or 2 substituents selected from:
• C1-4 alkyl, C1-4 haloalkyl, halo, ═O, —CN, —ORA9, —NRA9RB9, —SO2RA9 and C1-4 alkyl substituted by 1 or 2 substituents selected from:
• halo, —CN, —ORA10, —NRA10RB10 and —SO2RA10, and
• wherein said of phenyl, phenyl-C1-3 alkyl, 5- or 6-membered heteroaryl and 5- or 6-membered heteroaryl-C1-3 alkyl- of Q4 and Q5 are each independently optionally substituted by 1 or 2 substituents selected from:
• halo, C1-4alkyl, C1-4 haloalkyl, —CN, —ORA9, —NRA9RB9, —SO2RA9 and C1-4alkyl substituted by 1 or 2 substituents selected from:
• halo, —CN, —ORA10, —NRA10RB10 and —SO2RA10;
• L5 and L6 are independently absent or independently selected from:
• —O—, —NRA11—, —S(O)2—, —C(═O)—, —NRA11C(═O)—, —C(═O)NRA11—, —S(O)2NRA11—, —NRA11S(O)2—, —OC(═O)— and —C(═O)O—;
• RA1, RA2, RB2, RA3, RB3, RA4, RA5, RB5, RA6, RB6, RA7, RB7, RA8, RB8, RA9, RB9, RA10, RB10, RA11 and RA12 are each independently selected from:
• H, C1-4 alkyl and C1-4 haloalkyl, or any —NRA2RB2, —NR16RB2, —NRA3RB3, —NR17RB3, —NRA5RB5, —NRA6RB6, —NRA7RB7, —NRA8RB8, —NRA9RB9 and —NRA10RB10 within a substituent may form a 4 to 6 membered heterocyclyl, wherein said 4 to 6 membered heterocyclyl is optionally substituted by one or more substituents selected from:
• halo, ═O, C1-4 alkyl and C1-4 haloalkyl;
• and
• q is an integer selected from 0, 1, 2, 3 and 4.