Dopamine d2 receptor ligands

A compound of Formula I:

• or a stereoisomer, racemate, tautomer, polymorph, hydrate, or solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:
• X0 is C1-C6 alkyl, X—Cy1, C(O)NR4R4′, NR4C(O)R4′, or CR3R3′—NR4R4′, and is bonded to Z1 or Z2;
• X is C(O), CR3R3′, NR4, O, S, S(O), or S(O)2, and is bonded to Z1 or Z2, or
• Z2—Z1—X form a 4- to 7-membered heterocyclyl ring optionally substituted with one or more R18, wherein the heterocyclyl ring, ring G, and Cy1 form a three-ring fused ring structure, provided that R1 is not optionally substituted phenyl, 2-furyl or 3-furyl, or
• X—Z1—R1 form a 3- to 7-membered cycloalkyl or heterocyclyl ring optionally substituted with one or more R18, wherein the cycloalkyl or heterocyclyl ring is bonded to Cy1, or the cycloalkyl or heterocyclyl ring and Cy1 form a fused ring structure when n is 0 and v is 1 or 3, or
• X—Z2—R2 form a 3- to 7-membered cycloalkyl or heterocyclyl ring optionally substituted with one or more R18, wherein the cycloalkyl or heterocyclyl ring is bonded to Cy1, or the cycloalkyl or heterocyclyl ring and Cy1 form a fused ring structure;
• R3 and R3′ are each independently H, C1-C6 alkyl, OH, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or halogen;
• each R4 is independently H, C1-C6 alkyl, or C1-C6 haloalkyl;
• R4′ is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, heterocyclyl comprising one 4- to 7-membered ring and one to four heteroatoms independently selected from N, O, and S, C6-C10 aryl, or heteroaryl comprising one or two 5- or 6-membered rings and one to four heteroatoms independently selected from N, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are independently optionally substituted with one or more R17;
• or R4 and R4′ on the same nitrogen atom together with the nitrogen atom form a monocyclic, 4- to 7-membered heterocyclyl ring optionally substituted with one or more R18;
• Z1 is CR7, or
• Z2—Z1—X form a 4- to 7-membered heterocyclyl ring optionally substituted with one or more R18, wherein the heterocyclyl ring, ring G, and Cy1 form a three-ring fused ring structure, provided that R1 is not optionally substituted phenyl, 2-furyl or 3-furyl, or
• X—Z1—R1 form a 3- to 7-membered cycloalkyl or heterocyclyl ring optionally substituted with one or more R18, wherein the cycloalkyl or heterocyclyl ring is bonded to Cy1, or the cycloalkyl or heterocyclyl ring and Cy1 form a fused ring structure when n is 0 and v is 1 or 3;
• R7 is H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, or when X0 or X is bonded to Z1, absent;
• R1 is H, halogen, OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, NR20R21, C(O)NR20R21, S(O)q—C1-C6 alkyl, S(O)2NR20R21, NR20S(O)2—C1-C6 alkyl, C6-C10 aryl, benzyl, heteroaryl comprising one 5- or 6-membered ring and one to four heteroatoms independently selected from N, O, and S, C3-C6 cycloalkyl, or heterocyclyl comprising one 4- to 6-membered ring and one to four heteroatoms independently selected from N, O, and S, provided that when X0 or X forms a bond with Z1, R1 is not H and provided that when X is bonded to Z1 and is NR4, O, S, S(O), or S(O)2, R1 is not OH, C1-C6 alkoxy, NR20R21, C1-C6 haloalkoxy, S(O)q—C1-C6 alkyl, S(O)2NR20R21, or NR20S(O)2—C1-C6 alkyl;
• or
• X—Z1—R1 form a 3- to 7-membered cycloalkyl or heterocyclyl ring optionally substituted with one or more R18, wherein the cycloalkyl or heterocyclyl ring is bonded to Cy1, or the cycloalkyl or heterocyclyl ring and Cy1 form a fused ring structure when n is 0 and v is 1 or 3,
• wherein the aryl, benzyl, heteroaryl, cycloalkyl, and heterocyclyl are independently optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, OH, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy;
• Z2 is CR8, or
• Z2—Z1—X form a 4- to 7-membered heterocyclyl ring optionally substituted with one or more R18, wherein the heterocyclyl ring, ring G, and Cy1 form a three-ring fused ring structure, provided that R1 is not optionally substituted phenyl, 2-furyl or 3-furyl, or
• X—Z2—R2 form a 3- to 7-membered cycloalkyl or heterocyclyl ring optionally substituted with one or more R18, wherein the cycloalkyl or heterocyclyl ring is bonded to Cy1, or the cycloalkyl or heterocyclyl ring and Cy1 form a fused ring structure;
• R8 is H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl, or when X0 or X is bonded to Z2, absent;
• R2 is H, halogen, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, NR20R21, C(O)NR20R21, S(O)q—C1-C6 alkyl, S(O)2NR20R21, NR20S(O)2—C1-C6 alkyl, C6-C10 aryl, benzyl, heteroaryl comprising one 5- or 6-membered ring and one to four heteroatoms independently selected from N, O, and S, C3-C6 cycloalkyl, or heterocyclyl comprising one 4- to 6-membered ring and one to four heteroatoms independently selected from N, O, and S, provided that when X0 or X forms a bond with Z2, R2 is not H and provided that when X is bonded to Z2 and is NR4, O, S, S(O), or S(O)2, R2 is not OH, C1-C6 alkoxy, NR20R21, C1-C6 haloalkoxy, S(O)q—C1-C6 alkyl, S(O)2NR20R21, or NR20S(O)2—C1-C6 alkyl;
• or
• X—Z2—R2 form a 3- to 7-membered cycloalkyl or heterocyclyl ring optionally substituted with one or more R18, wherein the cycloalkyl or heterocyclyl ring is bonded to Cy1, or the cycloalkyl or heterocyclyl ring and Cy1 form a fused ring structure,
• wherein the aryl, benzyl, heteroaryl, cycloalkyl, and heterocyclyl are independently optionally substituted with one or more substituents independently selected from halogen, C1-C6 alkyl, OH, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy;
• each R18 is independently halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 haloalkoxy;
• or two R18 together with the carbon atom to which they are bonded form a C(O);
• q is 0, 1, or 2;
• R20 and R21 are each independently H, C1-C6 alkyl, C1-C6 haloalkyl, or C6-C10 aryl, wherein the aryl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and halogen;
• Cy1 is C6-C10 aryl, benzyl, or heteroaryl comprising one or two 5- or 6-membered rings and one to four heteroatoms independently selected from N, O, and S, wherein each ring is aromatic or partially unsaturated, or N—(C6-C10 aryl) when X is CR3R3′ and when X—Z1—R1 form a 3- to 7-membered heterocyclyl ring, wherein the aryl, benzyl, and heteroaryl are independently optionally substituted with one or more R16, provided that
• when p is 1, X is NH and is bonded to Z1, and R1 is C(O)NH2, then Cy1 is not unsubstituted phenyl,
• when p is 1, X is CH2 and is bonded to Z1, and R1 is OH or halogen, then Cy1 is not optionally substituted phenyl, benzoimidazolyl, benzoimidazolonyl, or dihydroquinoxaline-2,3-dione;
• and
• when p is 1, X is C(O) and is bonded to Z1, Y is O, and R1 is OH or methoxy, then Cy1 is not optionally substituted phenyl;
• each R16 is independently halogen, C1-C6 alkyl, OH, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C(O)—(C1-C3 alkyl), S(O)q—(C1-C3) alkyl, NH2, N(C1-C6 alkyl)2, CN, C6-C10 aryl, or NO2;
• Z3 is C(R9)2;
• each R9 is independently H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl;
• p is 0 or 1;
• Z′ is C(R12)2;
• or
• Z′ and Z3 together with the atom(s) to which they are bonded form a 4- to 7-membered cycloalkyl or heterocyclyl ring which, together with ring G, forms a fused ring structure;
• or
• Z′ and Z3 together with the atom(s) to which they are bonded form a 4- to 7-membered aryl or heteroaryl ring which, together with ring G, forms a fused ring structure;
• Z″ is C(R13)2;
• or
• Z″ and Z2 together with the atom(s) to which they are bonded form a 4- to 7-membered cycloalkyl or heterocyclyl ring which, together with ring G, forms a fused ring structure;
• or
• Z″ and Z2 together with the atom(s) to which they are bonded form a 4- to 7-membered aryl or heteroaryl ring which, together with ring G, forms a fused ring structure;
• each R12 is independently H, C1-C3 alkyl, C1-C3 haloalkyl, or halogen, or two R12 together with the carbon atom to which they are bonded form a 3- to 6-membered cycloalkyl or heterocyclyl ring which, together with ring G, forms a spirocyclic ring structure;
• each R13 is independently H, C1-C3 alkyl, C1-C3 haloalkyl, or halogen, or two R13 together with the carbon atom to which they are bonded form a 3- to 6-membered cycloalkyl or heterocyclyl ring which, together with ring G, forms a spirocyclic ring structure;
• or
• R12 and R3, together with the carbon atoms to which they are bonded and the nitrogen atom in ring G, form a 5- to 7-membered heterocyclyl ring, wherein the heterocyclyl ring and ring G form a bridged ring structure;
• Z6 is C(R14)2;
• v is 1, 2, or 3;
• each R14 is independently H or C1-C3 alkyl;
• Z4 is
• when n is 0 or 1, C(R10)2, or
• when n is 0, Y—Z4—R17 form a 4- to 7-membered cycloalkyl or heterocyclyl ring optionally substituted with one or more R19;
• each R17 is independently halogen, C1-C6 alkyl, OH, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C(O)—C1-C3 alkyl, S(O)q—C1-C3 alkyl, NH2, N(C1-C6 alkyl)2, CN, C6-C10 aryl, or NO2;
• or
• two R17 together with the carbon atoms to which they are bonded form a C6-C10 aryl or heteroaryl optionally substituted with one or more R19, or
• when n is 0, Y—Z4—R17 form a 4- to 7-membered heterocyclyl ring optionally substituted with one or more R19;
• each R19 is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or halogen;
• each R10 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or halogen;
• or two R10 together with the carbon atom to which they are bonded, form C(O);
• Y is
• when n is 0 or 1, C(O), CR5R5′, NR6, O, S, S(O), or S(O)2, or
• when n is 0 or 1, Y—Z4—Z6 form a 4- to 7-membered heterocyclyl ring optionally substituted with one or more R19, or
• when n is 0, Y—Z4—R17 form a 4- to 7-membered heterocyclyl ring optionally substituted with one or more R19, or
• when n is 0 and Cy2 is absent, pyridinonyl optionally substituted with one or more R17;
• R5 and R5′ are each independently H, C1-C6 alkyl, OH, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or halogen;
• R6 is H, C1-C6 alkyl, or C1-C6 haloalkyl;
• Z5 is C(R11)2;
• each R11 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or halogen;
• n is 0 or 1;
• Cy2 is C3-C8 cycloalkyl, heterocyclyl comprising one 4- to 7-membered ring and one to four heteroatoms independently selected from N, O, and S, C6-C10 aryl, or heteroaryl comprising one or two 5- or 6-membered rings and one to four heteroatoms independently selected from N, O, and S, or absent when n is 0 and Y is pyridinonyl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are independently optionally substituted with one or more R17;
• and
• provided that a compound of Formula (I) is not
• 1-(methylsulfonyl)-5-(3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)propyl)-1H-indole-3-carbonitrile;
• or
• 5-(3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)propyl)-1H-indole-3-carbonitrile.