Dopamine D2 receptor ligands

A method of treating a psychotic disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I:

• or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient or carrier, wherein:
• X0 is 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;
• 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 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;
• 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, 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;
• 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, 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, wherein the aryl, benzyl, and heteroaryl are independently optionally substituted with one or more R16;
• 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 1;
• Z′ is C(R12)2;
• each R12 is independently H, C1-C3 alkyl, C1-C3 haloalkyl, or halogen;
• Z″ is C(R13)2;
• each R13 is independently H, C1-C3 alkyl, C1-C3 haloalkyl, or halogen;
• Z6 is C(R14)2;
• v is 1;
• each R14 is independently H or C1-C3 alkyl;
• Z4 is C(R10)2;
• 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-Cio aryl or heteroaryl optionally substituted with one or more R19, or
• 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 NR6, O, S, or S(O)2;
• R6 is H, C1-C6 alkyl, or C1-C6 haloalkyl;
• n is 0;
• 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, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are independently optionally substituted with one or more R17;
• provided that:
• when X0 or X forms a bond with Z1, then R1 is not H;
• when X0 or X forms a bond with Z2, then R2 is not H;
• when X is bonded to Z1 and is NR4, O, S, S(O), or S(O)2, then 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;
• when X is bonded to Z2 and is NR4, O, S, S(O), or S(O)2, then 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;
• when X is NH and is bonded to Z1, and R1 is C(O) NH2, then Cy1 is not unsubstituted phenyl,
• when 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 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.

A method of preventing a psychotic disorder comprising administering to a subject in need thereof a prophylactically effective amount of a compound of Formula I:

• or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient or carrier, wherein:
• X0 is 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;
• 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 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;
• 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, 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;
• 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, 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, wherein the aryl, benzyl, and heteroaryl are independently optionally substituted with one or more R16;
• 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 1;
• Z′ is C(R12)2;
• each R12 is independently H, C1-C3 alkyl, C1-C3 haloalkyl, or halogen;
• Z″ is C(R13)2;
• each R13 is independently H, C1-C3 alkyl, C1-C3 haloalkyl, or halogen;
• Z6 is C(R14)2;
• v is 1;
• each R14 is independently H or C1-C3 alkyl;
• Z4 is C(R10)2;
• 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 Co-Cio aryl or heteroaryl optionally substituted with one or more R19, or
• 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 NR6, O, S, or S(O)2;
• R6 is H, C1-C6 alkyl, or C1-C6 haloalkyl;
• n is 0;
• 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, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are independently optionally substituted with one or more R17;
• provided that:
• when X0 or X forms a bond with Z1, then R1 is not H;
• when X0 or X forms a bond with Z2, then R2 is not H;
• when X is bonded to Z1 and is NR4, O, S, S(O), or S(O)2, then 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;
• when X is bonded to Z2 and is NR4, O, S, S(O), or S(O)2, then 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;
• when X is NH and is bonded to Z1, and R1 is C(O) NH2, then Cy1 is not unsubstituted phenyl,
• when 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 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.