IP Library › Granted Patent US 12,428,373
Granted Patent B2
US 12,428,373 · App. 17/962,346 · Granted Sep 30, 2025

Dopamine D2 receptor ligands

Inventors: Edward Holson (Cambridge, MA); Florence Fevrier Wagner (Cambridge, MA); Michel Weiwer (Cambridge, MA); Edward Scolnick (Cambridge, MA); Michelle Palmer (Cambridge, MA); Luka Dordevic (Cambridge, MA); Michael C. Lewis (Cambridge, MA); Jennifer Q. Pan (Cambridge, MA); Yan-Ling Zhang (Cambridge, MA); Qihong Xu (Cambridge, MA)
Assignees: The Broad Institute, Inc.; Massachusetts Institute of Technology
C07D207/12A61P25/16A61P25/18C07D211/18C07D211/22C07D211/38C07D211/42C07D211/48C07D211/58C07D211/62C07D211/70C07D401/04C07D401/06C07D401/12C07D405/06C07D413/12C07D417/12C07D451/06C07D471/10C07D491/048C07D491/052C07D491/056C07D491/107C07K14/70571
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Quick Facts
Patent No.
US 12,428,373
App. No.
17/962,346
Granted
Sep 30, 2025
Kind
B2
Abstract

The present invention relates to novel dopamine D2 receptor ligands. The invention further relates to functionally-biased dopamine D2 receptor ligands and the use of these compounds for treating or preventing central nervous system and systemic disorders associated with dysregulation of dopaminergic activity.

Claims (498)

1. A method of modulating D2 receptor activity, comprising administering to a subject in need thereof an effective amount of a compound of Formula I:

or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof,

wherein:

X 1 is X-Cy 1 , C(O)NR 4 R 4′ , NR 4 C(O)R 4′ , or CR 3 R 3′ —NR 4 R 4′ , and is bonded to Z 1 or Z 2 ;

X is C(O), CR 3 R 3′ , NR 4 , O, S, S(O), or S(O) 2 , and is bonded to Z 1 or Z 2 ;

R 3 and R 3′ are each independently H, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, or halogen;

each R 4 is independently H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

R 4′ is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, heterocyclyl comprising one 4- to 7-membered ring and one to four heteroatoms independently selected from N, O, and S, C 6 -C 10 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 R 17 ;

or R 4 and R 4′ 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 R 18 ;

Z 1 is CR 7 ;

R 7 is H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, or when X° or X is bonded to Z 1 , absent;

R 1 is H, halogen, OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, NR 20 R 21 , C(O)NR 20 R 21 , S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , NR 20 S(O) 2 —C 1 -C 6 alkyl, C 6 -C 10 aryl, benzyl, heteroaryl comprising one 5- or 6-membered ring and one to four heteroatoms independently selected from N, O, and S, C 3 -C 6 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, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy;

Z 2 is CR 8 ;

R 8 is H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, or when X 0 or X is bonded to Z 2 , absent;

R 2 is H, halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, NR 20 R 21 , C(O)NR 20 R 21 , S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , NR 20 S(O) 2 —C 1 -C 6 alkyl, C 6 -C 10 aryl, benzyl, heteroaryl comprising one 5- or 6-membered ring and one to four heteroatoms independently selected from N, O, and S, C 3 -C 6 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, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy;

each R 18 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, or C 1 -C 6 haloalkoxy; or two R 18 together with the carbon atom to which they are bonded form a C(O);

q is 0, 1, or 2;

R 20 and R 21 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 6 -C 10 aryl, wherein the aryl is optionally substituted with one or more substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, and halogen;

Cy 1 is C 6 -C 10 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 R 16 ;

each R 16 is independently halogen, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C(O)—(C 1 -C 3 alkyl), S(O) q —(C 1 -C 3 ) alkyl, NH 2 , N(C 1 -C 6 alkyl) 2 , CN, C 6 -C 10 aryl, or NO 2 ;

Z 3 is C(R 9 ) 2 ;

each R 9 is independently H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

p is 1;

Z′ is C(R 12 ) 2 ;

each R 12 is independently H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or halogen;

Z″ is C(R 13 ) 2 ;

each R 13 is independently H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or halogen;

Z 6 is C(R 14 ) 2 ;

v is 1;

each R 14 is independently H or C 1 -C 3 alkyl;

Z 4 is C(R 10 ) 2 ;

each R 17 is independently halogen, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C(O)—C 1 -C 3 alkyl, S(O) q —C 1 -C 3 alkyl, NH 2 , N(C 1 -C 6 alkyl) 2 , CN, C 6 -C 10 aryl, or NO 2 ; or

two R 17 together with the carbon atoms to which they are bonded form a C 6 -C 10 aryl or heteroaryl optionally substituted with one or more R 19 , or

each R 19 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, or halogen;

each R 10 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or halogen; or two R 10 together with the carbon atom to which they are bonded, form C(O);

Y is NR 6 , O, S, or S(O) 2 ;

R 6 is H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

n is 0;

Cy 2 is C 3 -C 8 cycloalkyl, heterocyclyl comprising one 4- to 7-membered ring and one to four heteroatoms independently selected from N, O, and S, C 6 -C 10 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 R 17 ;

provided that:

when X 0 or X forms a bond with Z 1 , then R 1 is not H;

when X 0 or X forms a bond with Z 2 , then R 2 is not H;

when X is bonded to Z 1 and is NR 4 , O, S, S(O), or S(O) 2 , then R 1 is not OH, C 1 -C 6 alkoxy, NR 20 R 21 , C 1 -C 6 haloalkoxy, S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , or NR 20 S(O) 2 —C 1 -C 6 alkyl;

when X is bonded to Z 2 and is NR 4 , O, S, S(O), or S(O) 2 , then R 2 is not OH, C 1 -C 6 alkoxy, NR 20 R 21 , C 1 -C 6 haloalkoxy, S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , or NR 20 S(O) 2 —C 1 -C 6 alkyl;

when X is NH and is bonded to Z 1 , and R 1 is C(O) NH 2 , then Cy 1 is not unsubstituted phenyl,

when X is CH 2 and is bonded to Z 1 , and R 1 is OH or halogen, then Cy 1 is not optionally substituted phenyl, benzoimidazolyl, benzoimidazolonyl, or dihydroquinoxaline-2,3-dione; and

when X is C(O) and is bonded to Z 1 , Y is O, and R 1 is OH or methoxy, then Cy 1 is not optionally substituted phenyl.

2. 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:

X 0 is X-Cy 1 , C(O)NR 4 R 4 , NR 4 C(O)R 4′ , or CR 3 R 3′ —NR 4 R 4′ , and is bonded to Z 1 or Z 2 ;

X is C(O), CR 3 R 3′ , NR 4 , O, S, S(O), or S(O) 2 , and is bonded to Z 1 or Z 2 ;

R 3 and R 3′ are each independently H, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, or halogen;

each R 4 is independently H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

R 4′ is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, heterocyclyl comprising one 4- to 7-membered ring and one to four heteroatoms independently selected from N, O, and S, C 6 -C 10 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 R 17 ;

or R 4 and R 4′ 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 R 18 ;

Z 1 is CR 7 ;

R 7 is H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, or when X 0 or X is bonded to Z 1 , absent;

R 1 is H, halogen, OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, NR 20 R 21 , C(O)NR 20 R 21 , S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , NR 20 S(O) 2 —C 1 -C 6 alkyl, C 6 -C 10 aryl, benzyl, heteroaryl comprising one 5- or 6-membered ring and one to four heteroatoms independently selected from N, O, and S, C 3 -C 6 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, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy;

Z 2 is CR 8 ;

R 8 is H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, or when X 0 or X is bonded to Z 2 , absent;

R 2 is H, halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, NR 20 R 21 , C(O)NR 20 R 21 , S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , NR 20 S(O) 2 —C 1 -C 6 alkyl, C 6 -C 10 aryl, benzyl, heteroaryl comprising one 5- or 6-membered ring and one to four heteroatoms independently selected from N, O, and S, C 3 -C 6 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, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy;

each R 18 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, or C 1 -C 6 haloalkoxy; or two R 18 together with the carbon atom to which they are bonded form a C(O);

q is 0, 1, or 2;

R 20 and R 21 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 6 -C 10 aryl, wherein the aryl is optionally substituted with one or more substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, and halogen;

Cy 1 is C 6 -C 10 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 R 16 ;

each R 16 is independently halogen, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C(O)—(C 1 -C 3 alkyl), S(O) q —(C 1 -C 3 ) alkyl, NH 2 , N(C 1 -C 6 alkyl) 2, CN, C 6 -C 10 aryl, or NO 2 ;

Z 3 is C(R 9 ) 2 ;

each R 9 is independently H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

p is 1;

Z′ is C(R 12 ) 2 ;

each R 12 is independently H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or halogen;

Z″ is C(R 13 ) 2 ;

each R 13 is independently H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or halogen;

Z 6 is C(R 14 ) 2 ;

v is 1;

each R 14 is independently H or C 1 -C 3 alkyl;

Z 4 is C(R 10 ) 2 ;

each R 17 is independently halogen, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C(O)—C 1 -C 3 alkyl, S(O) q —C 1 -C 3 alkyl, NH 2 , N(C 1 -C 6 alkyl) 2 , CN, C 6 -C 10 aryl, or NO 2 ; or

two R 17 together with the carbon atoms to which they are bonded form a C 6 -Cio aryl or heteroaryl optionally substituted with one or more R 19 , or

each R 19 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, or halogen;

each R 10 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or halogen; or two R 10 together with the carbon atom to which they are bonded, form C(O);

Y is NR 6 , O, S, or S(O) 2 ;

R 6 is H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

n is 0;

Cy 2 is C 3 -C 8 cycloalkyl, heterocyclyl comprising one 4- to 7-membered ring and one to four heteroatoms independently selected from N, O, and S, C 6 -C 10 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 R 17 ;

provided that:

when X 0 or X forms a bond with Z 1 , then R 1 is not H;

when X 0 or X forms a bond with Z 2 , then R 2 is not H;

when X is bonded to Z 1 and is NR 4 , O, S, S(O), or S(O) 2 , then R 1 is not OH, C 1 -C 6 alkoxy, NR 20 R 21 , C 1 -C 6 haloalkoxy, S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , or NR 20 S(O) 2 —C 1 -C 6 alkyl;

when X is bonded to Z 2 and is NR 4 , O, S, S(O), or S(O) 2 , then R 2 is not OH, C 1 -C 6 alkoxy, NR 20 R 21 , C 1 -C 6 haloalkoxy, S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , or NR 20 S(O) 2 —C 1 -C 6 alkyl;

when X is NH and is bonded to Z 1 , and R 1 is C(O) NH 2 , then Cy 1 is not unsubstituted phenyl,

when X is CH 2 and is bonded to Z 1 , and R 1 is OH or halogen, then Cy 1 is not optionally substituted phenyl, benzoimidazolyl, benzoimidazolonyl, or dihydroquinoxaline-2,3-dione; and when X is C(O) and is bonded to Z 1 , Y is O, and R 1 is OH or methoxy, then Cy 1 is not optionally substituted phenyl.

3. The method of claim 2 , wherein the compound is of Formula (II):

or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

R 1 is halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, NR 20 R 21 , C(O)NR 20 R 21 , S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , NR 20 S(O) 2 —C 1 -C 6 alkyl, C 6 -C 10 aryl, benzyl, heteroaryl comprising one 5- or 6-membered ring and one to four heteroatoms independently selected from N, O, and S, C 3 -C 6 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, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.

4. The method of claim 2 , wherein the compound is of Formula (III):

or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

X 0 is X-Cy 1 ; and

R 2 is halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, NR 20 R 21 , C(O)NR 20 R 21 , S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , NR 20 S(O) 2 —C 1 -C 6 alkyl, C 6 -C 10 aryl, benzyl, heteroaryl comprising one 5- or 6-membered ring and one to four heteroatoms independently selected from N, O, and S, C 3 -C 6 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, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.

5. The method of claim 2 , wherein the compound is of formula (XI):

or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, NR 20 R 21 , C(O)NR 20 R 21 , S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , NR 20 S(O) 2 —C 1 -C 6 alkyl, C 6 -C 10 aryl, benzyl, heteroaryl comprising one 5- or 6-membered ring and one to four heteroatoms independently selected from N, O, and S, C 3 -C 6 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, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy;

Cy 2 is C 3 -C 8 cycloalkyl, heterocyclyl comprising one 4- to 7-membered ring and one to four heteroatoms independently selected from N, O, and S, C 6 -C 10 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 R 17 ;

each R 30 is independently halogen, C 1-3 alkyl, or C 1-3 haloalkyl; and

r is 0, 1, 2, 3, or 4.

6. The method of claim 2 , wherein the compound is of formula (XII):

or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, NR 20 R 21 , C(O)NR 20 R 21 , S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , NR 20 S(O) 2 —C 1 -C 6 alkyl, C 6 -C 10 aryl, benzyl, heteroaryl comprising one 5- or 6-membered ring and one to four heteroatoms independently selected from N, O, and S, C 3 -C 6 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, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy;

Cy 2 is C 3 -C 8 cycloalkyl, heterocyclyl comprising one 4- to 7-membered ring and one to four heteroatoms independently selected from N, O, and S, C 6 -C 10 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 R 17 ;

each R 30 is independently halogen, C 1-3 alkyl, or C 1-3 haloalkyl; and

r is 0, 1, 2, 3, or 4.

7. The method of claim 2 , wherein the compound is of formula (XIII):

or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, NR 20 R 21 , C(O)NR 20 R 21 , S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , NR 20 S(O) 2 —C 1 -C 6 alkyl, C 6 -C 10 aryl, benzyl, heteroaryl comprising one 5- or 6-membered ring and one to four heteroatoms independently selected from N, O, and S, C 3 -C 6 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, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy;

Cy 2 is C 3 -C 8 cycloalkyl, heterocyclyl comprising one 4- to 7-membered ring and one to four heteroatoms independently selected from N, O, and S, C 6 -C 10 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 R 17 ;

each R 30 is independently halogen, C 1-3 alkyl, or C 1-3 haloalkyl; and

r is 0, 1, 2, 3, or 4.

8. The method of claim 2 , wherein the compound is of the formula:

Formula Number

Formula

38

67

68

69

70

71

72

74

75

76

80

82

83

86

87

88

89

90

91

103

104

105

106

107

109

110

111

112

122

125

126

127

128

129

141

143

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

173

174

175

182

183

184

185

186

187

188

189

190

191

192

215

217

61

62

63

96

97

98

99

100

108

198

199

200

201

219

220

or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof.

9. The method of claim 2 , wherein X 0 is X-Cy 1 , and X is O.

10. The method of claim 2 , wherein X 0 is C(O)NR 4 R 4′ or NR 4 C(O)R 4′ .

11. The method of claim 2 , wherein Cy 1 is phenyl optionally substituted with one or more R 16 .

12. The method of claim 2 , wherein R 1 is —CH 3 .

13. The method of claim 2 , wherein Y is O.

14. The method of claim 2 , wherein Cy 2 is phenyl optionally substituted with one or more R 17 .

15. The method of claim 2 , wherein the compound is of the formula:

Formula

Number

Formula

76

90

91

110

122

146

157

or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof.

16. The method of claim 3 , wherein the compound is of the formula:

or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof.

17. The method of claim 3 , wherein the compound is of the formula:

or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof.

18. The method of claim 3 , wherein the compound is of the formula:

or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein g is 0, 1, 2, 3, 4, or 5.

19. The method of claim 3 , wherein the compound is of the formula:

or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein g is 0, 1, 2, 3, 4, or 5; and t is 0, 1, 2, 3, 4, or 5.

20. The method of claim 3 , wherein the compound is of the formula:

or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein g is 0, 1, 2, 3, 4, or 5; and t is 0, 1, 2, 3, 4, or 5.

21. The method of claim 3 , wherein the compound is of the formula:

or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein t is 0, 1, 2, 3, 4, or 5.

22. The method of claim 10 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 4′ is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more R 17 .

23. The method of claim 2 , wherein the psychotic disorder is schizophrenia.

24. The method of claim 2 , wherein the psychotic disorder is brief psychotic disorder.

25. The method of claim 2 , wherein the psychotic disorder is delusional disorder.

26. The method of claim 2 , wherein the psychotic disorder is schizoaffective disorder.

27. The method of claim 2 , wherein the psychotic disorder is schizophreniform.

28. The method of claim 2 , wherein the psychotic disorder is shared psychotic disorder.

29. The method of claim 8 , wherein the psychotic disorder is schizophrenia.

30. 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:

X 0 is X-Cy 1 , C(O)NR 4 R 4′ , NR 4 C(O)R 4′ , or CR 3 R 3′ —NR 4 R 4′ , and is bonded to Z 1 or Z 2 ;

X is C(O), CR 3 R 3′ , NR 4 , O, S, S(O), or S(O) 2 , and is bonded to Z 1 or Z 2 ;

R 3 and R 3′ are each independently H, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, or halogen;

each R 4 is independently H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

R 4′ is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, heterocyclyl comprising one 4- to 7-membered ring and one to four heteroatoms independently selected from N, O, and S, C 6 -C 10 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 R 17 ;

or R 4 and R 4′ 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 R 18 ;

Z 1 is CR 7 ;

R 7 is H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, or when X 0 or X is bonded to Z 1 , absent;

R 1 is H, halogen, OH, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, NR 20 R 21 , C(O)NR 20 R 21 , S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , NR 20 S(O) 2 —C 1 -C 6 alkyl, C 6 -C 10 aryl, benzyl, heteroaryl comprising one 5- or 6-membered ring and one to four heteroatoms independently selected from N, O, and S, C 3 -C 6 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, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy;

Z 2 is CR 8 ;

R 8 is H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, or when X 0 or X is bonded to Z 2 , absent;

R 2 is H, halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, NR 20 R 21 , C(O)NR 20 R 21 , S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , NR 20 S(O) 2 —C 1 -C 6 alkyl, C 6 -C 10 aryl, benzyl, heteroaryl comprising one 5- or 6-membered ring and one to four heteroatoms independently selected from N, O, and S, C 3 -C 6 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, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy;

each R 18 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, or C 1 -C 6 haloalkoxy; or two R 18 together with the carbon atom to which they are bonded form a C(O);

q is 0, 1, or 2;

R 20 and R 21 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 6 -C 10 aryl, wherein the aryl is optionally substituted with one or more substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, and halogen;

Cy 1 is C 6 -C 10 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 R 16 ;

each R 16 is independently halogen, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C(O)—(C 1 -C 3 alkyl), S(O) q —(C 1 -C 3 ) alkyl, NH 2 , N(C 1 -C 6 alkyl) 2, CN, C 6 -C 10 aryl, or NO 2 ;

Z 3 is C(R 9 ) 2 ;

each R 9 is independently H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

p is 1;

Z′ is C(R 12 ) 2 ;

each R 12 is independently H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or halogen;

Z″ is C(R 13 ) 2 ;

each R 13 is independently H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or halogen;

Z 6 is C(R 14 ) 2 ;

v is 1;

each R 14 is independently H or C 1 -C 3 alkyl;

Z 4 is C(R 10 ) 2 ;

each R 17 is independently halogen, C 1 -C 6 alkyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C(O)—C 1 -C 3 alkyl, S(O) q —C 1 -C 3 alkyl, NH 2 , N(C 1 -C 6 alkyl) 2 , CN, C 6 -C 10 aryl, or NO 2 ; or

two R 17 together with the carbon atoms to which they are bonded form a Co-Cio aryl or heteroaryl optionally substituted with one or more R 19 , or

each R 19 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, or halogen;

each R 10 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or halogen; or two R 10 together with the carbon atom to which they are bonded, form C(O);

Y is NR 6 , O, S, or S(O) 2 ;

R 6 is H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

n is 0;

Cy 2 is C 3 -C 8 cycloalkyl, heterocyclyl comprising one 4- to 7-membered ring and one to four heteroatoms independently selected from N, O, and S, C 6 -C 10 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 R 17 ;

provided that:

when X 0 or X forms a bond with Z 1 , then R 1 is not H;

when X 0 or X forms a bond with Z 2 , then R 2 is not H;

when X is bonded to Z 1 and is NR 4 , O, S, S(O), or S(O) 2 , then R 1 is not OH, C 1 -C 6 alkoxy, NR 20 R 21 , C 1 -C 6 haloalkoxy, S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , or NR 20 S(O) 2 —C 1 -C 6 alkyl;

when X is bonded to Z 2 and is NR 4 , O, S, S(O), or S(O) 2 , then R 2 is not OH, C 1 -C 6 alkoxy, NR 20 R 21 , C 1 -C 6 haloalkoxy, S(O) q —C 1 -C 6 alkyl, S(O) 2 NR 20 R 21 , or NR 20 S(O) 2 —C 1 -C 6 alkyl;

when X is NH and is bonded to Z 1 , and R 1 is C(O) NH 2 , then Cy 1 is not unsubstituted phenyl,

when X is CH 2 and is bonded to Z 1 , and R 1 is OH or halogen, then Cy 1 is not optionally substituted phenyl, benzoimidazolyl, benzoimidazolonyl, or dihydroquinoxaline-2,3-dione; and when X is C(O) and is bonded to Z 1 , Y is O, and R 1 is OH or methoxy, then Cy 1 is not optionally substituted phenyl.

31. The method of claim 1 , wherein the compound is of the formula:

Formula

Number

Formula

38

67

68

69

70

71

72

74

75

76

80

82

83

86

87

88

89

90

91

103

104

105

106

107

109

110

111

112

122

125

126

127

128

129

141

143

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

173

174

175

182

183

184

185

186

187

188

189

190

191

192

215

217

61

62

63

96

97

98

99

100

108

198

199

200

201

219

220

or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof.

32. The method of claim 30 , wherein the compound is of the formula:

Formula

Number

Formula

38

67

68

69

70

71

72

74

75

76

80

82

83

86

87

88

89

90

91

103

104

105

106

107

109

110

111

112

122

125

126

127

128

129

141

143

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

173

174

175

182

183

184

185

186

187

188

189

190

191

192

215

217

61

62

63

96

97

98

99

100

108

198

199

200

201

219

220

or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof.

33. The method of claim 8 , wherein the psychotic disorder is brief psychotic disorder.

34. The method of claim 8 , wherein the psychotic disorder is delusional disorder.

35. The method of claim 8 , wherein the psychotic disorder is schizoaffective disorder.

36. The method of claim 8 , wherein the psychotic disorder is schizophreniform.

37. The method of claim 8 , wherein the psychotic disorder is shared psychotic disorder.

Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 10, 2023
From: SCOLNICK, EDWARD
To: THE BROAD INSTITUTE, INC.; MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Reel/Frame 062949/0520 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 10, 2023
From: DORDEVIC, LUKA
To: THE BROAD INSTITUTE, INC.
Reel/Frame 062949/0591 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 10, 2023
From: HOLSON, EDWARD; WAGNER, FLORENCE FEVRIER; WEIWER, MICHEL
To: THE BROAD INSTITUTE, INC.
Reel/Frame 062949/0683 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 10, 2023
From: PALMER, MICHELLE; LEWIS, MICHAEL C.; PAN, JENNIFER Q.; ZHANG, YAN-LING; XU, QIHONG
To: THE BROAD INSTITUTE, INC.
Reel/Frame 063028/0556 →
Continuity (4)
Continuation 16826028 · Mar 20, 2020
Continuation 15537741
Provisional Application 62094670 · Dec 19, 2014
Related Publication 20230143552A1 · May 11, 2023
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