IP Library › Granted Patent US 11,498,896

Granted Patent B2

US 11,498,896 · App. 16/826,028 · Granted Nov 15, 2022

Dopamine D2 receptor ligands

Inventors: Edward Holson (Newton Highlands, MA); Florence Fevrier Wagner (Ashland, MA); Michel Weiwer (Cambridge, MA); Edward Scolnick (Wayland, MA); Michelle Palmer (Harvard, MA); Luka Dordevic (Trieste, IT); Michael C. Lewis (Dedham, MA); Jennifer Q. Pan (Acton, MA); Yan-Ling Zhang (Lexington, MA); Qihong Xu (Newton, MA)

Assignees: The Broad Institute, Inc.; Massachusetts Institute of Technology

C07D207/12 A61P25/16 A61P25/18 C07D211/18 C07D211/22 C07D211/38 C07D211/42 C07D211/48 C07D211/58 C07D211/62 C07D211/70 C07D401/04 C07D401/06 C07D401/12 C07D405/06 C07D413/12 C07D417/12 C07D451/06 C07D471/10 C07D491/048 C07D491/052 C07D491/056 C07D491/107 C07K14/70571

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Quick Facts

Patent No.: US 11,498,896
App. No.: 16/826,028
Granted: Nov 15, 2022
Kind: B2

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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 (228)

1. A compound of Formula I:

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

X 0 is C 1 -C 6 alkyl, 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 ;

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

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 H, 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 absent;

R 1 is halogen, 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, 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, provided that when X is NR 4 , O, S, S(O), or S(O) 2 , R 1 is not 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; wherein the 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;

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, or C 1 -C 6 haloalkyl;

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, or N—(C 6 -C 10 aryl) when X is CR 3 R 3′ , wherein the aryl, benzyl, and heteroaryl are independently optionally substituted with one or more R 16 , provided that

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

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

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 ;

Z″ is C(R 13 ) 2 ;

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

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, 2, or 3;

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

Y—Z 4 —R 17 form a 4- to 7-membered, cycloalkyl or heterocyclyl ring, each of which is fused with Cy 2 and is optionally substituted with one or more R 19 , wherein the R 17 of Y—Z 4 —R 17 is an R 17 on Cy 2 ;

each remaining R 17 if present 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 ;

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;

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; and

each heterocyclyl is not aromatic.

2. The compound of claim 1 , having Formula (II):

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

X 0 is C 1 -C 6 alkyl, X-Cy 1 , C(O)NR 4 R 4′ , NR 4 C(O)R 4′ , or CR 3 R 3′ —NR 4 R 4′ ;

X is C(O), CR 3 R 3′ , NR 4 , O, S, S(O), or S(O) 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;

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

R 1 is halogen, 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, 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, provided that when X is NR 4 , O, S, S(O), or S(O) 2 , R 1 is not 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, wherein the 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;

q is 0, 1, or 2;

R 20 and R 21 are each independently H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

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 , provided that

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

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

R 12 and R 13 are each independently H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or halogen, or R 12 and R 13 , 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;

Z 6 is C(R 14 ) 2 ;

v is 1, 2, or 3;

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

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 heterocyclyl is not aromatic.

3. The compound of claim 1 , having formula (XI):

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

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

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 ;

R 1 is halogen, 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, 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 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 q is independently 0, 1, or 2;

R 20 and R 21 are each independently H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

Z 6 is C(R 14 ) 2 ;

v is 1, 2, or 3;

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

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

r is 0, 1, 2, 3, or 4; and

each heterocyclyl is not aromatic.

4. The compound of claim 1 , having formula (XII):

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

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

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 ;

R 1 is halogen, 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, 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 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 q is independently 0, 1, or 2;

R 20 and R 21 are each independently H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

Z 6 is C(R 14 ) 2 ;

v is 1, 2, or 3;

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

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

r is 0, 1, 2, 3, or 4; and

each heterocyclyl is not aromatic.

5. The compound of claim 1 , having formula (XIII):

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

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;

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

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 ;

R 1 is halogen, 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, 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 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 q is independently 0, 1, or 2;

R 20 and R 21 are each independently H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

Z 6 is C(R 14 ) 2 ;

v is 1, 2, or 3;

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

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

r is 0, 1, 2, 3, or 4; and

each heterocyclyl is not aromatic.

6. A pharmaceutical composition comprising a compound of claim 1 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients or carriers.

7. A method of modulating D2 receptor activity, treating a psychotic disorder, or preventing a psychotic disorder comprising administering to a subject in need thereof an effective amount of a compound of the formula:

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

X 0 is C 1 -C 6 alkyl, 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 ;

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

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;

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 absent;

R 1 is 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, 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, provided that when X is NR 4 , O, S, S(O), or S(O) 2 , 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; wherein the 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;

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;

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

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

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 ;

Z″ is C(R 13 ) 2 ;

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

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, 2, or 3;

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

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 heterocyclyl is not aromatic.

8. The method of claim 7 , wherein the method is a method of treating a psychotic disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compound, or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient or carrier.

9. The compound of claim 1 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X 0 is C(O)NR 4 R 4′ and is bonded to Z 1 .

10. The compound of claim 1 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X 0 is NR 4 C(O)R 4′ and is bonded to Z 1 .

11. The compound of claim 1 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is H or —CH 3 .

12. The compound of claim 1 , 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 .

13. The compound of claim 1 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1 -C 6 alkyl.

14. The compound of claim 1 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is —CH 3 .

15. The compound of claim 1 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is H, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

16. The compound of claim 1 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein v is 1.

17. The compound of claim 1 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y—Z 4 —R 17 form a 6-membered heterocyclyl ring, which is fused with Cy 2 and is optionally substituted with one or more R 19 , wherein the R 17 of Y—Z 4 —R 17 is an R 17 on Cy 2 .

18. The compound of claim 1 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Cy 2 is phenyl.

19. The compound of claim 1 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:

20. The compound of claim 1 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:

wherein:

each R 17 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, or halogen; and

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

21. The compound of claim 1 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:

wherein t is 0, 1, 2, 3, or 4.

22. The compound of claim 1 , or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of any one of the formulae:

For -

mula

Num-

ber

Formula

142

303

202

203

204

205

206

208

209

210

211

212

213

207

23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is of any one of the formulae:

Formula

Number

Formula

205

208

209

210

212

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

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

26. The method of claim 7 , wherein the method is a method of preventing a psychotic disorder, comprising administering to a subject in need thereof a prophylactically effective amount of the compound, or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient or carrier.

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

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

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

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

31. The method of claim 8 , wherein the compound is of any one of the formulae:

For-

mula

Num-

ber

Formula

142

303

202

203

204

205

206

208

209

210

211

212

213

207

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

32. The method of claim 7 , wherein the method is a method of modulating D2 receptor activity.

Assignments (7)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 22, 2020

From: SCOLNICK, EDWARD

To: MASSACHUSETTS INSTITUTE OF TECHNOLOGY

Reel/Frame 052997/0664 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 16, 2020

From: SCOLNICK, EDWARD

To: THE BROAD INSTITUTE, INC.

Reel/Frame 052952/0022 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 16, 2020

From: PALMER, MICHELLE

To: THE BROAD INSTITUTE, INC.

Reel/Frame 052952/0042 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 16, 2020

From: HOLSON, EDWARD; WAGNER, FLORENCE FEVRIER; WEIWER, MICHEL

To: THE BROAD INSTITUTE, INC.

Reel/Frame 052951/0916 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 16, 2020

From: PAN, JENNIFER Q.

To: THE BROAD INSTITUTE, INC.

Reel/Frame 052952/0281 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 16, 2020

From: ZHANG, YAN-LING; XU, QIHONG; LEWIS, MICHAEL C.

To: THE BROAD INSTITUTE, INC.

Reel/Frame 052954/0387 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 16, 2020

From: DORDEVIC, LUKA

To: THE BROAD INSTITUTE, INC.

Reel/Frame 052952/0153 →

Continuity (3)

Continuation 15537741

Provisional Application 62094670 · Dec 19, 2014

Related Publication 20210147355A1 · May 20, 2021

Cited By (1)

US 12,428,373