Dopamine D2 receptor ligands

Patent metadata

Field	Value
Publication number	US-10633336-B2
Application number	US-201515537741-A
Country	US
Kind code	B2
Filing date	Dec 18, 2015
Priority date	Dec 19, 2014
Publication date	Apr 28, 2020
Grant date	Apr 28, 2020

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. The present invention relates to novel compounds that modulate dopamine D2 receptors. In particular, compounds of the present invention show functional selectivity at the dopamine D2 receptors and exhibit selectivity downstream of the D2 receptors, on the 0-arrestin pathway and/or on the cAMP pathway.

First claim

What is claimed is:

1. A compound of Formula I:

or a stereoisomer, racemate, or tautomer thereof, or a pharmaceutically acceptable salt thereof, 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 -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, S(O), 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. The compound of claim 1 , having 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.

3. The compound of claim 1 , having Formula (III):

Assignees

• Broad Inst Inc
• Massachusetts Inst Technology

Inventors

• Holson Edward
• Wagner Florence Fevrier
• Weiwer Michel
• Scolnick Edward
• Palmer Michelle
• Dordevic Luka
• Lewis Michael C
• Pan Jennifer Q
• Zhang Yan-Ling
• Xu Qihong

Classifications

• C07D211/38

  Halogen atoms or nitro radicals · CPC title

• C07K14/70571

  for neuromediators, e.g. serotonin receptor, dopamine receptor · CPC title

• C07D211/58

  attached in position 4 · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D405/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title