TRIAZOLE DAGLAlpha INHIBITORS

Patent metadata

Field	Value
Publication number	US-2018344729-A1
Application number	US-201615778207-A
Country	US
Kind code	A1
Filing date	Dec 2, 2016
Priority date	Dec 2, 2015
Publication date	Dec 6, 2018
Grant date	—

Abstract

Provided herein are triazole compounds and pharmaceutical compositions comprising said compounds useful as modulators of DAGL(α) and DAGL(β). In some embodiments, the compounds described herein are selective DAGL(α) inhibitors. Furthermore, the subject compounds and compositions are useful for the treatment of neurodegenerative or neuroinflammatory disease.

First claim

We claim:

1 . A compound of Formula (I):

wherein:

R′ is H, C 1-6 alkyl, —C(═O)OR 10 , or —S(═O) 2 R 10 ,
each R 2 is independently halogen, —CN, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —OH, —C(═O)OH, —C(═O)O(C 1-6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1-6 alkyl), —C(═O)N(C 1-6 alkyl) 2 , —S(═O) 2 NH 2 , —S(═O) 2 NH(C 1-6 alkyl), —S(═O) 2 N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —O—C 1-6 alkenyl, —O—C 1-6 alkynyl, C 1-6 haloalkoxy, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 2-9 heteroaryl;
each R 3 is independently halogen, —CN, —C(═O)OH, —C(═O)O(C 1-6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1-6 alkyl), —C(═O)N(C 1-6 alkyl) 2 , —S(═O) 2 NH 2 , —S(═O) 2 NH(C 1-6 alkyl), —S(═O) 2 N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 2-9 heteroaryl;
R 4 is

each R 5 is independently halogen, —CN, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —OH, —C(═O)OH, —C(═O)O(C 1-6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1-6 alkyl), —C(═O)N(C 1-6 alkyl) 2 , —S(═O) 2 NH 2 , —S(═O) 2 NH(C 1-6 alkyl), —S(═O) 2 N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —O—C 1-6 alkenyl, —O—C 1-6 alkynyl, or C 1-6 haloalkoxy;
R 10 is C 1-6 alkyl;
m is 0, 1, 2, or 3;
n is 0, 1, or 2;
p is 0, 1, 2, or 3,
q is 0, 1, 2, or 3, and
t is 0, 1, 2, or 3;
or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof.

2 . A compound of Formula (II):

wherein:

R 1 is H, C 1-6 alkyl, —C(═O)OR 10 , or —S(═O) 2 R 10 ;
each R 2 is independently halogen, —CN, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —OH, —C(═O)OH, —C(═O)O(C 1-6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1-6 alkyl), —C(═O)N(C 1-6 alkyl) 2 , —S(═O) 2 NH 2 , —S(═O) 2 NH(C 1-6 alkyl), —S(═O) 2 N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —O—C 1-6 alkenyl, —O—C 1-6 alkynyl, C 1-6 haloalkoxy, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 2-9 heteroaryl;
each R 3 is independently halogen, —CN, —C(═O)OH, —C(═O)O(C 1-6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1-6 alkyl), —C(═O)N(C 1-6 alkyl) 2 , —S(═O) 2 NH 2 , —S(═O) 2 NH(C 1-6 alkyl), —S(═O) 2 N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 2-9 heteroaryl;
R 4 is

each R 5 is independently halogen, —CN, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —OH, —C(═O)OH, —C(═O)O(C 1-6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1-6 alkyl), —C(═O)N(C 1-6 alkyl) 2 , —S(═O) 2 NH 2 , —S(═O) 2 NH(C 1-6 alkyl), —S(═O) 2 N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —O—C 1-6 alkenyl, —O—C 1-6 alkynyl, or C 1-6 haloalkoxy;
R 10 is C 1-6 alkyl;
m is 0, 1, 2, or 3;
n is 0, 1, or 2;
p is 0, 1, 2, or 3,
q is 0, 1, 2, or 3, and
t is 0, 1, 2, or 3;
or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof.

3 . A compound of Formula (V):

wherein:

R 1 is H, C 1-6 alkyl, —C(═O)R 10 , —C(═O)OR 10 , or —S(═O) 2 R 10 ,
each R 2 is independently halogen, —CN, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —OH, —C(═O)OH, —C(═O)O(C 1-6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1-6 alkyl), —C(═O)N(C 1-6 alkyl) 2 , —S(═O) 2 NH 2 , —S(═O) 2 NH(C 1-6 alkyl), —S(═O) 2 N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —O—C 1-6 alkenyl, —O—C 1-6 alkynyl, C 1-6 haloalkoxy, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 2-9 heteroaryl;
each R 3 is independently halogen, —CN, —C(═O)OH, —C(═O)O(C 1-6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1-6 alkyl), —C(═O)N(C 1-6 alkyl) 2 , —S(═O) 2 NH 2 , —S(═O) 2 NH(C 1-6 alkyl), —S(═O) 2 N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 2-9 heteroaryl;
R 4 is

each R 5 is independently halogen, —CN, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —OH, —C(═O)OH, —C(═O)O(C 1-6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1-6 alkyl), —C(═O)N(C 1-6 alkyl) 2 , —S(═O) 2 NH 2 , —S(═O) 2 NH(C 1-6 alkyl), —S(═O) 2 N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —O—C 1-6 alkenyl, —O—C 1-6 alkynyl, C 1-6 haloalkoxy, optionally substituted phenyl, or optionally substituted C 2-9 heteroaryl, wherein optionally substituted phenyl and optionally substituted C 2-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;
R 10 is C 1-6 alkyl, C 1-6 alkenyl, or C 1-6 alkynyl;
m is 0, 1, 2, or 3;
n is 0, 1, or 2;
p is 0, 1, 2, or 3,
q is 0, 1, 2, or 3, and
t is 0, 1, 2, or 3;
or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof.

4 . A compound of Formula (VI):

wherein:

R 1 is H, C 1-6 alkyl, —C(═O)R 10 , —C(═O)OR 10 , or —S(═O) 2 R 10 ,
each R 2 is independently halogen, —CN, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —OH, —C(═O)OH, —C(═O)O(C 1-6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1-6 alkyl), —C(═O)N(C 1-6 alkyl) 2 , —S(═O) 2 NH 2 , —S(═O) 2 NH(C 1-6 alkyl), —S(═O) 2 N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 2-9 heteroaryl;
each R 3 is independently halogen, —CN, —C(═O)OH, —C(═O)O(C 1-6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1-6 alkyl), —C(═O)N(C 1-6 alkyl) 2 , —S(═O) 2 NH 2 , —S(═O) 2 NH(C 1-6 alkyl), —S(═O) 2 N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 2-9 heteroaryl;
R 4 is

each R 5 is independently halogen, —CN, —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , —OH, —C(═O)OH, —C(═O)O(C 1-6 alkyl), —C(═O)NH 2 , —C(═O)NH(C 1-6 alkyl), —C(═O)N(C 1-6 alkyl) 2 , —S(═O) 2 NH 2 , —S(═O) 2 NH(C 1-6 alkyl), —S(═O) 2 N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —O—C 1-6 alkenyl, —O—C 1-6 alkynyl, C 1-6 haloalkoxy, optionally substituted phenyl, or optionally substituted C 2-9 heteroaryl, wherein optionally substituted phenyl and optionally substituted C 2-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;
R 10 is C 1-6 alkyl, C 1-6 alkenyl, or C 1-6 alkynyl;
m is 0, 1, 2, or 3;
n is 0, 1, or 2;
p is 0, 1, 2, or 3;
q is 0, 1, 2, or 3; and
t is 0, 1, 2, or 3;
or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof.

5 . The compound of any one of claims 1 - 4 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R 1 is H.

6 . The compound of any one of claims 1 - 4 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R 1 is C 1-6 alkyl.

Assignees

• Scripps Research Inst
• Univ Leiden

Inventors

• Cravatt Benjamin F
• Ogasawara Daisuke
• Viader Andreu
• Deng Hui
• Van Der Wel Tom
• Van Der Stelt Marcelis

Classifications

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D513/12

  in which the condensed system contains three hetero rings · CPC title

• A61K31/4192

  1,2,3-Triazoles · CPC title