Triazole DAGLα inhibitors

Patent metadata

Field	Value
Publication number	US-10583137-B2
Application number	US-201615778207-A
Country	US
Kind code	B2
Filing date	Dec 2, 2016
Priority date	Dec 2, 2015
Publication date	Mar 10, 2020
Grant date	Mar 10, 2020

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 (XI):

wherein:
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 2-6 alkenyl, —O—C 2-6 alkynyl, C 1-6 haloalkoxy, C 2-9 heterocycloalkyl, C 6-10 aryl, or C 2-9 heteroaryl;
R 13 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, —O—C 2-6 alkenyl, —O—C 2-6 alkynyl, or —O—CH 2 C 3-6 cycloalkyl;
R 15 is a monocyclic C 2-5 heteroaryl 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; and
m is 0, 1, 2, or 3;
or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R 13 is hydrogen.

3. The compound of claim 2 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R 15 is pyridine optionally substituted with one or two groups selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.

4. The compound of claim 2 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R 15 is pyrimidine optionally substituted with one or two groups selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.

5. The compound of claim 2 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R 15 is pyridazine optionally substituted with one or two groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.

6. The compound of claim 2 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein each R 2 is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —O—C 2-6 alkenyl, —O—C 2-6 alkynyl, or C 1-6 haloalkoxy.

7. The compound of claim 2 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein each R 2 is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy.

8. The compound of claim 2 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein m is 0.

9. The compound of claim 2 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein m is 1.

10. The compound of claim 2 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein m is 2.

11. A compound having the structure:

or a solvate, hydrate, N-oxide, or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound of claim 1 , or a solvate, hydrate, tautomer, N-oxide, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

13. A method of treating a neurodegenerative disease, or neuroinflammatory disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 , or a solvate, hydrate, tautomer, N-oxide, or a pharmaceutically acceptable salt thereof.

14. The method of claim 13 wherein the neurodegenerative disease or neuroinflammatory disease is Parkinson's Disease, Alzheimer's Disease, Huntington's Disease, or Amyotrophic Lateral Sclerosis (ALS).

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

• A61K31/4192

  1,2,3-Triazoles · CPC title

• C07D401/06

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

• C07D513/12

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

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title