1,1,1-trifluoro-3-hydroxypropan-2-yl carbamate derivatives as MAGL inhibitors

Patent metadata

Field	Value
Publication number	US-10329308-B2
Application number	US-201815874987-A
Country	US
Kind code	B2
Filing date	Jan 19, 2018
Priority date	Jan 20, 2017
Publication date	Jun 25, 2019
Grant date	Jun 25, 2019

Abstract

The present invention provides, in part, compounds of Formula I:

and pharmaceutically acceptable salts thereof; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds or salts, and their uses for treating MAGL-mediated diseases and disorders including, e.g., pain, an inflammatory disorder, depression, anxiety, Alzheimer's disease, a metabolic disorder, stroke, or cancer.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, —P(═O)(OR 81 )(OR 82 ); or —S(═O) 2 OR 90 ;
each of R 81 , R 82 , and R 90 is independently selected from the group consisting of H and C 1-6 alkyl, wherein each of the C 1-6 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of —NH 2 , —NH(C 1-4 alkyl), and —N(C 1-4 alkyl) 2 ;
each R S is independently selected from the group consisting of OH, oxo, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-4 cycloalkyl, C 3-4 cycloalkyl-C 1-2 alkyl-, C 1-4 alkoxy, and C 1-4 haloalkoxy;
n1 is 0, 1, 2, 3, 4, 5, or 6;
the moiety of Formula M-1 of Formula I

is a moiety of Formula M-1a, M-1b, or M-1c:

each of R 2A and R 2C is, independently, —NR 3 S(═O) 2 R 4 , —NR 3 C(═O)R 4 ; R 5 , or —OR 5 ;
R 2B is selected from the group consisting of [4-(trifluoromethyl)-1H-pyrazol-1-yl]methyl-, (cyclopentylcarbonyl)(methyl)amino-, (tert-butylsulfonyl)(methyl)amino-, (2,2-dimethylpropanoyl)(methyl)amino-, 4-(trifluoromethyl)-1H-pyrazol-1-yl-, 4-fluoro-1H-pyrazol-1-yl-, 3-cyanophenyl-, 6-(trifluoromethyl)pyridin-2-yl-, 5-fluoropyridin-2-yl-, 4-(difluoromethyl)-1H-pyrazol-1-yl-, 4-tert-butyl-1H-pyrazol-1-yl-, 4-chlorol-1H-pyrazol-1-yl-, 4-cyclopropyl-1H-pyrazol-1-yl-, 4-methyl-1H-pyrazol-1-yl-, 2-fluorophenyl-, 4-cyano-3-fluorophenyl-, 3-cyano-4-fluorophenyl-, 5-cyano-2-fluorophenyl-, 4-cyanophenyl-, 2,6-difluorophenyl-, 2,4-difluorophenyl-, 4-fluorophenyl-, 4-(difluoromethyl)pyridin-2-yl-, 6-(difluoromethyl)pyridin-3-yl-, 5-cyanopyridin-2-yl-, 5-(difluoromethyl)pyridin-2-yl-, 5-(trifluoromethyl)pyridin-2-yl-, pyridin-2-yl-, 3-tert-butyl-1H-pyrazol-1-yl-, 3-(trifluoromethyl)-1H-pyrazol-1-yl-, 3,4-dimethyl-1H-pyrazol-1-yl-, {[(3,3-difluorocyclobutyl)methyl]sulfonyl}(methyl)amino-, [(3,3-difluorocyclobutyl)carbonyl](methyl)amino-, 1H-indazol-1-yl-, 3-cyano-2-fluorophenyl-, and 4-cyano-2-fluorophenyl-;
each R 3 is independently C 1-3 alkyl;
each R 4 is independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)-C 1-2 alkyl-, (C 6-10 aryl)-C 1-2 alkyl-, (5- or 10-membered heteroaryl)-C 1-2 alkyl-, 5- or 10-membered heteroaryl, and C 6-10 aryl, wherein each of the selections is substituted with 0, 1, 2, or 3 halogen;
or R 3 and R 4 , together with the intervening moiety of “—NS(═O) 2 —” or “—NC(═O)—” to which they are attached, form a 4- to 10-membered heterocycloalkyl that is substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of OH, oxo, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy, and wherein each of the ring-forming atoms of the 4- to 10-membered heterocycloalkyl is C, N, O, or S; and
each R 5 is phenyl or 5- or 6-membered heteroaryl, wherein each of the phenyl or 5- or 6-membered heteroaryl is substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of —CN, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy, and wherein each of the ring-forming atoms of the 5- or 6-membered heteroaryl is a carbon atom or a nitrogen atom.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R S is independently selected from the group consisting of halogen, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 alkoxy, and C 1-2 haloalkoxy.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein n1 is 0.

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently C 1-3 alkyl; and each R 4 is independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)-C 12 alkyl-, (C 6-10 aryl)-C 1-2 alkyl-, (5- or 10-membered heteroaryl)-C 1-2 alkyl-, 5- or 10-membered heteroaryl, and C 6-10 aryl, wherein each of the selections is substituted with 0, 1, 2, or 3 halogen.

5. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently C 1-3 alkyl; and each R 4 is independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)-C 1-2 alkyl-, (C 6-10 aryl)-C 1-2 alkyl-, and C 6-10 aryl, wherein each of the selections is substituted with 0, 1, 2, or 3 halogen.

6. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-1, I-2, or I-3:

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H or —P(═O)(OH)(OH).

8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H.

9. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-1.

10. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 2A is R 5 or —OR 5 .

11. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 2A is R 5 ; and R 5 is selected from the group consisting of phenyl, 1H-pyrazolyl, and pyridinyl, wherein each of the selections is substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of —CN, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy.

12. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 2A is R 5 ; and R 5 is selected from the group consisting of phenyl, 1H-pyrazol-1-yl-, pyridin-2-yl-, pyridin-3-yl-, and pyridin-4-yl, wherein each of the selections is substituted with 0 or 1 substituent selected from the group consisting of —CN, halogen, C 1-2 alkyl, C 3-4 cycloalkyl, C 1-2 alkoxy, C 1-2 haloalkyl, and C 1-2 haloalkoxy.

13. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 2A is —OR 5 ; and R 5 is selected from the group consisting of phenyl, 1H-pyrazolyl, and pyridinyl, wherein each of the selections is substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of —CN, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy.

14. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 2A is —OR 5 ; and R 5 is selected from the group consisting of phenyl, 1H-pyrazol-1-yl-, pyridin-2-yl-, pyridin-3-yl-, and pyridin-4-yl, wherein each of the selections is substituted with 0 or 1 substituent selected from the group consisting of —CN, halogen, C 1-2 alkyl, C 3-4 cycloalkyl, C 1-2 alkoxy, C 1-2 haloalkyl, and C 1-2 haloalkoxy.

15. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 2A is —NR 3 S(═O) 2 R 4 or —NR 3 C(═O)R 4 ; R 3 is methyl; each R 4 is independently selected from the group consisting of C 1-6 alkyl, C 3-7 cycloalkyl, (C 3-7 cycloalkyl)-C 1-2 alkyl-, (phenyl)-C 1-2 alkyl-, and phenyl.

16. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-2.

17. The compound of claim 6 , or a phar

Assignees

• Pfizer

Inventors

• Brodney Michael Aaron
• Butler Christopher Ryan
• Mcallister Laura Ann
• Helal Christopher John
• O'Neil Steven Victor
• Verhoest Patrick Robert

Classifications

• C07D491/10

  Spiro-condensed systems · CPC title

• C07D401/12

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

• C07D401/08 Primary

  linked by a carbon chain containing alicyclic rings · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61K31/4747

  spiro-condensed · CPC title