1,1,1-trifluoro-3-hydroxypropan-2-yl carbamate derivatives and 1,1,1-trifluoro-4-hydroxybutan-2-yl carbamate derivatives as MAGL inhibitors

Patent metadata

Field	Value
Publication number	US-10723711-B2
Application number	US-201916547037-A
Country	US
Kind code	B2
Filing date	Aug 21, 2019
Priority date	Jul 31, 2015
Publication date	Jul 28, 2020
Grant date	Jul 28, 2020

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, traumatic brain injury, depression, anxiety, Alzheimer's disease, a metabolic disorder, stroke, or cancer.

First claim

What is claimed is:

1. A compound of Formula I-a or I-a1:

or a pharmaceutically acceptable salt thereof, wherein:
the moiety of “N(R 1 )(R 2 )” is a moiety of Formula a-13:

t1 is 0, 1, 2, or 3;
each of R 5 and R 6 is independently H or C 1-4 alkyl;
R 7 is H, C 1-6 alkyl, C 3-7 cycloalkyl, or R 10 , wherein the C 1-6 alkyl of R 7 is optionally substituted with one or more substituents each independently selected from the group consisting of OH, halogen, C 1-4 alkoxy, C 1-4 haloalkoxy, and C 3-6 cycloalkyl, and wherein the C 3-7 cycloalkyl of R 7 is optionally substituted with one or more substituents each independently selected from the group consisting of OH, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;
R 8 is L 1 -R 11 , -L 2 -R 12 , -L 3 -R 13 , -L 4 -R 14 , —C(R 15 )(Cy 1 )(Cy 2 ), —C(R 15 )(Cy 1 )[—NR 23 —S(═O) 2 -Cy 2 ], or -L 5 -N(-L 6 -Cy 3 )(-L 7 -Cy 4 );
each R 9 is independently OH, oxo, halogen, optionally substituted C 1-4 alkyl, optionally substituted C 1-4 alkoxy, or optionally substituted C 3-6 cycloalkyl;
R 10 is —P(═O)(OR 81 )(OR 82 ) or —S(═O) 2 OR 90 ;
each of L 1 , L 2 , L 3 , and L 4 is independently absent, —(CR 21 R 22 ) m —, —NR 23 —, —O—, —C(═O)—, —S(═O) 2 —, —S(═O) 2 —(CR 21 R 22 ) n —, —C(═O)—(CR 21 R 22 ) n —, —S(═O) 2 —NR 23 —, —C(═O)—NR 23 —, —(CR 21 R 22 ) f1 —NR 23 —(CR 21 R 22 ) f2 —, —(CR 21 R 22 ) f1 —O—(CR 21 R 22 ) f2 —, —C(═O)—NR 23 —(CR 21 R 22 ) p , or —S(═O) 2 —NR 23 —(CR 21 R 22 ) p —;
L 5 is absent or —(CR 21 R 22 )—;
L 6 is absent or —(CR 21 R 22 )—;
L 7 is absent, —(CR 21 R 22 )—, or —S(═O) 2 —;
R 11 is 5- to 10-membered heteroaryl optionally substituted with one or more independently selected R 31 ;
R 12 is 4- to 14-membered heterocycloalkyl optionally substituted with one or more independently selected R 32 ;
R 13 is C 6-10 aryl optionally substituted with one or more independently selected R 33 ;
R 14 is C 3-14 cycloalkyl optionally substituted with one or more independently selected R 34 ;
R 15 is H, OH, halogen, C 1-4 alkoxy, C 1-4 alkyl, or cyclopropyl;
each of R 21 and R 22 is independently H, OH, halogen, C 1-3 alkyl, or cyclopropyl, wherein the C 1-3 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of OH, halogen, C 1-3 alkoxy, C 1-3 haloalkoxy, and cyclopropyl;
R 23 is H, C 1-4 alkyl, or cyclopropyl;
each of R 31 , R 32 , R 33 , and R 34 is independently selected from the group consisting of halogen, —N(R a )(R b ), —N(R c )(C(═O)R d ), —N(R c )(S(═O) 2 R d ), —C(═O)—N(R a )(R b ), —C(═O)—R d , —C(═O)—OR d , —OC(═O)—R d , —N(R c )(S(═O) 2 R d ), —S(═O) 2 —N(R a )(R b ), —SR d , —S(═O) 2 R d , —OR d , —OR 35 , —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, (C 3-10 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 14 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, and (5- to 10-membered heteroaryl)-C 1-4 alkyl-, wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, (C 3-10 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, and (5- to 10-membered heteroaryl)-C 1-4 alkyl- is optionally substituted with one or more independently selected R 36 ; and wherein each of the C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, (C 3-10 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, and (5- to 10-membered heteroaryl)-C 1-4 alkyl- is further optionally substituted one or more oxo;
each R 35 is independently selected from the group consisting of H, C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, (C 3-10 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, and (5- to 10-membered heteroaryl)-C 1-4 alkyl-, wherein each of the C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, (C 3-10 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, and (5- to 10-membered heteroaryl)-C 1-4 alkyl- is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —CN, —C(═O)C 1-4 alkyl, —C(═O)OH, —C(═O)O—C 1-4 alkyl, —C(═O)NHC 1-4 alkyl, —C(═O)N(C 1-4 alkyl) 2 , oxo, —OH, —OC(═O)—C 1-4 alkyl, —OC(═O)O—C 1-4 alkyl, —NH2, —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —NHC(═O)C 1-4 alkyl, —NHC(═O)OC 1-4 alkyl, —NHC(═O)NHC 1-4 alkyl, and C 1-4 alkoxy;
each R 36 is independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, —SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, a 4- to 10-membered heterocycloalkyl, —N(R a )(R b ), —N(R c )(C(═O)R d ), —C(═O)—N(R a )(R b ), —C(═O)—R d , —C(═O)—OR d , —OC(═O)—R d , —N(R c )(S(═O) 2 R d ), —S(═O) 2 —N(R a )(R b ), —SR d , —S(═O) 2 R d , and —OR d , wherein each of the C 1-6 alkyl, C 3-7 cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —CN, —OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, —N(R a )(R b ), —N(R c )(C(═O)R d ), —C(═O)—OR d , —C(═O)H, —C(═O)R d , —C(═O)N(R a )(R b ), —N(R c )(S(═O) 2 R d ), —S(═O) 2 —N(R a )(R b ), —SR d , —S(═O) 2 R d , and —OR d ;
each of R 81 , R 82 , and R 90 is independently selected from the group consisting of H, C 1-6 alkyl, C 3-7 cycloalkyl, and (C 3-7 cycloalkyl)-C 1-4 alkyl-, wherein each of the C 1-6 alkyl, C 3-7 cycloalkyl, and (C 3-7 cycloalkyl)-C 1-4 alkyl- is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —CN, —OH, oxo, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl;
or OR 81 and OR 82 , together with the P(═O) to which they are attached, form 4- to 10-membered heterocycloalkyl that is further optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —CN, —OH, oxo, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, and C 3-6 cycloalkyl;
each of Cy 1 , Cy 2 , Cy 3 , and Cy 4 is independently selected from the group consisting of R 11 , R 12 , R 13 , and R 14 ;
each R a is independently H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, or (C 3-7 cycloalkyl)-C 1-4 alkyl-;
each R b is independently H or selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, a 4- to 10-membered heterocycloalkyl, C 6-10 aryl, a 5- to 10-membered heteroaryl, (C 3-7 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, and (5- to 10-membered heteroaryl)-C 1-4 alkyl-, wherein each of the selections from the group is optionally substituted with one or more substituents each independently selected from the group consisting of —OH, —CN, C 1-4 alkyl, C 3-7 cycloalkyl, C 1-4 hydroxylalkyl, —S—C 1-4 alkyl,

Assignees

• Pfizer

Inventors

• Butler Christopher Ryan
• Mcallister Laura Ann
• Beck Elizabeth Mary
• Brodney Michael Aaron
• Gilbert Adam Matthew
• Helal Christopher John
• Johnson Douglas Scott
• Montgomery Justin Ian
• O'Neil Steven Victor
• Rogers Bruce Nelsen
• Verhoest Patrick Robert
• Webb Damien

Classifications

• C07D498/10

  Spiro-condensed systems · CPC title

• A61P13/12

  of the kidneys · CPC title

• A61P1/08 Primary

  for nausea, cinetosis or vertigo; Antiemetics · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title