Heterocyclic compounds as delta-5 desaturase inhibitors and methods of use

Patent metadata

Field	Value
Publication number	US-2021188874-A1
Application number	US-202017103389-A
Country	US
Kind code	A1
Filing date	Nov 24, 2020
Priority date	Nov 25, 2019
Publication date	Jun 24, 2021
Grant date	—

Abstract

The present disclosure provides compounds useful for the inhibition of Delta-5 Desaturase (“D5D”). The compounds have a general Formula Iwherein the variables of Formula I are defined herein. This disclosure also provides pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions for treatment of, for example, a metabolic or cardiovascular disorder. Further, the disclosure provides intermediates useful in the synthesis of compounds of Formula I.

First claim

1 . A compound of Formula I

or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer,
wherein

each R and R′ are independently selected from H, halogen, —OH, —CN, —CO(C 1-4 alkyl), —S(O) n (C 1-4 alkyl), —COOH, —COO(C 1-4 alkyl), —CONH 2 , —CONH(C 1-4 alkyl), —CO(diC 1-4 alkylamino), —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, —NH(COC 1-4 alkyl), —N(C 1-4 alkyl)C(═O)F, C 1-4 alkyl, —(CH 2 ) m (C 3-8 cycloalkyl), —CH 2 (C 3-8 heterocycloalkyl), C 1-4 deuteroalkyl, C 3-5 cycloalkyl, C 3-4 heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 deuteroalkoxy, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl;
wherein the C 1-4 alkyl group is optionally substituted with 1 to 4 F or optionally substituted with a substituent selected from —OH, —CN, C 1-4 alkoxy, —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, and —S(O) n (C 1-4 alkyl);
wherein the C 1-4 alkoxy group is optionally substituted with 1 to 4 independently selected halogens or optionally substituted with a substituent selected from —OH, —CN, C 1-4 alkoxy, —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, and —S(O) n (C 1-4 alkyl);
wherein the —CH 2 (C 3-5 cycloalkyl), C 3-4 heterocycloalkyl, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl groups are optionally substituted with 1 to 4 substituents independently selected from halogen, —OH, —CN, C 1-4 alkoxy, C 1-4 alkyl, —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, and —S(O) n (C 1-4 alkyl); and
wherein R of a first CR group and R of a second CR group, if present, together with the atoms to which they are attached, form a C 3-5 carbocycle;

each R″ is independently selected from H, —OH, —CO(C 1-4 alkyl), —S(O) n (C 1-4 alkyl), —COO(C 1-4 alkyl), —CONH 2 , —CONH(C 1-4 alkyl), —CO(diC 1-4 alkylamino), C 1-4 alkyl, —(CH 2 ) m (C 3-5 cycloalkyl), —CH 2 (C 3-5 heterocycloalkyl), C 1-4 deuteroalkyl, C 3-5 cycloalkyl, C 3-4 heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl;
wherein the C 1-4 alkyl group is optionally substituted with 1 to 4 F or optionally substituted with a substituent selected from —OH, —CN, C 1-4 alkoxy, —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, and —S(O) n (C 1-4 alkyl); and
wherein the —(CH 2 ) m (C 3-5 cycloalkyl), C 3-4 heterocycloalkyl, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl groups are optionally substituted with 1 to 4 substituents independently selected from halogen, —OH, —CN, C 1-4 alkoxy, C 1-4 alkyl, —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, and —S(O) n (C 1-4 alkyl);

R 1 is O, S, or NH;
R 2 is

 wherein
Ring A is a 5-membered heteroaryl containing one heteroatom selected from N, S, and O and optionally one or two further N atoms with the remaining ring atoms of the 5-membered heteroaryl being carbon, wherein
i) Ring A is attached via a C atom to the bicyclic core and R 3 is attached via an N atom; or
ii) Ring A is attached via an N atom to the bicyclic core and R 3 is attached via a C atom; or
iii) Ring A is attached via a C atom to the bicyclic core and R 3 is attached via a C atom;
and wherein the

 portion of R 2 is further optionally substituted with one or two independently selected substituents R 3′ ;

R 3 is C 1-6 alkyl, C 3-5 cycloalkyl, C 2-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, —S(O) n (C 1-6 alkyl), —CH 2 (C 3-5 cycloalkyl), —OCH 2 (C 3-5 cycloalkyl), —NHCH 2 (C 3-5 cycloalkyl), —S(O) n CH 2 (C 3-5 cycloalkyl), —CH 2 (C 3-5 heterocycloalkyl), or phenyl; wherein the C 1-6 alkyl, C 3-5 cycloalkyl, C 2-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, —S(O) n (C 1-6 alkyl), —CH 2 (C 3-5 cycloalkyl), —OCH 2 (C 3-5 cycloalkyl), —NHCH 2 (C 3-5 cycloalkyl), and —S(O) n CH 2 (C 3-5 cycloalkyl) groups are optionally substituted with 1-9 halogen atoms and are optionally substituted with —CN and wherein the phenyl is optionally substituted with 1-3 substituents selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;
R 3′ is independently halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;
R 4 is C 1-3 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-5 cycloalkyl, or C 3-5 cyclohaloalkyl;
n is 0, 1, or 2; and
m is 1 or 2;
(1) if any of R, or R″ is phenyl then R 3 is not an unsubstituted C 1-6 alkyl and R 3 is not C 1-2 alkoxy.

2 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein the compound is not 2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(pyrimidin-5-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one.

3 - 7 . (canceled)

8 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
each R is independently selected from H, halogen, —COO(C 1-4 alkyl), C 1-4 alkyl, —(CH 2 ) m (C 3-5 cycloalkyl), —CH 2 (C 3-8 heterocycloalkyl), C 1-4 deuteroalkyl, C 3-5 cycloalkyl, C 3-4 heterocycloalkyl, C 2-4 alkynyl, C 1-4 alkoxy, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl;
wherein the C 1-4 alkyl group is optionally substituted with 1 to 4 F or optionally substituted with a substituent selected from —OH, —CN, C 1-4 alkoxy, C 1-4 alkylamino, and diC 1-4 alkylamino; and
wherein the —(CH 2 ) m (C 3-5 cycloalkyl), 5-membered heteroaryl, and 6-membered heteroaryl groups are optionally substituted with 1 to 4 substituents independently selected from halogen, —OH, and C 1-4 alkyl.

9 - 10 . (canceled)

11 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
each R is independently selected from H, F, Cl, —COOMe, methyl, ethyl, isopropyl, fluoromethyl, trifluoromethyl, —CH 2 OH, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, —CH 2 CN, 2-hydroxypropyl, —CH 2 OCH 3 , —CH 2 CH 2 OCH 3 , methylaminomethyl, dimethylaminomethyl, 2-(dimethylamino)ethyl, cyclopropylmethyl, (2,2-difluorocyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, (1-hydroxycyclopropyl)ethyl, —CD 3 , cyclopropyl, (oxetan-3-yl)methyl, oxetan-3-yl, prop-2-yn-1-yl, methoxy, phenyl, pyrazolyl, 1-methyl-pyrazol-4-yl, pyridinyl, pyrazinyl, pyrimidinyl, 6-methylpyridin-2-yl, and 6-chloropyridin-2-yl.

12 - 13 . (canceled)

14 . The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
each R″, if present, is independently selected from H, —COO(C 1-4 alkyl), C 1-4 alkyl, —(CH 2 ) m (C 3-5 cycloalkyl), —CH 2 (C 3-5 heterocycloalkyl), C 1-4 deuteroalkyl, C 3-5 cycloalkyl, C 3-4 heterocycloalkyl, C 2-4 alkynyl, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl;
wherein the C 1-4 alkyl group is optionally substituted with 1 to 4 F or optionally substituted with a substituent selected from —OH, —CN, C 1-4 alkoxy, C 1-4 alkylamino, and diC 1-4 alkylamino; and
wherein the —(CH 2 ) m (C 3-5 cycloalkyl), 5-membered heteroaryl, and 6-membered heteroaryl groups are optionally substituted with 1 to 4 substituents independently selected from halogen, —OH, and C 1-4 alkyl.

15 - 16 . (canceled)

17 .

Assignees

• Amgen Inc

Inventors

• Allen Jennifer R
• Beltrani Michela
• Bourbeau Matthew P
• Damyanova Teodora P
• Lingard Iain
• Minatti Ana E
• Vincetti Paolo

Classifications

• C07D513/04 Primary

  Ortho-condensed systems · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title