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

Patent metadata

Field	Value
Publication number	US-11512097-B2
Application number	US-202017103389-A
Country	US
Kind code	B2
Filing date	Nov 24, 2020
Priority date	Nov 25, 2019
Publication date	Nov 29, 2022
Grant date	Nov 29, 2022

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

What is claimed is:

1. A compound of Formula I

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

each instance of R is 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 3-5 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, C 1-4 alkoxy, C 1-4 deuteroalkoxy, 5-membered heteroaryl, and 6-membered heteroaryl;
wherein the C 1-4 alkyl group is optionally substituted with 1 to 4 F atoms or is 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, 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, may, together with the atoms to which they are attached, form a C 3-5 carbocycle;

each R″, if present, 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, 5-membered heteroaryl, and 6-membered heteroaryl;
wherein the C 1-4 alkyl group is optionally substituted with 1 to 4 F atoms or is 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, 5-membered heteroaryl, or 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′ , if present, 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.

2. 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 3-5 heterocycloalkyl), C 1-4 deuteroalkyl, C 3-5 cycloalkyl, C 3-4 heterocycloalkyl, C 2-4 alkynyl, C 1-4 alkoxy, 5-membered heteroaryl, and 6-membered heteroaryl;
wherein the C 1-4 alkyl group is optionally substituted with 1 to 4 F atoms or is 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.

3. 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 3-5 heterocycloalkyl), C 1-4 deuteroalkyl, C 3-5 cycloalkyl, C 3-4 heterocycloalkyl, C 2-4 alkynyl, C 1-4 alkoxy, 5-membered heteroaryl, and 6-membered heteroaryl;
wherein the C 1-4 alkyl group is optionally substituted with 1 to 4 F atoms or is optionally substituted with a substituent selected from —OH, —CN, and C 1-4 alkoxy.

4. 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, C 1-4 alkyl, C 1-4 deuteroalkyl, and C 1-4 alkoxy; wherein the C 1-4 alkyl group is optionally substituted with a substituent selected from —OH and —CN.

5. 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 and methyl.

6. 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, 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.

7. 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, —COOMe, methyl, eth

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

• C07D498/04

  Ortho-condensed systems · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P3/00

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