Heterocyclic compounds as triggering receptor expressed on myeloid cells 2 agonists and methods of use

Patent metadata

Field	Value
Publication number	US-12252489-B2
Application number	US-202117923160-A
Country	US
Kind code	B2
Filing date	May 4, 2021
Priority date	May 4, 2020
Publication date	Mar 18, 2025
Grant date	Mar 18, 2025

Abstract

The present disclosure provides compounds of Formula (I), useful for the activation of Triggering Receptor Expressed on Myeloid Cells 2 (“TREM2”). This disclosure also provides pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions for treatment of, for example, a neurodegenerative disorder. Further, the disclosure provides intermediates useful in the synthesis of compounds of Formula (1).

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
X 1 is (1) CH or N and b is a single bond; or (2) C and b is a double bond;
X 2 is CH 2 , CHF, CF 2 , O, or NH;
wherein, optionally, R 5 is absent and the X 2 CR 6 group forms a 5- or 6-membered heteroaryl, wherein the 5-membered heteroaryl contains only one ring atom selected from N, O, and S and optionally only one further N ring atom and wherein the 6 membered heteroaryl contains only one or only two N ring atoms, and wherein said 5- or 6-membered heteroaryl is optionally substituted with halogen, C 1-3 alkyl, or C 1-3 alkoxy;
X 3 at each occurrence independently is CH or N;
R 1 is H, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl;
R 2 is H, C 1-3 alkyl, C 1-3 haloalkyl, or C 3-6 cycloalkyl;
R 3 is H or C 1-3 alkyl;
R 4 is H or C 1-3 alkyl;
R 5 is H or C 1-3 alkyl;
R 6 is C 2-6 alkyl, C 1-6 haloalkyl, diC 1-3 alkylamino, —C(═O)O(C 1-6 alkyl), C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl; wherein
(1) C 3-6 cycloalkyl or C 3-6 heterocycloalkyl is optionally substituted with C═O,
(2) the phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is optionally substituted with 1 to 3 substituents independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —(C 1-3 alkyl)O(C 1-3 alkyl), —(C 1-3 alkyl) NH 2 , —(C 1-3 alkyl) NH (C 1-3 alkyl), —(C 1-3 alkyl)N[(C 1-3 alkyl) (C 1-3 alkyl)], —CN, C 2-4 alkenyl, C 3-6 cycloalkyl, phenyl, and C 3-6 heterocycloalkyl; wherein
the C 1-6 alkyl and C 1-6 haloalkyl of subsection (2) are optionally substituted with OH; and wherein
the C 3-6 heterocycloalkyl of subsection (2) is optionally substituted with 1 to 3 substituents selected from halogen, C 1-3 alkyl, and —C(═O)O(C 1-6 alkyl);

R 7 is C 5-6 cycloalkyl, C 5-8 spiroalkyl, C 5-8 tricycloalkyl, phenyl, or 6-membered heteroaryl; wherein R 7 is further optionally substituted with 1 to 4 substituents independently selected from halogen, C 1-3 alkyl, and C 1-3 haloalkyl; and
n is 0 or 1; provided that when X 1 is N and n is 0, X 2 is not NH or O.

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
5-(5-chloro-3-methyl-2-pyridinyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;
5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-methyl-3-phenyl-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one; or
5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-(1-methyl-1H-imidazol-2-yl)-1-pyrrolidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one.

3. 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 a compound of Formula II

or wherein the compound is a compound of Formula IIA

or wherein the compound is a compound of Formula IIB

4. The compound according to claim 3 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
X 1 is CH.

5. The compound according to claim 3 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
X 1 is N.

6. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
X 2 is CH 2 , CF 2 , or O.

7. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein the

portion of Formula I is

8. The compound according to claim 3 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
X 3 is CH.

9. The compound according to claim 3 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
X 3 is N.

10. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
R 1 is methyl, ethyl, propyl, —CH 2 CF 3 , cyclopropyl, or cyclohexyl.

11. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
R 2 is H, methyl, trifluoromethyl, or cyclopropyl.

12. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
R 3 is H or methyl.

13. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
R 4 is H or methyl.

14. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
R 5 is H or methyl.

15. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
R 6 is difluoromethyl, trifluoromethyl, —CH 2 CF 3 , dimethylamino, —C(═O) OCH 2 CH 3 , optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted oxetanyl, optionally substituted azetidinyl, optionally substituted tetrahydrofuranyl, optionally substituted pyrrolidinyl, optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted 1,3-oxazolyl, optionally substituted 1,2,4-oxadiazolyl, optionally substituted 1,3,4-oxadiazolyl, optionally substituted thiophenyl, optionally substituted thiazolyl, optionally substituted pyridinyl, optionally substituted pyridazinyl, or optionally substituted pyrimidinyl.

16. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
R 6 is difluoromethyl, trifluoromethyl, —CH 2 CF 3 , dimethylamino, —C(═O) OCH 2 CH 3 , cyclopropyl, cyclobutyl, oxetan-2-yl, azetidine-1-yl, tetrahydrofuran-3-yl,

phenyl,

17. The compound according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein
R 6 is

Assignees

• Amgen Inc
• Vigil Neuroscience Inc

Inventors

• Czabaniuk Lara C
• Hopper Timothy
• Houze Jonathan B
• Rescourio Gwenaella
• Santora Vincent
• Wang Haoxuan
• White Ryan D
• Wong Alice R
• Wu Yongwei

Classifications

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title