Heterocyclic derivatives as PI3K inhibitors

Patent metadata

Field	Value
Publication number	US-11078204-B2
Application number	US-201916681014-A
Country	US
Kind code	B2
Filing date	Nov 12, 2019
Priority date	Nov 13, 2018
Publication date	Aug 3, 2021
Grant date	Aug 3, 2021

Abstract

This application relates to compounds of Formula (I):

or pharmaceutically acceptable salts thereof, which are inhibitors of PI3K-γ which are useful for the treatment of disorders such as autoimmune diseases, cancer, cardiovascular diseases, and neurodegenerative diseases.

First claim

What is claimed is:

1. A compound of Formula (IIu):

or a pharmaceutically acceptable salt thereof; wherein:
X 2 is N or CR 2 ;
R 2 is selected from H, D, halo, CN, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-7 cycloalkyl;
provided that:
when X 2 is N, then R 1 is selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a1 , SR a1 , NHOR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)NR c1 (OR a1 ), C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O)NR c1 R d1 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 1 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 1A substituents; or
when X 2 is CR 2 , then R 1 is selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a1 , SR a1 , NHOR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)NR c1 (OR a1 ), C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , and NR c1 C(O)NR c1 R d1 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 1 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 1A substituents;
each R a1 , R b1 , R c1 , and R d1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R a1 , R b1 , R c1 and R d1 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 1A substituents;
or, any R c1 and R d1 , attached to the same N atom, together with the N atom to which they are attached, form a 5-10 membered heteroaryl group or a 4-10 membered heterocycloalkyl group, wherein the 5-10 membered heteroaryl group or 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R 1A substituents;
each R 1A is selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a11 , SR a11 , NHOR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)NR c11 (OR a11 ), C(O)OR a11 , OC(O)R b11 , OC(O)NR c11 R d11 , NR c11 R d11 , NR c11 NR c11 R d11 , NR c11 C(O)R b11 , NR c11 C(O)OR a11 , and NR c11 C(O)NR c11 R d11 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R 1A are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R M substituents;
each R a11 , R b11 , R c11 , and R d11 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R a11 , R b11 , R c11 and R d11 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R M substituents;
or, any R c11 and R d11 , attached to the same N atom, together with the N atom to which they are attached, form a 5-10 membered heteroaryl group or a 4-10 membered heterocycloalkyl group, wherein the 5-10 membered heteroaryl group or 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R M substituents;
each R M is independently selected from D, OH, NO 2 , CN, halo, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 haloalkyl, cyano-C 1-3 alkyl, HO—C 1-3 alkyl, C 1-3 alkoxy-C 1-3 alkyl, C 3-6 cycloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, thio, C 1-3 alkylthio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, carbamyl, C 1-3 alkylcarbamyl, di(C 1-3 alkyl)carbamyl, carboxy, C 1-3 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-3 alkylcarbonylamino, C 1-3 alkoxycarbonylamino, C 1-3 alkylcarbonyloxy, aminocarbonyloxy, C 1-3 alkylaminocarbonyloxy, di(C 1-3 alkyl)aminocarbonyloxy, C 1-3 alkylsulfonylamino, aminosulfonyl, C 1-3 alkylaminosulfonyl, di(C 1-3 alkyl)aminosulfonyl, aminosulfonylamino, C 1-3 alkylaminosulfonylamino, di(C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 alkylaminocarbonylamino, and di(C 1-3 alkyl)aminocarbonylamino;
R 3 is selected from H, D, halo, CN, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano-C 1-6 alkyl, HO—C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, and C(O)NR a3 R b3 ;
each R a3 and R b3 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl- of R a3 and R b3 are each optionally substituted with 1, 2, 3 or 4 independently selected R M substituents;
or, any R a3 and R b3 , attached to the same N atom, together with the N atom to which they are attached, form a 5-6 membered heteroaryl group or a 4-7 membered heterocycloalkyl group,

Assignees

• Incyte Corp

Inventors

• Shepard Stacey
• Ai Yanran
• Combs Andrew P
• Falahatpisheh Nikoo
• Shao Lixin
• Shvartsbart Artem

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D519/00

  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

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title