Substituted imidazo[2,1-f][1,2,4]triazines, substituted imidazo[1,2-a]pyridines, substituted imidazo[1,2-b]pyridazines and substituted imidazo[1,2-a]pyrazines as PI3K-γ inhibitors

Patent metadata

Field	Value
Publication number	US-10138248-B2
Application number	US-201715631417-A
Country	US
Kind code	B2
Filing date	Jun 23, 2017
Priority date	Jun 24, 2016
Publication date	Nov 27, 2018
Grant date	Nov 27, 2018

Abstract

This application relates to compounds of Formula (I):

or pharmaceutically acceptable salts or stereoisomers 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 (I):

or a pharmaceutically acceptable salt or a tautomer thereof; wherein:
X 1 is CR 1 and X 2 is CR 2 ; or
X 1 is N and X 2 is N; or
X 1 is CR 1 and X 2 is N;
X 3 is N or CR 3 ;
X 4 is N or CR 4 ;
X 5 is N or CR 5 ;
X 6 is N or CR 6 ;
X 3 , X 4 , X 5 and X 6 are not simultaneously N;
R 7 is H or C 1-6 alkyl optionally substituted with 1, 2 or 3 groups independently selected from halo, OH, oxo, CN, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 aryl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, NH 2 , C 1-6 alkyl-NH— and (C 1-6 alkyl) 2 N—;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 8 are each independently selected from H, D, halo, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR a1 , SR a1 , NHOR a1 , C(O)R a1 , C(O)NR a1 R a1 , C(O)OR a1 , OC(O)R a1 , OC(O)NR a1 R a1 , NHR a1 , NR a1 R a1 , NR a1 C(O)R a1 , NR a1 C(O)OR a1 , NR a1 C(O)NR a1 R a1 , C(═NR a1 )R a1 , C(═NR a1 )NR a1 R a1 , NR a1 C(═NR a1 )NR a1 R a1 , NR a1 C(═NOH)NR a1 R a1 , NR a1 C(═NCN)NR a1 R a1 , NR a1 S(O)R a1 , NR a1 S(O) 2 R a1 , NR a1 S(O) 2 NR a1 R a1 , S(O)R a1 , S(O)NR a1 R a1 , S(O) 2 R a1 , SF 5 , —P(O)R a1 R a1 , —P(O)(OR a1 )(OR a1 )B(OR a1 ) 2 and S(O) 2 NR a1 R a1 , wherein the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 8 are each optionally substituted with 1, 2, 3, 4 or 5 independently selected R b substituents;
R 9 is H, D, CN, C(O), NH 2 , —OH, —COOH, —NH(C 1-6 alkyl), —NH(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, wherein the C 1-6 alkyl is optionally substituted with 1, 2 or 3 independently selected R q substituents;
R 10 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, OR a2 , SR a2 , NHOR a2 , C(O)R a2 , C(O)NR a2 R a2 , C(O)OR a2 , NHR a2 , NR a2 R a2 , NR a2 C(O)R a2 , NR a2 C(O)OR a2 , NR a2 C(O)NR a2 R a2 , C(═NR a2 )R a2 , C(═NR a2 )NR a2 R a2 , NR a2 C(═NR a2 )NR a2 R a2 , NR a2 S(O)R a2 , NR a2 S(O) 2 R a2 , NR a2 S(O) 2 NR a2 R a2 , S(O)R a2 , S(O)NR a2 R a2 , S(O) 2 R a2 , and S(O) 2 NR a2 R a2 , wherein the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R 10 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R b substituents;
L is

 or —SO 2 —, wherein each R 11 is independently H, C 1-6 alkyl, or C 3-10 cycloalkyl optionally substituted with 1 or 2 R q substituents and wherein the single wavy line indicates the point of attachment to R 10 and the double wavy line indicates the point of attachment to the 6-membered ring A;
or when L is

 R 10 and R 11 optionally taken together with the nitrogen atom to which they are attached, form 4 to 14 membered heterocycloalkyl or a 4 to 14 membered heterocycloalkyl-C 1-4 alkyl- having 0 to 4 additional heteroatoms as a ring member, each of which is independently selected from N, O and S, wherein the 4 to 14-membered heterocycloalkyl formed by R 10 , R 11 and N is optionally substituted with 1, 2, 3, 4, 5, 6, 7 or 8 independently selected R b substituents;
R a1 and R a2 are each independently selected from H, D, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-4 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, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R a1 and R a2 are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R d substituents;
each R b substituent is independently selected from D, halo, oxo, C 1-4 alkyl, C 1-6 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-14 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OH, NH 2 , NO 2 , NHOR c , OR c , SR c , C(O)R c , C(O)NR c R c , C(O)OR c , OC(O)R c , OC(O)NR c R c , C(═NR c )NR c R c , NR c C(═NR c )NR c R c , NR c C(═NOH)NR c R c , NR c C(═NCN)NR c R c , SF 5 , —P(O)R c R c , —P(O)(OR c )(OR c ), NHR c , NR c R c , NR c C(O)R c , NR c C(O)OR c , NR c C(O)NR c R c , NR c S(O)R c , NR c S(O) 2 R c , NR c S(O) 2 NR c R c , S(O)R c , S(O)NR c R c , S(O) 2 R c or S(O) 2 NR c R c ; wherein the C 1-4 alkyl, C 1-6 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-14 membered heterocycloalkyl)-C 1-4 alkyl- of R b are each further optionally substituted with 1, 2, or 3 independently selected R d substituents;
each R c is independently selected from H, D, C 1-6 alkyl, C 1-4 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 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 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 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl- and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R c are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R f substituents;
each R f is independently selected from C 1-4 alkyl, C 1-4 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 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, halo, CN, NHOR g , OR g , SR g , C(O)R g , C(O)NR g R g , C(O)OR g , OC(O)R g , OC(O)NR g R g , NHR g , NR g R g , NR g C(O)R g , NR g C(O)NR g R g , NR g C(O)OR g , C(═NR g )NR g R g , NR g C(═NR g )NR g R g , NR

Assignees

• Incyte Corp

Inventors

• Buesking Andrew W
• Sparks Richard B
• Combs Andrew P
• Douty Brent
• Falahatpisheh Nikoo
• Shao Lixin
• Shepard Stacey
• Yue Eddy W

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · 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

• C07D471/04

  Ortho-condensed systems · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title