HETEROCYCLIC COMPOUNDS AS PI3K-y INHIBITORS

Patent metadata

Field	Value
Publication number	US-2018009816-A1
Application number	US-201715631417-A
Country	US
Kind code	A1
Filing date	Jun 23, 2017
Priority date	Jun 24, 2016
Publication date	Jan 11, 2018
Grant date	—

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

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt or a tautomer thereof; wherein:
X 1 is N or CR 1 ;
X 2 is N or CR 2 ;
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 g C(═NOH)NR g R g , NR g C(

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

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · 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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title