IP Library › Granted Patent US 11,225,486

Granted Patent B2

US 11,225,486 · App. 16/913,488 · Granted Jan 18, 2022

Tertiary alcohols as PI3K-γ inhibitors

Inventors: Brent Douty (Fallowfield, PA); Andrew W. Buesking (Wilmington, DE); David M. Burns (Plymouth Meeting, PA); Andrew P. Combs (Kennett Square, PA); Nikoo Falahatpisheh (Wilmington, DE); Ravi Kumar Jalluri (Avondale, PA); Daniel Levy (Philadelphia, PA); Padmaja Polam (Kennett Square, PA); Lixin Shao (Wilmington, DE); Stacey Shepard (Wilmington, DE); Artem Shvartsbart (Kennett Square, PA); Richard B. Sparks (Hockessin, DE); Eddy W. Yue (Landenberg, PA)

Assignee: Incyte Corporation

C07D487/04 A61P25/28 A61P35/00 C07B2200/07 C07B2200/13

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Quick Facts

Patent No.: US 11,225,486
App. No.: 16/913,488
Granted: Jan 18, 2022
Kind: B2

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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.

Claims (294)

1. A method of treating a disease or disorder in a patient, wherein said disease or disorder is associated with abnormal expression or activity of PI3Kγ kinase, the method comprising administering to said patient a therapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein:

X 2 is N or CR 2 ;

X 4 is N or CR 4 ;

X 5 is N or CR 5 ;

X 6 is N or CR 6 ;

X 7 is N or CR 7 ;

provided that X 4 , X 5 , and X 6 are not all N;

Y 1 is a C 1-6 haloalkyl, wherein each halogen is selected from F or Cl, wherein the haloalkyl is optionally substituted with 1 or 2 independently selected Y 2 substituents;

R 1 is selected from H, D, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered 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 a , SR a , NHOR a , C(O)R a , C(O)NR a R a , C(O)OR a , OC(O)R a , OC(O)NR a R a , NR a R a , NR a NR a R a , NR a C(O)R a , NR a C(O)OR a , NR a C(O)NR a R a , C(═NR i )R a , C(═NR i )NR a R a , NR a C(═NR i )NR a R a , NR a C(═NOH)NR a R a , NR a C(═NCN)NR a R a , NR a S(O)R a , NR a S(O) 2 R a , NR a S(O)(═NR i )R a , NR a S(O) 2 NR a R a , S(O)R a , S(O)NR a R a , S(O) 2 R a , OS(O)(═NR i )R a , SF 5 , P(O)R a R a , P(O)(OR a )(OR a ), B(OR a ) 2 , and S(O) 2 NR a R a , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered 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 b substituents;

R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from H, D, halo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered 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, OH, NO 2 , amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered 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 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each optionally substituted with 1, 2, 3, or 4 independently selected R h substituents;

R 8 is selected from H, D, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered 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-, NO 2 , C(O)R a , C(O)NR a R a , C(O)OR a , C(═NR i )R a , C(═NR i )NR a R a , SF 5 , —P(O)R a R a , —P(O)(OR a )(OR a ), B(OR a ) 2 , and S(O) 2 NR a R a , wherein the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered 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 8 are each optionally substituted with 1, 2, 3, or 4 independently selected R 9 substituents;

or any two R 4 , R 5 , R 6 and R 7 substituents, together with the ring atoms to which they attached form a 4-, 5-, 6-, or 7-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R b substituents;

or Y 1 and R 8 , together with the carbon atom to which they are attached, form a 4-, 5-, 6-, or 7-membered cycloalkyl or heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R 9 substituents;

each R i is independently selected from H, CN, OH, C 1-4 alkyl, and C 1-4 alkoxy;

each Y 2 is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO—C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

each R a is independently selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered 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 1-6 haloalkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered 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 a is each optionally substituted with 1, 2, 3, or 4 independently selected R b substituents;

each R b is independently selected from D, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered 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 c , SR c , NHOR 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 , NR c R c , NR c C(O)R c , NR c C(O)OR c , NR c C(O)NR c R c , C(═NR i )R c , C(═NR i )NR c R c , NR c C(═NR i )NR c R c , NR c C(═NOH)NR c R c , NR c C(═NCN)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 , SF 5 , —P(O)R c R c , —P(O)(OR c )(OR c ), B(OR c ) 2 , and S(O) 2 NR c R c , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered 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 b is each optionally substituted with 1, 2, 3, or 4 independently selected R d substituents;

each R 9 is independently selected from D, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered 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 k , SR k , NHOR k , C(O)R k , C(O)NR k R k , C(O)OR k , OC(O)R k , OC(O)NR k R k , NR k R k , NR k C(O)R k , NR k C(O)OR k , NR k C(O)NR k R k , C(═NR i )R k , C(═NR i )NR k R k , NR k C(═NR i )NR k R k , NR k C(═NOH)NR k R k , NR k C(═NCN)NR k R k , NR k S(O)R k , NR k S(O) 2 R k , NR k S(O) 2 NR k R k , S(O)R k , S(O)NR k R k , S(O) 2 R k , SF 5 , —P(O)R k R k , —P(O)(OR k )(OR k ), B(OR k ) 2 , and S(O) 2 NR k R k , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered 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 9 is each optionally substituted with 1, 2, 3, or 4 independently selected R q substituents;

each R c is independently selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered 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 1-6 haloalkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered 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 c is each optionally substituted with 1, 2, 3, or 4 independently selected R d substituents;

or two R c substituents, together with the nitrogen atom to which they attached form a 4-, 5-, 6-, or 7-membered heteroaryl or heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 independently selected R d substituents;

each R d is independently selected from D, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered 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 e , SR e , NHOR e , C(O)R e , C(O)NR e R e , C(O)OR e , OC(O)R e , OC(O)NR e R e , NR e R e NR e C(O)R e , NR e C(O)OR e , NR e C(O)NR e R e , C(═NR i )R e , C(═NR i )NR e R e , NR e C(═NR i )NR e R e , NR e C(═NOH)NR e R e , NR e C(═NCN)NR e R e , NR e S(O)R e , NR e S(O) 2 R e , NR e S(O) 2 NR e R e , S(O)R e , S(O)NR e R e , S(O) 2 R e , SF 5 , —P(O)R e R e , —P(O)(OR e )(OR e ), B(OR e ) 2 , and S(O) 2 NR e R e , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered 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 d is each optionally substituted with 1, 2, 3 or 4 independently selected R f substituents;

each R e is independently selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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, C 1-6 haloalkyl, 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 e is each optionally substituted with 1, 2, 3 or 4 independently selected R f substituents;

each R f is independently selected from D, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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-, 4-7 membered heterocycloalkyl-C 1-6 alkyl-, CN, NO 2 , OR g , SR g , NHOR 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 , NR g R g , NR g C(O)R g , NR g C(O)OR g , NR g C(O)NR g R g , C(═NR i )R g , C(═NR i )NR g R g , NR g C(═NR i )NR g R g , NR g C(═NOH)NR g R g , NR g C(═NCN)NR g R g , NR g S(O)R g , NR g S(O) 2 R g , NR g S(O) 2 NR g R g , S(O)R g , S(O)NR g R g , S(O) 2 R g , SF 5 , —P(O)R g R g , —P(O)(OR g )(OR g ), B(OR g ) 2 , and S(O) 2 NR g R g , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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 f is each optionally substituted with 1, 2, 3 or 4 independently selected R h substituents;

each R g is independently selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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, C 1-6 haloalkyl, 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 g is each optionally substituted with 1, 2, 3 or 4 independently selected R h substituents;

each R h is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO—C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino;

each R k is independently selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered 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 1-6 haloalkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered 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 k is each optionally substituted with 1, 2, 3, or 4 independently selected R q substituents;

each R q is independently selected from D, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered 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 m , SR m , NHOR m , C(O)R m , C(O)NR m R m , C(O)OR m , OC(O)R m , OC(O)NR m R m , NHR m , NR m R m , NR m C(O)R m , NR m C(O)OR m , NR m C(O)NR m R m , C(═NR i )R m , C(═NR i )NR m R m , NR m C(═NR i )NR m R m , NR m C(═NOH)NR m R m , NR m C(═NCN)NR m R m , NR m S(O)R m , NR m S(O) 2 R m , NR m S(O) 2 NR m R m , S(O)R m , S(O)NR m R m , S(O) 2 R m , SF 5 , —P(O)R m R m , —P(O)(OR m )(OR m ), B(OR m ) 2 , and S(O) 2 NR m R m , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 6-10 membered 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 q is each optionally substituted with 1, 2, 3 or 4 independently selected R n substituents;

each R m is independently selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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, C 1-6 haloalkyl, 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 m is each optionally substituted with 1, 2, 3 or 4 independently selected R n substituents;

each R n is independently selected from D, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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-, 4-7 membered heterocycloalkyl-C 1-6 alkyl-, CN, NO 2 , OR o , SR o , NHOR o , C(O)R o , C(O)NR o R o , C(O)OR o , OC(O)R o , OC(O)NR o R o , NR o R o , NR o C(O)R o , NR o C(O)OR o , NR o C(O)NR o R o , C(═NR i )R o , C(═NR i )NR o R o , NR o C(═NR i )NR o R o , NR o C(═NOH)NR o R o , NR o C(═NCN)NR o R o , NR o S(O)R o , NR o S(O) 2 R o , NR o S(O) 2 NR o R o , S(O)R o , S(O)NR o R o , S(O) 2 R o , and S(O) 2 NR o R o , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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 n is each optionally substituted with 1, 2, 3 or 4 independently selected R h substituents; and

each R o is independently selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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, C 1-6 haloalkyl, 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 o is each optionally substituted with 1, 2, 3 or 4 independently selected R h substituents.

2. The method of claim 1 , wherein X 2 is N or CH.

3. The method of claim 1 , wherein X 4 is CR 4 .

4. The method of claim 1 , wherein R 4 is selected from H, D, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 1-6 haloalkoxy.

5. The method of claim 1 , wherein X 4 is N.

6. The method of claim 1 , wherein X 5 is CH.

7. The method of claim 1 , wherein X 5 is N.

8. The method of claim 1 , wherein X 6 is CR 6 .

9. The method of claim 1 , wherein R 6 is selected from H, D, and halo.

10. The method of claim 1 , wherein X 6 is N.

11. The method of claim 1 , wherein X 7 is CH.

12. The method of claim 1 , wherein X 7 is N.

13. The method of claim 1 , wherein R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from H, D, halo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, CN, OR a , and SR a , wherein the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl and C 1-6 haloalkoxy of R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each optionally substituted with 1, 2, 3, or 4 independently selected R h substituents.

14. The method of claim 1 , wherein R 1 is selected from H, D, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, OR a , C(O)R a , C(O)NR a R a , C(O)OR a , NR a R a , NR a C(O)R a , NR a C(O)OR a , NR a C(O)NR a R a , NR a S(O) 2 NR a R a , NR a S(O) 2 R a , S(O) 2 R a , and S(O) 2 NR a R a , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R b substituents.

15. The method of claim 1 , wherein Y 1 is selected from CF 3 , CCl 3 , CF 2 H, CCl 2 H, CF 2 Y 2 , CCl 2 Y 2 , CFH 2 , CClH 2 , CFHY 2 , CClHY 2 , CF(Y 2 ) 2 and CCl(Y 2 ) 2 .

16. The method of claim 1 , wherein R 8 is selected from H, D, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 9 substituents.

17. The method of claim 1 , wherein each R 9 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, phenyl-C 1-3 alkyl-, C 3-6 cycloalkyl-C 1-3 alkyl-, 5-6 membered heteroaryl-C 1-3 alkyl-, 4-6 membered heterocycloalkyl-C 1-3 alkyl-, CN, OR k , C(O)R k , C(O)NR k R k , C(O)OR k , NR k R k , NR k C(O)R k , NR k C(O)OR k , NR k C(O)NR k R k , NR k S(O) 2 R k , NR k S(O) 2 NR k R k , S(O) 2 R k , and S(O) 2 NR k R k , wherein the C 1-6 alkyl, C 1-6 haloalkyl, phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, phenyl-C 1-3 alkyl-, C 3-6 cycloalkyl-C 1-3 alkyl-, 5-6 membered heteroaryl-C 1-3 alkyl-, and 4-6 membered heterocycloalkyl-C 1-3 alkyl- of R 9 is each optionally substituted with 1, 2, 3, or 4 independently selected R q substituents.

18. The method of claim 1 , wherein:

each R k is independently selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-4 alkyl-, C 3-7 cycloalkyl-C 1-4 alkyl-, 5-6 membered heteroaryl-C 1-4 alkyl-, and 4-7 membered heterocycloalkyl-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-4 alkyl-, C 3-7 cycloalkyl-C 1-4 alkyl-, 5-6 membered heteroaryl-C 1-4 alkyl-, and 4-7 membered heterocycloalkyl-C 1-4 alkyl- of R k is each optionally substituted with 1, 2, 3, or 4 independently selected R q substituents;

each R q is independently selected from D, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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-, 4-7 membered heterocycloalkyl-C 1-6 alkyl-, OH, NO 2 , CN, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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-, 4-7 membered heterocycloalkyl-C 1-6 alkyl- of R q is each optionally substituted with 1, 2, 3 or 4 independently selected R n substituents; and

each R n is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO—C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, alkyl)aminosulfonyl, amino sulfonylamino, C 1-6 alkylaminosulfonylamino, alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino.

19. The method of claim 1 , wherein:

each R k is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-4 alkyl-, C 3-7 cycloalkyl-C 1-4 alkyl-, 5-6 membered heteroaryl-C 1-4 alkyl-, and 4-7 membered heterocycloalkyl-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 1-6 haloalkyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-4 alkyl-, C 3-7 cycloalkyl-C 1-4 alkyl-, 5-6 membered heteroaryl-C 1-4 alkyl-, and 4-7 membered heterocycloalkyl-C 1-4 alkyl- of R k is each optionally substituted with 1, 2, 3, or 4 independently selected R q substituents; and

each R q is independently selected halo, C 1-6 alkyl, C 1-6 haloalkyl, OH, CN, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, and di(C 1-6 alkyl)aminosulfonyl.

20. The method of claim 1 , wherein Y 1 and R 8 , together with the carbon atom to which they are attached, form a 4-, 5-, 6-, or 7-membered cycloalkyl group which is optionally substituted by 1 or 2 substituents independently selected from Cl and F.

21. The method of claim 1 , wherein R 3 is H.

22. The method of claim 1 , wherein R 3 , R 5 , and R 7 are each H.

23. The method of claim 1 , wherein each R a is independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 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 1-6 haloalkyl, 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 a is each optionally substituted with 1, 2, or 3 independently selected R b substituents.

24. The method of claim 1 , wherein each R b is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, OR 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 , NR c R c , NR c C(O)R c , NR c C(O)OR c , NR c C(O)NR c R c , S(O)R c , S(O)NR c R c , S(O) 2 R c , and S(O) 2 NR c R c , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1 or 2 independently selected R d substituents.

25. The method of claim 1 , wherein:

each R c is independently selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-4 alkyl-, C 3-7 cycloalkyl-C 1-4 alkyl-, 5-6 membered heteroaryl-C 1-4 alkyl-, and 4-7 membered heterocycloalkyl-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-4 alkyl-, C 3-7 cycloalkyl-C 1-4 alkyl-, 5-6 membered heteroaryl-C 1-4 alkyl-, and 4-7 membered heterocycloalkyl-C 1-4 alkyl- of R c is each optionally substituted with 1, 2, 3, or 4 independently selected R d substituents;

each R d is independently selected from D, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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-, 4-7 membered heterocycloalkyl-C 1-6 alkyl-, OH, NO 2 , CN, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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-, 4-7 membered heterocycloalkyl-C 1-6 alkyl- of R d is each optionally substituted with 1, 2, 3 or 4 independently selected R f substituents; and

each R f is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO—C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino.

26. The method of claim 1 , wherein:

X 2 is N or CR 2 ;

X 4 is CR 4 ;

X 5 is N or CR 5 ;

X 6 is N or CR 6 ;

X 7 is CR 7 ;

wherein 0 or 1 of X 5 and X 6 are N;

R 2 is H, halo, CN, C 1-6 alkyl, or C 1-6 haloalkyl;

R 3 is H, halo, CN, C 1-6 alkyl, or C 1-6 haloalkyl;

R 4 is H, halo, CN, C 1-6 alkyl, or C 1-6 haloalkyl;

R 5 is H, halo, CN, C 1-6 alkyl, or C 1-6 haloalkyl;

R 6 is H, halo, CN, C 1-6 alkyl, or C 1-6 haloalkyl;

R 7 is H, halo, CN, C 1-6 alkyl, or C 1-6 haloalkyl;

R 1 is selected from H, D, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, OR a , C(O)R a , C(O)NR a R a , C(O)OR a , NR a R a , NR a C(O)R a , NR a C(O)OR a , NR a C(O)NR a R a , NR a S(O) 2 NR a R a , NR a S(O) 2 R a , S(O) 2 R a , and S(O) 2 NR a R a , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R b substituents;

Y 1 is C 1-6 haloalkyl, wherein each halo is independently selected from Cl and F;

R 8 is selected from H, D, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 9 substituents; or

Y 1 and R 8 , together with the carbon atom to which they are attached, form a 4-, 5-, 6-, or 7-membered cycloalkyl group which is optionally substituted by 1 or 2 substituents independently selected from Cl and F;

each R 9 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, phenyl-C 1-3 alkyl-, C 3-6 cycloalkyl-C 1-3 alkyl-, 5-6 membered heteroaryl-C 1-3 alkyl-, 4-6 membered heterocycloalkyl-C 1-3 alkyl-, CN, OR k , C(O)R k , C(O)NR k R k , C(O)OR k , NR k R k , NR k C(O)R k , NR k C(O)OR k , NR k C(O)NR k R k , NR k S(O) 2 R k , NR k S(O) 2 NR k R k , S(O) 2 R k , and S(O) 2 NR k R k , wherein the C 1-6 alkyl, C 1-6 haloalkyl, phenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, phenyl-C 1-3 alkyl-, C 3-6 cycloalkyl-C 1-3 alkyl-, 5-6 membered heteroaryl-C 1-3 alkyl-, and 4-6 membered heterocycloalkyl-C 1-3 alkyl- of R 9 is each optionally substituted with 1, 2, 3, or 4 independently selected R q substituents;

each R a is independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 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 1-6 haloalkyl, 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 a is each optionally substituted with 1, 2, or 3 independently selected R b substituents;

each R b is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, OR 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 , NR c R c , NR c C(O)R c , NR c C(O)OR c , NR c C(O)NR c R c , S(O)R c , S(O)NR c R c , S(O) 2 R c , and S(O) 2 NR c R c , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1 or 2 independently selected R d substituents;

each R q is independently selected from D, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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-, 4-7 membered heterocycloalkyl-C 1-6 alkyl-, OH, NO 2 , CN, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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-, 4-7 membered heterocycloalkyl-C 1-6 alkyl- of R q is each optionally substituted with 1, 2,3 or 4 independently selected R n substituents; and

each R n is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO—C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino.

27. The method of claim 1 , wherein:

X 2 is N or CR 2 ;

X 4 is CR 4 ;

X 5 is N or CR 5 ;

X 6 is N or CR 6 ;

X 7 is CR 7 ;

wherein 0 or 1 of X 5 and X 6 are N;

R 2 is H;

R 3 is H;

R 4 is H, halo, or C 1-6 alkyl;

R 5 is H;

R 6 is H or halo;

R 7 is H;

R 1 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, 3-6 membered cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, C(O)NR a R a , and C(O)OR a , wherein the C 1-6 alkyl, phenyl, 3-6 membered cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl are each optionally substituted with 1 or 2 independently selected R b substituents;

Y 1 is C 1-6 haloalkyl, wherein each halo is F;

R 8 is selected from H, C 1-6 alkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, 6-10 membered aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 9 substituents; or

Y 1 and R 8 , together with the carbon atom to which they are attached, form a 4-, 5-, or 6-membered cycloalkyl group which is optionally substituted by 1 or 2 F;

each R 9 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, OR k , and NR k R k ; wherein the C 1-6 alkyl of R 9 is each optionally substituted with 1, 2, 3, or 4 independently selected R q substituents;

each R a is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, 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 1-6 haloalkyl, 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 a is each optionally substituted with 1, 2, or 3 independently selected R b substituents;

each R c is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl, wherein the C 1-6 alkyl and C 1-6 haloalkyl of R c is each optionally substituted with 1, 2, 3, or 4 independently selected R d substituents;

each R d is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, OH, CN, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, and di(C 1-6 alkyl)amino;

each R k is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-4 alkyl-, C 3-7 cycloalkyl-C 1-4 alkyl-, 5-6 membered heteroaryl-C1-4 alkyl-, and 4-7 membered heterocycloalkyl-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-4 alkyl-, C 3-7 cycloalkyl-C 1-4 alkyl-, 5-6 membered heteroaryl-C 1-4 alkyl-, and 4-7 membered heterocycloalkyl-C 1-4 alkyl- of R k is each optionally substituted with 1, 2, 3, or 4 independently selected R q substituents; and

28. The method of claim 1 , wherein:

X 2 is N or CR 2 ;

X 4 is CR 4 ;

X 5 is N or CR 5 ;

X 6 is N or CR 6 ;

X 7 is CR 7 ;

wherein 0 or 1 of X 5 and X 6 are N;

R 2 is H;

R 3 is H;

R 4 is H, halo, or C 1-6 alkyl;

R 5 is H;

R 6 is H or halo;

R 7 is H;

R 1 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C(O)OR a , C(O)NR a R a , phenyl, cyclopropyl, thiazolyl, pyrazolyl, oxazolyl, pyrimidinyl, pyridinyl, isoxazolyl, 1,2,4-triazolyl, and piperidinyl; wherein said C 1-6 alkyl, C 1-6 haloalkyl, phenyl, cyclopropyl, thiazolyl, pyrazolyl, oxazolyl, pyrimidinyl, pyridinyl, isoxazolyl, 1,2,4-triazolyl, and piperidinyl are each optionally substituted by 1, 2, 3, or 4 independently selected R b substituents;

Y 1 is C 1-6 haloalkyl, wherein each halo is F;

R 8 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, and 5-6 membered heteroaryl are each optionally substituted with 1 or 2 independently selected R 9 substituents; or

Y 1 and R 8 , together with the carbon atom to which they are attached, form a 4-5-, or 6-membered cycloalkyl group which is optionally substituted by one F;

each R 9 is independently selected from C 1-6 alkyl, OR k , and NR k R k ;

each R a is selected from H, C 1-6 alkyl, and isoxazol-5-ylmethyl; wherein said isoxazol-5-ylmethyl is substituted by methyl and said C 1-6 alkyl is optionally substituted by OH;

each R b is independently selected from halo, C 1-6 alkyl, C 3-6 cycloalkyl, OR c , and C(O)NR c R c , wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each optionally substituted with 1 or 2 independently selected R d substituents;

each R c group is independently selected from H and C 1-6 alkyl;

each R d is independently selected from D, C 1-6 alkyl and OH; and

each R k is independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl, and 4-7 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-7 cycloalkyl, and 4-7 membered heterocycloalkyl of R k is each optionally substituted with 1 or 2 independently selected C 1-6 alkyl groups.

29. The method of claim 1 , wherein:

X 2 is N or CR 2 ;

X 4 is CR 4 ;

X 5 is N or CR 5 ;

X 6 is N or CR 6 ;

X 7 is CR 7 ;

wherein 0 or 1 X 5 and X 6 are N;

R 2 is H;

R 3 is H;

R 4 is H, F, methyl, or CD 3 ;

R 5 is H;

R 6 is H or F;

R 7 is H;

Y 1 is CF 3 , CHF 2 , CH 2 F, or CF 2 CF 3 ;

R 1 is selected from H, methyl, CF 3 , C(O)OR a , C(O)NR a R a , phenyl, cyclopropyl, thiazolyl, pyrazolyl, oxazolyl, pyrimidinyl, pyridinyl, isoxazolyl, 1,2,4-triazolyl, and piperindinyl, wherein the phenyl, cyclopropyl, thiazolyl, pyrazolyl, oxazolyl, pyrimidinyl, pyridinyl, isoxazolyl, 1,2,4-triazolyl, and piperidinyl are each optionally substituted by 1 or 2 independently selected R b substituents;

R 8 is selected from H, methyl, hydroxymethyl, ethyl, 2-hydroxyethyl, 2-(N-methylamino)ethyl, 2-(N-{tetrahydro-2H-pyran-4-yl}amino)ethyl, cyclopropyl, and 1-methyl-1H-tetrazol-5-yl;

or Y 1 and R 8 , together with the carbon atom to which they are attached, form a 2-flourocyclopentyl ring;

each R a is independently selected from H, methyl, 2-hydroxy-2-methylpropyl, and (3-methylisoxazol-5-yl)methyl; and

each R b is independently selected from fluoro, methyl, CD 3 , hydroxymethyl, methoxy, C(O)NH 2 , and cyclopropyl.

30. The method of claim 1 , wherein the compound of Formula (I) is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof.

31. The method of claim 1 , wherein the compound of Formula (I) is a compound of Formula (III):

or a pharmaceutically acceptable salt thereof.

32. The method of claim 1 , wherein the compound of Formula (I) is a compound of Formula (IV):

or a pharmaceutically acceptable salt thereof.

33. The method of claim 1 , wherein the compound of Formula (I) is a compound of Formula (V):

or a pharmaceutically acceptable salt thereof.

34. The method of claim 1 , wherein the compound of Formula (I) is selected from:

2-(3-(4-Amino-2-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)-1,1,1-trifluoropropan-2-ol;

2-(3-(4-Amino-2-methylimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)-1,1,1-trifluoropropan-2-ol;

2-(3-(4-Aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)-1,1,1-trifluoropropan-2-ol;

2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1,1-trifluoropropan-2-ol;

2-(3-(8-Amino-6-methylimidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1,1-trifluoropropan-2-ol;

Methyl 8-amino-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxylate;

8-Amino-N-methyl-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide;

8-Amino-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)-N-((3-methylisoxazol-5-yl)methyl)imidazo[1,2-a]pyrazine-6-carboxamide;

2-(3-(8-Amino-6-(2-(hydroxymethyl)pyridin-4-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1,1-trifluoropropan-2-ol;

2-(3-(8-Amino-6-(2-cyclopropylthiazol-5-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1,1-trifluoropropan-2-ol;

2-(3-(8-Amino-6-(5-methoxythiazol-2-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1,1-trifluoropropan-2-ol;

1-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-2,2,2-trifluoro-1-(1-methyl-1H-tetrazol-5-yl)ethan-1-ol;

2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1,1-trifluoro-4-(methylamino)butan-2-ol;

2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1,1-trifluoro-4-((tetrahydro-2H-pyran-4-yl)amino)butan-2-ol;

3-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-4,4,4-trifluorobutane-1,3-diol;

1-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1-cyclopropyl-2,2,2-trifluoroethan-1-ol;

1-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-2,2,2-trifluoroethan-1-ol;

2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1-fluoropropan-2-ol;

2-(3-(8-Amino-6-(1-(methyl-d 3 )-1H-pyrazol-5-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

2-(3-(8-Amino-6-(2-methyloxazol-5-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

2-(3-(8-Amino-6-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

3-(8-Amino-3-(5-(1,1-difluoro-2-hydroxypropan-2-yl)-2-methylphenyl)imidazo[1,2-a]pyrazin-6-yl)-4-fluorobenzamide;

2-(3-(8-Amino-6-(pyrimidin-5-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

2-(3-(8-Amino-6-(2-methoxypyridin-3-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

2-(3-(8-Amino-6-(2-methylthiazol-5-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

2-(3-(8-Amino-6-(3-fluoro-2-methylpyridin-4-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

2-(3-(8-Amino-6-(1,5-dimethyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

2-(3-(8-Amino-6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

2-(3-(8-Amino-6-(1,3-dimethyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

2-(3-(8-Amino-6-(3,5-dimethyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

2-(3-(8-Amino-6-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

2-(3-(8-Amino-6-(1,3-dimethyl-1H-pyrazol-5-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

2-(3-(8-Amino-6-(1,4-dimethyl-1H-pyrazol-5-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

2-(3-(8-Amino-6-(1-methyl-1H-pyrazol-3-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

2-(3-(8-Amino-6-(2-(hydroxymethyl)pyridin-4-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

2-(3-(8-Amino-6-(6-(hydroxymethyl)pyridin-3-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

2-(3-(8-Amino-6-(3-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

2-(3-(8-Amino-6-(3-methylisoxazol-5-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

2-(3-(8-Amino-6-(1H-1,2,4-triazol-1-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

2-(3-(8-Amino-6-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluorobutan-2-ol;

2-(3-(4-Amino-2-(1-methyl-1H-pyrazol-5-yl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

2-(3-(4-Amino-2-(2-methyloxazol-5-yl)imidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

2-(5-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-2-fluoro-4-methylphenyl)-1,1,1-trifluoropropan-2-ol;

2-(4-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-5-methylpyridin-2-yl)-1,1,1-trifluoropropan-2-ol;

2-(5-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-2-fluorophenyl)-1,1,1-trifluoropropan-2-ol;

2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)phenyl)-1,1,1-trifluoropropan-2-ol;

2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-fluorophenyl)-1,1,1-trifluoropropan-2-ol;

245-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-6-methylpyridin-3-yl)-1,1,1-trifluoropropan-2-ol;

2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,4,4,4-pentafluorobutan-2-ol;

1-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-2-fluorocyclopentan-1-ol; and

8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide;

or a pharmaceutically acceptable salt thereof.

35. The method of claim 1 , wherein the compound of Formula (I) is selected from:

1-(8-Amino-3-(5-(1,1-difluoro-2-hydroxypropan-2-yl)-2-methylphenyl)imidazo[1,2-a]pyrazin-6-yl)piperidine-4-carbonitrile;

1-(8-Amino-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazin-6-yl)piperidin-4-ol;

2-(3-(8-Amino-6-(1-(methyl-d3)-1H-pyrazol-5-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol;

2-(3-(8-Amino-6-(2-methyloxazol-5-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol;

2-(3-(8-Amino-6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol;

2-(3-(8-Amino-6-(2-methylthiazol-5-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol;

2-(3-(8-Amino-6-(oxazol-5-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol;

2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol;

Ethyl 2-(8-amino-3-(5-(1,1-difluoro-2-hydroxypropan-2-yl)-2-methylphenyl)imidazo[1,2-a]pyrazin-6-yl)cyclopropane-1-carboxylate;

2-(8-Amino-3-(5-(1,1-difluoro-2-hydroxypropan-2-yl)-2-methylphenyl)imidazo[1,2-a]pyrazin-6-yl)-N-methylcyclopropane-1-carboxamide;

(2-(8-Amino-3-(5-(1,1-difluoro-2-hydroxypropan-2-yl)-2-methylphenyl)imidazo[1,2-a]pyrazin-6-yl)cyclopropyl)(4-methylpiperazin-1-yl)methanone;

2-(8-Amino-3-(5-(1,1-difluoro-2-hydroxypropan-2-yl)-2-methylphenyl)imidazo[1,2-a]pyrazin-6-yl)-N-(1-hydroxy-2-methylpropan-2-yl)cyclopropane-1-carboxamide;

2-(3-(8-Amino-6-(2-(hydroxymethyl)cyclopropyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol; and

8-Amino-N-(2-hydroxy-2-methylpropyl)-3-(2-(methyl-d3)-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide;

or a pharmaceutically acceptable salt thereof.

36. The method of claim 1 , wherein the compound of Formula (I) is selected from:

2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

8-Amino-3-(5-(3-amino-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)-2-methylphenyl)-N-(3-cyclopropyltetrahydrofuran-3-yl)imidazo[1,2-a]pyrazine-6-carboxamide;

8-Amino-3-(5-(3-amino-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)-2-methylphenyl)-N-(2,3-dimethyltetrahydrofuran-3-yl)imidazo[1,2-a]pyrazine-6-carboxamide;

8-Amino-3-(5-(3-amino-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)-2-methylphenyl)-N-(4-(trifluoromethyl)tetrahydro-2H-pyran-4-yl)imidazo[1,2-a]pyrazine-6-carboxamide;

3-(4-(8-Amino-3-(2-(methyl-d3)-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazin-6-yl)-1H-pyrazol-1-yl)-3-cyclobutylpropanenitrile;

2-(3-(8-Amino-6-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)imidazo[1,2-a]pyrazin-3-yl)-4-(methyl-d3)phenyl)-1,1,1-trifluoropropan-2-ol; and

Methyl 3-(4-(8-amino-3-(2-(methyl-d3)-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazin-6-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane-1-carboxylate;

or a pharmaceutically acceptable salt thereof.

37. The method of claim 1 , wherein the compound of Formula (I) is selected from:

2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3-difluoro-2-hydroxypropanamide;

2-(3-(4-(8-amino-3-(5-(1,1-difluoro-2-hydroxypropan-2-yl)-2-methylphenyl)imidazo[1,2-a]pyrazin-6-yl)-1H-pyrazol-1-yl)-1-(cyclobutanecarbonyl)azetidin-3-yl)acetonitrile;

2-(3-(8-Amino-6-(5-(methylsulfonyl)pyridin-3-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

(4-(8-amino-3-(5-(1,1-difluoro-2-hydroxypropan-2-yl)-2-methylphenyl)imidazo[1,2-a]pyrazin-6-yl)phenyl)boronic acid;

2-(3-(4-Amino-2-methylimidazo[2,1-f][1,2,4]triazin-7-yl)-4-methylphenyl)-1,1,3,3-tetrafluoropropan-2-ol;

((1 S)-(8-Amino-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamido)(cyclobutyl)methyl)boronic acid;

2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxy-N-methylpropanamide;

2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanoic acid;

2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxy-N-(3-methylazetidin-3-yl)propanamide;

2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-N-(bicyclo[1.1.1 pentan-1-yl)-3,3,3-trifluoro-2-hydroxypropanamide;

2-(3-(8-Amino-6-(6-(1-hydroxyethyl)pyridin-3-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1-difluoropropan-2-ol;

2-(3-(8-Amino-6-(cyclopropylethynyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1,1-trifluoropropan-2-ol;

2-(8-amino-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazin-6-yl)-N,N-dimethylacetamide;

2-(8-amino-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazin-6-yl)-1-morpholinoethanone;

2-(3-(8-amino-6-(3-(hydroxymethyl)cyclobutyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1,1-trifluoropropan-2-ol;

N-(2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropyl)acetamide;

N-(2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropyl)benzamide;

N-(2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropyl)-2-fluoroacetamide;

3-(5-(3-acetamido-1,1,1-trifluoro-2-hydroxypropan-2-yl)-2-methylphenyl)-8-amino-N-ethylimidazo[1,2-a]pyrazine-6-carboxamide;

2-(4-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-1-(phenylsulfonyl)-1H-indol-6-yl)-1,1,1-trifluoropropan-2-ol;

2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-(methyl-d 3 )phenyl)-1,1,1-trifluorobutane-2,3-diol;

2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-(methyl-d 3 )phenyl)-1,1,1-trifluoro-3-methylbutane-2,3-diol;

2-(3-(8-Amino-6-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyrazin-3-yl)-4-(methyl-d 3 )phenyl)-1,1,1-trifluoropropan-2-ol;

2-(3-(8-Amino-6-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide;

3-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-4,4,4-trifluoro-3-hydroxy-N,2,2-trimethylbutanamide;

2-(3-(8-Amino-6-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol;

2-(3-(8-Amino-6-(6-(1-hydroxyethyl)pyridin-3-yl)imidazo[1,2-a]pyrazin-3-yl)-4-(methyl-d 3 )phenyl)-1,1,1-trifluoropropan-2-ol;

2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-1-chloro-1,1-difluoropropan-2-ol;

8-Amino-N-(1-azabicyclo[2.2.1]heptan-4-yl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide;

8-Amino-N-(3-cyanobicyclo[1.1.1]pentan-1-yl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide;

8-Amino-N-(1-(hydroxymethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide;

8-Amino-N-((1-cyanocyclobutyl)methyl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide;

8-Amino-3-(5-(3-amino-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)-2-methylphenyl)-N-(2-hydroxy-2-methylpropyl)imidazo[1,2-a]pyrazine-6-carboxamide;

8-Amino-3-(5-(3-amino-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)-2-methylphenyl)-N-(4-hydroxybicyclo[2.2.1]heptan-1-yl)imidazo[1,2-a]pyrazine-6-carboxamide;

8-Amino-3-(5-(3-amino-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)-2-methylphenyl)-N-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-a]pyrazine-6-carboxamide;

8-Amino-3-(5-(3-amino-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)-2-methylphenyl)-N-(3-fluorobicyclo[1.1.1]pentan-1-yl)imidazo[1,2-a]pyrazine-6-carboxamide; and

8-Amino-N-(3-cyano-1,1,1-trifluoropropan-2-yl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxy-3-((methyl-d 3 )amino)-3-oxopropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide;

or a pharmaceutically acceptable salt thereof.

38. The method of claim 1 , wherein the disease or disorder is an autoimmune disease or disorder, cancer, cardiovascular disease, or neurodegenerative disease.

39. The method of claim 1 , wherein the disease or disorder is Burkitt's lymphoma, acute myeloblastic leukemia, chronic myeloid leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, hairy cell leukemia, Mantle cell lymphoma, small lymphocytic lymphoma, follicular lymphoma, xenoderoma pigmentosum, keratoctanthoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, Waldenstrom's macroglobulinemia, prolymphocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphatic tissue (MALT) lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphomatoid granulomatosis, splenic marginal zone lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, smouldering myeloma (aka asymptomatic myeloma), monoclonal gammopathy of undetermined significance (MGUS), or diffuse large B cell lymphoma.

40. The method of claim 39 , wherein the non-Hodgkin's lymphoma (NHL) is relapsed NHL, refractory NHL, recucurrent follicular NHL, indolent NHL (iNHL), or aggressive NHL (aNHL).

41. The method of claim 39 , wherein the diffuse large B cell lymphoma is activated B-cell like (ABC) diffuse large B cell lymphoma, or germinal center B cell (GCB) diffuse large B cell lymphoma.

42. The method of claim 1 , wherein the disease or disorder is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematous, asthma, allergy, allergic rhinitis, pancreatitis, psoriasis, anaphylaxis, glomerulonephritis, inflammatory bowel disease, thrombosis, meningitis, encephalitis, diabetic retinopathy, benign prostatic hypertrophy, myasthenia gravis, Sjögren's syndrome, osteoarthritis, restenosis, or atherosclerosis.

43. The method of claim 1 , wherein the disease or disorder is heart hypertropy, cardiac myocyte dysfunction, acute coronary syndrome, chronic obstructive pulmonary disease (COPD), chronic bronchitis, elevated blood pressure, ischemia, ischemia-reperfusion, vasoconstriction, anemia, bacterial infection, viral infection, graft rejection, kidney disease, anaphylactic shock fibrosis, skeletal muscle atrophy, skeletal muscle hypertrophy, angiogenesis, sepsis, graft-versus-host disease, allogeneic or xenogeneic transplantation, glomerulosclerosis, progressive renal fibrosis, idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia, vasculitis, systemic lupus erythematosus, lupus nephritis, pemphigus, or membranous nephropathy.

44. The method of claim 1 , wherein the disease or disorder is Mantle cell lymphoma.

45. The method of claim 1 , wherein the disease or disorder is follicular lymphoma.

46. The method of claim 1 , wherein the disease or disorder is extranodal marginal zone lymphoma.

47. The method of claim 1 , wherein the disease or disorder is myelofibrosis.

48. The method of claim 1 , wherein the disease or disorder is splenic marginal zone lymphoma.

49. The method of claim 1 , wherein the disease or disorder is diffuse large B cell lymphoma.

50. The method of claim 1 , wherein the disease or disorder is Sjögren's syndrome.

51. The method of claim 1 , wherein the disease or disorder is autoimmune hemolytic anemia.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 14, 2020

From: DOUTY, BRENT; BUESKING, ANDREW W.; BURNS, DAVID M.; COMBS, ANDREW P.; FALAHATPISHEH, NIKOO; JALLURI, RAVI KUMAR; LEVY, DANIEL; POLAM, PADMAJA; SHAO, LIXIN; SHEPARD, STACEY; SHVARTSBART, ARTEM; SPARKS, RICHARD B.; YUE, EDDY W.

To: INCYTE CORPORATION

Reel/Frame 053199/0533 →

Continuity (5)

Division 16163341 · Oct 17, 2018

Provisional Application 62574057 · Oct 18, 2017

Provisional Application 62608897 · Dec 21, 2017

Provisional Application 62727316 · Sep 5, 2018

Related Publication 20200385392A1 · Dec 10, 2020

Cited By (1)

US 12,516,065