AMINOPYRAZINE DIOL COMPOUNDS AS PI3K-y INHIBITORS

Abstract

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.

1 .- 43 . (canceled) 
     
     
         44 . A method of treating a disease or disorder in a patient, wherein the disease or disorder is associated with abnormal expression or activity of PI3Kγ kinase, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein:
 X 1  is N or CR 1 ; 
 R 1  is 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, OH, and NH 2 ; 
 R 2  is C(O)NR c1 R d1 ; 
 R 3 , R 4  and R 5  are each independently selected from H, D, halo, CN, OH, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  alkoxy, 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, amino, C 1-6  alkylamino, di(C 1-6  alkyl)amino, and C(O)NR c R d , wherein the C 1-6  alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 D; 
 R 6 , R 7  and R 8  are each independently selected from H, D, 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-, C(O)R b3 , C(O)NR c3 R d3 , C(O)NR c3 (OR a3 ), C(O)OR a3 , C(═NR e3 )R b3 , C(═NOH)R b3 , C(═NCN)R b3 , and C(═NR e3 )NR c3 R d3  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 6 , R 7 , and R 8  are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R B  substituents; and wherein the C 1-6  haloalkyl of R 6 , R 7 , or R 8  is optionally substituted by 1, 2, 3, or 4 independently selected Y substituents; 
 each Y is independently selected from D, halo, C 1-6  alkyl, and C 1-6  haloalkyl; 
 or R 6  and R 7  substituents, together with the ring atoms to which they are attached, form a C 3-10  cycloalkyl or 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected R B  substituents; 
 or R 7  and R 8  substituents, together with the ring atoms to which they are attached, form a C 3-10  cycloalkyl or 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected R B  substituents; 
 R c  and R d  are each 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 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  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 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  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  and R d , are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R M  substituents; 
 each 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 3-10  cycloalkyl, 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 3-10  cycloalkyl, 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 c1  and R d1  are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R A  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 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R A  substituents; 
 each R a3 , R b3 , R c3 , and R d3  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 a3 , R b3 , R c3 , and R d3  are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R B  substituents; 
 or, any R c3  and R d3 , attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R B  substituents; 
 each R e3  is independently selected from H, OH, CN, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, C 1-6  haloalkoxy, 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-; 
 each R A  is independently 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 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  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 a4 , SR a4 , NHOR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)NR c4 (OR b4 ), C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 NR c4 R d4  NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , C(═NR c4 )R b4 , C(═NOH)R b4 , C(═NCN)R b4 , C(═NR 4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , NR 4 C(═NR 4 )R b4 , NR c4 C(═NOH)NR c4 R d4  NR c4 C(═NCN)NR c4 R d4 , NR c4 S(O)R b4 , NR c4 S(O)NR c4 R d4 , NR c4 S(O)R b4  NR c4 S(O)NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , OS(O)(═NR e4 )R b4 , OS(O) 2 R b4 , SF 5 , P(O)R f4 R g4 , OP(O)(OR h4 )(OR i4 ), P(O)(OR h4 )(OR i4 ), and BR j4 R k4 , wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  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 optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R D  substituents; 
 each R B  is independently 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 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  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 a2 , SR a2 , NHOR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)NR 2 (OR b2 ), C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 NR c2 R d2  NR e2 C(O)R b2 , NR c2 C(O)OR a2 , NR e2 C(O)NR c2 R d2 , C(═NR e2 )R b2 , C(═NOH)R b2 , C(═NCN)R b2 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )R b2 , NR c2 C(═NOH)NR c2 R d2  NR e2 C(═NCN)NR c2 R d2 , NR c2 S(O)R b2 , NR e2 S(O)NR c2 R d2 , NR c2 S(O) 2 R b2  NR 2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , S(O) 2 NR c2 R d2 , OS(O)(═NR e2 )R b2 , OS(O) 2 R b2 , SF 5 , P(O)R f2 R g2 , OP(O)(OR h2 )(OR i2 ), P(O)(OR h2 )(OR i2 ), and BR j2 R k2 , wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  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 optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R M  substituents; 
 each R a2 , R b2 , R c2 , and R d2  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 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  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 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  cycloalkyl-C 1-6  alkyl-, (5-10 membered heteroaryl)-C 1-6  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6  alkyl- of R a2 , R b2 , R e2 , and R d2  are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R M  substituents; 
 or, any R e2  and R d2  attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R M  substituents; 
 each R e2  is independently selected from H, OH, CN, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  cycloalkyl-C 1-6  alkyl-, (5-10 membered heteroaryl)-C 1-6  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6  alkyl-; each R f2  and R g2  is independently selected from H, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  cycloalkyl-C 1-6  alkyl-, (5-10 membered heteroaryl)-C 1-6  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6  alkyl-; 
 each R h2  and R i2  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 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  cycloalkyl-C 1-6  alkyl-, (5-10 membered heteroaryl)-C 1-6  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6  alkyl-; each R j2  and R k2  is independently selected from OH, C 1-6  alkoxy, and C 1-6  haloalkoxy; 
 or any R j2  and R k2  attached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6  alkyl and C 1-6  haloalkyl; 
 each R a4 , R b4 , R c4 , and R d4  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 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  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 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  cycloalkyl-C 1-6  alkyl-, (5-10 membered heteroaryl)-C 1-6  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6  alkyl- of R a4 , R b4 , R c4 , and R d4  are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R D  substituents; 
 or, any R c4  and R d4  attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R D  substituents; 
 each R e4  is independently selected from H, OH, CN, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  cycloalkyl-C 1-6  alkyl-, (5-10 membered heteroaryl)-C 1-6  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6  alkyl-; each R f4  and R g4  is independently selected from H, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  cycloalkyl-C 1-6  alkyl-, (5-10 membered heteroaryl)-C 1-6  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6  alkyl-; 
 
       each R h4  and R i4  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 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  cycloalkyl-C 1-6  alkyl-, (5-10 membered heteroaryl)-C 1-6  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6  alkyl-;
 each R j4  and R k4  is independently selected from OH, C 1-6  alkoxy, and C 1-6  haloalkoxy; or any R j4  and R k4  attached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6  alkyl and C 1-6  haloalkyl; 
 each R D  is independently 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 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  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 a5 , SR a5 , NHOR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)NR c5 (OR b5 ), C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)OR a5 , NR c5 C(O)NR c5 R d5 , C(═NR e1 )R b5 , C(═NOH)R b5 , C(═NCN)R b5 , C(═NR e5 )NR c5 R d5 , NR c5 C(═NR e5 )NR c5 R d5 , NR c5 C(═NR)R b5 , NR c5 C(═NOH)NR c5 R d5 , NR c5 C(═NCN)NR c5 R d5 , NR c5 S(O)R b5 , NR c5 S(O)NR c5 R d5 , NR c5 S(O) 2 R b5 , NR c5 S(O)NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R c5 , S(O) 2 NR c5 R d5 , OS(O)(═NR e5 )R b5 , OS(O) 2 R b5 , SF 5 , P(O)R f5 R g5 , OP(O)(OR h5 )(OR i5 ), P(O)(OR h5 )(OR i5 ), and BR j5 R k5 , wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  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  are each optionally substituted with 1, 2, 3, or 4 independently selected R E  substituents; 
 each R a5 , R b5 , R c5 , and R d5  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 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  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 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  cycloalkyl-C 1-6  alkyl-, (5-10 membered heteroaryl)-C 1-6  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6  alkyl- of R a5 , R b5 , R c5 , and R d5  are each optionally substituted with 1, 2, 3, or 4 independently selected R E  substituents; 
 or, any R c5  and R d5  attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R E  substituents; 
 
       each R e5  is independently selected from H, OH, CN, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  cycloalkyl-C 1-6  alkyl-, (5-10 membered heteroaryl)-C 1-6  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6  alkyl-; 
       each R f5  and R g5  is independently selected from H, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  cycloalkyl-C 1-6  alkyl-, (5-10 membered heteroaryl)-C 1-6  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6  alkyl-;
 each R h5  and R i5  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 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  cycloalkyl-C 1-6  alkyl-, (5-10 membered heteroaryl)-C 1-6  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6  alkyl-; 
 each R j5  and R k5  is independently selected from OH, C 1-6  alkoxy, and C 1-6  haloalkoxy; or any R j5  and R k5  attached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6  alkyl and C 1-6  haloalkyl; 
 each R E  is independently 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 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  cycloalkyl-C 1-6  alkyl-, (5-10 membered heteroaryl)-C 1-6  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6  alkyl-, CN, NO 2 , OR a6 , SR a6 , NHOR a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)NR c6 (OR b6 ), C(O)OR a6 , OC(O)R b6 , OC(O)NR c6 R d6 , NR c6 R d6 , NR c6 NR c6 R d6 , NR c6 C(O)R b6 , NR c6 C(O)OR a6 , NR c6 C(O)NR c6 R d6 , C(═NR e6 )R b6 , C(═NOH)R b6 , C(═NCN)R b6 , C(═NR e6 )NR c6 R d6 , NR c6 C(═NR e6 )NR c6 R d6 , NR c6 C(═NR e6 )R b6 , NR c6 C(═NOH)NR c6 R d6 , NR c6 C(═NCN)NR c6 R d6 , NR c6 S(O)R b6 , NR c6 S(O)NR c6 R d6 , NR c6 S(O) 2 R b6 , NR c6 S(O) 2 NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O) 2 R c6 , S(O) 2 NR c6 R d6 , OS(O)(═NR e6 )R b6 , OS(O) 2 R b6 , SF 5 , P(O)R f6 R g6 , OP(O)(OR h6 )(OR i6 ), P(O)(OR h6 )(OR i6 ), and BR j6 R k6 , wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  cycloalkyl-C 1-6  alkyl-, (5-10 membered heteroaryl)-C 1-6  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6  alkyl- of R E  are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R G  substituents; 
 each R a6 , R b6 , R c6 , and R d6  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 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  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 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  cycloalkyl-C 1-6  alkyl-, (5-10 membered heteroaryl)-C 1-6  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6  alkyl- of R a6 , R b6 , R c6 , and R d6  are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R G  substituents; 
 or, any R c6  and R d6  attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R G  substituents; 
 each R e6  is independently selected from H, OH, CN, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  cycloalkyl-C 1-6  alkyl-, (5-10 membered heteroaryl)-C 1-6  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6  alkyl-; each R f6  and R g6  is independently selected from H, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  cycloalkyl-C 1-6  alkyl-, (5-10 membered heteroaryl)-C 1-6  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6  alkyl-; 
 each R h6  and R i6  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 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  cycloalkyl-C 1-6  alkyl-, (5-10 membered heteroaryl)-C 1-6  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6  alkyl-; 
 each R j6  and R k6  is independently selected from OH, C 1-6  alkoxy, and C 1-6  haloalkoxy; or any R j6  and R k6  attached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6  alkyl and C 1-6  haloalkyl; 
 each R G  is independently selected from H, D, halo, CN, NO 2 , SF 5 , C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-10  aryl, C 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  cycloalkyl-C 1-6  alkyl-, (5-10 membered heteroaryl)-C 1-6  alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6  alkyl; and each R M  is independently selected from H, D, 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 6-10  aryl, C 3-7  cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10  aryl-C 1-6  alkyl-, C 3-7  cycloalkyl-C 1-6  alkyl-, (5-10 membered heteroaryl)-C 1-6  alkyl-, (4-10 membered heterocycloalkyl)-C 1-6  alkyl, 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. 
 
     
     
         45 . The method of  claim 44 , wherein the disease or disorder is an autoimmune disease or disorder, cancer, cardiovascular disease, or neurodegenerative disease. 
     
     
         46 .- 50 . (canceled) 
     
     
         51 . The method of  claim 44 , 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. 
     
     
         52 . The method of  claim 51 , wherein the non-Hodgkin's lymphoma (NHL) is relapsed NHL, refractory NHL, recurrent follicular NHL, indolent NHL (iNHL), or aggressive NHL (aNHL). 
     
     
         53 . The method of  claim 51 , 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. 
     
     
         54 . (canceled) 
     
     
         55 . The method of  claim 44 , 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. 
     
     
         56 . The method of  claim 44 , 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. 
     
     
         57 .- 59 . (canceled) 
     
     
         60 . The method of  claim 44 , wherein the disease or disorder is Mantle cell lymphoma. 
     
     
         61 . The method of  claim 44 , wherein the disease or disorder is follicular lymphoma. 
     
     
         62 . The method of  claim 44 , wherein the disease or disorder is extranodal marginal zone lymphoma. 
     
     
         63 . The method of  claim 44 , wherein the disease or disorder is myelofibrosis. 
     
     
         64 . The method of  claim 44 , wherein the disease or disorder is splenic marginal zone lymphoma. 
     
     
         65 . The method of  claim 44 , wherein the disease or disorder is diffuse large B cell lymphoma. 
     
     
         66 . The method of  claim 44 , wherein the disease or disorder is Sjögren's syndrome. 
     
     
         67 . The method of  claim 44 , wherein the disease or disorder is autoimmune hemolytic anemia. 
     
     
         68 . The method of  claim 44 , wherein each R A  is independently selected from D, halo, C 1-6  alkyl, C 1-6  haloalkyl, CN, OR a4 , and NR c4 R d4 ; wherein the C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl of R A  are each optionally substituted with 1, 2, 3, or 4 independently selected R D  substituents;
 each R a4 , R c4 , and R d4  is independently selected from H, C 1-6  alkyl, and C 1-6  haloalkyl, wherein the C 1-6  alkyl of R a4 , R c4 , and R d4  are each optionally substituted with 1, 2, 3, or 4 independently selected R D  substituents; and   each R D  is independently selected from D, OH, CN, halo, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, amino, C 1-6  alkylamino, and di(C 1-6  alkyl)amino.   
     
     
         69 . The method of  claim 44 , wherein each R c1  and R d1  is independently selected from H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl, 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 3-10  cycloalkyl, 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 c1  and R d1  are each optionally substituted with 1, 2, 3, or 4 independently selected R A  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 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R A  substituents.   
     
     
         70 . The method of  claim 44 , wherein:
 each R c1  and R d1  is independently selected from H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl, 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 3-10  cycloalkyl, 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 c1  and R d1  are each optionally substituted with 1, 2, 3, or 4 independently selected R A  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 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R A  substituents;   each R A  is independently selected from D, halo, oxo, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, and C 2-6  alkynyl, CN, NO 2  and OR a4 , wherein the C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl of R A  is optionally substituted with 1 or 2 independently selected R D  substituents; each R a4  is independently selected from H and C 1-6  alkyl, wherein the C 1-6  alkyl is optionally substituted CN, NO 2  or OH; and   each R D  is OH.   
     
     
         71 . The method of  claim 44 , wherein:
 R c1  is H;   R d1  is selected from C 1-6  alkyl, C 3-7  cycloalkyl, 4-7 membered heterocycloalkyl, phenyl-C 1-4  alkyl-, and C 3-7  cycloalkyl-C 1-4  alkyl-, wherein the C 1-6  alkyl, C 3-7  cycloalkyl, 4-7 membered heterocycloalkyl, phenyl-C 1-4  alkyl-, and C 3-7  cycloalkyl-C 1-4  alkyl- of R c1  and R d1  are each optionally substituted with 1 or 2 independently selected R A  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 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1 or 2 independently selected R A  substituent; and   each R A  is independently selected from oxo, methyl, CH 2 F, CHF 2 , CF 3 , —OCH 3 , —CH 2 OH, CN and OH.   
     
     
         72 . The method of  claim 44 , wherein:
 R c1  is H;   R d1  is selected from ethyl, propyl, isopropyl, butyl, tert-butyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methyl-cyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrorolidinyl, and thianyl, wherein the ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methyl-cyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrorolidinyl and thianyl of R d1  are each optionally substituted with 1 or 2 independently selected R A  substituents;   or, any R c1  and R d1 , attached to the same N atom, together with the N atom to which they are attached, for a azetidinyl or pyrrolidinyl, wherein the azetidinyl or pyrrolidinyl is optionally substituted with 1 or 2 independently selected R A  substituents; and   
       each R A  is independently selected from oxo, methyl, CH 2 F, CHF 2 , CF 3 , —OCH 3 , —CH 2 OH, CN and OH. 
     
     
         73 . The method of  claim 44 , wherein R 3  is 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, OH, and NH 2 , wherein C 1-6  alkyl is optionally substituted with 1, 2, or 3 D. 
     
     
         74 . The method of  claim 44 , wherein R 3  is C 1-6  alkyl, which is optionally substituted with 1, 2, or 3 D. 
     
     
         75 . The method of  claim 44 , wherein R 3  is methyl or CD 3 . 
     
     
         76 . The method of  claim 44 , wherein R 3  is methyl. 
     
     
         77 . The method of  claim 44 , wherein R 3  is CD 3 . 
     
     
         78 . The method of  claim 44 , wherein R 4  is H, D, or C 1-6  alkyl, wherein the C 1-6  alkyl is optionally substituted with 1, 2, or 3 D. 
     
     
         79 . The method of  claim 44 , wherein R 4  is H. 
     
     
         80 . The method of  claim 44 , wherein R 5  is H, D, or C 1-6  alkyl, wherein the C 1-6  alkyl is optionally substituted with 1, 2, or 3 D. 
     
     
         81 . The method of  claim 44 , wherein R 5  is H. 
     
     
         82 . The method of  claim 44 , wherein R 6  is H, D, C 1-6  alkyl or C 1-6  haloalkyl, wherein each halogen is F, wherein the haloalkyl is optionally substituted with 1 or 2 independently selected Y substituents, wherein each Y substituent is independently selected from D, halo, C 1-6  alkyl, and C 1-6  haloalkyl. 
     
     
         83 . The method of  claim 44 , wherein R 6  is C 1-6  haloalkyl, wherein each halogen is F. 
     
     
         84 . The method of  claim 44 , wherein R 6  is CH 2 F, CHF 2  or CF 3 . 
     
     
         85 . The method of  claim 44 , wherein R 7  is selected from H, D, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 6-10  aryl, C 3-7  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 is optionally substituted with 1, 2, or 3 D. 
     
     
         86 . The method of  claim 44 , wherein R 7  is H. 
     
     
         87 . The method of  claim 44 , wherein R 8  is selected from H, D, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 6-10  aryl, C 3-7  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 is optionally substituted with 1, 2, or 3 D. 
     
     
         88 . The method of  claim 44 , wherein R 8  is H. 
     
     
         89 . The method of  claim 44 , wherein the compound of Formula (I) is a compound having Formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         90 . The method of  claim 44 , wherein:
 X 1  is N or CH;   R 2  is C(O)NR c1 R d1 ;   each R c1  and R d1  is independently selected from H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl, 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 3-10  cycloalkyl, 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 c1  and R d1  are each optionally substituted with 1, 2, 3, or 4 independently selected R A  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 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1 or 2 independently selected R A  substituents;
 each R A  is independently selected from D, halo, oxo, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, CN, NO 2  and OR a4 , wherein the C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl of R A  is optionally substituted with 1 or 2 independently selected R D  substituents; 
 each R a4  is independently selected from H and C 1-6  alkyl, wherein the C 1-6  alkyl is optionally substituted CN, NO 2  or OH; 
 each R D  is OH; 
 
       each R 3 , R 4 , and R 5  is independently selected from H, D, halo, CN, OH, C 1-3  alkyl, and C 1-3  haloalkyl, wherein the C 1-3  alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 D; and
 each R 6 , R 7 , and R 8  is independently selected from H, D, C 1-6  alkyl and C 1-6  haloalkyl. 
 
     
     
         91 . The method of  claim 44 , wherein:
 X 1  is N;   R 2  is C(O)NR c1 R d1 ;   R c1  is H;   R d1  is selected from ethyl, propyl, isopropyl, butyl, tert-butyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methyl-cyclobutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and thianyl, wherein the ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methyl-cyclobutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and thianyl of R d1  is optionally substituted with 1 or 2 independently selected R A  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 an azetidinyl or pyrrolidinyl, wherein the azetidinyl or pyrrolidinyl is optionally substituted with 1 or 2 independently selected R A  substituents;   each R A  is independently selected from oxo, methyl, CH 2 F, CHF 2 , CF 3 , —OCH 3 , —CH 2 OH, CN, and OH;   R 3  is selected from H, methyl, and CD 3 ;   R 4  and R 5  are each H;   R 6  is selected from CH 2 F, CHF 2  and CF 3 ; and   R 7  and R 8  are each H.   
     
     
         92 . The method of  claim 44 , wherein the compound of Formula (I) is selected from:
 3-amino-6-(2-(methyl-d 3 )-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide;   3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d 3 )phenyl)-N-(4-hydroxybicyclo[2.2.1]heptan-1-yl)pyrazine-2-carboxamide;   3-amino-6-(2-(methyl-d 3 )-5-(1,1,1-trifluoro-2,3-dihydroxybutan-2-yl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide;   3-amino-6-(2-methyl-5-(1,1,1-trifluoro-2,3-dihydroxy-3-methylbutan-2-yl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide;   3-amino-N-((1s,3R)-3-cyanocyclobutyl)-6-(2-(methyl-d 3 )-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide;   3-amino-N-((1S,2S)-2-hydroxycyclohexyl)-6-(2-(methyl-d 3 )-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide;   3-amino-N-((trans)-3-hydroxytetrahydro-2H-pyran-4-yl)-6-(2-(methyl-d 3 )-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide;   3-amino-N-((1s,3R)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)-6-(2-(methyl-d 3 )-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide;   3-amino-N-((1s,3R)-3-hydroxy-1-methylcyclobutyl)-6-(2-(methyl-d 3 )-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide;   (S)-3-amino-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-6-(2-(methyl-d 3 )-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide;   (S)-3-amino-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-6-(2-(methyl-d 3 )-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide;   3-amino-N—((S)-1-hydroxypropan-2-yl)-6-(2-(methyl-d 3 )-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide;   (S)-3-amino-N-(2-cyano-2-methylpropyl)-6-(2-(methyl-d 3 )-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide;   (S)-3-amino-N-(4-hydroxybicyclo[2.2.1]heptan-1-yl)-6-(2-(methyl-d 3 )-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide;   3-amino-N—((R)-1-hydroxypropan-2-yl)-6-(2-(methyl-d 3 )-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide;   (S)-3-amino-N-(4-hydroxybicyclo[2.1.1]hexan-1-yl)-6-(2-(methyl-d 3 )-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide;   3-amino-6-(5-((S)-1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d 3 )phenyl)-N-((1S,2S)-2-hydroxycyclohexyl)pyrazine-2-carboxamide;   3-amino-6-(5-((S)-1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d 3 )phenyl)-N-((1R,2R)-2-hydroxycyclohexyl)pyrazine-2-carboxamide;   (S)-3-amino-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d 3 )phenyl)pyrazine-2-carboxamide;   (S)-3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d3)phenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide;   (S)-3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide;   3-amino-6-(5-((S)-1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-N—((S)-1-hydroxypropan-2-yl)pyrazine-2-carboxamide;   3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-N-(4-hydroxybicyclo[2.2.1]heptan-1-yl)pyrazine-2-carboxamide;   (3-amino-6-(5-((S)-1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)pyrazin-2-yl)((R)-2-(hydroxymethyl)pyrrolidin-1-yl)methanone;   (S)-3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-N-isopropylpyrazine-2-carboxamide;   3-amino-6-(5-((S)-1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-N-(3-methyltetrahydrofuran-3-yl)pyrazine-2-carboxamide; and   3-amino-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)pyrazine-2-carboxamide;   or an enantiomer, diastereomer or tautomer thereof,   or a pharmaceutically acceptable salt thereof.   
     
     
         92 . The method of  claim 44 , wherein the compound of Formula (I) is (S)-3-amino-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d 3 )phenyl)pyrazine-2-carboxamide; or an enantiomer, diastereomer or tautomer thereof, or a pharmaceutically acceptable salt thereof. 
     
     
         93 . The method of  claim 44 , wherein the compound of Formula (I) is (S)-3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide; or an enantiomer, diastereomer or tautomer thereof, or a pharmaceutically acceptable salt thereof.