Imidazopyrimidines and triazolopyrimidines as a2a / a2b inhibitors

Abstract

This application relates to compounds of Formula (I): or pharmaceutically acceptable salts or stereoisomers thereof, which modulate the activity of adenosine receptors, such as subtypes A2A and A2B receptors, and are useful in the treatment of diseases related to the activity of adenosine receptors including, for example, cancer, inflammatory diseases, cardiovascular diseases, and neurodegenerative diseases.

1 . (canceled) 
     
     
         2 . A method of treating a disease or disorder in a patient, wherein the disease or disorder is bladder cancer, lung cancer, breast cancer, ovarian cancer, colorectal cancer, pancreatic cancer, prostate cancer, or head and neck cancer, comprising administering to said patient a therapeutically effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein:
 X is N; 
 R 1  is selected from H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 1-6  haloalkyl; 
 R 2  is selected from C 1-6  alkyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, (4-14 membered heterocycloalkyl)-C 1-6  alkyl-, C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , and NR c2 R d2 , wherein the C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl- are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R c  substituents; and 
 wherein the C 1-6  alkyl of R 2  is substituted with 1, 2, 3, 4, or 5 independently selected R C  substituents; 
 Cy 1  is 3 cyanophenyl; 
 Cy 2  is C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocycloalkyl, wherein the C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R F  substituents; 
 each R a2 , 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 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl-, wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl- of R a2 , R c2 , and R d2  are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R G  substituents; 
 or any R c2  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 4-14 membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-14 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R G  substituents; 
 each R b2  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl-, wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl- of R b2  are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R G  substituents; 
 each R C , R F , and R G  is independently selected from D, halo, oxo, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, (4-14 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 a4 ), C(O)OR a4 , C(O)OR b4 , OC(O)R 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 e4 )R b4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )R b4 , NR c4 S(O)R b4  NR c4 S(O)NR c4 R d4 , NR c4 S(O) 2 R b4 , NR c4 S(O)(═NR e4 )R b4 , NR c4 S(O) 2 NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , S(O) 2 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 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl- of R C , R E , R M , R F , and R G  are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R H  substituents; 
 each R a4 , 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 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl-, wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl- of R a4 , R c4  and R d4  are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R H  substituents; 
 or, any R c4  and R d4  attached to the same N atom, together with the N atom to which they are attached, optionally form a 5- or 6-membered heteroaryl or a 4-14 membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-14 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R H  substituents; 
 each R b4  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl-, wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl- of R b4  are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R H  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 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 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 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 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 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 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 H  is independently selected from D, halo, oxo, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, (4-14 membered heterocycloalkyl)-C 1-6  alkyl-, CN, NO 2 , OR a5 , SR a5 , NHOR a5 , C(O)R b5 , C(O)N c5 R d5 , C(O)NR c5 (OR a5 ), 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 e5 )R b5 , C(═NR e5 )NR c5 R d5 , NR c5 C(═NR e5 )NR c5 R d5 , NR c5 C(═NR e5 )R b5 , 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 e5 )R b5 , NR c5 S(O) 2 NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , 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 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl- of R H  are each optionally substituted with 1, 2, 3, or 4 independently selected R I  substituents; 
 each R a5 , 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 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl-, wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl- of R a5 , R c5 , and R d5  are each optionally substituted with 1, 2, 3, or 4 independently selected R I  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 4-14 membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-14 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R I  substituents; 
 each R b5  is independently selected from H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl-, wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl- of R b5  are each optionally substituted with 1, 2, 3, or 4 independently selected R I  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 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 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 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 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 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 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 I  is independently selected from D, halo, oxo, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, (4-14 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 a6 ), 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 c5 R d6 , C(═NR e6 )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 S(O)R b6  NR c6 S(O)N c6 R d6 , NR c6 S(O) 2 R b6 , NR c6 S(O)(—NR e6 )R b6 , NR c6 S(O) 2 NR c6 R d6 , S(O)R b6 , S(O)N c6 R d6 , S(O) 2 R b6 , 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 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl- of R I  are each optionally substituted with 1, 2, 3, or 4 independently selected R J  substituents; 
 each R a6 , 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 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl-, wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl- of R a6 , R c6 , and R d6  are each optionally substituted with 1, 2, 3, or 4 independently selected R J  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 4-14 membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-14 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R J  substituents; 
 each R b6  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl-, wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl- of R b6  are each optionally substituted with 1, 2, 3, or 4 independently selected R J  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 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 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 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl-; 
 each R h6  and R k6  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 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 J  is independently selected from D, halo, oxo, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl-, CN, NO 2 , OR a7 , SR a7 , NHOR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)NR c7 (OR a7 ), C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)OR a7 , NR c7 C(O)NR c7 R d7 , C(═NR e7 )R b7 , C(═NR e7 )NR c7 R d7 , NR c7 C(═NR e7 )NR c7 R d7 , NR c7 C(═NR e7 )R b7 , NR c7 S(O)R b7 , NR c7 S(O)NR c7 R d7 , NR c7 S(O) 2 R b7 , NR c7 S(O)(═NR e7 )R b7 , NR c7 S(O) 2 NR c7 R d7 , S(O)R b7 , S(O)NR c7 R d7 , S(O) 2 R b7 , S(O) 2 NR c7 R d7 , OS(O)(═NR e7 )R b7 , OS(O) 2 R b7 , SF 5 , P(O)R f7 R g7 , OP(O)(OR h7 )(OR i7 ), P(O)(OR h7 )(OR i7 ), and BR j7 R k7 , wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl- of R J  are each optionally substituted with 1, 2, 3, or 4 independently selected R K  substituents; 
 each R a7 , R c7 , and R d7  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl- wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl- of R a7 , R c7 , and R d7  are each optionally substituted with 1, 2, 3, or 4 independently selected R K  substituents; 
 or any R c7  and R d7  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 4-14 membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-14 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R K  substituents; 
 each R b7  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl-, wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl- of R b7  are each optionally substituted with 1, 2, 3, or 4 independently selected R K  substituents; 
 each R e7  is independently selected from H, OH, CN, C 1-6  alkyl, C 2-6  alkenyl, C 1-6  alkoxy, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl; 
 each R f7  and R g7  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 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl-; 
 each R h7  and R i7  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl-; 
 each R j7  and R k7  is independently selected from OH, C 1-6  alkoxy, and C 1-6  haloalkoxy; 
 or, any R j7  and R k7  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 K  is independently selected from H, D, OH, halo, oxo, CN, C(O)OH, NH 2 , NO 2 , SF 5 , C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl-; and 
 wherein any heteroaryl group of any of the above-recited substituents optionally comprises an N-oxide on any ring-forming nitrogen. 
 
     
     
         3 . The method of  claim 2 , wherein:
 each R J  is independently selected from D, halo, oxo, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl-, CN, NO 2 , OR a7 , SR a7 , NHOR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)NR c7 (OR a7 ), C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)OR a7 , NR c7 C(O)NR c7 R d7 , C(═NR e7 )R b7 , C(═NR e7 )NR c7 R d7 , NR c7 C(═NR e7 )NR c7 R d7 , NR c7 C(═NR e7 )R b7 , NR c7 S(O)R b7 , NR c7 S(O)NR c7 R d7 , NR c7 S(O) 2 R b7 , NR c7 S(O)(═NR e7 )R b7 , NR c7 S(O) 2 NR c7 R d7 , S(O)R b7 , S(O)NR c7 R c7 , S(O) 2 R b7 , S(O) 2 NR c7 R d7 , OS(O)(═NR e7 )R b7 , OS(O) 2 R b7 , SF 5 , P(O)R f7 R g7 , OP(O)(OR h7 )(OR i7 ), P(O)(OR h7 )(OR i7 ), and BR j7 R k7 ;   each R a7 , R c7 , and R d7  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 16  alkyl-;   or any R c7  and R d7  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 4-14-membered heterocycloalkyl group; and   each R b7  is independently selected from H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl-.   
     
     
         4 . The method of  claim 2 , wherein:
 each R I  is independently selected from D, halo, oxo, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, (4-14 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 a6 ), 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 c5 R d6 , C(═NR e6 )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 S(O)R b6 , NR c6 S(O)NR c6 R d6 , NR c6 S(O) 2 R b6 , NR c6 S(O)(═NR e6 )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 b6 , 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 ;   each R a6 , R 6b  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 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 16  alkyl-;   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 4-14-membered heterocycloalkyl group; and   each R b6  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl-.   
     
     
         5 .- 13 . (canceled) 
     
     
         14 . The method of  claim 2 , wherein Cy 2  is C 6-14  aryl, wherein the C 6-14  aryl is optionally substituted with 1, 2, 3, or 4 independently selected R F  substituents. 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 2 , or a wherein Cy 2  is 5-14 membered heteroaryl, wherein the 5-14 membered heteroaryl is optionally substituted with 1, 2, 3, or 4 independently selected R F  substituents. 
     
     
         17 . The method of  claim 2 , wherein Cy 2  is 4-14 membered heterocycloalkyl, wherein the 4-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 independently selected R F  substituents. 
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 2 , wherein Cy 2  is selected from pyridinyl, tetrahydropyridinyl, piperidinyl, pyridine-N-oxide, oxo-dihydropyridinyl, phenyl, pyrazolo[1,5-a]pyridin-3-yl, pyrazolo[1,5-b]pyridazinyl, pyrazolyl, pyrimidinyl, quinolinyl, oxazolyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl, and triazolyl each of which is optionally substituted with 1,2, or 3 substituents selected from C 1-3  alkyl, C 1-3  alkyl-OH, halo, CN, C 1-3  alkoxy, and C(O)NH 2 . 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 2 , wherein the optionally substituted Cy 2  is selected from 2,6-dimethylpyridin-4-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 1-carbamoyl-1,2,3,6-tetrahydropyridin-4-yl, 1-carbamoylpiperidin-4-yl, 2-methoxypyridin-4-yl, 2-methoxy-6-methylpyridin-4-yl, 2,6-dimethylpyridin-4-yl-1-oxide, 1-ethyl-6-oxo-1,6-dihydropyridin-3-yl, 3-methylpyridin-4-yl, 3-fluoropyridin-4-yl, 3-chloropyridin-4-yl, 3-methoxypyridin-4-yl, 3-cyanopyridin-4-yl, 4-carbamoylphenyl, pyrazolo[1,5-a]pyridin-3-yl, pyrazolo[1,5-b]pyridazin-3-yl, 5-methyl-1H-pyrazol-4-yl, 1-ethyl-1H-pyrazol-5-yl, 1-isopropyl-1H-pyrazol-5-yl, 1-propyl-1H-pyrazol-5-yl, pyrimidin-4-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl, quinolin-5-yl, 5-fluoropyrimidin-4-yl, oxazol-5-yl, 4-methyloxazol-5-yl, 4-ethyloxazol-5-yl, 4-(hydroxymethyl)-2-methyloxazol-5-yl, 4-(methoxymethyl)-2-methyloxazol-5-yl, 4-(hydroxymethyl)-2-methyloxazol-5-yl, 1-ethyl-1H-1,2,3-triazol-5-yl, and cyclopropyl. 
     
     
         22 . The method of  claim 2 , wherein R 1  is selected from H and C 1-6  alkyl. 
     
     
         23 . The method of  claim 2 , wherein R 1  is H or C 1-3  alkyl. 
     
     
         24 . The method of  claim 2 , wherein R 1  is H or ethyl. 
     
     
         25 . The method of  claim 2 , wherein R 1  is H. 
     
     
         26 .- 31 . (canceled) 
     
     
         32 . The method of  claim 2 , wherein the optionally substituted R 2  is selected from pyridinylmethyl, hydroxy(phenyl)methyl, hydroxyethylamino(phenyl)ethyl, cyclohexylmethyl, fluorobenzyl, hydroxy(fluorophenyl)methyl, (methylpyridinyl)methyl, (fluoropyridinyl)methyl, (trifluoromethylpyridinyl)methyl, ((hydroxymethyl)pyridinyl)methyl, (methoxypyridinyl)methyl, (methylpyrazolyl)benzyl, (methylpyrazolyl)methyl, benzoisoxazolylmethyl, (methylindazolyl)methyl, (hydroxyazetidinyl)methyl, benzoyl, phenylcyclopropyl, (cyano(phenyl)methyl)amino, tetrahydrofuranyl, phenyl(pyridinyloxy)methyl, fluoro ((fluorohydroxypyrrolidinyl)methyl)benzyl, ((carboxypiperidinyl)methyl)fluorobenzyl, fluoro((N-methylmethylsulfonamido)methyl)benzyl, ((dioxoimidazolidinyl)methyl)fluorobenzyl, (difluorophenyl)(hydroxy)methyl, (pyridinyl-1H-tetrazolyl)methyl, (pyrazolyl-1H-tetrazolyl)methyl, (thiazolyl-1H-tetrazolyl)methyl, (methyltrifluoromethylpyrazolyl)methyl, ((1,1-dioxidoisothiazolidinyl)methyl)fluorobenzyl, ((methyl-2,5-dioxoimidazolidinyl)methyl)benzyl, and (cyanophenoxy)methyl. 
     
     
         33 . The method of  claim 2 , wherein the optionally substituted R 2  is selected from pyridin-2-ylmethyl, hydroxy(phenyl)methyl, (2-hydroxyethylamino)(phenyl)methyl, cyclohexylmethyl, 2-fluorobenzyl, (2-fluorophenyl)(hydroxy)methyl, (6-methylpyridin-2-yl)methyl, (3-fluoropyridin-2-yl)methyl, (3-methoxypyridin-2-yl)methyl, 2-(1-methyl-1H-pyrazol-4-yl)benzyl, benzo[d]isoxazol-3-ylmethyl, (1-methyl-1H-indazol-3-yl)methyl, (3-hydroxyazetidin-1-yl)methyl, benzoyl, 1-phenylcyclopropyl, (cyano(phenyl)methyl)amino, tetrahydrofuran-3-yl, phenyl(pyridin-2-yloxy)methyl, 2-fluoro-6-(((3R,4R)-3-fluoro-4-hydroxypyrrolidin-1-yl)methyl)benzyl, 2-((4-carboxypiperidin-1-yl)methyl)-6-fluorobenzyl, 2-fluoro-6-((N-methylmethylsulfonamido)methyl)benzyl, 2-((2,5-dioxoimidazolidin-1-yl)methyl)-6-fluorobenzyl, (2,6-difluorophenyl)(hydroxy)methyl, (5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl, (5-(1H-pyrazol-1-yl)-1H-tetrazol-1-yl)methyl, (5-(thiazol-4-yl)-1H-tetrazol-1-yl)methyl, (5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl, (3-methylpyridin-2-yl)methyl, 2-((1,1-dioxidoisothiazolidin-2-yl)methyl)-6-fluorobenzyl, 2-fluoro-6-((3-methyl-2,5-dioxoimidazolidin-1-yl)methyl)benzyl, (6-(trifluoromethyl)pyridin-2-yl)methyl, (3-(hydroxymethyl)pyridin-2-yl)methyl, (1-methyl-1H-pyrazol-3-yl)methyl, and (2-cyanophenoxy)methyl, (3-methylpyridin-2-yl)methoxy, (6-methylpyridin-2-yl)methoxy, and ((3-methylpyridin-2-yl)methyl)amino. 
     
     
         34 . The method of  claim 2 , wherein each R C  is independently selected from halo, C 1-6  alkyl, C 6-14  aryl, 5-14 membered heteroaryl, (4-14 membered heterocycloalkyl)-C 1-6  alkyl-, OR a4 , C(O)OR a4 , and NR c4 R d4  wherein the C 1-6  alkyl, 5-14 membered heteroaryl, and (4-14 membered heterocycloalkyl)-C 1-6  alkyl- are optionally substituted with 1,2, or 3 independently selected R H  substituents. 
     
     
         35 . The method of  claim 2 , wherein each R H  is independently selected from halo, oxo, C 1-6  alkyl, C 1-6  haloalkyl, OR a5 , C(O)OR a5 , and NR c5 S(O) 2 R b5 . 
     
     
         36 .- 40 . (canceled) 
     
     
         41 . The method of  claim 2 ,
 wherein:   R 1  is selected from H and C 1-6  alkyl;   R 2  is selected from C 6-14  aryl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, (4-14 membered heterocycloalkyl)-C 1-6  alkyl-, NR c2 R d2 , C(O)R b2 , C(O)NR c2 R d2 , and C(O)OR a2 , wherein the C 6-14  aryl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14  aryl-C 1-6  alkyl-, (5-14 membered heteroaryl)-C 1-6  alkyl-, (4-14 membered heterocycloalkyl)-C 1-6  alkyl- of R 2  are each optionally substituted with 1, 2, 3, or 4 independently selected R C  substituents;   Cy 2  is C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl or 4-14 membered heterocycloalkyl, wherein the C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl and 4-14 membered heterocycloalkyl of Cy 2  are each optionally substituted with 1, 2, 3, or 4 independently selected R F  substituents;   each R a2 , R c2 , and R d2  is independently selected from H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 6-14  aryl-C 1-6  alkyl-, C 3-14  cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl of R a2 , R c2 , and R d2  are each optionally substituted with 1, 2, 3, or 4 independently selected R G  substituents;   each R b2  is independently selected from C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R G  substituents;   each R C , R F , and R G  is independently selected from D, halo, oxo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, CN, NO 2 , OR a4 , SR a4 , NHOR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , 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 e4 )R b4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , NR c4 S(O)R b4 , NR c4 S(O) 2R   b4 , and NR c4 S(O) 2 NR c4 R d4 , wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl of R C , R F , and R G  are each optionally substituted with 1, 2, 3, or 4 independently selected R H  substituents;   each R a4 , R c4 , and R d4  is independently selected from H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl of R a4 , R c4 , and R d4  are each optionally substituted with 1, 2, 3, or 4 independently selected R H  substituents;   each R b4  is independently selected from C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R H  substituents;   each R H  is independently selected from D, halo, oxo, 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)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , 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 e5 )R b5 , C(═NR e5 )NR c5 R d5 , NR c5 C(—NR e5 )NR c5 R d5 , NR c5 S(O)R b5 , NR c5 S(O) 2 R b5  and NR c5 S(O) 2 NR c5 R d5 ; and   each R a5 , R c5 , and R d5  is independently selected from H, and C 1-6  alkyl;   each R b5  is independently selected from C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 6-14  aryl, C 3-14  cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl; and   each R e5  is independently selected from H and C 1-6  alkyl.   
     
     
         42 . (canceled) 
     
     
         43 . The method of  claim 2 , wherein the compound is selected from:
 3-(5-amino-2-(pyridin-2-ylmethyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-8-(1-ethyl-1H-pyrazol-5-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-8-(1-propyl-1H-pyrazol-5-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-2-(pyridin-2-ylmethyl)-8-(quinolin-5-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-8-(5-fluoropyrimidin-4-yl)-2-(hydroxy(phenyl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-8-(5-fluoropyrimidin-4-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-2-((2-hydroxyethylamino)(phenyl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-2-(cyclohexylmethyl)-8-(1-ethyl-1H-pyrazol-5-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-2-(2-fluorobenzyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-2-((2-fluorophenyl)(hydroxy)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-2-((6-methylpyridin-2-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-8-(1-ethyl-1H-pyrazol-5-yl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-8-(1-ethyl-1H-pyrazol-5-yl)-2-((3-methoxypyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-2-(2-(1-methyl-1H-pyrazol-4-yl)benzyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-2-(benzo[d]isoxazol-3-ylmethyl)-8-(1-ethyl-1H-pyrazol-5-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-8-(1-ethyl-1H-pyrazol-5-yl)-2-((1-methyl-1H-indazol-3-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-2-((3-hydroxyazetidin-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-8-(3-methylpyridin-4-yl)-2-(pyri din-2-ylmethyl)-[1,2,4]tri azolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-8-(2-methoxy-6-methylpyridin-4-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-8-(pyrazolo[1,5-b]pyridazin-3-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-8-(4-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-8-(4-(hydroxymethyl)-2-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-8-(4-(methoxymethyl)-2-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   (S)-3-(5-amino-2-(hydroxy(phenyl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   (R)-3-(5-amino-2-(hydroxy(phenyl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-2-benzoyl-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-8-(1-ethyl-1H-pyrazol-5-yl)-2-(1-phenylcyclopropyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-2-((cyano(phenyl)methyl)amino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-8-(pyridin-4-yl)-2-(tetrahydrofuran-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; and   3-(5-amino-2-(phenyl(pyridin-2-yloxy)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   or a pharmaceutically acceptable salt thereof.   
     
     
         44 . The method of  claim 2 , wherein the compound is selected from:
 3-(5-amino-2-(2-fluoro-6-(((3R,4R)-3-fluoro-4-hydroxypyrrolidin-1-yl)methyl)benzyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   1-(2-((5-amino-7-(3-cyanophenyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methyl)-3-fluorobenzyl)piperidine-4-carboxylic acid;   N-(2-((5-amino-7-(3-cyanophenyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methyl)-3-fluorobenzyl)-N-methylmethanesulfonamide;   3-(5-amino-2-(2-((2,5-dioxoimidazolidin-1-yl)methyl)-6-fluorobenzyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile; and   3-(5-amino-2-((2,6-difluorophenyl)(hydroxy)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   or a pharmaceutically acceptable salt thereof.   
     
     
         45 . The method of  claim 2 , wherein the compound is selected from:
 3-(5-amino-2-((5-(pyridin-2-yl)-1H-tetrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(2-((5-(1H-pyrazol-1-yl)-1H-tetrazol-1-yl)methyl)-5-amino-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-8-(pyrimidin-4-yl)-2-((5-(thiazol-4-yl)-1H-tetrazol-1-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-2-((5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-8-(4-ethyloxazol-5-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-8-(1-ethyl-1H-1,2,3-triazol-5-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-8-(4-methyloxazol-5-yl)-2-((3-methylpyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-2-((3-fluoropyridin-2-yl)methyl)-8-(4-(hydroxymethyl)-2-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-2-(2-((1,1-dioxidoisothiazolidin-2-yl)methyl)-6-fluorobenzyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-2-(2-fluoro-6-((3-methyl-2,5-dioxoimidazolidin-1-yl)methyl)benzyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-2-((3-fluoropyridin-2-yl)methyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-8-(4-methyloxazol-5-yl)-2-((6-(trifluoromethyl)pyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-8-(4-methyloxazol-5-yl)-2-(pyridin-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)-2-fluorobenzonitrile;   3-(5-amino-2-((3-(hydroxymethyl)pyridin-2-yl)methyl)-8-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-2-((1-methyl-1H-pyrazol-3-yl)methyl)-8-(4-methyloxazol-5-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   3-(5-amino-2-((1-methyl-1H-pyrazol-3-yl)methyl)-8-(oxazol-5-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   2-((5-amino-7-(3-cyanophenyl)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methoxy)benzonitrile; and   3-(5-amino-2-(((3-methylpyridin-2-yl)methyl)amino)-8-(pyrimidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile;   or a pharmaceutically acceptable salt thereof.   
     
     
         46 .- 61 . (canceled) 
     
     
         62 . The method of  claim 2 , wherein the disease or disorder is head and neck cancer. 
     
     
         63 . The method of  claim 62 , wherein the head and neck cancer is head and neck squamous cell carcinoma. 
     
     
         64 . The method of  claim 2 , wherein the disease or disorder is lung cancer. 
     
     
         65 . The method of  claim 64 , wherein the lung cancer is non-small cell lung cancer (NSCLC). 
     
     
         66 . The method of  claim 2 , wherein the disease or disorder is ovarian cancer. 
     
     
         67 . The method of  claim 2 , wherein the disease or disorder is prostate cancer. 
     
     
         68 . The method of  claim 67 , wherein the prostate cancer is metastatic castration-resistant prostate cancer. 
     
     
         69 . The method of  claim 2 , wherein the disease or disorder is breast cancer. 
     
     
         70 . The method of  claim 2 , wherein the disease or disorder is bladder cancer. 
     
     
         71 . The method of  claim 2 , wherein the disease or disorder is colorectal cancer. 
     
     
         72 . The method of  claim 2 , wherein the disease or disorder is pancreatic cancer.