XU MEIZHONG (US)
YE MIN (US)
CHEN YINGNAN (US)
FAVATA MARGARET (US)
LO YVONNE (US)
YE YINGDA (US)
LI ZHENWU (US)
QIAN DING-QUAN (US)
WINTERTON SARAH (US)
XIAO KAIJIONG (US)
WU LIANGXING (US)
YAO WENQING (US)
HUMMEL JOSHUA (US)
XU MEIZHONG (US)
YE MIN (US)
CHEN YINGNAN (US)
FAVATA MARGARET (US)
LO YVONNE (US)
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What is claimed is: 1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; ---- is a single or a double bond; X is N, Y is C, and Ring X is C, Y is N, and Ring Z is CR2 or N; Ring moiety A is selected from C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl; Ring moiety B is 4-10 membered heterocycloalkyl, wherein Ring moiety B is attached to the -NH- group of Formula (I) at a ring member of a saturated or partially saturated ring of said 4-10 membered heterocycloalkyl; R1 is independently selected from H, D, halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, ORa1, SRa1, NHORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)NRc1(ORa1), C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, C(=NRe1)Rb1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1C(=NRe1)Rb1, NRc1S(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, NRc1S(O)(=NRe1)Rb1, NRc1S(O)2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, S(O)2NRc1Rd1, OS(O)(=NRe1)Rb1, OS(O)2Rb1, S(O)(=NRe1)Rb1, SF5, P(O)Rf1Rg1, OP(O)(ORh1)(ORi1), P(O)(ORh1)(ORi1), and BRj1Rk1, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R1A substituents; each Ra1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R1A substituents; or, any Rc1 and Rd1 attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R1A substituents; each Rb1 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected R1A substituents; each Re1 is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 6-10 membered aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl; each Rf1 and Rg1 are independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 6-10 membered aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl; each Rh1 and Ri1 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl; each Rj1 and Rk1 is independently selected from OH, C1-6 alkoxy, and C1-6 haloalkoxy; or any Rj1 and Rk1 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 C1-6 alkyl and C1-6 haloalkyl; each R1A is independently selected from H, D, halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, 5-6 membered heteroaryl-C1-4 alkyl, ORa11, SRa11, NHORa11, C(O)Rb11, C(O)NRc11Rd11, C(O)NRc11(ORa11), C(O)ORa11, OC(O)Rb11, OC(O)NRc11Rd11, NRc11Rd11, NRc11NRc11Rd11, NRc11C(O)Rb11, NRc11C(O)ORa11, NRc11C(O)NRc11Rd11, C(=NRe11)Rb11, C(=NRe11)NRc11Rd11, NRc11C(=NRe11)NRc11Rd11, NRc11C(=NRe11)Rb11, NRc11S(O)NRc11Rd11, NRc11S(O)Rb11, NRc11S(O)2Rb11, NRc11S(O)(=NRe11)Rb11, NRc11S(O)2NRc11Rd11, S(O)Rb11, S(O)NRc11Rd11, S(O)2Rb11, S(O)2NRc11Rd11, OS(O)(=NRe11)Rb11, OS(O)2Rb11, S(O)(=NRe11)Rb11, SF5, P(O)Rf11Rg11, OP(O)(ORh11)(ORi11), P(O)(ORh11)(ORi11), and BRj11Rk11, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R1B substituents; each Ra11, Rc11, and Rd11 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R1B substituents; or, any Rc11 and Rd11 attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R1B substituents; each Rb11 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5- 6 membered heteroaryl-C1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected R1B substituents; each Re11 is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl; each Rf11 and Rg11 are independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl; each Rh11 and Ri11 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl; each Rj11 and Rk11 is independently selected from OH, C1-6 alkoxy, and C1-6 haloalkoxy; or any Rj11 and Rk11 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 C1-6 alkyl and C1-6 haloalkyl; each R1B is independently selected from H, D, halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, 5-6 membered heteroaryl-C1-4 alkyl, ORa12, SRa12, NHORa12, C(O)Rb12, C(O)NRc12Rd12, C(O)NRc12(ORa12), C(O)ORa12, OC(O)Rb12, OC(O)NRc12Rd12, NRc12Rd12, NRc12NRc12Rd12, NRc12C(O)Rb12, NRc12C(O)ORa12, NRc12C(O)NRc12Rd12, C(=NRe12)Rb12, C(=NRe12)NRc12Rd12, NRc12C(=NRe12)NRc12Rd12, NRc12C(=NRe12)Rb12, NRc12S(O)NRc12Rd12, NRc12S(O)Rb12, NRc12S(O)2Rb12, NRc12S(O)(=NRe12)Rb12, NRc12S(O)2NRc12Rd12, S(O)Rb12, S(O)NRc12Rd12, S(O)2Rb12, S(O)2NRc12Rd12, OS(O)(=NRe12)Rb12, OS(O)2Rb12, S(O)(=NRe12)Rb12, SF5, P(O)Rf12Rg12, OP(O)(ORh12)(ORi12), P(O)(ORh12)(ORi12), and BRj12Rk12, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; each Ra12, Rc12, and Rd12 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; or, any Rc12 and Rd12 attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; each Rb12 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5- 6 membered heteroaryl-C1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; each Re12 is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl; each Rf12 and Rg12 are independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl; each Rh12 and Ri12 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl; each Rj12 and Rk12 is independently selected from OH, C1-6 alkoxy, and C1-6 haloalkoxy; or any Rj12 and Rk12 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 C1-6 alkyl and C1-6 haloalkyl; R2 is independently selected from H, D, halo, CN, OH, NO2, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, cyano-C1-4 alkyl, HO-C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C3-4 cycloalkyl, thio, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, carbamyl, C1-4 alkylcarbamyl, di(C1-4 alkyl)carbamyl, carboxy, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-4 alkylcarbonyloxy, C1-4 alkylcarbonylamino, C1-4 alkoxycarbonylamino, C1-4 alkylaminocarbonyloxy, C1-4 alkylsulfonylamino, aminosulfonyl, C1-4 alkylaminosulfonyl, di(C1-4 alkyl)aminosulfonyl, aminosulfonylamino, C1-4 alkylaminosulfonylamino, di(C1-4 alkyl)aminosulfonylamino, aminocarbonylamino, C1-4 alkylaminocarbonylamino, and di(C1-4 alkyl)aminocarbonylamino; each R3 is independently selected from H, D, halo, CN, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, OH, C1-3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, di(C1-3 alkyl)amino, cyano-C1-4 alkyl, HO-C1-4 alkyl, C1-3 alkoxy-C1-4 alkyl, and C3-4 cycloalkyl; R4 is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl; wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R4A substituents; each R4A is independently selected from H, D, halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, ORa41, SRa41, NHORa41, C(O)Rb41, C(O)NRc41Rd41, C(O)NRc41(ORa41), C(O)ORa41, OC(O)Rb41, OC(O)NRc41Rd41, NRc41Rd41, NRc41NRc41Rd41, NRc41C(O)Rb41, NRc41C(O)ORa41, NRc41C(O)NRc41Rd41, C(=NRe41)Rb41, C(=NRe41)NRc41Rd41, NRc41C(=NRe41)NRc41Rd41, NRc41C(=NRe41)Rb41, NRc41S(O)NRc41Rd41, NRc41S(O)Rb41, NRc41S(O)2Rb41, NRc41S(O)(=NRe41)Rb41, NRc41S(O)2NRc41Rd41, S(O)Rb41, S(O)NRc41Rd41, S(O)2Rb41, S(O)2NRc41Rd41, OS(O)(=NRe41)Rb41, OS(O)2Rb41, S(O)(=NRe41)Rb41, SF5, P(O)Rf41Rg41, OP(O)(ORh41)(ORi41), P(O)(ORh41)(ORi41), and BRj41Rk41, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R4B substituents; each Ra41, Rc41, and Rd41 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R4B substituents; or, any Rc41 and Rd41 attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R4B substituents; each Rb41 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected R4B substituents; each Re41 is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl; each Rf41 and Rg41 are independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 6-10 membered aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl; each Rh41 and Ri41 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl; each Rj41 and Rk41 is independently selected from OH, C1-6 alkoxy, and C1-6 haloalkoxy; or any Rj41 and Rk41 attached to the same B atom, together with the B atom to which they are attached, form a 5- or 10-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C1-6 alkyl and C1-6 haloalkyl; each R4B is independently selected from H, D, halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, 5-6 membered heteroaryl-C1-4 alkyl, ORa42, SRa42, NHORa42, C(O)Rb42, C(O)NRc42Rd42, C(O)NRc42(ORa42), C(O)ORa42, OC(O)Rb42, OC(O)NRc42Rd42, NRc42Rd42, NRc42NRc42Rd42, NRc42C(O)Rb42, NRc42C(O)ORa42, NRc42C(O)NRc42Rd42, C(=NRe42)Rb42, C(=NRe42)NRc42Rd42, NRc42C(=NRe42)NRc42Rd42, NRc42C(=NRe42)Rb42, NRc42S(O)NRc42Rd42, NRc42S(O)Rb42, NRc42S(O)2Rb42, NRc42S(O)(=NRe42)Rb42, NRc42S(O)2NRc42Rd42, S(O)Rb42, S(O)NRc42Rd42, S(O)2Rb42, S(O)2NRc42Rd42, OS(O)(=NRe42)Rb42, OS(O)2Rb42, S(O)(=NRe42)Rb42, SF5, P(O)Rf42Rg42, OP(O)(ORh42)(ORi42), P(O)(ORh42)(ORi42), and BRj42Rk42, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R4C substituents; each Ra42, Rc42, and Rd42 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R4C substituents; or, any Rc42 and Rd42 attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R4C substituents; each Rb42 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5- 6 membered heteroaryl-C1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected R4C substituents; each Re42 is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl; each Rf42 and Rg42 are independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl; each Rh42 and Ri42 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl; each Rj42 and Rk42 is independently selected from OH, C1-6 alkoxy, and C1-6 haloalkoxy; or any Rj42 and Rk42 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 C1-6 alkyl and C1-6 haloalkyl; each R4C is independently selected from H, D, halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, 5-6 membered heteroaryl-C1-4 alkyl, ORa43, SRa43, NHORa43, C(O)Rb43, C(O)NRc43Rd43, C(O)NRc43(ORa43), C(O)ORa43, OC(O)Rb43, OC(O)NRc43Rd43, NRc43Rd43, NRc43NRc43Rd43, NRc43C(O)Rb43, NRc43C(O)ORa43, NRc43C(O)NRc43Rd43, C(=NRe43)Rb43, C(=NRe43)NRc43Rd43, NRc43C(=NRe43)NRc43Rd43, NRc43C(=NRe43)Rb43, NRc43S(O)NRc43Rd43, NRc43S(O)Rb43, NRc43S(O)2Rb43, NRc43S(O)(=NRe43)Rb43, NRc43S(O)2NRc43Rd43, S(O)Rb43, S(O)NRc43Rd43, S(O)2Rb43, S(O)2NRc43Rd43, OS(O)(=NRe43)Rb43, OS(O)2Rb43, S(O)(=NRe43)Rb43, SF5, P(O)Rf43Rg43, OP(O)(ORh43)(ORi43), P(O)(ORh43)(ORi43), and BRj43Rk43, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; each Ra43, Rc43, and Rd43 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; or, any Rc43 and Rd43 attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; each Rb43 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5- 6 membered heteroaryl-C1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; each Re43 is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl; each Rf43 and Rg43 are independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl; each Rh43 and Ri43 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl; each Rj43 and Rk43 is independently selected from OH, C1-6 alkoxy, and C1-6 haloalkoxy; or any Rj43 and Rk43 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 C1-6 alkyl and C1-6 haloalkyl; each R5 is independently selected from H, D, halo, NO2, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, ORa5, SRa5, NHORa5, C(O)Rb5, C(O)NRc5Rd5, C(O)NRc5(ORa5), C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, C(=NRe5)Rb5, C(=NRe5)NRc5Rd5, NRc5C(=NRe5)NRc5Rd5, NRc5C(=NRe5)Rb5, NRc5S(O)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)2Rb5, NRc5S(O)(=NRe5)Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, S(O)2NRc5Rd5, OS(O)(=NRe5)Rb5, OS(O)2Rb5, S(O)(=NRe5)Rb5, SF5, P(O)Rf5Rg5, OP(O)(ORh5)(ORi5), P(O)(ORh5)(ORi5), and BRj5Rk5; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R5A substituents; each Ra5, Rc5, and Rd5 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R5A substituents; or, any Rc5 and Rd5 attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, which is optionally substituted with 1, 2, 3, or 4 independently selected R5A substituents; each Rb5 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected R5A substituents; each Re5 is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 6-10 membered aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl; each Rf5 and Rg5 are independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 6-10 membered aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl; each Rh5 and Ri5 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl; each Rj5 and Rk5 is independently selected from OH, C1-6 alkoxy, and C1-6 haloalkoxy; or any Rj5 and Rk5 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 C1-6 alkyl and C1-6 haloalkyl; each R5A is independently selected from H, D, halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, 5-10 membered heteroaryl-C1-4 alkyl, ORa51, SRa51, NHORa51, C(O)Rb51, C(O)NRc51Rd51, C(O)NRc51(ORa51), C(O)ORa51, OC(O)Rb51, OC(O)NRc51Rd51, NRc51Rd51, NRc51NRc51Rd51, NRc51C(O)Rb51, NRc51C(O)ORa51, NRc51C(O)NRc51Rd51, C(=NRe51)Rb51, C(=NRe51)NRc51Rd51, NRc51C(=NRe51)NRc51Rd51, NRc51C(=NRe51)Rb51, NRc51S(O)NRc51Rd51, NRc51S(O)Rb51, NRc51S(O)2Rb51, NRc51S(O)(=NRe51)Rb51, NRc51S(O)2NRc51Rd51, S(O)Rb51, S(O)NRc51Rd51, S(O)2Rb51, S(O)2NRc51Rd51, OS(O)(=NRe51)Rb51, OS(O)2Rb51, S(O)(=NRe51)Rb51, SF5, P(O)Rf51Rg51, OP(O)(ORh51)(ORi51), P(O)(ORh51)(ORi51), and BRj51Rk51, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R5B substituents; each Ra51, Rc51, and Rd51 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl- C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R5B substituents; or, any Rc51 and Rd51 attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, which is optionally substituted with 1, 2, 3, or 4 independently selected R5B substituents; each Rb51 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected R5B substituents; each Re51 is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 6-10 membered aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl; each Rf51 and Rg51 are independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 6-10 membered aryl, 4- 10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl; each Rh51 and Ri51 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, 6-10 membered aryl-C1-4 alkyl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl; each Rj51 and Rk51 is independently selected from OH, C1-6 alkoxy, and C1-6 haloalkoxy; or any Rj51 and Rk51 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 C1-6 alkyl and C1-6 haloalkyl; each R5B is independently selected from H, D, halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, 5-6 membered heteroaryl-C1-4 alkyl, ORa52, SRa52, NHORa52, C(O)Rb52, C(O)NRc52Rd52, C(O)NRc52(ORa52), C(O)ORa52, OC(O)Rb52, OC(O)NRc52Rd52, NRc52Rd52, NRc52NRc52Rd52, NRc52C(O)Rb52, NRc52C(O)ORa52, NRc52C(O)NRc52Rd52, C(=NRe52)Rb52, C(=NRe52)NRc52Rd52, NRc52C(=NRe52)NRc52Rd52, NRc52C(=NRe52)Rb52, NRc52S(O)NRc52Rd52, NRc52S(O)Rb52, NRc52S(O)2Rb52, NRc52S(O)(=NRe52)Rb52, NRc52S(O)2NRc52Rd52, S(O)Rb52, S(O)NRc52Rd52, S(O)2Rb52, S(O)2NRc52Rd52, OS(O)(=NRe52)Rb52, OS(O)2Rb52, S(O)(=NRe52)Rb52, SF5, P(O)Rf52Rg52, OP(O)(ORh52)(ORi52), P(O)(ORh52)(ORi52), and BRj52Rk52, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R5C substituents; each Ra52, Rc52, and Rd52 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R5C substituents; or, any Rc52 and Rd52 attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, which is optionally substituted with 1, 2, 3, or 4 independently selected R5C substituents; each Rb52 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5- 6 membered heteroaryl-C1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected R5C substituents; each Re52 is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl; each Rf52 and Rg52 are independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl; each Rh52 and Ri52 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl; each Rj52 and Rk52 is independently selected from OH, C1-6 alkoxy, and C1-6 haloalkoxy; or any Rj52 and Rk52 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 C1-6 alkyl and C1-6 haloalkyl; each R5C is independently selected from H, D, halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, 5-6 membered heteroaryl-C1-4 alkyl, ORa53, SRa53, NHORa53, C(O)Rb53, C(O)NRc53Rd53, C(O)NRc53(ORa53), C(O)ORa53, OC(O)Rb53, OC(O)NRc53Rd53, NRc53Rd53, NRc53NRc53Rd53, NRc53C(O)Rb53, NRc53C(O)ORa53, NRc53C(O)NRc53Rd53, C(=NRe53)Rb53, C(=NRe53)NRc53Rd53, NRc53C(=NRe53)NRc53Rd53, NRc53C(=NRe53)Rb53, NRc53S(O)NRc53Rd53, NRc53S(O)Rb53, NRc53S(O)2Rb53, NRc53S(O)(=NRe53)Rb53, NRc53S(O)2NRc53Rd53, S(O)Rb53, S(O)NRc53Rd53, S(O)2Rb53, S(O)2NRc53Rd53, OS(O)(=NRe53)Rb53, OS(O)2Rb53, S(O)(=NRe53)Rb53, SF5, P(O)Rf53Rg53, OP(O)(ORh53)(ORi53), P(O)(ORh53)(ORi53), and BRj53Rk53, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; each Ra53, Rc53, and Rd53 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; or, any Rc53 and Rd53 attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, which is optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; each Rb53 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5- 6 membered heteroaryl-C1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; each Re53 is independently selected from H, OH, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl; each Rf53 and Rg53 are independently selected from H, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl; each Rh53 and Ri53 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl; each Rj53 and Rk53 is independently selected from OH, C1-6 alkoxy, and C1-6 haloalkoxy; or any Rj53 and Rk53 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 C1-6 alkyl and C1-6 haloalkyl; and each RG is independently selected from OH, NO2, CN, halo, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, cyano-C1-3 alkyl, HO-C1-3 alkyl, C1-3 alkoxy-C1-3 alkyl, C3-7 cycloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, di(C1-3 alkyl)amino, thio, C1- 3 alkylthio, C1-3 alkylsulfinyl, C1-3 alkylsulfonyl, carbamyl, C1-3 alkylcarbamyl, di(C1-3 alkyl)carbamyl, carboxy, C1-3 alkylcarbonyl, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyloxy, C1-3 alkylcarbonylamino, C1-3 alkoxycarbonylamino, C1-3 alkylaminocarbonyloxy, C1-3 alkylsulfonylamino, aminosulfonyl, C1-3 alkylaminosulfonyl, di(C1-3 alkyl)aminosulfonyl, aminosulfonylamino, C1-3 alkylaminosulfonylamino, di(C1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C1-3 alkylaminocarbonylamino, and di(C1-3 alkyl)aminocarbonylamino. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is independently selected from H, halo, CN, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, 5-6 membered heteroaryl-C1-4 alkyl, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)2Rb1, NRc1S(O)2NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R1A substituents. 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-3 alkyl, phenyl- C1-3 alkyl, 4-7 membered heterocycloalkyl-C1-3 alkyl, 5-6 membered heteroaryl-C1-3 alkyl, ORa1, SRa1, and NRc1Rd1, wherein said C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-3 alkyl, phenyl-C1-3 alkyl, 4-7 membered heterocycloalkyl-C1-3 alkyl, and 5-6 membered heteroaryl-C1-3 alkyl are each optionally substituted with 1 or 2 independently selected R1A substituents. 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is independently selected from H, C1-6 alkyl, phenyl, 5-7 membered heterocycloalkyl, ORa1, SRa1, and NRc1Rd1, wherein said C1-6 alkyl, phenyl, and 5-7 membered heterocycloalkyl are each optionally substituted with 1 or 2 independently selected R1A substituents. 5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is independently selected from H and ORa1. 6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein: each Ra1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl- C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R1A substituents; each Rb1 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl- C1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected R1A substituents; each R1A is independently selected from H, D, halo, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, 5-6 membered heteroaryl-C1-4 alkyl, ORa11, C(O)Rb11, C(O)NRc11Rd11, C(O)ORa11, OC(O)Rb11, OC(O)NRc11Rd11, NRc11Rd11, NRc11C(O)Rb11, NRc11C(O)ORa11, NRc11C(O)NRc11Rd11, NRc11S(O)2Rb11, NRc11S(O)2NRc11Rd11, S(O)2Rb11, and S(O)2NRc11Rd11, wherein said C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R1B substituents; each Ra11, Rc11, and Rd11 is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl; each Rb11 is independently selected from C1-6 alkyl and C1-6 haloalkyl; each R1B is independently selected from H, D, and ORa12; and each Ra12 is independently selected from H and C1-6 alkyl. 7. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein: each Ra1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, C3-6 cycloalkyl-C1-3 alkyl, and 4-6 membered heterocycloalkyl-C1-3 alkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, C3-6 cycloalkyl-C1-3 alkyl, and 4-6 membered heterocycloalkyl-C1-3 alkyl are each optionally substituted with 1, 2, or 3 independently selected R1A substituents; each Rb1 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C3-6 cycloalkyl-C1-2 alkyl, and 4-6 membered heterocycloalkyl- C1-2 alkyl, which are each optionally substituted with 1 or 2 independently selected R1A substituents; and each R1A is independently selected from H, D, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa11, and C(O)ORa11, wherein said C1-6 alkyl, and C1-6 haloalkyl, are each optionally substituted with 1, 2, or 3 independently selected R1B substituents; each Ra11 is independently selected from H and C1-4 alkyl, wherein said C1-4 alkyl is optionally substituted by 1, 2, or 3 independently selected R1B substituents; and each R1B is independently selected from H, D, and O-C1-4 alkyl. 8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is ORa1 and Ra1 is C1-3 alkyl. 9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, OH, C1-3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, di(C1-3 alkyl)amino, cyano-C1-4 alkyl, HO-C1-4 alkyl, C1-3 alkoxy-C1-4 alkyl, and C3-4 cycloalkyl. 10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R2 is H or halo. 11. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R2 is H or F. 12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein Ring moiety B is monocyclic 4-7 membered heterocycloalkyl. 13. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein Ring moiety B is piperidinyl. 14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1. 15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein each R3 is independently selected from H, F, and methyl. 16. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein each R3 is independently selected from H and methyl. 17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl; wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5- 6 membered heteroaryl-C1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R4A substituents. 18. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from C1-6 alkyl, C3-6 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl-C1-4 alkyl; wherein said C1-6 alkyl, C3-6 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl-C1-4 alkyl are each optionally substituted by 1 or 2 independently selected R4A substituents. 19. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from C1-6 alkyl, C3-6 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl-C1-4 alkyl; wherein said C1-6 alkyl, C3-6 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted by 1 or 2 independently selected R4A substituents. 20. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R4 is C1-6 alkyl and C3-6 cycloalkyl. 21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein: each R4A is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C3-4 cycloalkyl, ORa41, C(O)Rb41, C(O)NRc41Rd41, C(O)ORa41, OC(O)Rb41, OC(O)NRc41Rd41, NRc41Rd41, NRc41C(O)Rb41, NRc41C(O)ORa41, NRc41C(O)NRc41Rd41, NRc41S(O)2Rb41, NRc41S(O)2NRc41Rd41, S(O)2Rb41, and S(O)2NRc41Rd41, wherein said C1-6 alkyl, C1-6 haloalkyl, and C3-4 cycloalkyl are each optionally substituted with 1, 2, or 3 independently selected R4B substituents; each Ra41, Rc41, and Rd41 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, and C3-4 cycloalkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, and C3-4 cycloalkyl are each optionally substituted with 1 or 2 independently selected R4B substituents; each Rb41 is independently selected from C1-6 alkyl, C1-6 haloalkyl, and C3-4 cycloalkyl, which are each optionally substituted with 1 or 2 independently selected R4B substituents; each R4B is independently selected from H, halo, CN, C1-3 alkyl, C1-3 haloalkyl, ORa42, and NRc42Rd42; each Ra42, Rc42, and Rd42 is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl; and each Rb42 is independently selected from C1-3 alkyl and C1-3 haloalkyl. 22. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein: each R4A is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C3-4 cycloalkyl, ORa41, C(O)Rb41, C(O)NRc41Rd41, C(O)ORa41, OC(O)Rb41, OC(O)NRc41Rd41, NRc41Rd41, NRc41C(O)Rb41, NRc41C(O)ORa41, NRc41C(O)NRc41Rd41, NRc41S(O)2Rb41, NRc41S(O)2NRc41Rd41, S(O)2Rb41, and S(O)2NRc41Rd41; each Ra41, Rc41, and Rd41 is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl; and each Rb41 is independently selected from C1-3 alkyl and C1-3 haloalkyl. 23. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein: each R4A is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, ORa41, and NRc41Rd41; each Ra41, Rc41, and Rd41 is independently selected from H and C1-3 alkyl, and C1-3 haloalkyl; and each Rb41 is independently C1-3 alkyl. 24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein Ring moiety A is 5-10 membered heteroaryl. 25. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein Ring moiety A is 5-6 membered heteroaryl. 26. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein Ring moiety A is 1H-pyrrolo[2,3-b]pyridinyl, pyridinyl, or pyrazolyl. 27. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein Ring moiety A is pyrazolyl. 28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1. 29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein each R5 is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C3-4 cycloalkyl, ORa5, and NRc5Rd5; and each Ra5, Rc5, and Rd5 is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl. 30. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein each R5 is independently selected from CH3 or NH2. 31. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; p is 0, 1, or 2; Ring moiety A is selected from C3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl; Ring moiety B is azetidinyl, pyrrolidinyl or piperidinyl; R1 is H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl-C1-3 alkyl, phenyl-C1-3 alkyl, 4-7 membered heterocycloalkyl-C1-3 alkyl, 5-6 membered heteroaryl-C1-3 alkyl, ORa1, SRa1, and NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6 cycloalkyl-C1-3 alkyl, phenyl-C1-3 alkyl, 4-7 membered heterocycloalkyl-C1-3 alkyl, and 5-6 membered heteroaryl- C1-3 alkyl are each optionally substituted with 1, 2, or 3 independently selected R1A substituents; each Ra1, Rc1, and Rd1 is independently selected from H, D, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and C3-7 cycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and C3-7 cycloalkyl-C1-4 alkyl are each optionally substituted with 1, 2, or 3 independently selected R1A substituents; each R1A is independently selected from H, D, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C3- 4 cycloalkyl, ORa11, C(O)Rb11, C(O)NRc11Rd11, C(O)ORa11, OC(O)Rb11, OC(O)NRc11Rd11, NRc11Rd11, NRc11C(O)Rb11, NRc11C(O)ORa11, NRc11C(O)NRc11Rd11, NRc11S(O)2Rb11, NRc11S(O)2NRc11Rd11, S(O)2Rb11, and S(O)2NRc11Rd11, wherein said C1-6 alkyl, C1-6 haloalkyl, and C3-4 cycloalkyl are each optionally substituted by 1, 2, or 3 independently selected R1B substituents; each Ra11, Rc11, and Rd11 is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl; each Rb11 is independently selected from C1-6 alkyl and C1-6 haloalkyl; each R1B is independently selected from H, D, and ORa12; each Ra12 is independently selected from H and C1-6 alkyl; R2 is selected from H, halo, CN, C1-3 alkyl, and C1-3 haloalkyl; each R3 is independently selected from H, halo, C1-3 alkyl, and cyclopropyl; R4 is selected from C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl-C1-4 alkyl; wherein said C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl-C1-4 alkyl are each optionally substituted by 1 or 2 independently selected R4A substituents; each R4A is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C3-4 cycloalkyl, ORa41, C(O)Rb41, C(O)NRc41Rd41, C(O)ORa41, OC(O)Rb41, OC(O)NRc41Rd41, NRc41Rd41, NRc41C(O)Rb41, NRc41C(O)ORa41, NRc41C(O)NRc41Rd41, NRc41S(O)2Rb41, NRc41S(O)2NRc41Rd41, S(O)2Rb41, and S(O)2NRc41Rd41, wherein said C1-6 alkyl, C1-6 haloalkyl, and C3-4 cycloalkyl are each optionally substituted with 1, 2, or 3 independently selected R4B substituents; each Ra41, Rc41, and Rd41 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, and C3-4 cycloalkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, and C3-4 cycloalkyl are each optionally substituted with 1 or 2 independently selected R4B substituents; each Rb41 is independently selected from C1-6 alkyl, C1-6 haloalkyl, and C3-4 cycloalkyl, which are each optionally substituted with 1 or 2 independently selected R4B substituents; each R4B is independently selected from H, halo, CN, C1-3 alkyl, C1-3 haloalkyl, ORa42, and NRc42Rd42; each Ra42, Rc42, and Rd42 is independently selected from H, C1-3 alkyl, and C1-3 haloalkyl; each Rb42 is independently selected from C1-3 alkyl and C1-3 haloalkyl. each R5 is independently selected from H, halo, NO2, CN, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, 5-6 membered heteroaryl-C1-4 alkyl, ORa5, SRa5, NHORa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, S(O)2Rb5, and S(O)2NRc5Rd5; wherein said C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5- 6 membered heteroaryl-C1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R5A substituents; each Ra5, Rc5, and Rd5 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl- C1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R5A substituents; and each Rb5 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl- C1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected R5A substituents. each R5A is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C3-4 cycloalkyl, ORa51, SRa51, NHORa51, C(O)Rb51, C(O)NRc51Rd51, C(O)ORa51, OC(O)Rb51, OC(O)NRc51Rd51, NRc51Rd51, NRc51C(O)Rb51, NRc51C(O)ORa51, NRc51C(O)NRc51Rd51, NRc51S(O)2Rb51, NRc51S(O)2NRc51Rd51, S(O)2Rb51, and S(O)2NRc51Rd51; each Ra51, Rc51, and Rd51 is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl; and each Rb51 is independently selected from C1-6 alkyl and C1-6 haloalkyl. 32. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: n is 0 or 1; p is 0 or 1; Ring moiety A is 5-10 membered heteroaryl having 1 or 2 N ring forming atoms; Ring moiety B is piperidinyl; R1 is independently selected from H, C1-6 alkyl, phenyl, 5-7 membered heterocycloalkyl, ORa1, SRa1, and NRc1Rd1, wherein said C1-6 alkyl, phenyl, and 5-7 membered heterocycloalkyl are each optionally substituted with 1 or 2 independently selected R1A substituents; each Ra1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, C3-6 cycloalkyl-C1-3 alkyl, and 4-6 membered heterocycloalkyl-C1-3 alkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, C3-6 cycloalkyl-C1-3 alkyl, and 4-6 membered heterocycloalkyl-C1-3 alkyl are each optionally substituted with 1, 2, or 3 independently selected R1A substituents; each R1A is independently selected from D, halo, CN, C1-3 alkyl, C1-3 haloalkyl, C3-4 cycloalkyl, ORa11, and C(O)ORa11, wherein said C1-6 alkyl, and C1-6 haloalkyl are each optionally substituted with 1, 2, or 3 independently selected R1B substituents; each Ra11 is independently selected from H and C1-4 alkyl, wherein said C1-4 alkyl is optionally substituted by 1, 2, or 3 independently selected R1B substituents; each R1B is independently selected from H, D, and O-C1-4 alkyl; R2 is H or F; each R3 is independently selected from H or methyl; R4 is selected from C1-6 alkyl, C3-6 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl-C1-4 alkyl; wherein said C1-6 alkyl, C3-6 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl-C1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R4A substituents; each R4A is independently selected from H, C1-6 alkyl, OH, and NRc41Rd41; each Rc41 and Rd41 is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl; each R5 is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C3-4 cycloalkyl, ORa5, and NRc5Rd5; and each Ra5, Rc5, and Rd5 is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl. 33. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: n is 0 or 1; p is 0 or 1; Ring moiety A is 5-10 membered heteroaryl having 1 or 2 N ring forming atoms; Ring moiety B is piperidinyl; R1 is independently selected from H and ORa1; each Ra1 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C3-6 cycloalkyl-C1-3 alkyl, and 4-6 membered heterocycloalkyl-C1-3 alkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C3-6 cycloalkyl-C1-3 alkyl, and 4-6 membered heterocycloalkyl- C1-3 alkyl are each optionally substituted with 1 or 2 independently selected R1A substituents; each R1A is independently selected from C1-3 alkyl, C1-3 haloalkyl, C3-4 cycloalkyl, OH, C1-3 alkoxy, and C1-3 haloalkoxy; R2 is H or F; each R3 is independently selected from H or methyl; R4 is selected from C1-6 alkyl and C3-6 cycloalkyl; wherein said C1-6 alkyl and C3-6 cycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R4A substituents; each R4A is independently selected from H and C1-6 alkyl; each R5 is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C3-4 cycloalkyl, ORa5, and NRc5Rd5; and each Ra5, Rc5, and Rd5 is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl. 34. The compound of any one of claims 1-33, having Formula (Va), or (Vb), or (Vc), or (Vd): or a pharmaceutically acceptable salt of any of the aforementioned. 35. The compound of any one of claims 1-33, having Formula (VIa), or (VIIa), or (VIIIa), or (IXa): or a pharmaceutically acceptable salt of any of the aforementioned. 36. The compound of any one of claims 1-33, having Formula (VIb), or (VIIIb), or (IXb): (VIb), or (VIIIb), or or a pharmaceutically acceptable salt of any of the aforementioned. 37. The compound of any one of claims 1-33, having Formula (VIc), or (VIIIc), or (IXc): or a pharmaceutically acceptable salt of any of the aforementioned. 38. The compound of claim 1, selected from: N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5- a]pyridin-2-amine; 8-ethoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine; 8-isobutoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine; 8-(cyclopropylmethoxy)-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine; N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8-((tetrahydro-2H-pyran-4- yl)oxy)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; 8-(2-methoxyethoxy)-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine; 6-fluoro-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine; N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5- a]pyrazin-2-amine; 8-(2,2-difluoroethoxy)-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine; N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8-(2,2,2-trifluoroethoxy)- [1,2,4]triazolo[1,5-a]pyridin-2-amine; N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8-((tetrahydrofuran-3- yl)methoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; N-((3R,4S)-1-(cyclopropylsulfonyl)-3-methylpiperidin-4-yl)-8-ethoxy-7-(1H-pyrazol- 4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; 8-isopropoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine; 8-isobutoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrrolo[2,3-b]pyridin-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine; and 7-(2-aminopyridin-4-yl)-8-isobutoxy-N-(1-(methylsulfonyl)piperidin-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine; or a pharmaceutically acceptable salt thereof. 39. The compound of claim 1, selected from: 8-ethoxy-7-(3-methyl-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine; Methyl 4-((2-((1-(methylsulfonyl)piperidin-4-yl)amino)-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-8-yl)oxy)piperidine-1-carboxylate; (R)-1-(2-(((3R,4S)-4-((8-ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2- yl)amino)-3-methylpiperidin-1-yl)sulfonyl)ethyl)pyrrolidin-3-ol; 8-ethoxy-N-((3R,4S)-3-methyl-1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4- yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; 8-ethoxy-N-((3R,4S)-3-methyl-1-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)piperidin- 4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; N-(1-(methylsulfonyl)piperidin-4-yl)-8-phenyl-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine; 8-(4-fluoropiperidin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine; N2-(1-(methylsulfonyl)piperidin-4-yl)-N8-phenyl-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridine-2,8-diamine; 8-(4-fluorophenyl)-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine; N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8-(3- (trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; 8-ethoxy-N-((3R,4S)-3-methyl-1-((3-(piperidin-1-yl)propyl)sulfonyl)piperidin-4-yl)- 7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; N-((3R,4S)-1-((3-(dimethylamino)propyl)sulfonyl)-3-methylpiperidin-4-yl)-8-ethoxy- 7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; 8-ethoxy-N-((3R,4S)-3-methyl-1-((3-(pyrrolidin-1-yl)propyl)sulfonyl)piperidin-4-yl)- 7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8-(4- (trifluoromethyl)piperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; 8-(3-fluoropiperidin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine; 8-Ethoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine; 8-isopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol- 4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine; 8-(4-methylpiperidin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine; N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8-(3- (trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine; 2-fluoro-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-8-yl)benzonitrile; N-(1-(methylsulfonyl)piperidin-4-yl)-8-propyl-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine; 8-isopropoxy-N-((3R,4S)-3-methyl-1-((2-(pyrrolidin-1-yl)ethyl)sulfonyl)piperidin-4- yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine; 8-((4,4-difluorocyclohexyl)oxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4- yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8- ((tetrahydrofuran-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; 8-(ethoxy-d5)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol- 4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8- ((tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; 8-isopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol- 4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; 8-Isobutoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine; 8-(2,2-difluoroethoxy)-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine; N-(1-(Methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8-(3,3,3-trifluoropropoxy)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine; 8-Butoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine; N-(1-(Methylsulfonyl)piperidin-4-yl)-8-propoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine; N-(1-(Methylsulfonyl)piperidin-4-yl)-8-(piperidin-1-yl)-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine; N-(3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-8-(piperidin-1-yl)-7-(1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine; 8-(4-(2-Methoxyethyl)piperazin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine; N-(1-(Methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8-(pyrrolidin-1-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine; N-((3R,4S)-1-(Cyclopropylsulfonyl)-3-methylpiperidin-4-yl)-8-isopropoxy-7-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine; N-((3R,4S)-1-(Ethylsulfonyl)-3-methylpiperidin-4-yl)-8-isopropoxy-7-(1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine; N-((3R,4S)-1-((3-(Ethyl(methyl)amino)propyl)sulfonyl)-3-methylpiperidin-4-yl)-8- isopropoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine; N-((3R,4S)-1-((3-(Dimethylamino)propyl)sulfonyl)-3-methylpiperidin-4-yl)-8- isopropoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine; 8-Isopropoxy-N-((3R,4S)-1-((3-(isopropyl(methyl)amino)propyl)sulfonyl)-3- methylpiperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine; 8-Isopropoxy-N-((3R,4S)-3-methyl-1-((3-(piperidin-1-yl)propyl)sulfonyl)piperidin-4- yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine; 8-Isopropoxy-N-((3R,4S)-3-methyl-1-((3-(pyrrolidin-1-yl)propyl)sulfonyl)piperidin- 4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine; N-((3R,4S)-1-((3-(Diethylamino)propyl)sulfonyl)-3-methylpiperidin-4-yl)-8- isopropoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine; 8-Isopropoxy-N-((3R,4S)-3-methyl-1-((3-(4-methylpiperazin-1- yl)propyl)sulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2- amine; N-((3R,4S)-1-((3-(4-Ethylpiperazin-1-yl)propyl)sulfonyl)-3-methylpiperidin-4-yl)-8- isopropoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine; 8-Isopropoxy-N-((3R,4S)-3-methyl-1-((4-morpholinobutyl)sulfonyl)piperidin-4-yl)-7- (1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine; N-((3R,4S)-1-((4-((2,2-Difluoroethyl)amino)butyl)sulfonyl)-3-methylpiperidin-4-yl)- 8-isopropoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine; N-((3R,4S)-1-((4-(Ethyl(methyl)amino)butyl)sulfonyl)-3-methylpiperidin-4-yl)-8- isopropoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine; N-((3R,4S)-1-((4-(Dimethylamino)butyl)sulfonyl)-3-methylpiperidin-4-yl)-8- isopropoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine; N-((3R,4S)-1-((4-((R)-3-(Difluoromethyl)pyrrolidin-1-yl)butyl)sulfonyl)-3- methylpiperidin-4-yl)-8-isopropoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2- amine; 5-Isopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol- 4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; 5-Cyclobutoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; 5-Isobutoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-5-propoxy-6-(1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; 5-(2,2-Difluoroethoxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6- (1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-5- (2,2,3,3-tetrafluoropropoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; 5-Cyclopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; 5-((3,3-Difluorocyclopentyl)oxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin- 4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; 5-(Cyclobutylmethoxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6- (1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; 5-(Cyclopentylmethoxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6- (1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; N-(1-(Methylsulfonyl)piperidin-4-yl)-5-propoxy-6-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine; 5-Isobutoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine; 5-(2,2-Difluoroethoxy)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine; N-(1-(Methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-5-(2,2,3,3- tetrafluoropropoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; 5-(Cyclopropylmethoxy)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine; N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(piperidin-1-yl)-6-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; N-((3R,4S)-1-(Ethylsulfonyl)-3-methylpiperidin-4-yl)-5-(piperidin-1-yl)-6-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; N-((3R,4S)-1-(Cyclopropylsulfonyl)-3-methylpiperidin-4-yl)-5-(piperidin-1-yl)-6- (1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; N-((3R,4S)-3-Methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5- (piperidin-1-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; 5-Isopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol- 4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; N-((3R,4S)-1-(Ethylsulfonyl)-3-methylpiperidin-4-yl)-5-isopropoxy-6-(1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; N-((3R,4S)-1-(Cyclopropylsulfonyl)-3-methylpiperidin-4-yl)-5-isopropoxy-6-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-5- ((tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; N-((3R,4S)-1-(Ethylsulfonyl)-3-methylpiperidin-4-yl)-6-(1H-pyrazol-4-yl)-5- ((tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; N-((3R,4S)-1-(Cyclopropylsulfonyl)-3-methylpiperidin-4-yl)-6-(1H-pyrazol-4-yl)-5- ((tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; 5-Cyclobutoxy-N-((3R,4S)-1-(ethylsulfonyl)-3-methylpiperidin-4-yl)-6-(1H-pyrazol- 4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; 5-Cyclobutoxy-N-((3R,4S)-3-methyl-1-((1-methyl-1H-pyrazol-4- yl)sulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; 5-Cyclobutoxy-N-((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; N-((3R,4S)-1-(Ethylsulfonyl)-3-methylpiperidin-4-yl)-5-isopropoxy-6-(1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; N-((3R,4S)-1-(Cyclopropylsulfonyl)-3-methylpiperidin-4-yl)-5-isopropoxy-6-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-5- ((tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; N-((3R,4S)-3-Methyl-1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-6-(1H- pyrazol-4-yl)-5-((tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyridin-2-amine; 5-Cyclobutoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; 5-Isobutoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-5-propoxy-6-(1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; 5-Butoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; 5-Isobutoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyrazin-2-amine; N-(1-(Methylsulfonyl)piperidin-4-yl)-5-propoxy-6-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyrazin-2-amine; 5-Butoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyrazin-2-amine; N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(3-methylcyclobutoxy)-6- (1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; 5-(3-(Difluoromethyl)cyclobutoxy)-N-((3R,4S)-3-methyl-1- (methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; 5-Cyclopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; 5-((4,4-Difluorocyclohexyl)oxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4- yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-5-((3-methyltetrahydro-2H- pyran-4-yl)oxy)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-5-((2-methyltetrahydro-2H- pyran-4-yl)oxy)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-5-((2- (trifluoromethyl)tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-5-((1- (trifluoromethyl)cyclobutyl)methoxy)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; 5-(Cyclopropylmethoxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6- (1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; 5-(Isopentyloxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; 5-Cyclobutoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyrazin-2-amine; 5-(3,3-Difluorocyclobutoxy)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; N-(1-(Methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-5-((2- (trifluoromethyl)tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; N-(1-(Methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-5-((1- (trifluoromethyl)cyclobutyl)methoxy)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; 5-(Isopentyloxy)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyrazin-2-amine; 5-Ethoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyrazin-2-amine; 5-(Ethylthio)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyrazin-2-amine; 5-(Isopropylthio)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyrazin-2-amine; N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(piperidin-1-yl)-6-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; N-(1-(Methylsulfonyl)piperidin-4-yl)-5-(piperidin-1-yl)-6-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyrazin-2-amine; 5-(3,3-Difluoropiperidin-1-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4- yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; (R)-5-(3-Fluoropiperidin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; (S)-5-(3-Fluoropiperidin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; 5-(3,3-Difluoropyrrolidin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol- 4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; 5-(2-Azabicyclo[2.2.1]heptan-2-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; (S)-5-(2-Methylpiperidin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; (S)-5-(2-Methylpyrrolidin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol- 4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; (S)-5-(3-(Difluoromethyl)pyrrolidin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-6- (1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; 5-(7-Azabicyclo[2.2.1]heptan-7-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; N-(1-(Methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-5-(3- (trifluoromethyl)piperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-5-((propan-2-yl-2-d)oxy)-6- (1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-5-((propan-2-yl-1,1,1,3,3,3- d6)oxy)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-5-((propan-2-yl-d7)oxy)-6- (1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; 5-(Cyclopentyloxy)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-6-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine; 5-Isopropoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyrazin-2-amine; and N-(1-(Methylsulfonyl)piperidin-4-yl)-5-((propan-2-yl-2-d)oxy)-6-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyrazin-2-amine; or a pharmaceutically acceptable salt thereof. 40. A pharmaceutical composition comprising the compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 41. A method of inhibiting CDK2, comprising contacting the CDK2 with the compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof. 42. A method of inhibiting CDK2 in a patient, comprising administering to the patient a compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof. 43. A method of treating a disease or disorder associated with CDK2 in a patient, comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-39, or pharmaceutically acceptable salt thereof. 44. The method of claim 43, wherein the disease or disorder is associated with an amplification of the cyclin E1 (CCNE1) gene and/or overexpression of CCNE1. 45. A method of treating a human subject having a disease or disorder associated with cyclin-dependent kinase 2 (CDK2), comprising administering to the human subject a compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein the human subject has been previously determined to: (i) (a) have a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1; and/or (b) have a cyclin dependent kinase inhibitor 2A (CDKN2A) gene lacking one or more inactivating nucleic acid substitutions and/or deletions; (ii) (a) have an amplification of the cyclin E1 (CCNE1) gene; and/or (b) have an expression level of CCNE1 in a biological sample obtained from the human subject that is higher than a control expression level of CCNE1. 46. A method of treating a human subject having a disease or disorder associated with cyclin-dependent kinase 2 (CDK2), comprising: (i) identifying, in a biological sample obtained from the human subject: (a) a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1; and/or (b) a cyclin dependent kinase inhibitor 2A (CDKN2A) gene lacking one or more inactivating nucleic acid substitutions; (ii) identifying, in a biological sample obtained from the human subject: (a) an amplification of the cyclin E1 (CCNE1) gene; and/or (b) an expression level of CCNE1 that is higher than a control expression level of CCNE1; and (iii) administering a compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, to the human subject. 47. The method of claim 46, comprising: (i) identifying, in a biological sample obtained from the human subject: (a) a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1; and/or (b) a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and/or deletions; (ii) identifying, in a biological sample obtained from the human subject: (a) an amplification of the CCNE1 gene; and (iii) administering the compound or the salt to the human subject. 48. A method of evaluating the response of a human subject having a disease or disorder associated with cyclin-dependent kinase 2 (CDK2) to a compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, comprising: (a) administering the compound or the salt, to the human subject, wherein the human subject has been previously determined to have an amplification of the cyclin E1 (CCNE1) gene and/or an expression level of CCNE1 that is higher than a control expression level of CCNE1; (b) measuring, in a biological sample of obtained from the subject subsequent to the administering of step (a), the level of retinoblastoma (Rb) protein phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3, wherein a reduced level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3, as compared to a control level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3, is indicative that the human subject responds to the compound or the salt. 49. The method of any one of claims 43-48, wherein the disease or disorder is cancer. |
The disclosure also features a method of treating a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2, comprising: (i) identifying, in a biological sample obtained from the human subject: (a) a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1, (b) a CDKN2A gene lacking one or more inactivating nucleic acid substitutions, and/or (c) the presence of a p16 protein; (ii) identifying, in a biological sample obtained from the human subject: (a) an amplification of the CCNE1 gene and/or (b) an expression level of CCNE1 that is higher than a control expression level of CCNE1; and (iii) administering a CDK2 inhibitor to the human subject. In some embodiments, the subject has a disease or disorder associated with CDK2. In some embodiments, the subject is suspected of having or is at risk of developing a disease or disorder associated with CDK2. In some embodiments, the method comprises: (i) identifying, in a biological sample obtained from the human subject: (a) a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1, (b) a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and/or deletions, and/or (c) the presence of a p16 protein; (ii) identifying, in a biological sample obtained from the human subject: (a) an amplification of the CCNE1 gene; and (iii) administering a CDK2 inhibitor to the human subject. The disclosure also features a method of predicting the response of a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2 to a CDK2 inhibitor, comprising: (i) determining, from a biological sample obtained from the human subject: (a) the nucleotide sequence of a CDKN2A gene, (b) the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and/or deletions, and/or (c) the presence of a p16 protein; and (ii) determining, from a biological sample obtained from the human subject: (a) the copy number of the CCNE1 gene and/or (b) the expression level of CCNE1, wherein (1) (a) the presence of a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1, (b) the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and/or deletions, and/or (c) the presence of a p16 protein, and (2) (a) an amplification of the CCNE1 gene and/or (b) an expression level of CCNE1 that is higher than a control expression level of CCNE1, is predictive that the human subject will respond to the CDK2 inhibitor. In some embodiments, the subject has a disease or disorder associated with CDK2. In some embodiments, the subject is suspected of having or is at risk of developing a disease or disorder associated with CDK2. In some embodiments, the method comprises: (i) determining, from a biological sample obtained from the human subject: (a) the nucleotide sequence of a CDKN2A gene and/or (b) the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and/or deletions; and (ii) determining, from a biological sample obtained from the human subject: (a) the copy number of the CCNE1 gene, wherein (1) (a) the presence of a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1 and/or (b) the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and/or deletions, and (2) (a) an amplification of the CCNE1 gene, is predictive that the human subject will respond to the CDK2 inhibitor. In specific embodiments, the (i) determining of (a) the nucleotide sequence of a CDKN2A gene, (b) the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and/or deletions, and/or (c) the presence of a p16 protein is performed before (e.g., at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, or at least 4 weeks, or from 6 hours to 16 hours, from 6 hours to 20 hours, or from 6 hours to 24 hours, from 2 days to 3 days, from 2 days to 4 days, from 2 days to 5 days, from 2 days to 6 days, from 2 days to 7 days, from 1 week to 2 weeks, from 1 week to 3 weeks, or from 1 week to 4 weeks before) administering to the human subject the CDK2 inhibitor. In specific embodiments, the (ii) determining of (a) the copy number of the CCNE1 gene and/or (b) the expression level of CCNE1 in the biological sample obtained from the human subject is performed before (e.g., at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, or at least 4 weeks, or from 6 hours to 16 hours, from 6 hours to 20 hours, or from 6 hours to 24 hours, from 2 days to 3 days, from 2 days to 4 days, from 2 days to 5 days, from 2 days to 6 days, from 2 days to 7 days, from 1 week to 2 weeks, from 1 week to 3 weeks, or from 1 week to 4 weeks before) administering to the human subject the CDK2 inhibitor. An amplification of the CCNE1 gene and/or an expression level of CCNE1 that is higher than a control expression level of CCNE1, combined with the presence of a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1, the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and/or deletions, and/or the presence of a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO:1), is indicative/predictive that a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2 will respond to a CDK2 inhibitor. In some embodiments, the CCNE1 gene is amplified to a gene copy number from 3 to 25. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 3. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 5. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 7. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 10. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 12. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 14. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 21. In specific embodiments, the expression level of CCNE1 is the level of CCNE1 mRNA. In specific embodiments, the expression level of CCNE1 is the level of CCNE1 protein. In some embodiments of the foregoing methods, the control expression level of CCNE1 is a pre-established cut-off value. In some embodiments of the foregoing methods, the control expression level of CCNE1 is the expression level of CCNE1 in a sample or samples obtained from one or more subjects that have not responded to treatment with the CDK2 inhibitor. In some embodiments of the foregoing methods, the expression level of CCNE1 is the expression level of CCNE1 mRNA. In some embodiments of the foregoing methods, the expression level of CCNE1 is the expression level of CCNE1 protein. In some embodiments in which the expression level of CCNE1 is the expression level of CCNE1 mRNA, the expression level of CCNE1 is measured by RNA sequencing, quantitative polymerase chain reaction (PCR), in situ hybridization, nucleic acid array or RNA sequencing. In some embodiments in which the expression level of CCNE1 is the expression level of CCNE1 protein, the expression level of CCNE1 is measured by western blot, enzyme-linked immunosorbent assay, or immunohistochemistry staining. Rb S780 The disclosure also features a method for assessing the CDKN2A gene and the CCNE1 gene, comprising determining, from a biological sample or biological samples obtained from a human subject having a disease or disorder associated with CDK2, (i) (a) the nucleotide sequence of a CDKN2A gene or (b) the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and/or deletions, and (ii) the copy number of the CCNE1 gene. The disclosure also features a method of evaluating the response of a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2 to a CDK2 inhibitor, comprising: (a) administering a CDK2 inhibitor to the human subject, wherein the human subject has been previously determined to have an amplification of the CCNE1 gene and/or an expression level of CCNE1 that is higher than a control expression level of CCNE1; (b) measuring, in a biological sample of obtained from the subject subsequent to the administering of step (a), the level of retinoblastoma (Rb) protein phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3, wherein a reduced level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3, as compared to a control level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3, is indicative that the human subject responds to the CDK2 inhibitor. In some embodiments, the subject has a disease or disorder associated with CDK2. In some embodiments, the subject is suspected of having or is at risk of developing a disease or disorder associated with CDK2. In some embodiments, the biological sample comprises a blood sample or a tumor biopsy sample. Phosphorylation of Rb at the serine corresponding to amino acid position 780 of SEQ ID NO:3 (referred to herein as “Ser780” or “S780”) has been identified in the Examples as a pharmacodynamic marker useful in assessing responsiveness (e.g., inhibition by CDK2) of a human subject having a disease or disorder having CCNE1 amplification to a CDK2 inhibitor. Rb is a regulator of the cell cycle and acts as a tumor suppressor. Rb is activated upon phosphorylation by cyclin D-CDK4/6 at Ser780 and Ser795 and by cyclin E/CDK2 at Ser807 and Ser811. Rb is encoded by the RB transcriptional corepressor 1 (“RB1”) gene (GenBank Accession No. NM_000321). The amino acid sequence of human Rb is provided below (GenBank Accession No. NP_000312 / UniProtKB Accession No. P06400) (S780 is in bold and underlined): As stated above, the Examples demonstrate CDK2-knockdown inhibits proliferation in CCNE1-amplified cell lines, but not in CCNE1-non-amplified cell lines. The Examples further demonstrate CDK2-knockdown or inhibition blocks Rb phosphorylation at the S780 in CCNE1-amplified cell lines, but not in CCNE1-non- amplified cell lines. Accordingly, Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3 is a pharmacodynamic marker for assessing response to CDK2 inhibition in CCNE1 amplified cancer cells or patients with diseases or disorders having CCNE1 amplification. Thus, provided herein are methods relating to the use of the level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3 in a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2 as a marker for indicating the response of the human subject to a CDK2 inhibitor, wherein the human subject has an increased expression level of CCNE1. Thus, the disclosure features a method for measuring the amount of a protein in a sample, comprising: (a) providing a biological sample obtained from a human subject having a disease or disorder associated with CDK2; and (b) measuring the level of Rb protein phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3 in the biological sample. In some embodiments, the biological sample comprises a blood sample or a tumor biopsy sample. In a specific embodiment, provided herein is a method of evaluating the response of a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2 to a CDK2 inhibitor, comprising: (a) administering a CDK2 inhibitor to the human subject, wherein the human subject has been previously determined to have an amplification of the CCNE1 gene and/or an expression level of CCNE1 that is higher than a control expression level of CCNE1; and (b) measuring, in a biological sample obtained from the human subject subsequent to the administering of step (a), the level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3, wherein a reduced level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3, as compared to a control level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3, is indicative that the human subject responds to the CDK2 inhibitor. In specific embodiments, the human subject has a disease or disorder associated with CDK2. A reduced level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3, as compared to a control level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3, combined with an amplification of the CCNE1 gene and/or an expression level of CCNE1 that is higher than a control expression level of CCNE1, is indicative that a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2 responds to a CDK2 inhibitor. For example, in a subject having an amplification of the CCNE1 gene and/or an expression level of CCNE1 that is higher than a control expression level of CCNE1, a biological sample, obtained from the subject after treatment with a CDK2 inhibitor, having low (e.g., reduced as compared to a control) or undetectable levels of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO:3 is indicative that the subject responds to the CDK2 inhibitor. A biological sample, obtained from a subject after administration of a CDK2 inhibitor to the subject, having a reduced level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3, as compared to a control level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3, combined with: (i) an amplification of the CCNE1 gene and/or an expression level of CCNE1 that is higher than a control expression level of CCNE1, and (ii) presence of a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1, presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and/or deletions, and/or presence of a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO:1), is indicative that a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2 responds to a CDK2 inhibitor. For example, in a human subject having (i) an amplification of the CCNE1 gene and/or an expression level of CCNE1 that is higher than a control expression level of CCNE1, and (ii) the presence of a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1, the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and/or deletions, and/or the presence of a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO:1), a biological sample, obtained from the human subject after administration of a CDK2 inhibitor to the subject, having low (e.g., reduced as compared to a control) or undetectable levels of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3 is indicative that the human subject responds to the CDK2 inhibitor In some embodiments, the CCNE1 gene is amplified to a gene copy number from 3 to 25. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 3. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 5. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 7. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 10. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 12. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 14. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 21. In specific embodiments, the expression level of CCNE1 is the level of CCNE1 mRNA. In specific embodiments, the expression level of CCNE1 is the level of CCNE1 protein. Controls As described above, the methods related to biomarkers and pharmacodynamic markers can involve, measuring one or more markers (e.g., a biomarker or a pharmacodynamics marker, e.g., the amplification of the CCNE1 gene, the expression level of CCNE1, the presence of a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1, the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and/or deletions, the presence of a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO:1), and Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3) in a biological sample from a human subject having, suspected of having or at risk of developing a disease or disorder associated with CDK2. In specific embodiments, the human subject has a disease or disorder associated with CDK2. In specific embodiments, the human subject is suspected of having or is at risk of developing a disease or disorder associated with CDK2. In certain aspects, the level (e.g., amplification (e.g., for the CCNE1 gene), expression level (e.g., for CCNE1 or p16 protein), or phosphorylation level (e.g., for Rb)) of one or more biomarkers, compared to a control level of the one or more biomarkers, predicts/indicates the response of a human subject to treatment comprising a CDK2 inhibitor. In certain embodiments, when (i) the CCNE1 gene is amplified and/or an expression level of CCNE1 that is higher than a control expression level of CCNE1, and (ii) a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1 is present, a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and/or deletions is present, and/or a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO:1) is present, the human subject is identified as likely to respond to a CDK2 inhibitor. In other embodiments, when (i) the CCNE1 gene is amplified and/or an expression level of CCNE1 that is higher than a control expression level of CCNE1, and (ii) in a biological sample from the human subject after the human subject has been administered a CDK2 inhibitor, the level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3 is less than the control level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3, the human subject is identified as responding to a CDK2 inhibitor. In yet another embodiment, when (i) the CCNE1 gene is amplified and/or an expression level of CCNE1 that is higher than a control expression level of CCNE1, (ii) a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1 is present, a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and/or deletions is present, and/or a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO:1) is present, and (iii) in a biological sample from the human subject after the human subject has been administered a CDK2 inhibitor, the level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3 is less than the control level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3, the human subject is identified as responding to a CDK2 inhibitor. In this context, the term “control” includes a sample (from the same tissue type) obtained from a human subject who is known to not respond to a CDK2 inhibitor. The term “control” also includes a sample (from the same tissue type) obtained in the past from a human subject who is known to not respond to a CDK2 inhibitor and used as a reference for future comparisons to test samples taken from human subjects for which therapeutic responsiveness is to be predicted. The “control” level (e.g., gene copy number, expression level, or phosphorylation level) for a particular biomarker (e.g., CCNE1, p16, or Rb phosphorylation) in a particular cell type or tissue may be pre-established by an analysis of biomarker level (e.g., expression level or phosphorylation level) in one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40 or more) human subjects that have not responded to treatment with a CDK2 inhibitor. This pre-established reference value (which may be an average or median level (e.g., gene copy number, expression level, or phosphorylation level) taken from multiple human subjects that have not responded to the therapy) may then be used for the “control” level of the biomarker (e.g., CCNE1, p16, or Rb phosphorylation) in the comparison with the test sample. In such a comparison, the human subject is predicted to respond to a CDK2 inhibitor if the CCNE1 gene is amplified and/or the expression level of CCNE is higher than the pre- established reference, and a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1 is present, a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and/or deletions is present, and/or a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO:1) is present. In another such a comparison, the human subject is predicted to respond to a CDK2 inhibitor if (i) CCNE1 gene is amplified and/or the expression level of CCNE is higher than the pre-established reference, and (ii) after administering to the human subject a CDK2 inhibitor, the level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3 is lower than the pre-established reference. In yet another such a comparison, the human subject is indicated to respond to a CDK2 inhibitor if (i) CCNE1 gene is amplified and/or the expression level of CCNE is higher than the pre-established reference, (ii) a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1 is present, a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and/or deletions is present, and/or a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO:1) is present, and (iii) after administering to the human subject a CDK2 inhibitor, the level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3 is lower than the pre- established reference. The “control” level for a particular biomarker in a particular cell type or tissue may alternatively be pre-established by an analysis of biomarker level in one or more human subjects that have responded to treatment with a CDK2 inhibitor. This pre- established reference value (which may be an average or median level (e.g., expression level or phosphorylation level) taken from multiple human subjects that have responded to the therapy) may then be used as the “control” level (e.g., expression level or phosphorylation level) in the comparison with the test sample. In such a comparison, the human subject is indicated to respond to a CDK2 inhibitor if the level (e.g., copy number of the CCNE1 gene, expression level of CCNE1, expression level of p16, or phosphorylation level of Rb at the serine corresponding to amino acid position 780 of SEQ ID NO:3) of the biomarker being analyzed is equal or comparable to (e.g., at least 85% but less than 115% of), the pre-established reference. In certain embodiments, the “control” is a pre-established cut-off value. A cut-off value is typically a level (e.g., a copy number, an expression level, or a phosphorylation level) of a biomarker above or below which is considered predictive of responsiveness of a human subject to a therapy of interest. Thus, in accordance with the methods and compositions described herein, a reference level (e.g., of CCNE1 gene copy number, CCNE1 expression, p16 expression, or Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3) is identified as a cut-off value, above or below of which is predictive of responsiveness to a CDK2 inhibitor. Cut-off values determined for use in the methods described herein can be compared with, e.g., published ranges of concentrations but can be individualized to the methodology used and patient population. In some embodiments, the expression level of CCNE1 is increased as compared to the expression level of CCNE1 in a control. For example, the expression level of CCNE1 analyzed can be at least 1.5, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 25, at least 50, at least 75, or at least 100 times higher, or at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 200%, at least 300%, at least 400%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, at least 1,000%, at least 1,500%, at least 2,000%, at least 2,500%, at least 3,000%, at least 3,500%, at least 4,000%, at least 4,500%, or at least 5,000% higher, than the expression level of CCNE1 in a control. A p16 protein is present if the protein is detectable by any assay known in the art or described herein, such as, for example, western blot, immunohistochemistry, fluorescence-activated cell sorting, and enzyme-linked immunoassay. In some embodiments, a p16 protein is present at an expression level that is within at least 5%, at least 10%, at least 20%, or at least 30% of the p16 expression level in a healthy control. In some embodiments, the level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3 being analyzed is reduced as compared to the level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3 in a control. For example, the level of the Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3 being analyzed can be at least 1.5, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 25, at least 50, at least 75, or at least100 times lower, or at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% lower, than the level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3 in a control. Biological Samples Suitable biological samples for the methods described herein include any sample that contains blood or tumor cells obtained or derived from the human subject in need of treatment. For example, a biological sample can contain tumor cells from biopsy from a patient suffering from a solid tumor. A tumor biopsy can be obtained by a variety of means known in the art. Alternatively, a blood sample can be obtained from a patients suffering from a hematological cancer. A biological sample can be obtained from a human subject having, suspected of having, or at risk of developing, a disease or disorder associated with CDK2. In some embodiments, the disease or disorder associated with CDK2 is a cancer (such as those described supra). Methods for obtaining and/or storing samples that preserve the activity or integrity of molecules (e.g., nucleic acids or proteins) in the sample are well known to those skilled in the art. For example, a biological sample can be further contacted with one or more additional agents such as buffers and/or inhibitors, including one or more of nuclease, protease, and phosphatase inhibitors, which preserve or minimize changes in the molecules in the sample. Evaluating Biomarkers and Pharmacodynamic Markers Expression levels of CCNE1 or p16 can be detected as, e.g., RNA expression of a target gene (i.e., the genes encoding CCNE1 or p16). That is, the expression level (amount) of CCNE1 or p16 can be determined by detecting and/or measuring the level of mRNA expression of the gene encoding CCNE1. Alternatively, expression levels of CCNE1 or p16 can be detected as, e.g., protein expression of target gene (i.e., the genes encoding CCNE1 or p16). That is, the expression level (amount) of CCNE1 or p16 can be determined by detecting and/or measuring the level of protein expression of the genes encoding CCNE1 or p16. In some embodiments, the expression level of CCNE1 or p16 is determined by measuring RNA levels. A variety of suitable methods can be employed to detect and/or measure the level of mRNA expression of a gene. For example, mRNA expression can be determined using Northern blot or dot blot analysis, reverse transcriptase-PCR (RT-PCR; e.g., quantitative RT-PCR), in situ hybridization (e.g., quantitative in situ hybridization), nucleic acid array (e.g., oligonucleotide arrays or gene chips) and RNA sequencing analysis. Details of such methods are described below and in, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual Second Edition vol.1, 2 and 3. Cold Spring Harbor Laboratory Press: Cold Spring Harbor, New York, USA, Nov.1989; Gibson et al. (1999) Genome Res., 6(10):995-1001; and Zhang et al. (2005) Environ. Sci. Technol., 39(8):2777-2785; U.S. Publication No. 2004086915; European Patent No.0543942; and U.S. Patent No.7,101,663; Kukurba et al. (2015) Cold Spring Harbor Protocols., 2015 (11): 951–69; the disclosures of each of which are incorporated herein by reference in their entirety. In one example, the presence or amount of one or more discrete mRNA populations in a biological sample can be determined by isolating total mRNA from the biological sample (see, e.g., Sambrook et al. (supra) and U.S. Patent No. 6,812,341) and subjecting the isolated mRNA to agarose gel electrophoresis to separate the mRNA by size. The size-separated mRNAs are then transferred (e.g., by diffusion) to a solid support such as a nitrocellulose membrane. The presence or amount of one or more mRNA populations in the biological sample can then be determined using one or more detectably-labeled-polynucleotide probes, complementary to the mRNA sequence of interest, which bind to and thus render detectable their corresponding mRNA populations. Detectable-labels include, e.g., fluorescent (e.g., umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride, allophycocyanin, or phycoerythrin), luminescent (e.g., europium, terbium, Qdot™ nanoparticles supplied by the Quantum Dot Corporation, Palo Alto, CA), radiological (e.g., 125I, 131I, 35S, 32P, 33P, or 3H), and enzymatic (horseradish peroxidase, alkaline phosphatase, beta- galactosidase, or acetylcholinesterase) labels. In some embodiments, the expression level of CCNE1 or p16 is determined by measuring protein levels. A variety of suitable methods can be employed to detect and/or measure the level of protein expression of target genes. For example, CCNE1 or p16 protein expression can be determined using western blot, enzyme-linked immunosorbent assay (“ELISA”), fluorescence activated cell sorting, or immunohistochemistry analysis (e.g., using a CCNE1-specific or p16-specific antibody, respectively). Details of such methods are described below and in, e.g., Sambrook et al., supra. In one example, the presence or amount of one or more discrete protein populations (e.g., CCNE1 or p16) in a biological sample can be determined by western blot analysis, e.g., by isolating total protein from the biological sample (see, e.g., Sambrook et al. (supra)) and subjecting the isolated protein to agarose gel electrophoresis to separate the protein by size. The size-separated proteins are then transferred (e.g., by diffusion) to a solid support such as a nitrocellulose membrane. The presence or amount of one or more protein populations in the biological sample can then be determined using one or more antibody probes, e.g., a first antibody specific for the protein of interest (e.g., CCNE1 or p16), and a second antibody, detectably labeled, specific for the first antibody, which binds to and thus renders detectable the corresponding protein population. Detectable-labels suitable for use in western blot analysis are known in the art. Methods for detecting or measuring gene expression (e.g., mRNA or protein expression) can optionally be performed in formats that allow for rapid preparation, processing, and analysis of multiple samples. This can be, for example, in multi- welled assay plates (e.g., 96 wells or 386 wells) or arrays (e.g., nucleic acid chips or protein chips). Stock solutions for various reagents can be provided manually or robotically, and subsequent sample preparation (e.g., RT-PCR, labeling, or cell fixation), pipetting, diluting, mixing, distribution, washing, incubating (e.g., hybridization), sample readout, data collection (optical data) and/or analysis (computer aided image analysis) can be done robotically using commercially available analysis software, robotics, and detection instrumentation capable of detecting the signal generated from the assay. Examples of such detectors include, but are not limited to, spectrophotometers, luminometers, fluorimeters, and devices that measure radioisotope decay. Exemplary high-throughput cell-based assays (e.g., detecting the presence or level of a target protein in a cell) can utilize ArrayScan® VTI HCS Reader or KineticScan® HCS Reader technology (Cellomics Inc., Pittsburg, PA). In some embodiments, the presence of a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1 and/or the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and/or deletions is determined by evaluating the DNA sequence of the CDKN2A gene (e.g., genomic DNA or cDNA) or by evaluating the RNA sequence of the CDKN2A gene (e.g., RNA, e.g., mRNA). Methods of performing nucleic acid sequencing analyses are known in the art and described above. Nonlimiting examples of inactivating nucleic acid substitutions and/or deletions preventing the CDKN2A gene from encoding a protein comprising the amino acid sequence of SEQ ID NO:1 are described in Table A, above. In specific embodiments, the one or more inactivating nucleic acid substitutions and/or deletions in the CDKN2A gene is as described in Yarbrough et al., Journal of the National Cancer Institute, 91(18):1569-1574, 1999; Liggett and Sidransky, Biology of Neoplasia, Journal of Oncology, 16(3):1197-1206, 1998, and Cairns et al., Nature Genetics, 11:210-212, 1995, each of which is incorporated by reference herein in its entirety. In some embodiments, the expression level of a gene or the presence of a gene lacking one or more inactivating nucleic acid substitutions or deletions is determined by evaluating the copy number variation (CNV) of the gene. The CNV of genes (e.g., the CCNE1 gene and/or the CDKN2A gene) can be determined/identified by a variety of suitable methods. For example, CNV can be determined using fluorescent in situ hybridization (FISH), multiplex ligation dependent probe amplification (MLPA), array comparative genomic hybridization (aCGH), single-nucleotide polymorphisms (SNP) array, and next-generation sequencing (NGS) technologies. In one example, the copy number variation of one or more discrete genes in a biological sample can be determined by MLPA, e.g., by extracting DNA specimens from the biological sample (see, e.g., Sambrook et al. (supra) and U.S. Patent No. 6,812,341), and amplifying DNA sequence of interest (e.g., CCNE1 or CDKN2A) using a mixture of MLPA probes. Each MLPA probe consists of two oligonucleotides that hybridize to immediately adjacent target DNA sequence (e.g., CCNE1 or CDKN2A) in order to be ligated into a single probe. Ligated probes are amplified though PCR with one PCR primer fluorescently labeled, enabling the amplification products to be visualized during fragment separation by capillary electrophoresis. The presence, absence or amplification of one or more genes of interest in the biological sample is calculated by measuring PCR derived fluorescence, quantifying the amount of PCR product after normalization and comparing it with control DNA samples. The level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3 can be detected by a variety of suitable methods. For example, phosphorylation status can be determined using western blot, ELISA, fluorescence activated cell sorting, or immunohistochemistry analysis. Details of such methods are described below and in, e.g., Sambrook et al., supra. As with the methods for detecting or measuring gene expression (above), methods for detecting or measuring the level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3 can optionally be performed in formats that allow for rapid preparation, processing, and analysis of multiple samples. The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non-critical parameters which can be changed or modified to yield essentially the same results. EXAMPLES Experimental procedures for compounds of the invention are provided below. Preparatory LC-MS purifications of some of the compounds prepared were performed on Waters mass directed fractionation systems. The basic equipment setup, protocols, and control software for the operation of these systems have been described in detail in the literature. See e.g., “Two-Pump at-Column Dilution Configuration for Preparative LC-MS,” K. Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification,” K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and “Preparative LC-MS Purification: Improved Compound Specific Method Optimization,” K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004). The separated compounds were typically subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity check under the following conditions: Instrument: Agilent 1100 series, LC/MSD; Column: Waters Sunfire TM C185 µm particle size, 2.1 x 5.0 mm; Buffers: mobile phase A: 0.025% TFA in water and mobile phase B: acetonitrile; gradient 2% to 80% of B in 3 minutes with flow rate 2.0 mL/minute. Some of the compounds prepared were also separated on a preparative scale by reverse-phase high performance liquid chromatography (RP-HPLC) with MS detector or flash chromatography (silica gel) as indicated in the Examples. Typical preparative reverse-phase high performance liquid chromatography (RP-HPLC) column conditions are as follows: pH = 2 purifications: Waters Sunfire TM C185 µm particle size, 19 x 100 mm column, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile; the flow rate was 30 mL/minute, the separating gradient was optimized for each compound using the Compound Specific Method Optimization protocol as described in the literature (see “Preparative LCMS Purification: Improved Compound Specific Method Optimization,” K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)). Typically, the flow rate used with the 30 x 100 mm column was 60 mL/minute. pH = 10 purifications: Waters XBridge C185 µm particle size, 19 x 100 mm column, eluting with mobile phase A: 0.15% NH4OH in water and mobile phase B: acetonitrile; the flow rate was 30 mL/minute, the separating gradient was optimized for each compound using the Compound Specific Method Optimization protocol as described in the literature (See “Preparative LCMS Purification: Improved Compound Specific Method Optimization,” K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)). Typically, the flow rate used with 30 x 100 mm column was 60 mL/minute. Intermediate 1.8-Isopropoxy-N-((3R,4S)-3-methylpiperidin-4-yl)-7-(1H-pyra zol- 4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine To a mixture of tert-butyl (3R,4S)-4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)- 8-isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-m ethylpiperidine-1- carboxylate (Example 33, Step 3, 528.7 mg, 1.00 mmol) in MeOH (5.0 mL) was added a 4 M solution of HCl in 1,4-dioxane (5.0 mL, 20 mmol) and the reaction mixture was stirred at 70 °C for 1 h. After cooling to r.t., the reaction mixture was concentrated in vacuo to provide the desired product as its HCl salt. The crude material obtained was used directly without further purification. LC-MS calculated for C17H 2 5N8O (M+H) + : m/z = 357.2; found 357.1. Intermediate 2.2-Bromo-5-chloro-6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridine Step 1: 6-Chloro-5-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)pyridin-2-amin e A mixture of 5-bromo-6-chloropyridin-2-amine (25.0 g, 121 mmol), 1-(1- ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (32.1 g, 121 mmol), Pd(dppf)Cl 2 CH 2 Cl 2 adduct (4.92 g, 6.03 mmol), and potassium phosphate, tribasic (51.1 g, 241 mmol) in 1,4-dioxane (502 mL) and water (100 mL) was purged with nitrogen and stirred at 100 °C for 4 h. After cooling to r.t., the reaction mixture was diluted with water and extracted with CH 2 Cl 2 . The combined organic phases were dried over MgSO 4 , filtered, and concentrated. The crude material obtained was used directly without further purification. LC-MS calculated for C12H16ClN4O (M+H) + : m/z = 267.1; found 267.1. Step 2: 5-Chloro-6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-[1,2,4]triazo lo[1,5-a]pyridin- 2-amine To a mixture of 6-chloro-5-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)pyridin-2- amine (Step 1) in CH 3 CN (603 mL) was added O-ethyl carbonisothiocyanatidate (21.3 mL, 181 mmol) and the reaction mixture was purged with nitrogen and stirred at 90 °C for 2 h. The reaction mixture was concentrated in vacuo, and to the crude residue was added a mixture of hydroxylamine hydrochloride (25.1 g, 362 mmol) and N- ethyl-N-isopropylpropan-2-amine (63.1 mL, 362 mmol) in MeOH (301 mL) and EtOH (301 mL) and the reaction mixture was stirred under nitrogen at 90 °C for 2 h. After cooling to r.t., the reaction mixture was diluted with saturated aqueous NH4Cl and extracted with CH 2 Cl 2 . The combined organic phases were dried over MgSO 4 , filtered, and concentrated. The crude material obtained was used directly without further purification. LC-MS calculated for C13H16ClN6O (M+H) + : m/z = 307.1; found 307.1. Step 3: 2-Bromo-5-chloro-6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-[1,2, 4]triazolo[1,5- a]pyridine A mixture of copper(II) bromide (26.9 g, 121 mmol) and tert-butyl nitrite (90 wt%, 38.2 mL, 289 mmol) in CH 3 CN (603 mL) was heated to 60 °C for 30 min. The mixture was poured into a mixture of 5-chloro-6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine (Step 2) in CH 3 CN (603 mL), and the reaction mixture was stirred at ambient temperature for 30 min before heating to 60 °C for 30 min. After cooling to r.t., the reaction mixture was diluted with sat. aq. NaHCO 3 and extracted with CH 2 Cl 2 . The combined organic phases were dried over MgSO 4 and filtered over a pad of SiO 2 (25 g). The filter cake was washed with CH 2 Cl 2 and the filtrate was concentrated. The crude residue obtained was purified by flash column chromatography (330 g SiO 2 , EtOAc/hexanes) to afford 2-bromo-5-chloro-6-(1-(1- ethoxyethyl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine . LC-MS calculated for C13H14BrClN5O (M+H) + : m/z = 370.0; found 370.0. Intermediate 3. (3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-amine Step 1: tert-Butyl (3R,4S)-4-(((benzyloxy)carbonyl)amino)-3-methylpiperidine-1- carboxylate A stirred mixture of tert-butyl (3R,4S)-4-amino-3-methylpiperidine-1- carboxylate (1.072 g, 5.00 mmol) in CH 2 Cl 2 (10.0 mL) and saturated aqueous NaHCO 3 (10.0 mL) was cooled to 0 °C before benzyl carbonochloridate (1.43 mL, 10.0 mmol) was added dropwise and the reaction mixture allowed to warm to r.t. overnight. The organic phase was collected, and the aqueous phase was extracted with CH 2 Cl 2 (3 x 5 mL). The combined organic phases were dried over MgSO 4 , concentrated, and the crude residue was purified by flash column chromatography (20 g SiO 2 , EtOAc/hexanes). LC-MS calculated for C15H 2 1N2O 4 (M+H-C4H8) + : m/z = 293.1; found 293.1. Step 2: Benzyl ((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)carbamate To a mixture of tert-butyl (3R,4S)-4-(((benzyloxy)carbonyl)amino)-3- methylpiperidine-1-carboxylate (Step 1) in MeOH (20.0 mL) was added a 4 M solution of HCl in 1,4-dioxane (10.0 mL, 40.0 mmol) and the reaction mixture was stirred at r.t. for 6 h before the mixture was concentrated in vacuo. A stirred mixture of the crude residue in CH 2 Cl 2 (25 mL) and saturated aqueous NaHCO 3 (25 mL) was cooled to 0 °C before methanesulfonyl chloride (0.78 mL, 10.0 mmol) was added dropwise and the reaction mixture allowed to warm to r.t. overnight. The organic phase was collected, and the aqueous phase was extracted with CH 2 Cl 2 (3 x 5 mL). The combined organic phases were dried over MgSO 4 and concentrated. The residue was triturated with hexanes to afford benzyl ((3R,4S)-3-methyl-1- (methylsulfonyl)piperidin-4-yl)carbamate as a white solid. The crude material obtained was used directly without further purification. LC-MS calculated for C15H 2 3N2O 4 S (M+H) + : m/z = 327.1; found 327.1. 1 H NMR (600 MHz, DMSO-d6) δ 7.42 – 7.28 (m, 6H), 5.08 – 5.00 (m, 2H), 3.74 – 3.68 (m, 1H), 3.17 – 3.02 (m, 3H), 2.97 – 2.91 (m, 1H), 2.81 (s, 3H), 2.02 – 1.93 (m, 1H), 1.71 – 1.62 (m, 2H), 0.83 (d, J = 6.9 Hz, 3H). Step 3: (3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-amine To a mixture of benzyl ((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4- yl)carbamate (Step 2) in MeOH (20.0 mL) was added Pd/C (10 wt%, 1.065 g, 1.00 mmol) and the reaction mixture was stirred under a balloon of hydrogen at r.t. overnight. The reaction mixture was filtered over a pad of Celite, and the filter cake was washed with MeOH (5 mL) and CH 2 Cl 2 (2 x 5 mL) and the filtrate was concentrated. The residue was dissolved in CH 3 CN and H 2 O, and the resulting mixture was frozen and lyophilized to afford (3R,4S)-3-methyl-1- (methylsulfonyl)piperidin-4-amine as a white solid. The crude material obtained was used directly without further purification. LC-MS calculated for C7H17N2O 2 S (M+H) + : m/z = 193.1; found 193.1. Intermediate 4.2-Bromo-6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-5-isopropoxy - [1,2,4]triazolo[1,5-a]pyrazine Step 1: 5-Bromo-6-isopropoxypyrazin-2-amine In an oven-dried microwave vial with a stir bar, to a mixture of propan-2-ol (0.764 mL, 10.0 mmol) in 1,4-dioxane (10.0 mL) was added NaH (240 mg, 10.00 mmol) portionwise and the reaction mixture was stirred under nitrogen at r.t. for 15 min.5-Bromo-6-chloropyrazin-2-amine (2.084 g, 10.0 mmol) was added and the reaction mixture was stirred under nitrogen at r.t. for 15 min before the mixture was irradiated in a microwave reactor at 150 °C for 2 h. After cooling to r.t., the mixture was diluted with saturated aqueous NaHCO 3 and extracted with EtOAc and CH 2 Cl 2 . The combined organic phases were dried over MgSO 4 , concentrated, and the crude residue was purified by flash column chromatography (SiO 2 , EtOAc/hexanes). LC- MS calculated for C7H11BrN3O (M+H) + : m/z = 232.0; found 232.1. Step 2: 5-(1-(1-Ethoxyethyl)-1H-pyrazol-4-yl)-6-isopropoxypyrazin-2- amine A mixture of 5-bromo-6-isopropoxypyrazin-2-amine (Step 1), 1-(1- ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (2.93 g, 11.0 mmol), Pd(dppf)Cl 2 CH 2 Cl 2 adduct (817 mg, 1.00 mmol), and potassium phosphate, tribasic (4.24 g, 20.0 mmol) in CH 3 CN (41.7 mL) and H 2 O (8.33 mL) was purged with nitrogen and stirred at 90 °C overnight. After cooling to r.t., the reaction mixture was diluted with water and extracted with CH 2 Cl 2 . The combined organic phases were dried over MgSO 4 , concentrated, and the crude residue was purified by flash column chromatography (SiO 2 , EtOAc/hexanes). LC-MS calculated for C14H 2 2N5O 2 (M+H) + : m/z = 292.2; found 292.1. Step 3: 6-(1-(1-Ethoxyethyl)-1H-pyrazol-4-yl)-5-isopropoxy-[1,2,4]tr iazolo[1,5- a]pyrazin-2-amine To a mixture of 5-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-6-isopropoxypyrazin- 2-amine (Step 2) in CH 3 CN (50.0 mL) was added O-ethyl carbonisothiocyanatidate (2.66 mL, 15.0 mmol) and the reaction mixture was purged with nitrogen and stirred at 90 °C for 2 h. The reaction mixture was concentrated in vacuo, and to the residue was added a mixture of hydroxylamine hydrochloride (2.084 g, 30.0 mmol) and N- ethyl-N-isopropylpropan-2-amine (5.24 mL, 30.0 mmol) in MeOH (25.0 mL) and EtOH (25.0 mL) and the reaction mixture was stirred under nitrogen at 90 °C for 2 h. After cooling to r.t., the reaction mixture was diluted with saturated aqueous NH4Cl and extracted with CH 2 Cl 2 . The combined organic layers were dried over MgSO 4 , filtered, and concentrated. The crude material obtained was used directly without further purification. LC-MS calculated for C15H 2 2N7O 2 (M+H) + : m/z = 332.2; found 332.1. Step 4: 2-Bromo-6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-5-isopropoxy- [1,2,4]triazolo[1,5-a]pyrazine To a mixture of copper(II) bromide (2.23 g, 10.0 mmol) in CH 3 CN (50.0 mL) was added tert-butyl nitrite (90 wt%, 3.17 mL, 24.0 mmol) and the reaction mixture was stirred at 60 °C for 30 min. The mixture was then poured into a mixture of 6-(1- (1-ethoxyethyl)-1H-pyrazol-4-yl)-5-isopropoxy-[1,2,4]triazol o[1,5-a]pyrazin-2-amine (Step 3) in CH 3 CN (50.0 mL) and the reaction mixture was stirred at r.t. for 2 h. The mixture was diluted with saturated aqueous NaHCO 3 and CH 2 Cl 2 and the mixture was filtered over a pad of Celite. The filtrate was then extracted with CH 2 Cl 2 and the combined organic phases were dried over MgSO 4 , concentrated, and the crude residue was purified by flash column chromatography (SiO 2 , EtOAc/hexanes). LC-MS calculated for C15H 2 0BrN6O 2 (M+H) + : m/z = 395.1; found 395.1. Intermediate 5.6-Chloro-5-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)pyrazin-2-am ine A mixture of 5-bromo-6-chloropyrazin-2-amine (5.00 g, 24.0 mmol), 1-(1- ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (6.38 g, 24.0 mmol), Pd(dppf)Cl 2 CH 2 Cl 2 adduct (0.980 g, 1.20 mmol), and potassium phosphate, tribasic (10.18 g, 48.0 mmol) in 1,4-dioxane (100 mL) and water (20.0 mL) was purged with nitrogen and stirred at 90 °C overnight. After cooling to r.t., the reaction mixture was diluted with water and extracted with CH 2 Cl 2 . The combined organic phases were dried over MgSO 4 , filtered, and concentrated. The crude residue was purified by flash column chromatography (120 g SiO 2 , EtOAc/hexanes) to afford 6-chloro-5-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)pyrazin-2-amin e (5.07 g, 79% yield) as a light yellow waxy solid. LC-MS calculated for C11H15ClN5O (M+H) + : m/z = 268.1; found 268.1. Intermediate 6.2-Bromo-5-chloro-6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyrazine Step 1: 5-Chloro-6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-[1,2,4]triazo lo[1,5- a]pyrazin-2-amine To a mixture of 6-chloro-5-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)pyrazin-2- amine (Intermediate 5, 5.07 g, 18.9 mmol) in CH 3 CN (95 mL) was added O-ethyl carbonisothiocyanatidate (3.35 mL, 28.4 mmol) and the reaction mixture was purged with nitrogen and stirred at 90 °C for 2 h. The reaction mixture was concentrated in vacuo, and to the residue was added a mixture of hydroxylamine hydrochloride (3.95 g, 56.8 mmol) and N-ethyl-N-isopropylpropan-2-amine (9.92 mL, 56.8 mmol) in MeOH (47.3 mL) and EtOH (47.3 mL) and the reaction mixture was stirred under nitrogen at 90 °C for 2 h. After cooling to r.t., the reaction mixture was diluted with saturated aqueous NH4Cl and extracted with CH 2 Cl 2 . The combined organic phases were dried over MgSO 4 , filtered, and concentrated. The crude material obtained was used directly without further purification. LC-MS calculated for C12H15ClN7O (M+H) + : m/z = 308.1; found 308.2. Step 2: 2-Bromo-5-chloro-6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-[1,2, 4]triazolo[1,5- a]pyrazine A mixture of copper(II) bromide (4.23 g, 18.94 mmol) and tert-butyl nitrite (90 wt%, 6.01 mL, 45.5 mmol) in CH 3 CN (95 mL) was stirred at 60 °C for 30 min. The mixture was poured into a mixture of 5-chloro-6-(1-(1-ethoxyethyl)-1H-pyrazol- 4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine (Step 1) in CH 3 CN (95 mL), and the reaction mixture was stirred at ambient temperature for 30 min before heating to 60 °C for 30 min. After cooling to r.t., the reaction mixture was diluted with sat. aq. NaHCO 3 and extracted with CH 2 Cl 2 . The combined organic phases were dried over MgSO 4 and filtered over a pad of SiO 2 (5 g). The filter cake was washed with CH 2 Cl 2 and the filtrate was concentrated. The crude residue obtained was purified by flash column chromatography (120 g SiO 2 , EtOAc/hexanes). Fractions containing the desired product were concentrated, and the residue was dissolved in a minimal amount of THF followed by slow addition of hexanes and the resulting mixture was slurried for 30 min. The solid precipitate was collected via filtration, washed with hexanes, and dried under air to afford 2-bromo-5-chloro-6-(1-(1-ethoxyethyl)-1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine as an off-white solid. LC-MS calculated for C12H13BrClN6O (M+H) + : m/z = 371.0; found 371.0. Example 1. N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine To a solution of 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine (AstaTech, cat# 67344: 60.0 mg, 0.217 mmol), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (AstaTech, cat# 67344: 57.7 mg, 0.217 mmol), and potassium phosphate (138 mg, 0.65 mmol) in dioxane (2 mL) and water (0.4 mL) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-bi phenyl)(2-(2'- amino-1,1'-biphenyl))palladium(II) (17.05 mg, 0.022 mmol). The vial was flushed with nitrogen, and the reaction was stirred at 100 °C for 2 h. The reaction mixture was quenched with NH4OH aqueous solution and then extracted into ethyl acetate. The organic phases were combined, dried over MgSO 4 , filtered, and concentrated. The crude residue was used directly in the next step without further purification. LC-MS calculated for C13H15BrN5O (M+H) + : m/z = 336.1, 338.1; found 336.2, 338.2. Step 2: N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1, 2,4]triazolo[1,5- a]pyridin-2-amine To a solution of 2-bromo-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridine (27.4 mg, 0.082 mmol), 1-(methylsulfonyl)piperidin-4- amine (Combi-Blocks, cat# ST-7136: 16 mg, 0.09 mmol), and sodium tert-butoxide (31.4 mg, 0.326 mmol) in dioxane (2 mL) was added AdBrettPhos Pd G3 (7 mg, 0.0008 mmol). The vial was flushed with nitrogen, and the reaction was stirred at 100 °C for 5 h. After the reaction was cooled to room temperature, 1 M aqueous solution of HCl (1 mL) was added, and the reaction mixture was stirred for 30 min. The reaction mixture was diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C15H 2 0N7O 2 S (M+H) + : m/z = 362.1; found 362.1. Example 2.8-ethoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazo l-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine Step 1: 3-(benzyloxy)-4-chloropyridin-2-amine To a solution of tert-butyl 4-chloro-3-hydroxypyridin-2-ylcarbamate (Matrix, cat# 032309: 1.0 g, 4.09 mmol) and (bromomethyl)benzene (699 mg, 4.09 mmol) in THF (14 mL) at 0° C was added sodium hydride (60 % dispersion in mineral oil, 196 mg, 4.9 mmol). The reaction was stirred at room temperature for 2 h. The reaction mixture was quenched with NH4OH aqueous solution and then extracted into ethyl acetate. The organic phases were combined, dried over MgSO 4 , filtered, and concentrated. The crude residue was then dissolved in dioxane (10 mL). HCl (4 M in dioxane, 2 mL) was added, and the reaction mixture was stirred at room temperature for another 2 h. The reaction was concentrated, and the crude residue was used directly in the next step without further purification. LC-MS calculated for C12H12ClN2O (M+H) + : m/z = 235.1; found 235.1. Step 2: 8-(benzyloxy)-7-chloro-[1,2,4]triazolo[1,5-a]pyridin-2-amine To a solution of 3-(benzyloxy)-4-chloropyridin-2-amine (939 mg, 4.0 mmol) and O-ethyl carbonisothiocyanatidate (525 mg, 4.0 mmol) in dioxane (16 mL) was added DIPEA (0.7 mL, 4.0 mmol). The reaction was stirred at room temperature for 2 h. The reaction mixture was then quenched with NH4OH aqueous solution and extracted into ethyl acetate. The organic phases were combined, dried over MgSO 4 , filtered, and concentrated. The crude residue was then dissolved in ethanol (15 mL). In a separate vial, hydroxylamine hydrochloride (1.39 g, 20.0 mmol) and DIPEA (2.1 mL, 12 mmol) were stirred in ethanol (10 mL) for 5 min at room temperature. The two reaction mixtures were then combined and stirred at 80 °C for 2 h. The reaction mixture was then quenched with NH4OH aqueous solution and extracted into ethyl acetate. The organic phases were combined, dried over MgSO 4 , filtered, and concentrated. The crude residue was used directly in the next step without further purification. LC-MS calculated for C13H12ClN4O (M+H) + : m/z = 275.1; found 275.1. Step 3: 8-(benzyloxy)-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-[1,2,4]t riazolo[1,5- a]pyridin-2-amine This compound was prepared using similar procedures as described for Example 1, Step 1 with 8-(benzyloxy)-7-chloro-[1,2,4]triazolo[1,5-a]pyridin-2-amine replacing 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine. LC-MS calculated for C20H 2 3N6O 2 (M+H) + : m/z = 379.2; found 379.2. Step 4: 8-(benzyloxy)-2-bromo-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridine To a mixture of 8-(benzyloxy)-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine (568.0 mg, 1.5 mmol) and Cu(II)Br2 (335 mg, 1.5 mmol) in acetonitrile (7.5 mL) was added tert-butyl nitrite (0.428 mL, 3.6 mmol). The mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM, and washed with water and brine. The organic phase was dried over MgSO 4 , filtered, and then concentrated. The crude product was purified by flash chromatography on a silica gel column eluting with 0 to 5% MeOH in DCM to afford the desired product. LC-MS calculated for C20H 2 1BrN5O 2 (M+H) + : m/z = 442.1, 444.1; found 442.1, 444.1. Step 5: 7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-2-(1-(methylsulfonyl)p iperidin-4- This compound was prepared using similar procedures as described for Example 1, Step 2 with 8-(benzyloxy)-2-bromo-7-(1-(1-ethoxyethyl)-1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-a]pyridine replacing 2-bromo-7-(1-(1-ethoxyethyl)-1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine. The Buchwald coupling step afforded 8- (benzyloxy)-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-N-(1-(meth ylsulfonyl)piperidin-4- yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine. However, around 40% of the initial product was converted into the deprotected alcohol under the reaction conditions. The crude product was purified by flash chromatography on a silica gel column eluting with 0 to 5% MeOH in DCM to afford the desired alcohol product. LC-MS calculated for C19H 2 8N7O 4 S (M+H) + : m/z = 450.2; found 450.2. Step 6: 8-ethoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol- 4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine To a solution of 7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-2-(1- (methylsulfonyl)piperidin-4-ylamino)-[1,2,4]triazolo[1,5-a]p yridin-8-ol (33.0 mg, 0.073 mmol) and iodoethane (11.5 mg, 0.073 mmol) in dry DMF (1.0 ml) was added Cs2CO 3 (36 mg, 0.110 mmol). The resulting solution was stirred at 50 °C for 1 h. After the reaction was cooled to room temperature, 1 M aqueous solution of HCl (0.5 mL) was added, and the reaction mixture was stirred for 30 min. The reaction mixture was diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C17H 2 4N7O 3 S (M+H) + : m/z = 406.2; found 406.2. Example 3.8-isobutoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyr azol-4- yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine This compound was prepared using similar procedures as described for Example 2, Step 6 with 1-bromo-2-methylpropane replacing iodoethane. The reaction mixture was diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C19H 2 8N7O 3 S (M+H) + : m/z = 434.2; found 434.2. Example 4.8-(cyclopropylmethoxy)-N-(1-(methylsulfonyl)piperidin-4-yl )-7-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine This compound was prepared using similar procedures as described for Example 2, Step 6 with (bromomethyl)cyclopropane replacing iodoethane. The reaction mixture was diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C19H 2 6N7O 3 S (M+H) + : m/z = 432.2; found 432.2. Example 5. N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8- ((tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triazolo[1,5-a]pyridi n-2-amine This compound was prepared using similar procedures as described for Example 2, Step 6 with 4-bromotetrahydro-2H-pyran replacing iodoethane. The reaction mixture was diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C20H 2 8N7O 4 S (M+H) + : m/z = 462.2; found 462.2. Example 6.8-(2-methoxyethoxy)-N-(1-(methylsulfonyl)piperidin-4-yl)-7 -(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine This compound was prepared using similar procedures as described for Example 2, Step 6 with 1-bromo-2-methoxyethane replacing iodoethane. The reaction mixture was diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C18H 2 6N7O 4 S (M+H) + : m/z = 436.2; found 436.2. Example 7.6-fluoro-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazo l-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine This compound was prepared using similar procedures as described for Example 1, Step 1 with 5-fluoro-4-iodopyridin-2-amine replacing 2,7-dibromo- [1,2,4]triazolo[1,5-a]pyridine. LC-MS calculated for C12H16FN4O (M+H) + : m/z = 251.2; found 251.2. Step 2: 7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-6-fluoro-[1,2,4]triazo lo[1,5-a]pyridin- 2-amine This compound was prepared using similar procedures as described for Example 2, Step 2 with 4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-5-fluoropyridin-2- amine replacing 3-(benzyloxy)-4-chloropyridin-2-amine. LC-MS calculated for C13H16FN6O (M+H) + : m/z = 291.2; found 291.2. Step 3: 2-bromo-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-6-fluoro-[1,2, 4]triazolo[1,5- a]pyridine This compound was prepared using similar procedures as described for Example 2, Step 4 with 7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-6-fluoro- [1,2,4]triazolo[1,5-a]pyridin-2-amine replacing 8-(benzyloxy)-7-(1-(1-ethoxyethyl)- 1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine. LC-MS calculated for C13H14BrFN5O (M+H) + : m/z = 354.1, 356.1; found 354.1, 356.1. Step 4: 6-fluoro-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol- 4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine This compound was prepared using similar procedures as described for Example 1, Step 2 with 2-bromo-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-6-fluoro- [1,2,4]triazolo[1,5-a]pyridine replacing 2-bromo-7-(1-(1-ethoxyethyl)-1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-a]pyridine. The reaction mixture was diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C15H19FN7O 2 S (M+H) + : m/z = 380.2; found 380.2. Example 8. N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyrazin-2-amine Step 1: 6-bromo-[1,2,4]triazolo[1,5-a]pyrazin-2-amine To a solution of 5-bromopyrazin-2-amine (500 mg, 2.87 mmol) (Ark Pharm, cat#187079) in 1,4-dioxane (14.4 mL) was added O-ethyl carbonisothiocyanatidate (356 µL, 3.02 mmol) (Aldrich, cat#226327). The resulting solution was stirred for 18 h and then concentrated to dryness. MeOH (12 mL), DIPEA (1.51 mL, 8.62 mmol) and hydroxylamine hydrochloride (998 mg, 14.4 mmol) were added. After stirring at room temperature for 2 h, the reaction mixture was heated at 60 °C for another 3 h before dilution with H 2 O (100 mL). The reaction mixture was filtered through a sintered glass funnel and the filter cake was rinsed with water (5 mL x 3) and dried under vacuum to afford the product as a white powder (441 mg, 72%). LC-MS calculated for C5H5BrN5 (M+H) + : m/z = 214.0, 216.0; found 214.1, 216.1. Step 2: 6-bromo-N-(1-(methylsulfonyl)piperidin-4-yl)-[1,2,4]triazolo [1,5-a]pyrazin- 2-amine To a solution of 6-bromo-[1,2,4]triazolo[1,5-a]pyrazin-2-amine (50 mg, 0.234 mmol) in DCM (2 mL) was added 1-(methylsulfonyl)piperidin-4-one (41.4 mg, 0.234 mmol) and HOAc (10 µL). After 30 min, sodium triacetoxyborohydride (99 mg, 0.467 mmol) was added. After 1 h, saturated NaHCO 3 (2 mL) was added to the reaction mixture followed by extraction with dichloromethane (1 mL x 5). The combined organic layers were dried with Na2SO 4 , filtered and concentrated. The crude product was used in the next step without further purification. LC-MS calculated for C11H16BrN6O 2 S (M+H) + : m/z = 375.0; found 375.1. Step 3: N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1, 2,4]triazolo[1,5- a]pyrazin-2-amine To a solution of the above crude product, tert-butyl 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (137 mg, 0.467 mmol) and sodium carbonate (49.5 mg, 0.467 mmol) in dioxane (1.6 mL) and water (0.4 mL) was added PdCl 2 (dppf)-CH 2 Cl 2 adduct (38.2 mg, 0.047 mmol). The reaction mixture was heated to 100 °C. After 12 h, trifluoroacetic acid (0.5 mL) was added to the reaction mixture. After 3 h, the reaction mixture was diluted with MeOH and was then purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as the TFA salt. LC-MS calculated for C14H19N8O 2 S (M+H) + : m/z = 363.1; found 363.2. Example 9.8-(2,2-difluoroethoxy)-N-(1-(methylsulfonyl)piperidin-4-yl )-7-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine This compound was prepared using similar procedures as described for Example 2, Step 6 with 1,1-difluoro-2-iodoethane replacing iodoethane. The reaction mixture was diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C17H 2 2F 2 N7O 3 S (M+H) + : m/z = 442.2; found 442.2. Example 10. N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8-( 2,2,2- trifluoroethoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-amine This compound was prepared using similar procedures as described for Example 2, Step 6 with 1,1,1-trifluoro-2-iodoethane replacing iodoethane. The reaction mixture was diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C17H 2 1F3N7O 3 S (M+H) + : m/z = 460.2; found 460.2. Example 11. N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8- ((tetrahydrofuran-3-yl)methoxy)-[1,2,4]triazolo[1,5-a]pyridi n-2-amine This compound was prepared using similar procedures as described for Example 2, Step 6 with 3-(iodomethyl)tetrahydrofuran replacing iodoethane. The reaction mixture was diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C20H 2 8N7O 4 S (M+H) + : m/z = 462.2; found 462.2. Example 12. 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-y l)-7- (1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine Step 1: 2-bromo-8-ethoxy-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-[1,2, 4]triazolo[1,5- a]pyridine This compound was prepared using similar procedures as described for Example 2, Steps 1 to 4 with iodoethane replacing (bromomethyl)benzene in Step 1. LC-MS calculated for C15H19BrN5O 2 (M+H) + : m/z = 380.1, 382.1; found 380.2, 382.2. Step 2: tert-butyl (3R,4S)-4-((8-ethoxy-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)- This compound was prepared using similar procedures as described for Example 1, Step 2 with 2-bromo-8-ethoxy-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridine replacing 2-bromo-7-(1-(1-ethoxyethyl)-1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-a]pyridine, and tert-butyl (3R,4S)-4-amino-3-methylpiperidine- 1-carboxylate (J & W PharmLab, cat# 60R1020) replacing 1- (methylsulfonyl)piperidin-4-amine. LC-MS calculated for C26H40N7O 4 (M+H) + : m/z = 514.3; found 514.4. Step 3: 8-ethoxy-N-((3R,4S)-3-methylpiperidin-4-yl)-7-(1H-pyrazol-4- yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine The crude sample of tert-butyl (3R,4S)-4-((8-ethoxy-7-(1-(1-ethoxyethyl)-1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-3-me thylpiperidine-1- carboxylate was dissolved in 10% TFA in DCM. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C14H 2 4N7O (M+H) + : m/z = 342.2; found 342.3. Step 4: 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-y l)-7-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine To a solution of 8-ethoxy-N-((3R,4S)-3-methylpiperidin-4-yl)-7-(1H-pyrazol- 4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (5.0 mg, 0.015 mmol) and DIPEA (5.12 µL, 0.029 mmol) in MeCN (1.0 mL) was added methanesulfonyl chloride (1.020 µL, 0.013 mmol). The resulting solution was stirred at room temperature for 10 min. The reaction mixture was diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C18H 2 6N7O 3 S (M+H) + : m/z = 420.2; found 420.2. 1 H NMR (600 MHz, DMSO-d6) δ 8.31 (d, J = 7.0 Hz, 1H), 8.22 (s, 2H), 7.17 (d, J = 7.0 Hz, 1H), 6.74 (d, J = 8.6 Hz, 1H), 4.52 (q, J = 7.0 Hz, 2H), 3.86 (m, 1H), 3.25 (ddd, J = 12.0, 8.5, 3.5 Hz, 1H), 3.17 – 3.06 (m, 3H), 2.86 (s, 3H), 2.18 (m, 1H), 1.84 (dtd, J = 13.5, 6.9, 3.6 Hz, 1H), 1.75 (ddt, J = 12.7, 8.0, 3.9 Hz, 1H), 1.35 (t, J = 7.0 Hz, 3H), 0.92 (d, J = 6.9 Hz, 3H). Example 13. N-((3R,4S)-1-(cyclopropylsulfonyl)-3-methylpiperidin-4-yl)-8 - ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-a mine This compound was prepared using similar procedures as described for Example 12, Step 4 with cyclopropanesulfonyl chloride replacing methanesulfonyl chloride. The reaction mixture was diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C20H 2 8N7O 3 S (M+H) + : m/z = 446.2; found 446.3. Example 14. 8-isopropoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyra zol-4- yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine Step 1: 6-chloro-5-isopropoxypyrimidin-4-amine A solution of 4-amino-6-chloropyrimidin-5-ol (Aldlab, cat# AP95670: 200 mg, 1.4 mmol), 2-iodopropane (0.27 mL, 2.75 mmol), and K2CO 3 (380 mg, 2.75 mmol) in anhydrous DMF (4.58 mL, 0.3 M) was stirred at 60 °C for 1 h. Then, EtOAc and H 2 O were added to the reaction. The organic layer was washed with 10% LiCl (aq) (2x) and brine, dried over Na2SO 4 , and concentrated under reduced pressure to yield 6-chloro-5-isopropoxypyrimidin-4-amine as a cream-colored solid (246.4 mg, 96% yield). LC-MS calculated for C7H11ClN3O (M+H) + : m/z = 188.1; found 188.0. A solution of 6-chloro-5-isopropoxypyrimidin-4-amine (246.4 mg, 1.3 mmol) and ethoxycarbonyl isothiocyanate (0.16 mL, 1.4 mmol) in anhydrous dioxane (4.4 mL) was stirred at 60 °C overnight. Then, the reaction was heated to 100 °C, and the reaction was stirred at 100 °C for 24 h. The reaction mixture was cooled, washed with H 2 O, extracted into EtOAc 3x, dried over Na2SO 4 , and concentrated under reduced pressure. The crude residue was dissolved in anhydrous methanol (3 mL) and ethanol (3 mL), and hydroxylamine hydrochloride (456.0 mg, 6.6 mmol) and DIPEA (0.69 ml, 3.9 mmol) were subsequently added. The reaction mixture was stirred at 60 °C for 5 h. The reaction was cooled and water was added to the reaction. The solution was extracted into EtOAc 3x, dried over Na2SO 4 , and concentrated under reduced pressure to yield 7-chloro-8-isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-amin e as a cream- colored solid (187.3 mg, 63% yield). LC-MS calculated for C8H11ClN5O (M+H) + : m/z = 228.1; found 228.0. Step 3: 7-chloro-8-isopropoxy-N-(1-(methylsulfonyl)piperidin-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine A solution of 7-chloro-8-isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-amin e (30.0 mg, 0.13 mmol) and 1-(methylsulfonyl)piperidin-4-one (70.0 mg, 0.4 mmol) in DMF (0.3 mL)/TFA (0.3 mL) (1:1) was stirred at room temperature for 24 h. Then, a solution of sodium triacetoxyborohydride (98.0 mg, 0.46 mmol) in DMF (0.3 mL)/TFA (0.3 mL) (1:1) was added dropwise at room temperature and the reaction was stirred for 30 min. Then, additional 1-(methylsulfonyl)piperidin-4-one (35 mg) was added. The reaction was allowed to stir overnight at room temperature. Then, the reaction was quenched with H 2 O and sat. NaHCO 3 . The solution was extracted into EtOAc 3x, washed with 10% LiCl (aq) and brine, dried over Na2SO 4 , and concentrated under reduced pressure. The residue was purified by column chromatography (ISCO, 4 g silica, 0 to 100% EtOAc in hexanes) to yield 7-chloro-8- isopropoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-[1,2,4]triaz olo[1,5-c]pyrimidin-2- amine as a clear oil (33.8 mg, 66% yield). LC-MS calculated for C14H 2 2ClN6O 3 S (M+H) + : m/z = 389.1; found 389.3. Step 4: 7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy-N-(1- (methylsulfonyl)piperidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimi din-2-amine A mixture of 7-chloro-8-isopropoxy-N-(1-(methylsulfonyl)piperidin-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine (33.8 mg, 0.09 mmol) and chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2 -(2'-amino-1,1'- biphenyl))palladium(II) (6.8 mg, 8.7 µmol), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole (35.0 mg, 0.1 mmol), and potassium phosphate (55.0 mg, 0.261 mmol) were added to a 4-dram vial. The vial was purged with nitrogen 3x and then dioxane (2.6 mL) and water (0.6 mL) were added. The solution was heated to 100 °C, and the reaction was stirred at 100 °C overnight. The reaction was cooled and EtOAc and H 2 O were added. The solution was extracted into EtOAc 3x, washed with brine, dried over Na2SO 4 , and concentrated under reduced pressure. The residue was purified by column chromatography (ISCO, 4 g silica, 0 to 100% EtOAc in hexanes) to yield 7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy-N- (1-(methylsulfonyl)piperidin-4-yl)-[1,2,4]triazolo[1,5-c]pyr imidin-2-amine as a light yellow oil (16.8 mg, 39% yield). LC-MS calculated for C21H33N8O 4 S (M+H) + : m/z = 493.2; found 493.2. Step 5: 8-isopropoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyra zol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine A solution of 7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy-N-(1- (methylsulfonyl)piperidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimi din-2-amine (16.8 mg, 0.03 mmol) and 1M HCl (aq) (0.5 mL, 0.5 mmol) in dioxane (1 mL) was stirred at room temperature for 2 h. Then, the reaction was diluted with CH 3 CN/MeOH, filtered, and purified by prep-HPLC (pH 2, acetonitrile/water+TFA) to yield the desired product as its TFA salt. LC-MS calculated for C17H 2 5N8O 3 S (M+H) + : m/z = 421.2; found 421.2. 1 H NMR (600 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.24 (s, 2H), 7.11 (s, 1H), 5.59-5.51 (m, 1H), 3.68-3.61 (m, 1H), 3.55-3.49 (m, 2H), 2.94-2.88 (m, 2H), 2.88 (s, 3H), 2.07-2.01 (m, 2H), 1.63-1.55 (m, 2H), 1.31 (d, J = 6.2 Hz, 6H). Example 15.8-isobutoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-py rrolo[2,3- b]pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine To a solution of tert-butyl (4-chloro-3-hydroxypyridin-2-yl)carbamate (Adesis, cat# 2-492: 1.20 g, 4.90 mmol), 2-methylpropan-1-ol (0.727 g, 9.81 mmol) and triphenylphosphine (.058 g, 7.85 mmol) in THF (15 mL) was added DEAD (1.242 mL, 7.85 mmol) at 0 ° C. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was purified by flash column with 0-20% EA in hexanes to afford the desired product. LC-MS calculated for C14H 2 2ClN2O 3 (M+H) + : m/z = 301.1; found 301.1. Step 2: 4-chloro-3-isobutoxypyridin-2-amine 4N HCl in 1,4-dioxane (4 mL) was added to tert-butyl (4-chloro-3- isobutoxypyridin-2-yl)carbamate (from Step 1) in MeOH (4 mL). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to afford the desired product as HCl salt. LC-MS calculated for C9H14ClN2O (M+H) + : m/z = 201.1; found 201.1. Step 3: 7-chloro-8-isobutoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine This compound was prepared using similar procedures as described for Example 2, Step 2 with 4-chloro-3-isobutoxypyridin-2-amine replacing 3- (benzyloxy)-4-chloropyridin-2-amine. LC-MS calculated for C10H14ClN4O (M+H) + : m/z = 241.1; found 241.0. Step 4: 7-chloro-8-isobutoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-[1 ,2,4]triazolo[1,5- a]pyridin-2-amine A reaction mixture of 7-chloro-8-isobutoxy-[1,2,4]triazolo[1,5-a]pyridin-2- amine (0.84 g, 3.49 mmol) and 1-(methylsulfonyl)piperidin-4-one (1.86 g, 10.47 mmol) in DMF (6.0 mL) and TFA (6.0 mL) was stirred at room temperature overnight. Then, a solution of sodium triacetoxyborohydride (2.56 g, 12.08 mmol) in DMF (2 mL) and TFA (2 mL) was added dropwise at room temperature. The reaction mixture was allowed to stir at room temperature for another 30 min. The mixture was then quenched with saturated aqueous NaHCO 3 , and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine, dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash column with 0-10% ethyl acetate in DCM to afford the desired product. LC-MS calculated for C16H 2 5ClN5O 3 S (M+H) + : m/z = 402.1; found 402.1. Step 5: 8-isobutoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrro lo[2,3- b]pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine This compound was prepared using similar procedures as described for Example 1, Step 1 with 7-chloro-8-isobutoxy-N-(1-(methylsulfonyl)piperidin-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrrolo[2,3-b]pyridine replacing 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine and 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazole. The reaction mixture was diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C23H30N7O 3 S (M+H) + : m/z = 484.2; found 484.2. Example 16.7-(2-aminopyridin-4-yl)-8-isobutoxy-N-(1- (methylsulfonyl)piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridi n-2-amine This compound was prepared using similar procedures as described for Example 1, Step 1 with 7-chloro-8-isobutoxy-N-(1-(methylsulfonyl)piperidin-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyridin-2-amine replacing 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine and 1-(1- ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole. The reaction mixture was diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C21H30N7O 3 S (M+H) + : m/z = 460.2; found 460.2. Example 17.8-ethoxy-7-(3-methyl-1H-pyrazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridi n-2-amine Step 1: 7-chloro-8-ethoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-[1,2, 4]triazolo[1,5- a]pyridin-2-amine This compound was prepared using similar procedures as described for Example 15, steps 1 to 4 with ethanol replacing 2-methylpropan-1-ol in Step 1. LC- MS calculated for C14H 2 1ClN5O 3 S (M+H) + : m/z = 374.1; found 374.1. Step 2: 8-ethoxy-7-(3-methyl-1H-pyrazol-4-yl)-N-(1-(methylsulfonyl)p iperidin-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine This compound was prepared using similar procedures as described for Example 1, Step 1 with 7-chloro-8-ethoxy-N-(1-(methylsulfonyl)piperidin-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole replacing 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine and 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazole. The reaction mixture was diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C18H 2 6N7O 3 S (M+H) + : m/z = 420.2; found 420.2. Example 18. Methyl 4-((2-((1-(methylsulfonyl)piperidin-4-yl)amino)-7-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)oxy)piperid ine-1-carboxylate Step 1: 7-chloro-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine This compound was prepared using similar procedures as described for Example 2, steps 1 to 2 with methyl iodide replacing (bromomethyl)benzene in Step 1. LC-MS calculated for C7H8ClN4O (M+H) + : m/z = 199.1; found 199.1. Step 2: 7-chloro-8-methoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-[1,2 ,4]triazolo[1,5- a]pyridin-2-amine This compound was prepared using similar procedures as described for Example 15, step 4 with 7-chloro-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine replacing 7-chloro-8-isobutoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine. LC-MS calculated for C13H19ClN5O 3 S (M+H) + : m/z = 360.1; found 360.2. Step 3: 7-chloro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-[1,2,4] triazolo[1,5- a]pyridin-8-ol In a round-bottomed flask, 7-chloro-8-methoxy-N-(1- (methylsulfonyl)piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridi n-2-amine (0.72 g, 2 mmol) was dissolved in 6.7 mL of DCM.1 M BBr3 in DCM (8 mL, 8 mmol) was added to the flask dropwise. The reaction was heated at 60 ºC for 3 h. The crude mixture was cooled to room temperature. Saturated NaHCO 3 aqueous solution was added and the mixture was washed with ethyl acetate. The aqueous phase was then acidified with 1 M HCl aqueous solution and extracted with ethyl acetate. The organic phases were combined, dried over MgSO 4 , filtered, and concentrated. The crude residue was used directly in the next step without further purification. LC-MS calculated for C12H17ClN5O 3 S (M+H) + : m/z = 346.1; found 346.2. Step 4: 7-chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-8-(piperidin-4 -yloxy)- [1,2,4]triazolo[1,5-a]pyridin-2-amine The Boc-protected piperidine was prepared using similar procedures as described for Example 2, step 1 with tert-butyl 4-bromopiperidine-1-carboxylate replacing (bromomethyl)benzene. The crude residue was then dissolved in dioxane.4 M HCl in dioxane was added, and the reaction mixture was stirred at room for another 2 h. The reaction was concentrated, and the crude residue was used directly in the next step without further purification. LC-MS calculated for C17H 2 6ClN6O 3 S (M+H) + : m/z = 429.2; found 429.4. Step 5: Methyl 4-((7-chloro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)- [1,2,4]triazolo[1,5-a]pyridin-8-yl)oxy)piperidine-1-carboxyl ate This compound was prepared using similar procedures as described for Example 12, step 4 with methyl chloroformate replacing methanesulfonyl chloride. LC-MS calculated for C19H 2 8ClN6O5S (M+H) + : m/z = 487.2; found 487.3. Step 6: 4-((2-((1-(methylsulfonyl)piperidin-4-yl)amino)-7-(1H-pyrazo l-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-8-yl)oxy)piperidine-1-carboxyl ate The precursor was prepared using similar procedures as described for Example 1, step 1 with methyl 4-((7-chloro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)- [1,2,4]triazolo[1,5-a]pyridin-8-yl)oxy)piperidine-1-carboxyl ate replacing 2,7- dibromo-[1,2,4]triazolo[1,5-a]pyridine. After the reaction was cooled to room temperature, 1 M aqueous solution of HCl was added, and the reaction mixture was stirred for 30 min. The reaction mixture was diluted with MeOH and purified by prep- HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C22H31N8O5S (M+H) + : m/z = 519.2; found 519.3. Example 19. (R)-1-(2-(((3R,4S)-4-((8-ethoxy-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-3-methylpiperidin- 1- yl)sulfonyl)ethyl)pyrrolidin-3-ol Step 1: 8-ethoxy-N-((3R,4S)-3-methyl-1-(vinylsulfonyl)piperidin-4-yl )-7-(1H-pyrazol- 4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine This compound was prepared using similar procedures as described for Example 12, step 4 with 2-chloroethane-1-sulfonyl chloride replacing methanesulfonyl chloride. LC-MS calculated for C19H 2 6N7O 3 S (M+H) + : m/z = 432.2; found 432.3. Step 2: (R)-1-(2-(((3R,4S)-4-((8-ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]t riazolo[1,5- a]pyridin-2-yl)amino)-3-methylpiperidin-1-yl)sulfonyl)ethyl) pyrrolidin-3-ol To the crude reaction mixture from step 1 was added additional DIPEA (2 equiv) and (R)-pyrrolidin-3-ol (2 equiv). The resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C23H35N8O 4 S (M+H) + : m/z = 519.3; found 519.4. Example 20.8-ethoxy-N-((3R,4S)-3-methyl-1-((1-methyl-1H-pyrazol-4- yl)sulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triaz olo[1,5-a]pyridin-2- amine This compound was prepared using similar procedures as described for Example 12, step 4 with 1-methyl-1H-pyrazole-4-sulfonyl chloride replacing methanesulfonyl chloride. LC-MS calculated for C21H 2 8N9O 3 S (M+H) + : m/z = 486.2; found 486.4. Example 21.8-ethoxy-N-((3R,4S)-3-methyl-1-((2-methyl-2H-1,2,3-triazo l-4- yl)sulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triaz olo[1,5-a]pyridin-2- amine This compound was prepared using similar procedures as described for Example 12, step 4 with 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride replacing methanesulfonyl chloride. LC-MS calculated for C20H 2 7N10O 3 S (M+H) + : m/z = 487.2; found 487.4. Example 22. N-(1-(methylsulfonyl)piperidin-4-yl)-8-phenyl-7-(1H-pyrazol- 4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine A reaction mixture of 3,4-dichloropyridin-2-amine (440 mg, 2.70 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-bi phenyl)(2-(2'-amino-1,1'- biphenyl))palladium(II) (212 mg, 0.270 mmol), potassium phosphate (1719 mg, 8.10 mmol), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H- pyrazole (790 mg, 2.97 mmol) in 1,4-dioxane (10 ml) and water (5 ml) was stirred under N2 at 60 °C for 2 h. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash column with 0-40% EtOAc in DCM to afford the desired product. LC-MS calculated for C12H16ClN4O (M+H) + : m/z = 267.1; found 267.1. Step 2: 8-chloro-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-[1,2,4]triazo lo[1,5-a]pyridin- 2-amine To a solution of the above product 3-chloro-4-(1-(1-ethoxyethyl)-1H-pyrazol- 4-yl)pyridin-2-amine (0.70 g, 2.62 mmol) in MeCN (20 mL) was added dropwise O- ethyl carbonisothiocyanatidate (0.464 mL, 3.94 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. In a separate flask, hydroxylamine hydrochloride (0.547 g, 7.87 mmol) and DIPEA (1.375 mL, 7.87 mmol) were stirred in a mixture of methanol and ethanol (v/v, 1:1, 20 mL) at room temperature for 5 min. The two reaction mixtures were then combined and stirred at room temperature for 2 h, followed by 50 °C for another 2 h. The volatiles were removed under reduced pressure and the residue was treated with saturated aqueous NaHCO 3 solution, extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash column with 0-5% MeOH in DCM to afford the desired product. LC-MS calculated for C13H16ClN6O (M+H) + : m/z = 307.1; found 307.1. Step 3: 8-chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol- 4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine A reaction of 8-chloro-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine and 1-(methylsulfonyl)piperidin-4-one (0.698 g, 3.94 mmol) in DMF/TFA (5 mL/4 mL) was stirred at room temperature for 1 h. A solution of sodium triacetoxyborohydride (0.890 g, 4.20 mmol) in DMF/TFA (4 mL/3 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 h and quenched with saturated aqueous NaHCO 3 solution, extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash column with 0-5% MeOH in DCM to afford the desired product. LC-MS calculated for C15H19ClN7O 2 S (M+H) + : m/z = 396.1; found 396.3. Step 4: N-(1-(methylsulfonyl)piperidin-4-yl)-8-phenyl-7-(1H-pyrazol- 4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine The reaction mixture of 8-chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (10.0 mg, 0.025 mmol), chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2 -(2'-amino-1,1'- biphenyl))palladium(II) (1.988 mg, 2.53 µmol), Na2CO 3 (8.03 mg, 0.076 mmol), phenylboronic acid (4.62 mg, 0.038 mmol in 1,4-dioxane (1 mL) and water (0.5 mL) was stirred under N2 at 120 °C overnight. The mixture was adjusted to pH 2 with TFA, and purified by HPLC (pH 2) to afford the desired product as its TFA salt. LC- MS calculated for C21H 2 4N7O 2 S (M+H) + : m/z = 438.2; found 438.2. Example 23.8-(4-fluoropiperidin-1-yl)-N-(1-(methylsulfonyl)piperidin -4-yl)-7- (1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine Step 1: 8-chloro-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridi n-2-amine A reaction mixture of 8-chloro-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine (Example 22, step 2, 0.35 g, 1.14 mmol) and 1- (methylsulfonyl)piperidin-4-one (607 mg, 3.42 mmol) in DMF (1.9 mL) and TFA (1.9 mL) was stirred at room temperature for 5 min. Then, a solution of sodium triacetoxyborohydride (725 mg, 3.42 mmol) in DMF (1 mL) was added dropwise at room temperature. The reaction mixture was allowed to stir at room temperature for another 30 min. The mixture was then quenched with saturated aqueous NaHCO 3 and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash column to afford the desired product. LC-MS calculated for C19H 2 7ClN7O 3 S (M+H) + : m/z = 468.2; found 468.2. Step 2: 8-(4-fluoropiperidin-1-yl)-N-(1-(methylsulfonyl)piperidin-4- yl)-7-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine To a solution of 8-chloro-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridi n-2-amine (20 mg, 0.043 mmol), 4-fluoropiperidine (4.41 mg, 0.043 mmol), and sodium tert-butoxide (16.43 mg, 0.171 mmol) in dioxane (2 mL) was added RuPhos Pd G3 (1.8 mg, 0.002 mmol). The vial was flushed with nitrogen, and the reaction was stirred at 100 °C for 12 h. After the reaction was cooled to room temperature, 1 M aqueous solution of HCl (1 mL) was added, and the reaction mixture was stirred for 30 min. The reaction mixture was diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C20H 2 8FN8O 2 S (M+H) + : m/z = 463.2; found 463.2. Example 24. N 2 -(1-(methylsulfonyl)piperidin-4-yl)-N 8 -phenyl-7-(1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine To a solution of 8-chloro-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridi n-2-amine (Example 23, step 1, 20 mg, 0.043 mmol), aniline (4 mg, 0.043 mmol), xantphos (2.473 mg, 4.27 µmol), and Cs 2 CO 3 (27.8 mg, 0.085 mmol) in dioxane (2 mL) was added Pd 2 (dba) 3 (3.91 mg, 4.27 µmol). The vial was flushed with nitrogen, and the reaction was stirred at 120 °C for 12 h. After the reaction was cooled to room temperature, 1 M aqueous solution of HCl (1 mL) was added, and the reaction mixture was stirred for 30 min. The reaction mixture was diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C21H 2 5N8O 2 S (M+H) + : m/z = 453.2; found 453.4. Example 25.8-(4-fluorophenyl)-N-(1-(methylsulfonyl)piperidin-4-yl)-7 -(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine This compound was prepared using similar procedures as described for Example 22, step 4 using (4-fluorophenyl)boronic acid as the boronic acid. LC-MS calculated for C21H 2 3FN7O 2 S (M+H) + : m/z = 456.2; found 456.1. Example 26. N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8-( 3- (trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ami ne This compound was prepared using similar procedures as described for Example 22, step 4 using (3-(trifluoromethyl)phenyl)boronic acid as the boronic acid. LC-MS calculated for C22H 2 3F3N7O 2 S (M+H) + : m/z = 506.2; found 506.1. Example 27.8-ethoxy-N-((3R,4S)-3-methyl-1-((3-(piperidin-1- yl)propyl)sulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2, 4]triazolo[1,5- a]pyridin-2-amine Step 1: N-((3R,4S)-1-((3-chloropropyl)sulfonyl)-3-methylpiperidin-4- yl)-8-ethoxy-7- (1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine This compound was prepared using similar procedures as described for Example 12, step 4 with 3-chloropropane-1-sulfonyl chloride replacing methanesulfonyl chloride. LC-MS calculated for C20H 2 9ClN7O 3 S (M+H) + : m/z = 482.2; found 482.1. Step 2: 8-ethoxy-N-((3R,4S)-3-methyl-1-((3-(piperidin-1-yl)propyl)su lfonyl)piperidin- 4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-am ine To the crude reaction mixture from step 1 was added additional DIPEA (2 equiv) and piperidine (2 equiv). The resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C25H39N8O 3 S (M+H) + : m/z = 531.3; found 531.4. Example 28. N-((3R,4S)-1-((3-(dimethylamino)propyl)sulfonyl)-3- methylpiperidin-4-yl)-8-ethoxy-7-(1H-pyrazol-4-yl)-[1,2,4]tr iazolo[1,5-a]pyridin- 2-amine This compound was prepared using similar procedures described for Example 27, with dimethylamine (2.0 M THF solution) replacing piperidine in Step 2. LC-MS calculated for C22H35N8O 3 S (M+H) + : m/z = 491.3; found 491.2. Example 29.8-ethoxy-N-((3R,4S)-3-methyl-1-((3-(pyrrolidin-1- yl)propyl)sulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2, 4]triazolo[1,5- a]pyridin-2-amine This compound was prepared using similar procedures described for Example 27, with pyrrolidine replacing piperidine in Step 2. LC-MS calculated for C24H37N8O 3 S (M+H) + : m/z = 517.3; found 517.3.
Example 30. N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8-( 4- (trifluoromethyl)piperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrid in-2-amine This compound was prepared in a similar fashion to Example 23, with 4- (trifluoromethyl)piperidine replacing 4-fluoropiperidine in Step 2. LC-MS calculated for C21H 2 8F3N8O 2 S (M+H) + : m/z = 513.2; found 513.2. Example 31.8-(3-fluoropiperidin-1-yl)-N-(1-(methylsulfonyl)piperidin -4-yl)-7- (1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine This compound was prepared in a similar fashion to Example 23, with 3- fluoropiperidine replacing 4-fluoropiperidine in Step 2. LC-MS calculated for C20H 2 8FN8O 2 S (M+H) + : m/z = 463.2; found 463.2. Example 32.8-Ethoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyraz ol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine A solution of 6-chloro-5-methoxypyrimidin-4-amine (1.0 g, 6.3 mmol) and O- ethyl carbonisothiocyanatidate (0.8 mL, 6.6 mmol) in anhydrous dioxane (12 mL) was stirred at 80 °C for 30 min. Additional O-ethyl carbonisothiocyanatidate (0.3 mL) was added and the solution was stirred at 80 °C overnight. The volatiles were removed under reduced pressure. Then, the residue was dissolved in anhydrous methanol/ethanol (v/v, 1:1, 6.6 mL). Hydroxylamine hydrochloride (2.18 g, 31.3 mmol) and Hunig’s base (2.2 mL, 12.5 mmol) were added. The solution was stirred at 60 °C for 90 min. The reaction was cooled and water was added to the reaction. The solution was extracted into ethyl acetate 3x, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by Teledyne ISCO CombiFlash ® Rf+ (0-100% ethyl acetate in hexanes) to the desired product as a light yellow solid. LC-MS calculated for C6H7ClN5O (M+H) + : m/z = 200.0; found 200.0. 1 H NMR (400 MHz, dmso-d6) δ 9.05 (s, 1H), 6.62 (s, 2H), 4.20 (s, 3H). Step 2.7-Chloro-8-methoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-[1 ,2,4]triazolo[1,5- c]pyrimidin-2-amine A solution of 7-chloro-8-methoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine (1.69 g, 8.17 mmol) and 1-(methylsulfonyl)piperidin-4-one (4.34 g, 24.5 mmol) in DMF (20 mL)/TFA (20 mL) was stirred at room temperature for 24 h. Then, a solution of sodium triacetoxyborohydride (6.06 g, 28.6 mmol) in DMF (20 mL)/TFA (20 mL) was added dropwise at room temperature. The reaction was stirred for 30 h at room temperature. The reaction was quenched dropwise with water and sodium bicarbonate until pH 7, then extracted into ethyl acetate 3x, washed with 10% lithium chloride (aq) and brine, dried over sodium sulfate, and concentrated under reduced pressure. Addition of dichloromethane and methanol yielded a slight yellow solid that would not dissolve. The solid was collected via filtration, rinsed with dichloromethane, and purified by Teledyne ISCO CombiFlash ® Rf+ (0-20% methanol in dichloromethane) to provide the desired product as a yellow solid (1.99 g, 65%). LC-MS calculated for C12H18ClN6O 3 S (M+H) + : m/z = 361.1; found 361.2. Step 3.7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-methoxy-N-(1- 7-Chloro-8-methoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-[1,2 ,4]triazolo[1,5- c]pyrimidin-2-amine (1.12 g, 3.10 mmol), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.24 g, 4.66 mmol), XPhos Pd G2 (0.131 mg, 0.166 mmol), and potassium phosphate (2.12 g, 9.98 mmol) were added to a 40-mL vial. [Three reactions were set up for a total of 2.16 g of 7-chloro-8-methoxy-N-(1- (methylsulfonyl)piperidin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimi din-2-amine.] The vial was purged with nitrogen 3x, and then dioxane (1.3 mL) and water (0.3 mL) were added. The solution was stirred at 100 °C overnight. The reaction was cooled, and ethyl acetate and water were added. All of the reactions were combined together for workup and purification. The solution was filtered through Celite, then extracted into ethyl acetate, washed with brine, dried over sodium sulfate, filtered through Celite, and concentrated under reduced pressure. The residue was purified by Teledyne ISCO CombiFlash ® Rf+ (0-100% ethyl acetate in hexanes) to provide the desired product as a white solid (276.4, mg, 18% overall yield). LC-MS calculated for C19H 2 9N8O 4 S (M+H) + : m/z = 465.2; found 465.4. Step 4.2-((1-(methylsulfonyl)piperidin-4-yl)amino)-7-(1H-pyrazol- 4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-8-ol A 1.0 M solution of boron tribromide in dichloromethane (1.8 mL, 1.8 mmol) was added dropwise to a solution of 7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8- methoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-[1,2,4]triazolo [1,5-c]pyrimidin-2- amine (0.276 g, 0.595 mmol) in anhydrous dichloromethane (3.0 mL) at 0 °C under nitrogen. The solution was stirred at 0 °C for 90 min. Additional 1.0 M solution of boron tribromide in dichloromethane (1.8 mL, 1.8 mmol) was added to the reaction at 0 °C. The solution was allowed to stir at room temperature for two h. Additional 1.0 M solution of boron tribromide in dichloromethane (1.8 mL, 1.8 mmol) was added to the reaction. The solution was allowed to stir over the weekend at room temperature. Additional 1.0 M solution of boron tribromide in dichloromethane (3 mL, 3 mmol) was added to the reaction. The solution was allowed to stir at room temperature for 3 h.1.0 M solution of boron tribromide in dichloromethane (3 mL) was added to the reaction, and the solution was allowed to stir at room temperature for 22 h. Additional 1.0 M solution of boron tribromide in dichloromethane (6 mL) was added to the reaction, and the solution was allowed to stir at room temperature for 3 h. Additional 1.0 M solution of boron tribromide in dichloromethane (6 mL) was added to the reaction, and the solution was allowed to stir at room temperature overnight. Then, the solution was cooled to 0 °C and quenched with methanol dropwise. The solution was stirred at room temperature overnight. The reaction was concentrated under reduced pressure to provide the product as a brown solid. LC-MS calculated for C14H19N8O 3 S (M+H) + : m/z = 379.1; found 379.1. Step 5.8-Ethoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazo l-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine A solution of 2-((1-(methylsulfonyl)piperidin-4-yl)amino)-7-(1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-ol (0.150 g, 0.396 mmol), iodoethane (0.03 mL, 0.4 mmol), and potassium carbonate (0.164 g, 1.19 mmol) in anhydrous DMF (2.0 mL) was stirred at 50 °C for 1 h. The reaction was filtered and then purified by prep- HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to provide the desired product as a white solid, as its TFA salt. LC-MS calculated for C16H 2 3N8O 3 S (M+H) + : m/z = 407.2; found 407.1. 1 H NMR (500 MHz, dmso-d6) δ 9.11 (s, 1H), 8.22 (s, 2H), 7.12 (d, J = 6.6 Hz, 1H), 4.62 (q, J = 7.0 Hz, 2H), 3.69-3.60 (m, 1H), 3.56-3.48 (m, 2H), 2.94-2.89 (m, 2H), 2.88 (s, 3H), 2.07-2.01 (m, 2H), 1.64-1.54 (m, 2H), 1.38 (t, J = 7.1 Hz, 3H). Example 33.8-isopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperi din-4- yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-am ine Step 1.7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy-[1,2,4] triazolo[1,5- c]pyrimidin-2-amine A mixture of 7-chloro-8-isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-amin e (Example 14, Step 2, 0.1 g, 0.44 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'- triisopropyl-1,1'-biphenyl)(2-(2'-amino-1,1'-biphenyl))palla dium(II) (42.0 mg, 0.053 mmol), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H- pyrazole (0.213 g, 7.99 mmol), and potassium phosphate (0.339 g, 1.60 mmol) were added to a 40-dram vial. The vial was purged with nitrogen 3x and then dioxane (16 mL) and water (4 mL) were added. The solution was heated to 100 °C, and the reaction was stirred at 100 °C overnight. The reaction was cooled to room temperature, and ethyl acetate and water were added. The solution was extracted into ethyl acetate 3x, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Teledyne ISCO CombiFlash ® Rf+ (0-100% ethyl acetate in hexanes) to provide the desired product as a brown solid (47.4 mg, 32% yield). LC-MS calculated for C15H 2 2N7O 2 (M+H) + : m/z = 332.2; found 332.2. Step 2.2-bromo-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy - [1,2,4]triazolo[1,5-c]pyrimidine A solution of copper(II) bromide (0.030 g, 0.136 mmol) and tert-butylnitrite (0.039 mL, 0.326 mmol) in anhydrous acetonitrile (0.7 mL) was heated to 60 °C for 10 min. Then, the solution was added to a solution of 7-(1-(1-ethoxyethyl)-1H- pyrazol-4-yl)-8-isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2 -amine (0.045 g, 0.136 mmol) in anhydrous acetonitrile (0.7 mL). The solution was stirred at room temperature for 90 min. [Three reactions were set up with a total of 127 mg of 7-(1- (1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy-[1,2,4]triazol o[1,5-c]pyrimidin-2- amine. The reactions were combined for workup.] The solution was diluted with dichloromethane, filtered through Celite, washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Teledyne ISCO CombiFlash ® Rf+ (0-100% ethyl acetate in hexanes) to provide the desired product as a light yellow solid (85.5 mg, 56% yield). LC-MS calculated for C11H12BrN6O (M+H-PG) + : m/z = 323.0; found 323.0. Step 3. tert-butyl (3R,4S)-4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropo xy- [1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-methylpiperidi ne-1-carboxylate 2-Bromo-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8-isopropoxy- [1,2,4]triazolo[1,5-c]pyrimidine (0.0829 g, 0.210 mmol), tert-butyl (3R,4S)-4-amino- 3-methylpiperidine-1-carboxylate (0.045 g, 0.210 mmol), AdBrettPhos Pd G3 (10.6 mg, 10.5 µmol), and sodium tert-butoxide (0.081 g, 0.839 mmol) were added to a 4- dram vial. The vial was vacuum/nitrogen purged 3x and anhydrous dioxane (3 mL) was added. The solution was degassed via nitrogen sparge. The solution was added to a pre-heated stir plate at 100 °C, and the solution was stirred at 100 °C for 21 h. The reaction was cooled to room temperature, and ethyl acetate and water were added. The aqueous layer was extracted into ethyl acetate 3x. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Teledyne ISCO CombiFlash ® Rf+ (0-100% ethyl acetate in hexanes) to provide the desired product as a light yellow solid (11.5 mg, 10% yield). LC-MS calculated for C26H41N8O 4 (M+H) + : m/z = 529.3; found 529.3. Step 4.8-isopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperid in-4-yl)-7-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine A solution of tert-butyl (3R,4S)-4-((7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-8- isopropoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)amino)-3-met hylpiperidine-1- carboxylate (19.4 mg, 0.037 mmol) and 4 M HCl in dioxane (0.15 mL, 0.6 mmol) in anhydrous methanol (0.2 mL) was stirred at room temperature for 1 h. Then, the reaction was concentrated under reduced pressure. The residue was dissolved in anhydrous THF (1 mL) and methanesulfonyl chloride (2.86 µL, 0.037 mmol) and Hunig’s base (13 µL, 0.073 mmol) were added at 0 °C. The solution was stirred at 0 °C for 10 min. The solution was diluted with methanol/acetonitrile, filtered, and was purified by prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to provide the desired product as a white solid, as its TFA salt. LC-MS calculated for C18H 2 7N8O 3 S (M+H) + : m/z = 435.2; found 435.2. Example 34.8-(4-methylpiperidin-1-yl)-N-(1-(methylsulfonyl)piperidin -4-yl)-7- (1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine Step 1.6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine A mixture of 6-chloropyrimidin-4-amine (0.5 g, 3.9 mmol), 1-(1-ethoxyethyl)- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.54 g, 5.79 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-bi phenyl)(2-(2'-amino-1,1'- biphenyl))palladium(II) (0.304 g, 0.386 mmol), and potassium phosphate (2.45 g, 11.6 mmol) were added to a 40-mL vial. The vial was purged with nitrogen 3x and then dioxane (10.3 mL)/water (2.6 mL) were added. [Six reactions were set up for a total of 3.6 grams of 6-chloropyrimidin-4-amine.] The solution was stirred at 100 °C overnight. The reaction was cooled to room temperature, and ethyl and water were added. All of the reactions were combined together for workup and purification. The solution was extracted into ethyl acetate 3x, washed with brine, dried over sodium sulfate, filtered through Celite, and concentrated under reduced pressure. The residue was purified by Teledyne ISCO CombiFlash™ RF+ (0-40% ethyl acetate in hexanes, then 0-20% methanol in dichloromethane) to provide the desired product (3.34 g, 52% overall yield). LC-MS calculated for C11H16N5O (M+H) + : m/z = 234.1; found 234.1. 1 H NMR (400 MHz, dmso-d6) δ 8.42 (s, 1H), 8.31 (d, J = 0.98 Hz, 1H), 7.97 (s, 1H), 6.74 (s, 2H), 6.60 (d, J = 1.1 Hz, 1H), 5.58 (q, J = 6.0 Hz, 1H), 3.49-3.39 (m, 1H), 3.26-3.15 (m, 1H), 1.61 (d, J = 6.0 Hz, 3H), 1.04 (t, J = 7.1 Hz, 3H). Step 2.5-bromo-6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-a mine A solution of 6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (0.879 g, 3.77 mmol) and N-bromosuccinimide (0.704 g, 3.96 mmol) in ethanol (5.62 mL) was stirred at 82 °C for 1 h. [Four reactions were set up, for a total of 3.34 grams of 6- (1-(1-ethoxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-amine.] Then, the reactions were cooled to room temperature and were concentrated under reduced pressure. The four reactions were combined for workup. The residue was diluted with water and ethyl acetate, extracted into ethyl acetate 3x, washed with sodium bicarbonate and brine, and concentrated under reduced pressure. The organic residue was purified by Teledyne ISCO CombiFlash™ RF+ (0-100% ethyl acetate in hexanes) to provide the desired product (1.99 g, 45% overall yield). LC-MS calculated for C11H15BrN5O (M+H) + : m/z = 312.1; found 312.1. Step 3.8-bromo-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-[1,2,4]triaz olo[1,5- c]pyrimidin-2-amine A solution of 5-bromo-6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)pyrimidin-4- amine (1.99 g, 6.38 mmol) and O-ethyl carbonisothiocyanatidate (0.790 mL, 6.70 mmol) in anhydrous dioxane (12.8 mL) was stirred at 80 °C overnight. [Four reactions were set up for a total of 2.0 g of 5-bromo-6-(1-(1-ethoxyethyl)-1H-pyrazol- 4-yl)pyrimidin-4-amine.] Additional O-ethyl carbonisothiocyanatidate (0.08 mL, 6.8 mmol) was added, and the reaction was stirred for 3 h. The volatiles were removed under reduced pressure. Then, the residue was dissolved in anhydrous methanol/ethanol (v/v, 1:1, 2 mL). Hydroxylamine hydrochloride (2.22 g, 31.9 mmol) and Hunig’s base (3.3 mL, 19.1 mmol) were added. The reaction was stirred at 60 °C for 1 h. Then, the reaction was cooled, and water was added to the reaction. The solution was extracted into ethyl acetate 3x, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by Teledyne ISCO CombiFlash™ RF+ (0-100% ethyl acetate in hexanes) to provide the desired product as a white solid (1.19 g, 53% overall yield). LC-MS calculated for C12H15BrN7O (M+H) + : m/z = 352.1; found 352.1. Step 4.8-bromo-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol -4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine A solution of 8-bromo-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine (0.150 g, 0.426 mmol) and 1- (methylsulfonyl)piperidin-4-one (0.226 g, 1.28 mmol) in DMF (1.1 mL)/TFA (1.1 mL) was stirred at room temperature for 24 h. Then, a solution of sodium triacetoxyborohydride (0.316 g, 1.491 mmol) in DMF (1.1 mL)/TFA (1 mL) was added dropwise at room temperature and additional 1-(methylsulfonyl)piperidin-4- one (0.226 g, 1.28 mmol) was added to the reaction. The reaction was stirred for 30 min at room temperature. Then, additional 1-(methylsulfonyl)piperidin-4-one (100 mg, 0.6 mmol) was added to the reaction. The reaction was stirred for an additional hour before adding more 1-(methylsulfonyl)piperidin-4-one (150 mg, 0.85 mmol). The reaction was stirred for an additional 2.5 h, before the addition of 1- (methylsulfonyl)piperidin-4-one (150 mg, 0.85 mmol). The reaction was stirred over the weekend. Then, the reaction was quenched dropwise with water and sat. sodium bicarbonate until pH 7, then extracted into ethyl acetate 3x, dried over sodium sulfate, and concentrated under reduced pressure. [Two reactions were combined for workup and yield.] The residue was purified by Teledyne ISCO CombiFlash™ RF+ (0-20% methanol in dichloromethane) to yield the desired product as a yellow sticky residue (135.4 mg, 33% yield). LC-MS calculated for C14H18BrN8O 2 S (M+H) + : m/z = 441.1; found 441.1. Step 5.8-(4-methylpiperidin-1-yl)-N-(1-(methylsulfonyl)piperidin- 4-yl)-7-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine A solution of 8-bromo-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4 - yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine (0.017 g, 0.039 mmol), 4- methylpiperidine (0.01 mL, 0.077 mmol), and potassium carbonate (10.7 mg, 0.085 mmol) in anhydrous DMSO (0.2 mL) was stirred at 80 °C for 90 min. Additional 4- methylpiperidine (0.02 mL, 0.17 mmol) was added to the reaction, and the reaction was stirred at 80 °C for 1.5 h. Additional 4-methylpiperidine (0.01 mL, 0.077 mmol) was added to the reaction, and the reaction was stirred at 80 °C overnight. The solution was cooled, diluted with methanol/acetonitrile, and filtered. The solution was purified by prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to provide the desired product as its TFA salt. LC-MS calculated for C20H30N9O 2 S (M+H) + : m/z = 460.2; found 460.3. Example 35. N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8-( 3- (trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-a mine A solution of 5,6-dichloropyrimidin-4-amine (450 mg, 2.74 mmol), 1-(1- ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (803 mg, 3.02 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (224 mg, 0.274 mmol), and sodium carbonate (873 mg, 8.23 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL) was stirred under nitrogen at 80 °C for 2 h. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (0-100% ethyl acetate in hexanes) to provide the desired product as a light yellow solid. LC-MS calculated for C11H15ClN5O (M+H) + : m/z = 268.1; found 268.1. Step 2.8-chloro-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-[1,2,4]tria zolo[1,5- c]pyrimidin-2-amine O-Ethyl carbonisothiocyanatidate (0.264 mL, 2.24 mmol) was added to a solution of 5-chloro-6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)pyrimidin-4-am ine (0.4 g, 1.5 mmol) in acetonitrile (15 mL), and the reaction mixture was stirred at 80 °C for 5 h. The volatiles were removed under reduced pressure. Then, the residue was dissolved in methanol and ethanol (v/v, 1:1, 20 mL). Hydroxylamine hydrochloride (0.311 g, 4.48 mmol) and Hunig’s base (0.78 mL, 4.48 mmol) were added. The reaction was stirred at 60 °C for 3 h. The volatiles were removed under reduced pressure, and the residue was treated with water and sodium bicarbonate and extracted into ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (0-5% methanol in dichloromethane) to provide the desired product as a light yellow solid. LC-MS calculated for C12H15ClN7O (M+H) + : m/z = 308.1; found 308.0. Step 3.8-chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazo l-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine A solution of 8-chloro-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine (200 mg, 0.650 mmol) and 1- (methylsulfonyl)piperidin-4-one (173 mg, 0.975 mmol) in DMF (2.2 mL)/TFA (1.1 mL) was stirred at room temperature for 1 h. A solution of sodium triacetoxyborohydride (220 mg, 1.04 mmol) in DMF (2.2 mL) and TFA (1.1 mL) was added dropwise. Water (2 mL) was added to the reaction. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with sodium bicarbonate, and the reaction was extracted into ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (0-5% methanol in dichloromethane) to provide the desired product as a light yellow solid. LC-MS calculated for C14H18ClN8O 2 S (M+H) + : m/z = 397.1; found 397.1. Step 4. N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8-( 3- (trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-a mine A mixture of 8-chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol- 4- yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine (10 mg, 0.025 mmol), (4- (hydroxymethyl)phenyl)boronic acid (7.66 mg, 0.050 mmol), chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2 -(2'-amino-1,1'- biphenyl))palladium(II) (1.98 mg, 2.52 µmol), and sodium carbonate (8.01 mg, 0.076 mmol) in 1,4-dioxane (1 mL) and water (0.5 mL) was purged with nitrogen, and the reaction was stirred at 110 °C for 2 h. The reaction was quenched with sat. sodium bicarbonate solution and extracted into dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to provide the desired product as its TFA salt. LC-MS calculated for C21H 2 2F3N8O 2 S (M+H) + : m/z = 507.2; found 507.2. Example 36.2-fluoro-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-7 -(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)benzonitr ile This compound was prepared in a similar fashion to Example 35, step 4 using 3-cyano-2-fluorophenyl)boronic acid as the boronic acid. LC-MS calculated for C21H 2 1FN9O 2 S (M+H) + : m/z = 482.2; found 482.1. Example 37. N-(1-(methylsulfonyl)piperidin-4-yl)-8-propyl-7-(1H-pyrazol- 4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine Step 1: (E)-N-(1-(methylsulfonyl)piperidin-4-yl)-8-(prop-1-en-1-yl)- 7-(1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine A mixture of 8-chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol- 4- yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (10.0 mg, 0.025 mmol), chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2 -(2'-amino-1,1'- biphenyl))palladium(II) (1.988 mg, 2.53 µmol), Na2CO 3 (8.03 mg, 0.076 mmol), (E)- prop-1-en-1-ylboronic acid (3.25 mg, 0.038 mmol) in 1,4-dioxane (1 mL) and water (0.5 mL) was stirred under N2 at 120 °C overnight. The mixture was adjusted to pH 2 with TFA, and purified by HPLC (pH 2) to afford the desired product as its TFA salt. LC-MS calculated for C18H 2 4N7O 2 S (M+H) + : m/z = 402.2; found 402.2. Step 2: N-(1-(methylsulfonyl)piperidin-4-yl)-8-propyl-7-(1H-pyrazol- 4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine A mixture of (E)-N-(1-(methylsulfonyl)piperidin-4-yl)-8-(prop-1-en-1-yl)- 7- (1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (2.072 mg, 5.16 µmol) and Pd/C (1 mg) in MeOH (1.00 mL) was stirred under H 2 at room temperature for 1 h. The mixture was filtered, adjusted to pH 2 with TFA, and purified by HPLC (pH 2) to afford the desired product as its TFA salt. LC-MS calculated for C18H 2 6N7O 2 S (M+H) + : m/z = 404.2; found 404.2. Example 38.8-isopropoxy-N-((3R,4S)-3-methyl-1-((2-(pyrrolidin-1- yl)ethyl)sulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4 ]triazolo[1,5- c]pyrimidin-2-amine 2-Chloroethane-1-sulfonyl chloride (0.056 g, 0.343 mmol) was added to a solution of 8-isopropoxy-N-((3R,4S)-3-methylpiperidin-4-yl)-7-(1H-pyrazo l-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine HCl salt (0.080 g, 0.172 mmol) and DIPEA (0.150 mL, 0.859 mmol) in acetonitrile/water (10 mL/2 mL). After stirring at room temperature for 30 min, the mixture was quenched with aqueous NaHCO 3 , extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was dissolved in DMF (1.0 mL). Pyrrolidine (0.043 mL, 0.515 mmol) and DIPEA (0.090 mL, 0.515 mmol) were added, and the mixture was stirred at 110 ºC for 2 h. The reaction mixture was diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C23H36N9O 3 S (M+H) + : m/z = 518.3; found 518.4. Example 39.8-((4,4-difluorocyclohexyl)oxy)-N-((3R,4S)-3-methyl-1- (methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]t riazolo[1,5-a]pyridin- 2-amine Step 1: 8-(benzyloxy)-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-N-((3R,4 S)-3-methyl-1- (methylsulfonyl)piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridi n-2-amine To a solution of 8-(benzyloxy)-2-bromo-7-(1-(1-ethoxyethyl)-1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-a]pyridine (Example 2, step 4, 325 mg, 0.735 mmol), (3R,4S)- 3-methyl-1-(methylsulfonyl)piperidin-4-amine (170 mg, 0.882 mmol), and sodium tert-butoxide (282 mg, 2.94 mmol) in dioxane (3 mL) was added AdBrettPhos Pd G3 (37 mg, 0.037 mmol). The vial was flushed with nitrogen, and the reaction was stirred at 100 °C for 4 h. The reaction mixture was then quenched with NH4Cl aqueous solution and extracted into ethyl acetate. The organic phases were combined, dried over MgSO 4 , filtered, and concentrated. The crude product was purified by flash chromatography on a silica gel column to give the desired product. LC-MS calculated for C27H36N7O 4 S (M+H) + : m/z = 554.2; found 554.1. Step 2: 7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-2-(((3R,4S)-3-methyl-1 - (methylsulfonyl)piperidin-4-yl)amino)-[1,2,4]triazolo[1,5-a] pyridin-8-ol Palladium on carbon (10 wt.% loading, 40 mg) was added into a solution of 8- (benzyloxy)-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-N-((3R,4S) -3-methyl-1- (methylsulfonyl)piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridi n-2-amine (407 mg, 0.735 mmol) in MeOH (5 mL). The mixture was stirred under 4 bar of hydrogen at 50 °C for 48 h. The resulting mixture was filtered and concentrated. The crude product was purified by flash chromatography on a silica gel column to give the desired product. LC-MS calculated for C20H30N7O 4 S (M+H) + : m/z = 464.2; found 464.1. Step 3: 8-((4,4-difluorocyclohexyl)oxy)-N-((3R,4S)-3-methyl-1- (methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]t riazolo[1,5-a]pyridin-2- amine To a solution of 7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-2-(((3R,4S)-3-methyl- 1-(methylsulfonyl)piperidin-4-yl)amino)-[1,2,4]triazolo[1,5- a]pyridin-8-ol (5.0 mg, 0.011 mmol) and 4-bromo-1,1-difluorocyclohexane (2.2 mg, 0.011 mmol) in MeCN (0.5 mL) was added Cs2CO 3 (10.5 mg, 0.032 mmol). The resulting solution was stirred at 50 °C for 1 h. After the reaction was cooled to room temperature, 1 M aqueous solution of HCl (0.5 mL) was added, and the reaction mixture was stirred for 30 min. The reaction mixture was diluted with MeOH and purified by prep-HPLC (pH = 2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C22H30F 2 N7O 3 S (M+H) + : m/z = 510.2; found 510.1. Example 40. N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H- pyrazol-4-yl)-8-((tetrahydrofuran-3-yl)oxy)-[1,2,4]triazolo[ 1,5-a]pyridin-2-amine This compound was prepared using similar procedures described for Example 39, with 3- 3-bromotetrahydrofuran replacing 4-bromo-1,1-difluorocyclohexane in Step 3. LC-MS calculated for C20H 2 8N7O 4 S (M+H) + : m/z = 462.2; found 461.1. Example 41.8-(ethoxy-d5)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piper idin-4- yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amin e This compound was prepared using similar procedures described for Example 39, with iodoethane-d5 replacing 4-bromo-1,1-difluorocyclohexane in Step 3. LC-MS calculated for C18H 2 1D5N7O 2 S (M+H) + : m/z = 425.2; found 425.1. Example 42. N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H- pyrazol-4-yl)-8-((tetrahydro-2H-pyran-4-yl)oxy)-[1,2,4]triaz olo[1,5-a]pyridin-2- amine This compound was prepared using similar procedures described for Example 39, with 4-bromotetrahydro-2H-pyran replacing 4-bromo-1,1-difluorocyclohexane in Step 3. LC-MS calculated for C21H30N7O 4 S (M+H) + : m/z = 476.2; found 476.1. Example 43.8-isopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperi din-4- yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amin e This compound was prepared using similar procedures described for Example 39, with 2-iodopropane replacing 4-bromo-1,1-difluorocyclohexane in Step 3. LC-MS calculated for C19H 2 8N7O 3 S (M+H) + : m/z = 434.2; found 434.1. Example 44.8-Isobutoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-py razol-4- yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine This compound was prepared in a similar fashion to Example 14, with 1-iodo- 2-methylpropane replacing 2-iodopropane in Step 1, to provide the desired product as its TFA salt, a white solid. LC-MS calculated for C18H27N8O3S (M+H)+: m/z = 435.2; found 435.2. Example 45.8-(2,2-difluoroethoxy)-N-(1-(methylsulfonyl)piperidin-4-y l)-7-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine This compound was prepared using a modified procedure for Example 32, with 1,1-difluoro-2-iodoethane replacing iodoethane in Step 5. Additional potassium carbonate (0.022 g, 0.159 mmol, 2 equiv) and 1,1-difluoro-2-iodoethane (0.02 mL, 2 equiv) were added, and the reaction mixture was stirred for an additional 2 h. The mixture was diluted with methanol and acetonitrile, filtered, and purified by prep- HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH at a flow rate of 60 mL/min). Fractions containing the desired product were concentrated and purified by prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to provide the desired product as its TFA salt, a clear residue. LC-MS calculated for C16H 2 1F 2 N8O 3 S (M+H) + : m/z = 443.1; found 443.2. Example 46. N-(1-(Methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8-( 3,3,3- trifluoropropoxy)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine This compound was prepared using a modified procedure for Example 32, with 1,1,1-trifluoro-3-iodopropane replacing iodoethane in Step 5. Additional potassium carbonate (0.022 g, 0.159 mmol, 2 equiv) and 1,1,1-trifluoro-3- iodopropane (0.02 mL, 2 equiv) were added, and the reaction was stirred for an additional 2 h. The mixture was diluted with methanol and acetonitrile, filtered, and purified by prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to provide the desired product as its TFA salt, a white solid. LC-MS calculated for C17H 2 2F3N8O 3 S (M+H) + : m/z = 475.2; found 475.2. Example 47.8-Butoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyraz ol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine This compound was prepared in a similar fashion to Example 32, with 1- iodobutane replacing iodoethane in Step 5 to provide the desired product as its TFA salt, a white solid. LC-MS calculated for C18H 2 7N8O 3 S (M+H) + : m/z = 435.2; found 435.2. Example 48. N-(1-(Methylsulfonyl)piperidin-4-yl)-8-propoxy-7-(1H-pyrazol -4- yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine This compound was prepared in a similar fashion to Example 32, with 1- iodopropane replacing iodoethane in Step 5 to provide the desired product as its TFA salt, a white solid. LC-MS calculated for C17H 2 5N8O 3 S (M+H) + : m/z = 421.2; found 421.2. Example 49. N-(1-(Methylsulfonyl)piperidin-4-yl)-8-(piperidin-1-yl)-7-(1 H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine Step 1.8-Chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazo l-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine A solution of 8-chloro-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine (0.1515 g, 0.492 mmol) and 1- (methylsulfonyl)piperidin-4-one (0.262 g, 1.477 mmol) in DMF (1.2 mL)/TFA (1.2 mL) (1:1) was stirred at room temperature for 24 h. Then, a solution of sodium triacetoxyborohydride (0.365 g, 1.723 mmol) in DMF (1.2 mL)/TFA (1.2 mL) (1:1) was added dropwise at room temperature. The reaction was stirred for 30 min at room temperature. Additional 1-(methylsulfonyl)piperidin-4-one (0.262 g, 1.477 mmol) was added and the reaction was stirred overnight. The reaction was quenched dropwise with water and sat. sodium bicarbonate (aq) until pH 7, then extracted into ethyl acetate 3x, washed with 10% lithium chloride (aq) and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by Teledyne ISCO CombiFlash ® Rf+ (ISCO, 20 g silica, 0 to 20% methanol in dichloromethane) to yield the desired product as a white solid (61.8 mg, 32%). LC- MS calculated for C14H18ClN8O 2 S (M+H) + : m/z = 397.1; found 397.1. Step 2. N-(1-(Methylsulfonyl)piperidin-4-yl)-8-(piperidin-1-yl)-7-(1 H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine A solution of 8-chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol- 4- yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine (0.015 g, 0.038 mmol), piperidine (10 µL, 0.101 mmol), and potassium carbonate (10.45 mg, 0.076 mmol) in anhydrous DMSO (0.189 mL) was stirred at 80 °C for 1 h. Additional piperidine (0.02 mL) was added to the reaction and the reaction was stirred at 80 °C for 90 min. Additional piperidine (0.04 mL) and potassium carbonate (10.45 mg, 0.076 mmol) were added to the reaction, and the reaction was stirred at 80 °C overnight. The solution was diluted with methanol and acetonitrile, and filtered. The solution was purified by prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to provide the desired product as its TFA salt, a white solid. LC-MS calculated for C19H 2 8N9O 2 S (M+H) + : m/z = 446.2; found 446.3. Example 50. N-(3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-8-(piperidin-1 -yl)-7- (1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine Step 1.8-Chloro-N-(3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-( 1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-2-amine This compound was prepared in a similar fashion to Example 49, with 3- methyl-1-(methylsulfonyl)piperidin-4-one replacing 1-(methylsulfonyl)piperidin-4- one in Step 1 to yield the desired product as a cream-colored solid (13.6 mg, 13%). LC-MS calculated for C15H 2 0ClN8O 2 S (M+H) + : m/z = 411.1; found 411.1. Step 2. N-(3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-8-(piperidin-1 -yl)-7-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine A solution of 8-chloro-N-(3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H - pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine (13.6 mg, 0.033 mmol) and piperidine (10 µL, 0.101 mmol) in anhydrous DMSO (0.165 mL) was stirred at 80 °C for 30 min. Potassium carbonate (9.15 mg, 0.066 mmol) was added, and the solution was stirred at 80 °C for 1 h. Additional piperidine (0.02 mL) and DMSO (0.4 mL) were added to the reaction, and the reaction was stirred at 80 °C for 1 h. Additional potassium carbonate (9.15 mg, 0.066 mmol) was added to the reaction, and the reaction was stirred at 80 °C for 2 h. The reaction was cooled and left sitting for two months at room temperature, during which time complete conversion to the desired product formed. The reaction was diluted with methanol and acetonitrile, and filtered. The solution was purified by prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to provide the desired product as its TFA salt, a white solid. LC-MS calculated for C20H30N9O 2 S (M+H) + : m/z = 460.2; found 460.4. Example 51.8-(4-(2-Methoxyethyl)piperazin-1-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]t riazolo[1,5- c]pyrimidin-2-amine This compound was prepared in a similar fashion to Example 49, with 1-(2- methoxyethyl)piperazine replacing piperidine in Step 2 to yield the desired product as the TFA salt, a white solid. LC-MS calculated for C21H33N10O 3 S (M+H) + : m/z = 505.3; found 505.3. Example 52. N-(1-(Methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-8- (pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine This compound was prepared in a similar fashion to Example 34, with pyrrolidine replacing 4-methylpiperidine in Step 5 to yield the desired product as the TFA salt, a white solid. LC-MS calculated for C18H 2 6N9O 2 S (M+H) + : m/z = 432.2; found 432.3. Example 53. N-((3R,4S)-1-(Cyclopropylsulfonyl)-3-methylpiperidin-4-yl)-8 - isopropoxy-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimid in-2-amine To a mixture of 8-isopropoxy-N-((3R,4S)-3-methylpiperidin-4-yl)-7-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine hydrochloride (Intermediate 1, 547.5 mg, 1.39 mmol) in CH 3 CN (5.80 mL) and H 2 O (1.16 mL) was added N-ethyl- N-isopropylpropan-2-amine (487 µL, 2.79 mmol) followed by dropwise addition of cyclopropanesulfonyl chloride (196 mg, 1.39 mmol) and the reaction mixture was stirred at r.t. for 30 min. The reaction mixture was diluted with water and acetonitrile and purified by prep-HPLC (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford the desired product as its TFA salt. LC-MS calculated for C20H 2 9N8O 3 S (M+H) + : m/z = 461.2; found 461.2. Example 54. N-((3R,4S)-1-(Ethylsulfonyl)-3-methylpiperidin-4-yl)-8-isopr opoxy- 7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine This compound was prepared according to the procedures described in Example 53, with ethanesulfonyl chloride replacing cyclopropanesulfonyl chloride. LC-MS calculated for C19H 2 9N8O 3 S (M+H) + : m/z = 449.2; found 449.1. Example 55. N-((3R,4S)-1-((3-(Ethyl(methyl)amino)propyl)sulfonyl)-3- methylpiperidin-4-yl)-8-isopropoxy-7-(1H-pyrazol-4-yl)-[1,2, 4]triazolo[1,5- c]pyrimidin-2-amine To a mixture of 8-isopropoxy-N-((3R,4S)-3-methylpiperidin-4-yl)-7-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine hydrochloride (Intermediate 1, 392.9 mg, 1.00 mmol) in CH 3 CN (4.17 ml) and H 2 O (0.833 mL) was added N-ethyl- N-isopropylpropan-2-amine (348 µL, 2.00 mmol) followed by dropwise addition of 3- chloropropane-1-sulfonyl chloride (177 mg, 1.00 mmol) and the reaction mixture was stirred at r.t. for 30 min. Cesium carbonate (1.63 g, 5.00 mmol), potassium iodide (830 mg, 5.00 mmol), and N-methylethanamine (296 mg, 5.00 mmol) were added and the reaction mixture was purged with nitrogen and irradiated in a microwave reactor at 130 °C for 1 h. After cooling to r.t., the reaction mixture was diluted with water and acetonitrile and purified by prep-HPLC (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford the desired product as its TFA salt. LC-MS calculated for C23H38N9O 3 S (M+H) + : m/z = 520.3; found 520.2. 1 H NMR (TFA salt, 600 MHz, DMSO-d6) δ 9.32 (br s, 1H), 9.10 (s, 1H), 8.24 (s, 2H), 7.15 (d, J = 8.4 Hz, 1H), 5.59 – 5.52 (m, 1H), 3.93 – 3.86 (m, 1H), 3.40 – 3.32 (m, 1H), 3.28 – 3.07 (m, 9H), 2.78 (d, J = 4.9 Hz, 3H), 2.24 – 2.15 (m, 1H), 2.13 – 1.99 (m, 2H), 1.88 – 1.72 (m, 2H), 1.34 – 1.28 (m, 6H), 1.21 (t, J = 7.2 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H). Example 56. N-((3R,4S)-1-((3-(Dimethylamino)propyl)sulfonyl)-3- methylpiperidin-4-yl)-8-isopropoxy-7-(1H-pyrazol-4-yl)-[1,2, 4]triazolo[1,5- c]pyrimidin-2-amine This compound was prepared according to the procedures described in Example 55, with dimethylamine (2.0 M solution in THF) replacing N- methylethanamine. LC-MS calculated for C22H36N9O 3 S (M+H) + : m/z = 506.3; found 506.3. 1 H NMR (TFA salt, 600 MHz, DMSO-d6) δ 9.51 (br s, 1H), 9.10 (s, 1H), 8.24 (s, 2H), 7.14 (d, J = 8.4 Hz, 1H), 5.60 – 5.52 (m, 1H), 3.93 – 3.86 (m, 1H), 3.40 – 3.32 (m, 1H), 3.28 – 3.10 (m, 7H), 2.81 (d, J = 4.6 Hz, 6H), 2.24 – 2.15 (m, 1H), 2.10 – 2.02 (m, 2H), 1.88 – 1.72 (m, 2H), 1.34 – 1.29 (m, 6H), 0.92 (d, J = 6.9 Hz, 3H). Example 57.8-Isopropoxy-N-((3R,4S)-1-((3- (isopropyl(methyl)amino)propyl)sulfonyl)-3-methylpiperidin-4 -yl)-7-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine This compound was prepared according to the procedures described in Example 55, with N-methylpropan-2-amine replacing N-methylethanamine. LC-MS calculated for C24H40N9O 3 S (M+H) + : m/z = 534.3; found 534.3. 1 H NMR (TFA salt, 600 MHz, DMSO-d6) δ 9.19 (br s, 1H), 9.10 (s, 1H), 8.24 (s, 2H), 7.15 (d, J = 8.4 Hz, 1H), 5.59 – 5.52 (m, 1H), 3.93 – 3.87 (m, 1H), 3.60 – 3.54 (m, 1H), 3.40 – 3.33 (m, 1H), 3.28 – 3.11 (m, 6H), 3.11 – 3.03 (m, 1H), 2.71 (d, J = 4.9 Hz, 3H), 2.24 – 2.16 (m, 1H), 2.15 – 2.00 (m, 2H), 1.88 – 1.80 (m, 1H), 1.80 – 1.72 (m, 1H), 1.34 – 1.29 (m, 6H), 1.24 (d, J = 6.6 Hz, 3H), 1.21 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.9 Hz, 3H). Example 58.8-Isopropoxy-N-((3R,4S)-3-methyl-1-((3-(piperidin-1- yl)propyl)sulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5- c]pyrimidin-2-amine This compound was prepared according to the procedures described in Example 55, with piperidine replacing N-methylethanamine. LC-MS calculated for C25H40N9O 3 S (M+H) + : m/z = 546.3; found 546.4. Table 1. The compounds in Table 1 were prepared in accordance with the synthetic protocols set forth in Example 55 using the appropriate starting materials.
Example 63.8-Isopropoxy-N-((3R,4S)-3-methyl-1-((4- morpholinobutyl)sulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl) -[1,2,4]triazolo[1,5- c]pyrimidin-2-amine To a mixture of 8-isopropoxy-N-((3R,4S)-3-methylpiperidin-4-yl)-7-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine hydrochloride (Intermediate 1, 47.2 mg, 0.120 mmol) in CH 3 CN (0.5 mL) and H 2 O (0.1 mL) was added N-ethyl-N- isopropylpropan-2-amine (41.7 µL, 0.240 mmol) followed by 4-chlorobutane-1- sulfonyl chloride (22.9 mg, 0.120 mmol) and the reaction mixture was stirred at r.t. for 30 min before heating to 100 °C for 2 h. After cooling to r.t., cesium carbonate (195 mg, 0.599 mmol), potassium iodide (99.0 mg, 0.599 mmol), and morpholine (52.2 mg, 0.599 mmol) were added and the reaction mixture was purged with nitrogen and irradiated in a microwave reactor at 130 °C for 1 h. After cooling to r.t., the reaction mixture was diluted with water and acetonitrile and purified by prep-HPLC (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford the desired product as its TFA salt. LC-MS calculated for C25H40N9O 4 S (M+H) + : m/z = 562.3; found 562.3. Table 2. The compounds in Table 2 were prepared in accordance with the synthetic protocols set forth in Example 63 using the appropriate starting materials. Example 68.5-Isopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperi din-4- yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amin e Step 1: 2-Bromo-6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-5-isopropoxy- [1,2,4]triazolo[1,5-a]pyridine In an oven-dried microwave vial with a stir bar, to a mixture of propan-2-ol (60.3 mg, 1.00 mmol) in 1,4-dioxane (2.0 mL) was added NaH (24.1 mg, 1.00 mmol) portionwise and the reaction mixture stirred under nitrogen at r.t. for 15 min.2- Bromo-5-chloro-6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-[1,2,4] triazolo[1,5-a]pyridine (Intermediate 2, 371.6 mg, 1.00 mmol) was added and the reaction mixture was stirred under nitrogen at r.t. for 15 min before the mixture was irradiated in a microwave reactor at 150 °C for 4 h. After cooling to r.t., the mixture was concentrated and the crude residue was purified by flash column chromatography (SiO 2 , EtOAc/hexanes). LC-MS calculated for C16H 2 1BrN5O 2 (M+H) + : m/z = 394.1; found 394.1. Step 2: 5-Isopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin -4-yl)-6-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine In an oven-dried vial with a stir bar, a mixture of 2-bromo-6-(1-(1- ethoxyethyl)-1H-pyrazol-4-yl)-5-isopropoxy-[1,2,4]triazolo[1 ,5-a]pyridine (Step 1), (3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-amine (Intermediate 3, 193 mg, 1.00 mmol), methanesulfonato[2-(di-1-adamantylphosphino)-3,6-dimethoxy-2 ',4',6'-tri-i- propyl-1,1'-biphenyl](2'-amino-1,1'-biphenyl-2-yl)palladium( II) (203 mg, 0.201 mmol), and sodium tert-butoxide (193 mg, 2.00 mmol) in 1,4-dioxane (5.0 mL) was sparged with nitrogen and stirred at 110 °C for 30 min. After cooling to r.t., the reaction mixture was diluted with MeOH (5 mL) and filtered over a SiliaPrep SPE silica-based thiol cartridge (2 g). To the filtrate was added a 4 M solution of HCl in 1,4-dioxane (2.5 mL, 10.0 mmol) and the reaction mixture was stirred at r.t. for 15 min. The mixture was diluted with water, filtered, and purified by prep-HPLC (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford the desired product as its TFA salt. LC-MS calculated for C19H 2 8N7O 3 S (M+H) + : m/z = 434.2; found 434.3. 1 H NMR (TFA salt, 600 MHz, DMSO-d6) δ 8.07 (s, 2H), 7.81 (d, J = 9.0 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1H), 6.87 (br s, 1H), 5.46 – 5.37 (m, 1H), 3.98 – 3.88 (m, 1H), 3.31 – 3.24 (m, 1H), 3.17 – 3.07 (m, 3H), 2.86 (s, 3H), 2.24 – 2.16 (m, 1H), 1.88 – 1.73 (m, 2H), 1.29 – 1.23 (m, 6H), 0.92 (d, J = 6.8 Hz, 3H). Table 3. The compounds in Table 3 were prepared in accordance with the synthetic protocols set forth in Example 68 using the appropriate starting materials. Example 83. N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(pip eridin- 1-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-am ine Step 1: 2-Bromo-6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-5-(piperidin-1 -yl)- [1,2,4]triazolo[1,5-a]pyridine To a mixture of 2-bromo-5-chloro-6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridine (Intermediate 2, 185.8 mg, 0.501 mmol) in DMSO (1.0 mL) was added piperidine (42.7 mg, 0.501 mmol), N-ethyl-N-isopropylpropan-2- amine (175 µL, 1.00 mmol), and cesium fluoride (76.0 mg, 0.501 mmol) and the reaction mixture was purged with nitrogen and irradiated in a microwave reactor at 150 °C for 2 h. After cooling to r.t., the reaction mixture was diluted with water and extracted with CH 2 Cl 2 . The combined organic phases were dried over MgSO 4 , concentrated, and the crude residue was purified by flash column chromatography (12 g SiO 2 , EtOAc/hexanes). LC-MS calculated for C18H 2 4BrN6O (M+H) + : m/z = 419.1; found 419.2. Step 2: tert-Butyl (3R,4S)-4-((6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-5-(piperid in-1- In an oven-dried vial with a stir bar, a mixture of 2-bromo-6-(1-(1- ethoxyethyl)-1H-pyrazol-4-yl)-5-(piperidin-1-yl)-[1,2,4]tria zolo[1,5-a]pyridine (64.1 mg, 0.153 mmol), tert-butyl (3R,4S)-4-amino-3-methylpiperidine-1-carboxylate (32.8 mg, 0.153 mmol), methanesulfonato[2-(di-1-adamantylphosphino)-3,6-dimethoxy- 2',4',6'-tri-i-propyl-1,1'-biphenyl](2'-amino-1,1'-biphenyl- 2-yl)palladium(II) (30.9 mg, 0.031 mmol), and sodium tert-butoxide (29.4 mg, 0.306 mmol) in 1,4-dioxane (0.76 mL) was sparged with nitrogen and stirred at 110 °C for 30 min. After cooling to r.t., the reaction mixture was diluted with water and extracted with CH 2 Cl 2 . The combined organic phases were dried over MgSO 4 , concentrated, and the crude residue was purified by flash column chromatography (12 g SiO 2 , EtOAc/hexanes). LC-MS calculated for C29H45N8O 3 (M+H) + : m/z = 553.4; found 553.4. Step 3: N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(pip eridin-1-yl)-6- (1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine To a mixture of tert-butyl (3R,4S)-4-((6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)- 5-(piperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino) -3-methylpiperidine-1- carboxylate (Step 1) in MeOH (0.76 mL) was added a 4 M solution of HCl in 1,4- dioxane (0.76 mL, 3.0 mmol) and the reaction mixture was stirred at r.t. for 30 min. The reaction mixture was concentrated in vacuo, and to a mixture of the crude residue in CH 3 CN (637 µL) and H 2 O (127 µL) was added N-ethyl-N-isopropylpropan-2- amine (53 µL, 0.30 mmol) followed by dropwise addition of methanesulfonyl chloride (17.5 mg, 0.153 mmol) and the reaction mixture was stirred at r.t. for 30 min. The mixture was diluted with water and acetonitrile and purified by prep-HPLC (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford the desired product as its TFA salt. LC-MS calculated for C21H31N8O 2 S (M+H) + : m/z = 459.2; found 459.2. Table 4. The compounds in Table 4 were prepared in accordance with the synthetic protocols set forth in Example 83 using the appropriate starting materials. Example 87.5-Isopropoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperi din-4- yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amin e In an oven-dried vial with a stir bar, a mixture of 2-bromo-6-(1-(1- ethoxyethyl)-1H-pyrazol-4-yl)-5-isopropoxy-[1,2,4]triazolo[1 ,5-a]pyrazine (Intermediate 4, 908.4 mg, 2.30 mmol), (3R,4S)-3-methyl-1- (methylsulfonyl)piperidin-4-amine (Intermediate 3, 442 mg, 2.30 mmol), methanesulfonato[2-(di-1-adamantylphosphino)-3,6-dimethoxy-2 ',4',6'-tri-i-propyl- 1,1'-biphenyl](2'-amino-1,1'-biphenyl-2-yl)palladium(II) (465 mg, 0.460 mmol), and sodium tert-butoxide (442 mg, 4.60 mmol) in 1,4-dioxane (11.5 mL) was sparged with nitrogen and stirred at 110 °C for 30 min. After cooling to r.t., the reaction mixture was diluted with MeOH (11.5 mL) and filtered over a SiliaPrep SPE silica- based thiol cartridge (2 g). To the filtrate was added a 4 M solution of HCl in 1,4- dioxane (5.75 mL, 23.0 mmol) and the reaction mixture was stirred at r.t. for 15 min. The mixture was diluted with water, filtered, and purified by prep-HPLC (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford the desired product as its TFA salt. LC-MS calculated for C18H 2 7N8O 3 S (M+H) + : m/z = 435.2; found 435.3. 1 H NMR (TFA salt, 600 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.13 (s, 2H), 7.21 (d, J = 8.5 Hz, 1H), 5.56 – 5.49 (m, 1H), 4.01 – 3.95 (m, 1H), 3.31 – 3.23 (m, 1H), 3.17 – 3.08 (m, 3H), 2.87 (s, 3H), 2.23 – 2.16 (m, 1H), 1.89 – 1.75 (m, 2H), 1.36 – 1.31 (m, 6H), 0.92 (d, J = 6.9 Hz, 3H). Example 88. N-((3R,4S)-1-(Ethylsulfonyl)-3-methylpiperidin-4-yl)-5-isopr opoxy- 6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine In an oven-dried vial with a stir bar, a mixture of 2-bromo-6-(1-(1- ethoxyethyl)-1H-pyrazol-4-yl)-5-isopropoxy-[1,2,4]triazolo[1 ,5-a]pyrazine (Intermediate 4, 110 mg, 0.278 mmol), tert-butyl (3R,4S)-4-amino-3- methylpiperidine-1-carboxylate (59.6 mg, 0.278 mmol), methanesulfonato[2-(di-1- adamantylphosphino)-3,6-dimethoxy-2',4',6'-tri-i-propyl-1,1' -biphenyl](2'-amino-1,1'- biphenyl-2-yl)palladium(II) (56.3 mg, 0.056 mmol), and sodium tert-butoxide (53.5 mg, 0.557 mmol) in 1,4-dioxane (1.39 mL) was sparged with nitrogen and stirred at 110 °C for 30 min. After cooling to r.t., the reaction mixture was diluted with water and extracted with CH 2 Cl 2 . The combined organic phases were dried over MgSO 4 , filtered, and concentrated. The crude residue was purified by flash column chromatography (SiO 2 , EtOAc/hexanes). LC-MS calculated for C26H41N8O 4 (M+H) + : m/z = 529.3; found 529.3. Step 2: N-((3R,4S)-1-(Ethylsulfonyl)-3-methylpiperidin-4-yl)-5-isopr opoxy-6-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine To a mixture of tert-butyl (3R,4S)-4-((6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)- 5-isopropoxy-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)amino)-3-met hylpiperidine-1- carboxylate (Step 1) in MeOH (1.39 mL) was added a 4 M solution of HCl in 1,4- dioxane (696 µL, 2.78 mmol) and the reaction mixture was stirred at r.t. for 2 h. The reaction mixture was concentrated in vacuo, and to a mixture of the crude residue in CH 3 CN (1.16 mL) and H 2 O (232 µL) was added N-ethyl-N-isopropylpropan-2-amine (97 µL, 0.557 mmol) followed by dropwise addition of ethanesulfonyl chloride (35.8 mg, 0.278 mmol) and the reaction mixture was stirred at r.t. for 30 min. The reaction mixture was diluted with water and acetonitrile and purified by prep-HPLC (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford the desired product as its TFA salt. LC-MS calculated for C19H 2 9N8O 3 S (M+H) + : m/z = 449.2; found 449.2. Example 89. N-((3R,4S)-1-(Cyclopropylsulfonyl)-3-methylpiperidin-4-yl)-5 - isopropoxy-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin -2-amine This compound was prepared according to the procedures described in Example 88, with cyclopropanesulfonyl chloride replacing ethanesulfonyl chloride in Step 2. LC-MS calculated for C20H 2 9N8O 3 S (M+H) + : m/z = 461.2; found 461.1. Table 5. The compounds in Table 5 were prepared in accordance with the synthetic protocols set forth in Example 88 using the appropriate starting materials. Example 100.5-Cyclobutoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)pipe ridin-4- yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amin e Step 1: 2-Bromo-5-cyclobutoxy-6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyrazine In an oven-dried vial with a stir bar, to a mixture of cyclobutanol (72.1 mg, 1.00 mmol) in 1,4-dioxane (2.00 mL) was added NaH (24.0 mg, 1.00 mmol) portionwise and the reaction mixture was stirred under nitrogen at r.t. for 15 min.2- Bromo-5-chloro-6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-[1,2,4] triazolo[1,5-a]pyrazine (Intermediate 6, 371.6 mg, 1.00 mmol) was added and the reaction mixture was stirred under nitrogen at r.t. for 15 min before the mixture was irradiated in a microwave reactor at 150 °C for 4 h. After cooling to r.t., the reaction mixture was concentrated and the crude residue was purified by flash column chromatography (20 g SiO 2 , EtOAc/hexanes). LC-MS calculated for C16H 2 0BrN6O 2 (M+H) + : m/z = 407.1; found 407.1. Step 2: 5-Cyclobutoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidi n-4-yl)-6-(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine In an oven-dried vial with a stir bar, a mixture of 2-bromo-5-cyclobutoxy-6- (1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]py razine (Step 1), (3R,4S)- 3-methyl-1-(methylsulfonyl)piperidin-4-amine (Intermediate 3, 192 mg, 1.00 mmol), methanesulfonato[2-(di-1-adamantylphosphino)-3,6-dimethoxy-2 ',4',6'-tri-i-propyl- 1,1'-biphenyl](2'-amino-1,1'-biphenyl-2-yl)palladium(II) (202 mg, 0.200 mmol), and sodium tert-butoxide (192 mg, 2.00 mmol) in 1,4-dioxane (5.00 mL) was sparged with nitrogen and stirred at 110 °C for 30 min. After cooling to r.t., the reaction mixture was diluted with MeOH (5 mL) and filtered over a SiliaPrep SPE silica-based thiol cartridge (2 g). A 4 M solution of HCl in dioxane (2.5 mL, 10.0 mmol) was added to the filtrate and the reaction mixture was stirred at r.t. for 15 min. The mixture was diluted with water, filtered, and purified by prep-HPLC (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford the desired product as its TFA salt. LC-MS calculated for C19H 2 7N8O 3 S (M+H) + : m/z = 447.2; found 447.2. Example 101.5-Isobutoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperi din-4- yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amin e This compound was prepared according to the procedures described in Example 100, with 2-methylpropan-1-ol replacing cyclobutanol in Step 1. LC-MS calculated for C19H 2 9N8O 3 S (M+H) + : m/z = 449.2; found 449.1. Example 102. N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-5-prop oxy- 6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine This compound was prepared according to the procedures described in Example 100, with propan-1-ol replacing cyclobutanol in Step 1. LC-MS calculated for C18H 2 7N8O 3 S (M+H) + : m/z = 435.2; found 435.2. Example 103.5-Butoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin -4-yl)-6- (1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine This compound was prepared according to the procedures described in Example 100, with butan-1-ol replacing cyclobutanol in Step 1. LC-MS calculated for C19H 2 9N8O 3 S (M+H) + : m/z = 449.2; found 449.2. Example 104.5-Isobutoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-p yrazol-4- yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine This compound was prepared according to the procedures described in Example 100, with 2-methylpropan-1-ol replacing cyclobutanol in Step 1 and 1- (methylsulfonyl)piperidin-4-amine replacing (3R,4S)-3-methyl-1- (methylsulfonyl)piperidin-4-amine in Step 2. LC-MS calculated for C18H 2 7N8O 3 S (M+H) + : m/z = 435.2; found 435.2. Example 105. N-(1-(Methylsulfonyl)piperidin-4-yl)-5-propoxy-6-(1H-pyrazol -4- yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine This compound was prepared according to the procedures described in Example 100, with propan-1-ol replacing cyclobutanol in Step 1 and 1- (methylsulfonyl)piperidin-4-amine replacing (3R,4S)-3-methyl-1- (methylsulfonyl)piperidin-4-amine in Step 2. LC-MS calculated for C17H 2 5N8O 3 S (M+H) + : m/z = 421.2; found 421.2. Example 106.5-Butoxy-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyra zol-4- yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine This compound was prepared according to the procedures described in Example 100, with butan-1-ol replacing cyclobutanol in Step 1 and 1- (methylsulfonyl)piperidin-4-amine replacing (3R,4S)-3-methyl-1- (methylsulfonyl)piperidin-4-amine in Step 2. LC-MS calculated for C18H 2 7N8O 3 S (M+H) + : m/z = 435.2; found 435.2. Table 6. The compounds in Table 6 were prepared in accordance with the synthetic protocols set forth in Example 100 using the appropriate starting materials.
Example 123.5-(Ethylthio)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H -pyrazol- 4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine Step 1: 2-Bromo-6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-5-(ethylthio)- [1,2,4]triazolo[1,5-a]pyrazine In an oven-dried microwave vial with a stir bar, to a mixture of ethanethiol (15.5 mg, 0.250 mmol) in 1,4-dioxane (0.50 mL) was added NaH (6.0 mg, 0.25 mmol) portionwise and the reaction mixture was stirred under nitrogen at r.t. for 15 min.2-Bromo-5-chloro-6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-[ 1,2,4]triazolo[1,5- a]pyrazine (Intermediate 6, 92.9 mg, 0.250 mmol) was added and the reaction mixture was stirred under nitrogen at r.t. for 15 min before the mixture was irradiated in a microwave reactor at 150 °C for 2 h. After cooling to r.t., the mixture was concentrated and the crude residue was purified by flash column chromatography (SiO 2 , EtOAc/hexanes). LC-MS calculated for C14H18BrN6OS (M+H) + : m/z = 397.0; found 397.1. Step 2: 5-(Ethylthio)-N-(1-(methylsulfonyl)piperidin-4-yl)-6-(1H-pyr azol-4-yl)- [1,2,4]triazolo[1,5-a]pyrazin-2-amine In an oven-dried vial with a stir bar, a mixture of 2-bromo-6-(1-(1- ethoxyethyl)-1H-pyrazol-4-yl)-5-(ethylthio)-[1,2,4]triazolo[ 1,5-a]pyrazine (Step 1), 1- (methylsulfonyl)piperidin-4-amine (44.6 mg, 0.250 mmol), methanesulfonato[2-(di-1- adamantylphosphino)-3,6-dimethoxy-2',4',6'-tri-i-propyl-1,1' -biphenyl](2'-amino-1,1'- biphenyl-2-yl)palladium(II) (50.5 mg, 0.050 mmol), and sodium tert-butoxide (24.0 mg, 0.250 mmol) in 1,4-dioxane (1.25 mL) was sparged with nitrogen and stirred at 110 °C for 30 min. After cooling to r.t., the reaction mixture was diluted with MeOH (1.25 mL) and filtered over a SiliaPrep SPE silica-based thiol cartridge (500 mg). To the filtrate was added a 4 M solution of HCl in 1,4-dioxane (625 µL, 2.50 mmol) and the reaction mixture was stirred at r.t. for 15 min. The mixture was diluted with water, filtered, and purified by prep-HPLC (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford the desired product as its TFA salt. LC-MS calculated for C16H 2 3N8O 2 S2 (M+H) + : m/z = 423.1; found 423.1. Example 124.5-(Isopropylthio)-N-(1-(methylsulfonyl)piperidin-4-yl)-6 -(1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine This compound was prepared according to the procedures described in Example 123, with propane-2-thiol replacing ethanethiol in Step 1. LC-MS calculated for C 17 H 25 N 8 O 2 S 2 (M+H) + : m/z = 437.2; found 437.1. Example 125. N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-5- (piperidin-1-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]p yrazin-2-amine Step 1: 2-Bromo-6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-5-(piperidin-1 -yl)- [1,2,4]triazolo[1,5-a]pyrazine To a mixture of 2-bromo-5-chloro-6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyrazine (Intermediate 6, 371.6 mg, 1.00 mmol) in DMSO (2.0 mL) was added piperidine (85.0 mg, 1.00 mmol), N-ethyl-N-isopropylpropan-2-amine (0.35 mL, 2.0 mmol), and CsF (152 mg, 1.00 mmol) and the reaction mixture was purged with nitrogen and irradiated in a microwave reactor at 150 °C for 2 h. After cooling to r.t., the reaction mixture was diluted with water and extracted with CH 2 Cl 2 . The combined organic phases were dried over MgSO 4 , concentrated, and the crude residue was purified by flash column chromatography (20 g SiO 2 , EtOAc/hexanes). LC-MS calculated for C17H 2 3BrN7O (M+H) + : m/z = 420.1; found 420.2. Step 2: N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(pip eridin-1-yl)-6- (1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine In an oven-dried vial with a stir bar, a mixture of 2-bromo-6-(1-(1- ethoxyethyl)-1H-pyrazol-4-yl)-5-(piperidin-1-yl)-[1,2,4]tria zolo[1,5-a]pyrazine (Step 1), (3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-amine (Intermediate 3, 192 mg, 1.00 mmol), methanesulfonato[2-(di-1-adamantylphosphino)-3,6-dimethoxy-2 ',4',6'- tri-i-propyl-1,1'-biphenyl](2'-amino-1,1'-biphenyl-2-yl)pall adium(II) (202 mg, 0.200 mmol), and sodium tert-butoxide (192 mg, 2.00 mmol) in 1,4-dioxane (5.0 mL) was sparged with nitrogen and stirred at 110 °C for 30 min. After cooling to r.t., the reaction mixture was diluted with MeOH (5 mL) and filtered over a SiliaPrep SPE silica-based thiol cartridge (2 g). A 4 M solution of HCl in 1,4-dioxane (2.5 mL, 10.0 mmol) was added to the filtrate and the reaction mixture was stirred at r.t. for 30 min. The mixture was diluted with water, filtered, and purified by prep-HPLC (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford the desired product as its TFA salt. LC-MS calculated for C20H30N9O 2 S (M+H) + : m/z = 460.2; found 460.2. 1 H NMR (TFA salt, 600 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.18 (s, 2H), 7.11 (d, J = 8.4 Hz, 1H), 4.01 – 3.94 (m, 1H), 3.35 – 3.20 (m, 5H), 3.20 – 3.08 (m, 3H), 2.87 (s, 3H), 2.25 – 2.18 (m, 1H), 1.90 – 1.76 (m, 2H), 1.76 – 1.69 (m, 4H), 1.67 – 1.58 (m, 2H), 0.92 (d, J = 6.9 Hz, 3H). Example 126. N-(1-(Methylsulfonyl)piperidin-4-yl)-5-(piperidin-1-yl)-6-(1 H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine This compound was prepared according to the procedures described in Example 125, with 1-(methylsulfonyl)piperidin-4-amine replacing (3R,4S)-3-methyl- 1-(methylsulfonyl)piperidin-4-in Step 2. LC-MS calculated for C19H 2 8N9O 2 S (M+H) + : m/z = 446.2; found 446.2. Example 127.5-(3,3-Difluoropiperidin-1-yl)-N-((3R,4S)-3-methyl-1- (methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]t riazolo[1,5-a]pyrazin- 2-amine This compound was prepared according to the procedures described in Example 125, with 3,3-difluoropiperidine hydrochloride replacing piperidine in Step 1. LC-MS calculated for C20H 2 8F 2 N9O 2 S (M+H) + : m/z = 496.2; found 496.3. Example 128. (R)-5-(3-Fluoropiperidin-1-yl)-N-(1-(methylsulfonyl)piperidi n-4- yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amin e This compound was prepared according to the procedures described in Example 125, with (R)-3-fluoropiperidine hydrochloride replacing piperidine in Step 1 and 1-(methylsulfonyl)piperidin-4-amine replacing (3R,4S)-3-methyl-1- (methylsulfonyl)piperidin-4-amine in Step 2. LC-MS calculated for C19H 2 7FN9O 2 S (M+H) + : m/z = 464.2; found 464.1. Example 129. (S)-5-(3-Fluoropiperidin-1-yl)-N-(1-(methylsulfonyl)piperidi n-4- yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amin e This compound was prepared according to the procedures described in Example 125, with (S)-3-fluoropiperidine hydrochloride replacing piperidine in Step 1 and 1-(methylsulfonyl)piperidin-4-amine replacing (3R,4S)-3-methyl-1- (methylsulfonyl)piperidin-4-amine in Step 2. LC-MS calculated for C19H 2 7FN9O 2 S (M+H) + : m/z = 464.2; found 464.1. Example 130.5-(3,3-Difluoropyrrolidin-1-yl)-N-(1-(methylsulfonyl)pip eridin-4- yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amin e This compound was prepared according to the procedures described in Example 125, with 3,3-difluoropyrrolidine replacing piperidine in Step 1 and 1- (methylsulfonyl)piperidin-4-amine replacing (3R,4S)-3-methyl-1- (methylsulfonyl)piperidin-4-amine in Step 2. LC-MS calculated for C18H 2 4F 2 N9O 2 S (M+H) + : m/z = 468.2; found 468.3. Example 131.5-(2-Azabicyclo[2.2.1]heptan-2-yl)-N-(1-(methylsulfonyl) piperidin- 4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-am ine This compound was prepared according to the procedures described in Example 125, with 2-azabicyclo[2.2.1]heptane hydrochloride replacing piperidine in Step 1 and 1-(methylsulfonyl)piperidin-4-amine replacing (3R,4S)-3-methyl-1- (methylsulfonyl)piperidin-4-amine in Step 2. LC-MS calculated for C20H 2 8N9O 2 S (M+H) + : m/z = 458.2; found 458.1. Example 132. (S)-5-(2-Methylpiperidin-1-yl)-N-(1-(methylsulfonyl)piperidi n-4- yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amin e This compound was prepared according to the procedures described in Example 125, with (S)-2-methylpiperidine replacing piperidine in Step 1 and 1- (methylsulfonyl)piperidin-4-amine replacing (3R,4S)-3-methyl-1- (methylsulfonyl)piperidin-4-amine in Step 2. LC-MS calculated for C20H30N9O 2 S (M+H) + : m/z = 460.2; found 460.2. Example 133. (S)-5-(2-Methylpyrrolidin-1-yl)-N-(1-(methylsulfonyl)piperid in-4- yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amin e This compound was prepared according to the procedures described in Example 125, with (S)-2-methylpyrrolidine replacing piperidine in Step 1 and 1- (methylsulfonyl)piperidin-4-amine replacing (3R,4S)-3-methyl-1- (methylsulfonyl)piperidin-4-amine in Step 2. LC-MS calculated for C19H 2 8N9O 2 S (M+H) + : m/z = 446.2; found 446.1. Example 134. (S)-5-(3-(Difluoromethyl)pyrrolidin-1-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]t riazolo[1,5-a]pyrazin- 2-amine This compound was prepared according to the procedures described in Example 125, with (S)-3-(difluoromethyl)pyrrolidine hydrochloride replacing piperidine in Step 1 and 1-(methylsulfonyl)piperidin-4-amine replacing (3R,4S)-3- methyl-1-(methylsulfonyl)piperidin-4-amine in Step 2. LC-MS calculated for C19H 2 6F 2 N9O 2 S (M+H) + : m/z = 482.2; found 482.3. Example 135.5-(7-Azabicyclo[2.2.1]heptan-7-yl)-N-(1-(methylsulfonyl) piperidin- 4-yl)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-am ine This compound was prepared according to the procedures described in Example 125, with 7-azabicyclo[2.2.1]heptane hydrochloride replacing piperidine in Step 1 and 1-(methylsulfonyl)piperidin-4-amine replacing (3R,4S)-3-methyl-1- (methylsulfonyl)piperidin-4-amine in Step 2. LC-MS calculated for C20H 2 8N9O 2 S (M+H) + : m/z = 458.2; found 458.3. Example 136. N-(1-(Methylsulfonyl)piperidin-4-yl)-6-(1H-pyrazol-4-yl)-5-( 3- (trifluoromethyl)piperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyraz in-2-amine This compound was prepared according to the procedures described in Example 125, with 3-(trifluoromethyl)piperidine replacing piperidine in Step 1 and 1- (methylsulfonyl)piperidin-4-amine replacing (3R,4S)-3-methyl-1- (methylsulfonyl)piperidin-4-amine in Step 2. LC-MS calculated for C20H 2 7F3N9O 2 S (M+H) + : m/z = 514.2; found 514.2. Example 137. N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-5-((pr opan- 2-yl-2-d)oxy)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyra zin-2-amine This compound was prepared according to the procedures described in Example 100, with propan-2-d-2-ol replacing cyclobutanol in Step 1. LC-MS calculated for C18H 2 6DN8O 3 S (M+H) + : m/z = 436.2; found 436.3. Example 138. N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-5-((pr opan- 2-yl-1,1,1,3,3,3-d6)oxy)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo [1,5-a]pyrazin-2-amine This compound was prepared according to the procedures described in Example 100, with propan-1,1,1,3,3,3-d6-2-ol replacing cyclobutanol in Step 1. LC- MS calculated for C18H 2 1D6N8O 3 S (M+H) + : m/z = 441.2; found 441.4. Example 139. N-((3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-yl)-5-((pr opan- 2-yl-d 7 )oxy)-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazi n-2-amine This compound was prepared according to the procedures described in Example 100, with propan-d7-2-ol replacing cyclobutanol in Step 1. LC-MS calculated for C18H 2 0D7N8O 3 S (M+H) + : m/z = 442.2; found 442.3. Table 7. The compounds in Table 7 were prepared in accordance with the synthetic protocols set forth in Example 100 using the appropriate starting materials. Example A. CDK2/Cyclin E1 HTRF Enzyme Activity Assay CDK2/Cyclin E1 enzyme activity assays utilize full-length human CDK2 co- expressed as N-terminal GST-tagged protein with FLAG-Cyclin E1 in a baculovirus expression system (Carna Product Number 04-165). Assays were conducted in white 384-well polystyrene plates in a final reaction volume of 8 µL. CDK2/Cyclin E1 (0.25 nM) was incubated with the compounds of the Examples (40 nL serially diluted in DMSO) in the presence of ATP (50 µM or 1 mM) and 50 nM ULight™-labeled eIF4E-binding protein 1 (THR37/46) peptide (PerkinElmer) in assay buffer (containing 50 mM HEPES pH 7.5, 1 mM EGTA, 10 mM MgCl 2 , 2 mM DTT, 0.05 mg/mL BSA, and 0.01% Tween 20) for 60 minutes at room temperature. The reactions were stopped by the addition of EDTA and Europium-labeled anti-phospho- 4E-BP1 antibody (PerkinElmer), for a final concentration of 15 mM and 1.5 nM, respectively. HTRF signals were read after 1 hour at room temperature on a PHERAstar FS plate reader (BMG Labtech). Data was analyzed with IDBS XLFit and GraphPad Prism 5.0 software using a three or four parameter dose response curve to determine IC50 for each compound. The IC50 data as measured for the compounds of the Examples at 1 mM ATP in the assay of Example A is shown in Table 8. Table 8
+ refers to ≤ 20 nM Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.