CHEN YINGNAN (US)
FAVATA MARGARET (US)
LO YVONNE (US)
YE QINDA (US)
LI JINGWEI (US)
MUKAI KEN (US)
SMITH BRANDON (US)
WU LIANGXING (US)
YAO WENQING (US)
YE MIN (US)
CHEN YINGNAN (US)
FAVATA MARGARET (GB)
LO YVONNE (US)
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US7488802B2 | 2009-02-10 | |||
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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; Ring moiety A is 4-14 membered heterocycloalkyl, wherein Ring moiety A is attached to the -NH- group of Formula (I) at a ring member of a saturated or partially aturated ring of said 4-14 membered heterocycloalkyl; R1 is 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; R2, R3, and R4 are defined as shown in Group (a), Group (b), or Group (c); Group (a): R2 is selected from H, D, halo, CN, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, OH, C1-4 alkoxy, C1-4 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; R3 is 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; and R4 is 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, 5-10 membered heteroaryl-C1-4 alkyl, C(O)Rb4, C(O)NRc4Rd4, C(O)NRc4(ORa4), C(O)ORa4, C(=NRe4)Rb4, C(=NRe4)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4; wherein said C1-6 alkyl, C1-6 haloalkyl C26 alkenyl C2 6 alkynyl C310 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; Group (b): R2 is 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, ORa2, SRa2, NHORa2, C(O)Rb2, C(O)NRc2Rd2, C(O)NRc2(ORa2), C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(=NRe2)Rb2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2C(=NRe2)Rb2, NRc2S(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2S(O)(=NRe2)Rb2, NRc2S(O)2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, S(O)2NRc2Rd2, OS(O)(=NRe2)Rb2, OS(O)2Rb2, S(O)(=NRe2)Rb2, SF5, P(O)Rf2Rg2, OP(O)(ORh2)(ORi2), P(O)(ORh2)(ORi2), and BRj2Rk2; 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 R2A substituents; R3 is 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; and R4 is selected from H, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, cyano-C1-4 alkyl, HO-C1-4 alkyl, C1-3 alkoxy-C1-4 alkyl, and C3-4 cycloalkyl; Group (c): R2 is 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 C13 alkylamino, di(C1-3 alkyl)amino, cyano-C1-4 alkyl, HO-C1-4 alkyl, C1-3 alkoxy- C1-4 alkyl, and C3-4 cycloalkyl; and R3 and R4, together with the atoms to which they are attached, form a 5-7 membered heterocycloalkyl ring, which is optionally substituted by 1, 2, 3, or 4 independently selected R4A substituents; each Ra2, Rc2, and Rd2 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 aid 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 4ndependently selected R2A substituents; or, any Rc2 and Rd2 attached to the same N atom, together with the N atom to whichhey are attached, form a 4-10 membered heterocycloalkyl group, which is optionally ubstituted with 1, 2, 3, or 4 independently selected R2A substituents; each Rb2 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 R2A substituents; each Re2 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 Rf2 and Rg2 is 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 Rh2 and Ri2 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 Rj2 and Rk2 is independently selected from OH, C1-6 alkoxy, and C1-6 haloalkoxy; or any Rj2 and Rk2 attached to the same B atom, together with the B atom to whichhey 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 R2A is independently selected from 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, ORa21, SRa21, NHORa21, C(O)Rb21, C(O)NRc21Rd21, C(O)NRc21(ORa21), C(O)ORa21, OC(O)Rb21, OC(O)NRc21Rd21, NRc21Rd21, NRc21NRc21Rd21, NRc21C(O)Rb21, NRc21C(O)ORa21, NRc21C(O)NRc21Rd21, C(=NRe21)Rb21, C(=NRe21)NRc21Rd21, NRc21C(=NRe21)NRc21Rd21, NRc21C(=NRe21)Rb21, NRc21S(O)NRc21Rd21, NRc21S(O)Rb21, NRc21S(O)2Rb21, NRc21S(O)(=NRe21)Rb21, NRc21S(O)2NRc21Rd21, S(O)Rb21, S(O)NRc21Rd21, S(O)2Rb21, S(O)2NRc21Rd21, OS(O)(=NRe21)Rb21, OS(O)2Rb21, S(O)(=NRe21)Rb21, SF5, P(O)Rf21Rg21, OP(O)(ORh21)(ORi21), P(O)(ORh21)(ORi21), and BRj21Rk21, 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 R2B ubstituents; each Ra21, Rc21, and Rd21 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 R2B substituents; or, any Rc21 and Rd21 attached to the same N atom, together with the N atom to whichhey are attached, form a 4-7 membered heterocycloalkyl group, which is optionally ubstituted with 1, 2, 3, or 4 independently selected R2B substituents; each Rb21 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 R2B substituents; each Re21 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 Rf21 and Rg21 is 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 Rh21 and Ri21 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 Rj21 and Rk21 is independently selected from OH, C1-6 alkoxy, and C1-6 haloalkoxy; or any Rj21 and Rk21 attached to the same B atom, together with the B atom to whichhey 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 R2B is independently selected from 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, ORa22, SRa22, NHORa22, C(O)Rb22, C(O)NRc22Rd22, C(O)NRc22(ORa22), C(O)ORa22, OC(O)Rb22, OC(O)NRc22Rd22, NRc22Rd22, NRc22NRc22Rd22, NRc22C(O)Rb22 NRc22C(O)ORa22 NRc22C(O)NRc22Rd22, C(=NRe22)Rb22, C(=NRe22)NRc22Rd22, NRc22C(=NRe22)NRc22Rd22, NRc22C(=NRe22)Rb22, NRc22S(O)NRc22Rd22, NRc22S(O)Rb22, NRc22S(O)2Rb22, NRc22S(O)(=NRe22)Rb22, NRc22S(O)2NRc22Rd22, S(O)Rb22, S(O)NRc22Rd22, S(O)2Rb22, S(O)2NRc22Rd22, OS(O)(=NRe22)Rb22, OS(O)2Rb22, S(O)(=NRe22)Rb22, SF5, P(O)Rf22Rg22, OP(O)(ORh22)(ORi22), P(O)(ORh22)(ORi22), and BRj22Rk22, 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 ubstituted with 1, 2, 3, or 4 independently selected R2C substituents; each Ra22, Rc22, and Rd22 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 R2C substituents; or, any Rc22 and Rd22 attached to the same N atom, together with the N atom to whichhey are attached, form a 4-7 membered heterocycloalkyl group, which is optionally ubstituted with 1, 2, 3, or 4 independently selected R2C substituents; each Rb22 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 4ndependently selected R2C substituents; each Re22 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 Rf22 and Rg22 is 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 Rh22 and Ri22 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 Rj22 and Rk22 is independently selected from OH, C1-6 alkoxy, and C1-6 haloalkoxy; or any Rj22 and Rk22 attached to the same B atom, together with the B atom to whichhey 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 R2C is independently selected from 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, ORa23, SRa23, NHORa23, C(O)Rb23, C(O)NRc23Rd23, C(O)NRc23(ORa23), C(O)ORa23, OC(O)Rb23, OC(O)NRc23Rd23, NRc23Rd23, NRc23NRc23Rd23, NRc23C(O)Rb23, NRc23C(O)ORa23, NRc23C(O)NRc23Rd23, C(=NRe23)Rb23, C(=NRe23)NRc23Rd23, NRc23C(=NRe23)NRc23Rd23, NRc23C(=NRe23)Rb23, NRc23S(O)NRc23Rd23, NRc23S(O)Rb23, NRc23S(O)2Rb23, NRc23S(O)(=NRe23)Rb23, NRc23S(O)2NRc23Rd23, S(O)Rb23, S(O)NRc23Rd23, S(O)2Rb23, S(O)2NRc23Rd23, OS(O)(=NRe23)Rb23, OS(O)2Rb23, S(O)(=NRe23)Rb23, SF5, P(O)Rf23Rg23, OP(O)(ORh23)(ORi23), P(O)(ORh23)(ORi23), and BRj23Rk23, 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 ubstituted with 1, 2, 3, or 4 independently selected RG substituents; each Ra23, Rc23, and Rd23 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 Rc23 and Rd23 attached to the same N atom, together with the N atom to whichhey are attached, form a 4-7 membered heterocycloalkyl group, which is optionally ubstituted with 1, 2, 3, or 4 independently selected RG substituents; each Rb23 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 4ndependently selected RG substituents; each Re23 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 Rf23 and Rg23 is 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 Rh23 and Ri23 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 Rj23 and Rk23 is independently selected from OH, C1-6 alkoxy, and C1-6 haloalkoxy; or any Rj23 and Rk23 attached to the same B atom, together with the B atom to whichhey 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 Ra4, Rc4, and Rd4 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 aid 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 4ndependently selected R4A substituents; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to whichhey are attached, form a 4-10 membered heterocycloalkyl group, which is optionally ubstituted with 1, 2, 3, or 4 independently selected R4A substituents; each Rb4 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 R4A substituents; each Re4 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 R4A is independently selected from 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 ubstituents; 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 whichhey are attached, form a 4-7 membered heterocycloalkyl group, which is optionally ubstituted 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, C3-10 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 is 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 whichhey 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 R4B is independently selected from 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 ubstituted 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 whichhey are attached, form a 4-7 membered heterocycloalkyl group, which is optionally ubstituted 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 4ndependently 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 is 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 whichhey 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 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 ubstituted 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 whichhey are attached, form a 4-7 membered heterocycloalkyl group, which is optionally ubstituted 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 4ndependently 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 is 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 whichhey 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; RZ is selected from R5 and NR5R5Z; R5 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 R5A substituents; R5Z is selected from H, C1-6 alkyl, and C1-6 haloalkyl; or, alternatively, R5 and R5Z, together with the nitrogen atom to which they are attached, form a 4-7 membered heterocycloalkyl ring, which is optionally substituted with 1, 2, 3, or 4 independently selected R5A substituents; 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 ubstituents; 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 whichhey 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 elected 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, C3-7 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 Rf51 and Rg51 is 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 whichhey 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 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 ubstituted 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 whichhey 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 R5C ubstituents; 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 4ndependently 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 is 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 whichhey 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 ubstituted 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 whichhey 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 ubstituents; 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 4ndependently 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 is 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 whichhey 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 R6 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; R7 is 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; 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- 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 halo, CN, or C1-3 haloalkyl. 3. The compound of any one of claims 1-2, or a pharmaceutically acceptable salthereof, wherein R7 is H. 4. The compound of any one of claims 1-5, or a pharmaceutically acceptable salthereof, wherein n is 0 or 1. 5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salthereof, wherein R5 is selected from C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membe d h t l C l lk l C lk l, 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 by 1, 2, or 3 independently selected R5A substituents. 6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salthereof, wherein: each R5A is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C3-4 cycloalkyl, ORa51, and NRc51Rd51, wherein said C1-6 alkyl, C1-6 haloalkyl, and C3-4 cycloalkyl are each optionally substituted with 1 or 2 independently selected R5B substituents; each Ra51, Rc51, and Rd51 is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl; and each R5B is independently selected from H, halo, CN, OH, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino. 7. The compound of any one of claims 1-5, or a pharmaceutically acceptable salthereof, wherein: each R5A is independently selected from H, halo, CN, C1-3 alkyl, C1-3 haloalkyl, and NRc51Rd51; and each Rc51 and Rd51 is independently selected from H and C1-3 alkyl. 8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salthereof, wherein R2, R3, and R4 are defined as in Group (a). 9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salthereof, wherein R2 is H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, cyano-C1-4 alkyl, HO-C1-4 alkyl, or C1-3 alkoxy-C1-4 alkyl. 10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salthereof, wherein R4 is 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 b d l C lk l 410 bered 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. 11. The compound of any one of claims 1-9, or a pharmaceutically acceptable salthereof, wherein R4 is selected from H, C1-6 alkyl, C1-6 haloalkyl, phenyl, 4-9 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-9 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl; wherein said C1-6 alkyl, C1-6 haloalkyl, phenyl, 4-9 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-9 membered heterocycloalkyl-C1-4 alkyl, and 5- 6 membered heteroaryl-C1-4 alkyl are each optionally substituted by 1, 2, or 3 independently elected R4A substituents. 12. The compound of any one of claims 1-9, or a pharmaceutically acceptable salthereof, wherein R4 is selected from H, C1-6 alkyl, C1-6 haloalkyl, phenyl, tetrahydropyranyl, pyridyl, pyrazolyl, isobenzofuran-1(3H)-one, and cyclopropylmethyl, wherein said C1-6 alkyl, C1-6 haloalkyl, phenyl, tetrahydropyranyl, pyridyl, pyrazolyl, isobenzofuran-1(3H)-one, and cyclopropylmethyl are each optionally substituted by 1, 2, or 3 independently selected R4A ubstituents. 13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salthereof, wherein: each R4A is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-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)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, C3-7 cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl C3 7 cycloalkyl-C1 4 alkyl phenyl-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, or 3 independently selected R4B substituents; each Ra41, Rc41, and Rd41 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-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, C3-7 cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-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, or 3 independently selected R4B substituents; each Rb41 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-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, or 3 independently elected R4B substituents; each R4B is independently selected from H, D, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C3- 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)ORa42, OC(O)Rb42, OC(O)NRc42Rd42, NRc42Rd42, NRc42C(O)Rb42, NRc42C(O)ORa42, NRc42C(O)NRc42Rd42, NRc42S(O)2Rb42, NRc42S(O)2NRc42Rd42, S(O)2Rb42, and S(O)2NRc42Rd42, 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, or 3 independently selected R4C substituents; each Ra42, Rc42, and Rd42 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, or 3 independently selected R4C ubstituents; each Rb42 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, or 3 independently selected R4C ubstituents; and each R4C is independently selected from H, D, halo, CN, OH, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino. 14. The compound of any one of claims 1-12, or a pharmaceutically acceptable salthereof, wherein: each R4A is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl-C1- alkyl, 5-10 membered heteroaryl-C1-4 alkyl, ORa41, C(O)NRc41Rd41, NRc41Rd41, and NRc41C(O)Rb41, wherein said C1-6 alkyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, or 3 independently selected R4B ubstituents; each Ra41, Rc41, and Rd41 is independently selected from H and C1-6 alkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected R4B substituents; each Rb41 is independently selected from C1-6 alkyl, which is optionally substituted with 1, 2, or 3 independently selected R4B substituents; each R4B is independently selected from H, D, halo, CN, C1-6 alkyl, 4-7 membered heterocycloalkyl, C3-7 cycloalkyl-C1-4 alkyl, ORa42, NRc42Rd42, and NRc42C(O)Rb42, wherein aid C1-6 alkyl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 independently selected R4C substituents; each Ra42, Rc42, and Rd42 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, and C3-7 cycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, and C3-7 cycloalkyl-C1-4 alkyl are each optionally substituted with 1, 2, or 3 independently selected R4C ubstituents; each Rb42 is independently selected from C1-6 alkyl, which is optionally substituted with 1, 2, or 3 independently selected R4C substituents; and each R4C is independently selected from D CN OH and C1 3 alkyl 15. The compound of any one of claims 1-12, or a pharmaceutically acceptable salthereof, wherein: each R4A 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-C1-4 alkyl, phenyl-C1-4 alkyl, 4-7 membered heterocycloalkyl-C1-4 alkyl, 5-6 membered heteroaryl-C1-4 alkyl, ORa41, SRa41, NHORa41, 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, 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, or 3 independently selected R4B substituents; each Ra41, Rc41, and Rd41 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, or 3 independently selected R4B ubstituents; each Rb41 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, or 3 independently selected R4B ubstituents; and each R4B is independently selected from H, halo, CN, OH, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino. 16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; Ring moiety A is an azetidine ring, a pyrrolidine ring, a piperidine ring, or an azepane ing; R1 is H, halo, CN, C1-3 alkyl, or C1-3 haloalkyl; R2 is H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, cyano-C1-4 alkyl, HO-C1-4 alkyl, or C1-3 alkoxy-C1-4 alkyl; R3 is H, halo, CN, C1-3 alkyl, or C1-3 haloalkyl; R4 is 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 by 1, 2, 3, or 4 independently selected R4A substituents; each R4A is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C3-4 cycloalkyl, ORa41, SRa41, 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 3ndependently selected R4B substituents; each Ra41, Rc41, and Rd41 is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl, and C1-6 haloalkyl are optionally substituted with 1 or 2ndependently selected R4B substituents; each Rb41 is independently selected from C1-6 alkyl and C1-6 haloalkyl, which are each optionally substituted with 1 or 2 independently selected R4B substituents; each R4B is independently selected from H, halo, CN, OH, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; RZ is R5; R5 is 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; 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 ubstituted by 1, 2, or 3 independently selected R5A substituents; each R5A is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C3-4 cycloalkyl, ORa51, and NRc51Rd51, wherein said C1-6 alkyl, C1-6 haloalkyl, and C3-4 cycloalkyl are each optionally substituted with 1 or 2 independently selected R5B substituents; each Ra51, Rc51, and Rd51 is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl; each R5B is independently selected from H, halo, CN, OH, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; each R6 is independently H, halo, C1-3 alkyl, or C1-3 haloalkyl; and R7 is H. 17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: n is 0 or 1; Ring moiety A is a piperidine ring; R1 is halo, CN, C1-3 alkyl, or C1-3 haloalkyl; R2 is H, halo, C1-6 alkyl, C1-6 haloalkyl, or HO-C1-6 alkyl; R3 is H, halo, CN, C1-3 alkyl, or C1-3 haloalkyl; R4 is selected from H, C1-6 alkyl, C1-6 haloalkyl, phenyl, 4-9 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-9 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl; wherein said C1-6 alkyl, C1-6 haloalkyl, phenyl, 4-9 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-9 membered heterocycloalkyl-C1-4 alkyl, and 5- 6 membered heteroaryl-C1-4 alkyl are each optionally substituted by 1, 2, or 3 independently elected R4A substituents; each R4A is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-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)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, C3-7 cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-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, or 3 independently selected R4B substituents; each Ra41, Rc41, and Rd41 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-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, C3-7 cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-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, or 3 independently selected R4B substituents; each Rb41 is independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-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, or 3 independently elected R4B substituents; each R4B is independently selected from H, D, halo, CN, C1-6 alkyl, C1-6 haloalkyl, C3- 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)ORa42, OC(O)Rb42, OC(O)NRc42Rd42, NRc42Rd42, NRc42C(O)Rb42, NRc42C(O)ORa42, NRc42C(O)NRc42Rd42, NRc42S(O)2Rb42, NRc42S(O)2NRc42Rd42, S(O)2Rb42, and S(O)2NRc42Rd42, 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, or 3 independently selected R4C substituents; each Ra42, Rc42, and Rd42 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, or 3 independently selected R4C ubstituents; each Rb42 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, or 3 independently selected R4C ubstituents; each R4C is independently selected from H, D, halo, CN, OH, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, amino, C1-3 alkylamino, and di(C1-3 alkyl)amino; RZ is NR5R5Z or R5; R5Z is H or methyl; R5 is 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; 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 ubstituted by 1, 2, or 3 independently selected R5A substituents; each R5A is independently selected from H, halo, CN, C1-3 alkyl, C1-3 haloalkyl, and NRc51Rd51; each Rc51 and Rd51 is independently selected from H and C1-3 alkyl; each R6 is independently H, halo, C1-3 alkyl, or C1-3 haloalkyl; and R7 is H. 18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: n is 0 or 1; Ring moiety A is a piperidine ring; R1 is halo, CN, C1-3 alkyl, or C1-3 haloalkyl; R2 is H, halo, C1-6 alkyl, C1-6 haloalkyl, or HO-C1-6 alkyl; R3 is H, halo, CN, C1-3 alkyl, or C1-3 haloalkyl; R4 is selected from C1-6 alkyl, C1-6 haloalkyl, phenyl, 4-9 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-9 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl; wherein said C1-6 alkyl, C1-6 haloalkyl, phenyl, 4-9 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-7 cycloalkyl-C1-4 alkyl, phenyl-C1-4 alkyl, 4-9 membered heterocycloalkyl-C1-4 alkyl, and 5-6 membered heteroaryl-C1-4 alkyl are each optionally substituted by 1, 2, or 3 independently elected R4A substituents; each R4A is independently selected from H, halo, CN, C1-6 alkyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl-C1- alkyl, 5-10 membered heteroaryl-C1-4 alkyl, ORa41, C(O)NRc41Rd41, NRc41Rd41, and NRc41C(O)Rb41, wherein said C1-6 alkyl, C1-6 haloalkyl, 4-10 membered heterocycloalkyl, 5- 10 membered heteroaryl, 4-10 membered heterocycloalkyl-C1-4 alkyl, and 5-10 membered heteroaryl-C1-4 alkyl are each optionally substituted with 1, 2, or 3 independently selected R4B ubstituents; each Ra41, Rc41, and Rd41 is independently selected from H and C1-6 alkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected R4B substituents; each Rb41 is independently selected from C1-6 alkyl, which is optionally substituted with 1, 2, or 3 independently selected R4B substituents; each R4B is independently selected from H, D, halo, CN, C1-6 alkyl, 4-7 membered heterocycloalkyl, C3-7 cycloalkyl-C1-4 alkyl, ORa42, NRc42Rd42, and NRc42C(O)Rb42, wherein aid C1-6 alkyl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 independently selected R4C substituents; each Ra42, Rc42, and Rd42 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, and C3-7 cycloalkyl-C1-4 alkyl, wherein said C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, 4-7 membered heterocycloalkyl, and C3-7 cycloalkyl-C1-4 alkyl are each optionally substituted with 1, 2, or 3 independently selected R4C ubstituents; each Rb42 is independently selected from C1-6 alkyl, which is optionally substituted with 1, 2, or 3 independently selected R4C substituents; each R4C is independently selected from D, CN, OH, and C1-3 alkyl; RZ is NR5R5Z or R5; R5Z is H or methyl; R5 is selected from C1-6 alkyl, C3-7 cycloalkyl, and 5-6 membered heteroaryl, each of which is optionally substituted by 1, 2, or 3 independently selected R5A substituents; each R5A is independently selected from CH3 and NH2; each R6 is selected from H, halo, or C1-3 haloalkyl; and R7 is H. 19. The compound of any one of claims 1-15 and 17-18, or a pharmaceutically acceptable alt thereof, wherein RZ is NR5R5Z. 20. The compound of any one of claims 1-15 and 17-18, or a pharmaceutically acceptable alt thereof, wherein RZ is N(CH3)2, NH(CH3), or NH(cyclopropyl). 21. The compound of any one of claims 1-18, or a pharmaceutically acceptable salthereof, wherein RZ is R5. 22. The compound of any one of claims 1-18, having Formula (II): or a pharmaceutically acceptable salt thereof. 23. The compound of any one of claims 1-18, wherein the moiety elected from: . 24. The compound of any one of claims 1-18 and 21-23, or a pharmaceutically acceptable alt thereof, wherein R5 is selected from C1-3 alkyl, C3-6 cycloalkyl, and 5-6 membered heteroaryl; wherein said C1-3 alkyl, C3-7 cycloalkyl, and 5-6 membered heteroaryl are each optionally substituted by 1 or 2 independently selected R5A substituents. 25. The compound of any one of claims 1-18 and 21-23, or a pharmaceutically acceptable alt thereof, wherein R5 is methyl, ethyl, cyclopropyl, imidazolyl, pyrazolyl, pyridinyl, and pyrimidinyl, each of which is optionally substituted by 1, 2, or 3 independently selected R5A ubstituents. 26. The compound of any one of claims 1-18 and 21-25, or a pharmaceutically acceptable alt thereof, wherein each R5A is independently selected from CH3 and NH2. 27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salthereof, wherein R1 is Cl, CN, or CF3. 28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salthereof, wherein Ring moiety A is piperidin-4-yl. 29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salthereof, wherein R3 is H, F, Cl, Br, CN, or CH3. 30. The compound of any one of claims 1-28, or a pharmaceutically acceptable salthereof, wherein R3 is H, Cl, Br, CN, or CH3. 31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salthereof, wherein R2 is H, halo, C1-4 alkyl, or HO-C1-4 alkyl. 32. The compound of claim 1, selected from: 3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 3-chloro-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 4-(1-(2-chloro-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 3-chloro-4-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 3-chloro-2-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 4-(1-(2-amino-5-fluoropyridin-4-yl)-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-imidazol- 4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 3-methyl-4-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile; N-(3-methyl-4-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)pyridin-2-yl)acetamide; 4-(1-(2-amino-3-methylpyridin-4-yl)-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-midazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-methyl-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- trifluoromethyl)pyrimidin-2-amine; 4-(2,5-dichloro-1-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- trifluoromethyl)pyrimidin-2-amine; 4-(5-bromo-1-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- trifluoromethyl)pyrimidin-2-amine; 4-(5-chloro-1-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- trifluoromethyl)pyrimidin-2-amine; 4-(1,5-dimethyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- trifluoromethyl)pyrimidin-2-amine; 1-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazole-5-carbonitrile; (1-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-2-yl)methanol; 2-methyl-1-(1-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-2-yl)propan-2-ol; 4-(1,2-dimethyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- trifluoromethyl)pyrimidin-2-amine; 4-(5-chloro-1-methyl-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2,2-difluoroethyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- trifluoromethyl)pyrimidin-2-amine; 2-methyl-1-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)propan-2-ol; N-(1-(methylsulfonyl)piperidin-4-yl)-4-(1-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl)-5- trifluoromethyl)pyrimidin-2-amine; N-(1-(methylsulfonyl)piperidin-4-yl)-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4- yl)-5-(trifluoromethyl)pyrimidin-2-amine; 3-cyclopropyl-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)propanenitrile; 4-(1-(2,2-difluoroethyl)-1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4- yl)amino)pyrimidine-5-carbonitrile; 4-(1-(2-hydroxy-2-methylpropyl)-1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin- 4-yl)amino)pyrimidine-5-carbonitrile; 4-(1-(2-chloro-4-cyanophenyl)-1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4- yl)amino)pyrimidine-5-carbonitrile; N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-4-(1-(2,2-difluoroethyl)-1H-imidazol-4-yl)- 5-(trifluoromethyl)pyrimidin-2-amine; 1-(4-(2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol; 2-(4-(2-((1-(Methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-1H-imidazol-1-yl)benzonitrile; N-(1-(Methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)-4-(1-(2- trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)pyrimidin-2-amine; 6-Methyl-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile; 3-(4-(2-((1-(Methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-1H-imidazol-1-yl)picolinonitrile; and 3-Methyl-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; or a pharmaceutically acceptable salt thereof. 33. The compound of claim 1, selected from: 6-methyl-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile; 4-(1-(2-(difluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-imidazol-1-yl)-2-(trifluoromethyl)benzonitrile; 6-methoxy-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile; 6-(2-(dimethylamino)ethoxy)-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile; 6-ethyl-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile; 3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylbenzonitrile; 2-methyl-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 4-(1-(6-methyl-2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 2-chloro-3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(6-methyl-2- trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile; N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)-4-(1-(2- trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)pyrimidin-2-amine; 5-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-methylpicolinonitrile; 4-(1-(2-(difluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-methylpicolinonitrile; 3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-methoxypicolinonitrile; 6-(2-(dimethylamino)ethoxy)-3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile; 4-(1-(2-chloro-6-fluorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4- yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- trifluoromethyl)pyrimidin-2-amine; 2-fluoro-6-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 4-fluoro-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-imidazol-1-yl)isophthalonitrile; 4-(1-(2,3-dichlorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- trifluoromethyl)pyrimidin-2-amine; 2-methyl-6-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 2-chloro-3-methyl-6-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 2-bromo-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-imidazol-1-yl)-6-(trifluoromethyl)picolinonitrile; 4-(1-(2-chloro-3-fluorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4- yl)-5-(trifluoromethyl)pyrimidin-2-amine; N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)-4-(1-(4- trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)pyrimidin-2-amine; 3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-imidazol-1-yl)isonicotinonitrile; 2-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-5-(trifluoromethyl)benzonitrile; 3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-(trifluoromethyl)benzonitrile; 4-(1-(6-methoxy-2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 2-methyl-4-((5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-(trifluoromethyl)pyridin-2- yl)oxy)butan-2-ol; 4-(1-(6-(2-(dimethylamino)ethoxy)-2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(6-((1-(dimethylamino)propan-2-yl)oxy)-2-(trifluoromethyl)pyridin-3-yl)-1H-midazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 2-((5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-imidazol-1-yl)-6-(trifluoromethyl)pyridin-2-yl)oxy)propanenitrile; 4-(1-(2-(difluoromethyl)-6-methoxypyridin-3-yl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 6-(2-(ethyl(methyl)amino)ethoxy)-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile; 4-(1-(2-chloro-3-((dimethylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-3-(((4-methyltetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)-1H-midazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-3-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-3-((cyclopropylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 1-(2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)azetidin-3-ol; 1-(2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)ethan-1-ol; (2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)methanol; 1-(2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)propan-1-ol; (2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)(cyclopropyl)methanol; 3-(4-(2-((1-(ethylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-imidazol-1-yl)-6-methylpicolinonitrile; 4-(1-(2-(difluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1-((1-methyl-1H- pyrazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 3-(4-(2-((1-(ethylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-imidazol-1-yl)picolinonitrile; 3-(4-(2-((1-((1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-methylpicolinonitrile; N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)-4-(1-(2- trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)pyrimidin-2-amine; 3-(4-(2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-1H-imidazol-1-yl)-2-(trifluoromethyl)benzonitrile; 5-(4-(2-((1-(ethylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-imidazol-1-yl)-6-methylpicolinonitrile; 3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-imidazol-1-yl)-6-propylpicolinonitrile; 4-(1-(6-ethyl-2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(3-(2-aminopyridin-4-yl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-3-(pyridin-3-yl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(6-(1-methyl-1H-pyrazol-4-yl)-2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-imidazol-1-yl)-6-(trifluoromethyl)picolinonitrile; 6-(difluoromethyl)-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile; 4-(1-(4-(4-(dimethylamino)piperidin-1-yl)-2-fluorophenyl)-2-methyl-1H-imidazol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl) piperidin-4- yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-fluoro-4-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)-2-methyl-1H-midazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-fluoro-4-(4-isopropylpiperazin-1-yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N- 1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; (S)-4-(1-(4-(3-(dimethylamino)piperidin-1-yl)-2-fluorophenyl)-2-methyl-1H-midazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-fluoro-4-(4-(methylamino)piperidin-1-yl)phenyl)-2-methyl-1H-imidazol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)-1-methylpiperazin-2-one; (R)-4-(1-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2-fluorophenyl)-2-methyl-1H-midazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; (S)-4-(1-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2-fluorophenyl)-2-methyl-1H-midazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-fluoro-4-(piperazin-1-yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-fluoro-4-((2-methoxyethyl)amino)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 2-((3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)(methyl)amino)ethan-1-ol; 4-(1-(2-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-2-methyl-1H-imidazol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; (R)-4-(1-(2-fluoro-4-(3-methylpiperazin-1-yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N- 1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; (S)-1-(3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)pyrrolidin-3-ol; (R)-4-(1-(2-fluoro-4-((1-methylpiperidin-3-yl)amino)phenyl)-2-methyl-1H-imidazol- 4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-(4-(dimethylamino)piperidin-1-yl)-2-fluorophenyl)-2-methyl-1H-imidazol-4- yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2- amine; 4-(1-(2-chloro-4-(1-methyl-1H-pyrazol-5-yl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)phenyl)-1H-imidazol-4-yl)-N- 1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-(1,4-dimethyl-1H-imidazol-5-yl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-(1-methyl-1H-imidazol-5-yl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 5-(1-methyl-1H-1,2,4-triazol-5-yl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 5-(difluoromethoxy)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 4-(1-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-fluoro-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-2-methyl-1H-imidazol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-fluoro-4-(1-methyl-1H-pyrazol-5-yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N- 1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 6-methyl-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinamide; 6-methyl-N-(methyl-d3)-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinamide; N,6-dimethyl-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinamide; N-isopropyl-6-methyl-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinamide; N-ethyl-6-methyl-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinamide; 3-chloro-N,N-dimethyl-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzamide; 3-chloro-2-fluoro-N,N-dimethyl-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzamide; 2,3-dichloro-N-methyl-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzamide; (R)-1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)pyrrolidin-3-ol; (S)-1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)pyrrolidin-3-ol; (S)-4-(1-(2-chloro-4-(3-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; (R)-4-(1-(2-chloro-4-(3-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)-1-methylpiperazin-2-one; 4-(1-(2-chloro-4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-((2-methoxyethyl)amino)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-(4-(dimethylamino)piperidin-1-yl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)-3-methylimidazolidin-2-one; 4-(1-(2-chloro-4-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; N1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)-N1,N2,N2-trimethylethane-1,2- diamine; 4-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)piperazin-2-one; 4-(1-(2-chloro-4-methoxyphenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 6-methyl-3-(4-(2-(((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1- yl)picolinonitrile; 3-(4-(2-(((3R,4S)-1-((2-aminopyrimidin-5-yl)sulfonyl)-3-methylpiperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-methylpicolinonitrile; 6-methyl-3-(4-(2-(((3R,4S)-3-methyl-1-((1-methyl-1H-pyrazol-3- yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1- yl)picolinonitrile; 2-chloro-3-(4-(2-(((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1- yl)benzonitrile; 4-(1-(5-bromoquinoxalin-6-yl)-1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-(2-(dimethylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-(2-(azetidin-1-yl)ethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenethyl)-1-methylpiperazin-2-one; 4-(1-(4-(azetidin-3-yl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-fluoro-4-(1-methylpiperidin-4-yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(5-bromoquinoxalin-6-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4- yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(8-bromoquinolin-7-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)- 5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(5-bromoquinolin-6-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)- 5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(8-chloroquinolin-7-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)- 5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(5-methylquinoxalin-6-yl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4- yl)-5-(trifluoromethyl)pyrimidin-2-amine; 6-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-imidazol-1-yl)quinoxaline-5-carbonitrile; 4-methyl-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile; 4-(1-(1,3-dimethyl-1H-pyrazol-4-yl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 3-chloro-4-(5-chloro-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 3-chloro-4-(4-(5-chloro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)- 1H-imidazol-1-yl)benzonitrile; 3-chloro-4-(4-(2-(((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 3-chloro-4-(4-(2-(((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; N-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-N-methylacetamide; 4-(1-(2-chloro-4-((dimethylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-(azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-((3-methylazetidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-(pyrrolidin-1-ylmethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((2-azabicyclo[2.2.2]octan-2-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((2-azabicyclo[2.2.1]heptan-2-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; (R)-1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylpyrrolidin-3-ol; 4-(1-(2-chloro-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3- methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-((dimethylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3- luoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-(azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3- luoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; N-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)acetamide; 4-(1-(2-chloro-4-(((2,2-difluoroethyl)amino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 2-((3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)amino)acetonitrile; 4-(1-(2-chloro-4-(((2,2,2-trifluoroethyl)amino)methyl)phenyl)-1H-imidazol-4-yl)-N- 1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-((ethylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-((cyclopropylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-(((cyclopropylmethyl)amino)methyl)phenyl)-1H-imidazol-4-yl)-N- 1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-((ethyl(methyl)amino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-((3,3-difluoroazetidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylazetidin-3-ol; 4-(1-(2-chloro-4-((3-methoxyazetidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-((3-fluoro-3-methylazetidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-((3-fluoroazetidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)azetidine-3-carbonitrile; 1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)azetidin-3-ol; 4-(1-(2-chloro-4-((3,3-dimethylazetidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; (1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-2-methylazetidin-2-yl)methanol; 2-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-2-azaspiro[3.3]heptan-6-ol; 2-(1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)azetidin-3-yl)propan-2-ol; (S)-1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylpyrrolidin-3-ol; (R)-1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)pyrrolidin-3-ol; (S)-1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)pyrrolidin-3-ol; (R)-4-(1-(2-chloro-4-((3-methoxypyrrolidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-(piperidin-1-ylmethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-(morpholinomethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-1-methylpiperazin-2-one; 4-(1-(2-chloro-4-((hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)phenyl)-1H-midazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)-2-chlorophenyl)-1H-midazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)methyl)-2-chlorophenyl)-1H-midazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)-2-chlorophenyl)-1H-imidazol- 4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((2-oxa-5-azabicyclo[2.2.2]octan-5-yl)methyl)-2-chlorophenyl)-1H-imidazol- 4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 2-((3-chloro-4-(4-(2-(((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)amino)acetonitrile; 4-(1-(2-chloro-4-((ethylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3- methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-(azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3- methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-((dimethylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3- methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-((cyclopropylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)- 1-(cyclopropylsulfonyl)-3-methylpiperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-((dimethylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-1- cyclopropylsulfonyl)-3-methylpiperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-1- cyclopropylsulfonyl)-3-methylpiperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-((3-methylazetidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N- (3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4R)-3- luoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-2-((1- methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile; 5-chloro-4-(1-(2-chloro-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)pyrimidin-2-amine; 4-(1-(4-(azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1- cyclopropylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-(azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1- ethylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-((4-(1-(4-(azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-5- trifluoromethyl)pyrimidin-2-yl)amino)-N-cyclopropylpiperidine-1-sulfonamide; (3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)methanol; 2-(hydroxymethyl)-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-imidazol-1-yl)isobenzofuran-1(3H)-one; (3-chloro-4-(4-(2-(((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)methanol; 3-(hydroxymethyl)-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 6-(hydroxymethyl)-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile; (2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-1H-imidazol-1-yl)phenyl)methanol; 4-(1-(4-((1H-imidazol-1-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((4H-1,2,4-triazol-4-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((1H-1,2,4-triazol-1-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((2H-1,2,3-triazol-2-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((1H-1,2,3-triazol-1-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((2H-tetrazol-2-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((1H-tetrazol-1-yl)methyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-(difluoromethyl)-6-((methylamino)methyl)pyridin-3-yl)-1H-imidazol-4-yl)-N- 1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(6-((dimethylamino)methyl)-2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(6-(azetidin-1-ylmethyl)-2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N- 1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)ethan-1-ol; 5-((methylamino)methyl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 4-(1-(4-((dimethylamino)methyl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-(azetidin-1-ylmethyl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(6-(azetidin-1-ylmethyl)-2-methylpyridin-3-yl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-((dimethylamino)methyl)-3-fluorophenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((methylamino)methyl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((ethylamino)methyl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((cyclopropylamino)methyl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-N- 1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((ethyl(methyl)amino)methyl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((diethylamino)methyl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 1-(4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-1H-imidazol-1-yl)-3-(trifluoromethyl)benzyl)azetidin-3-ol; (S)-1-(4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-3-(trifluoromethyl)benzyl)pyrrolidin-3- ol; (S)-3-methyl-1-(4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-3-(trifluoromethyl)benzyl)pyrrolidin-3- ol; 4-methyl-1-(4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-3-(trifluoromethyl)benzyl)piperidin-4-ol; 4-(1-(6-((dimethylamino)methyl)-2-methylpyridin-3-yl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-methyl-6-((3-methylazetidin-1-yl)methyl)pyridin-3-yl)-1H-imidazol-4-yl)-N- 1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(6-((3,3-dimethylazetidin-1-yl)methyl)-2-methylpyridin-3-yl)-1H-imidazol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-fluoro-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((dimethylamino)methyl)-2-fluorophenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-3-fluoro-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-(azetidin-1-ylmethyl)-2-chloro-3-fluorophenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-3-fluoro-4-((3-methylazetidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((dimethylamino)methyl)-2-methylphenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-methyl-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-(1-(ethylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-(1-(azetidin-1-yl)ethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-(1-(methylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-(1-(methylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-(piperidin-2-yl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-(piperidin-2-yl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((dimethylamino)methyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((bis(methyl-d3)amino)methyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-(azetidin-1-ylmethyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 2-(1-(3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)azetidin-3-yl)propan-2-ol; 4-(1-(2-fluoro-4-((3-methylazetidin-1-yl)methyl)phenyl)-2-methyl-1H-imidazol-4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-(azetidin-1-ylmethyl)-2-chlorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-(azetidin-1-ylmethyl)-2-methylphenyl)-2-methyl-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((dimethylamino)methyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N- (3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(2-fluoro-4- (methylamino)methyl)phenyl)-2-methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- amine; 4-(1-(2-chloro-4-((dimethylamino)methyl)phenyl)-2-methyl-1H-imidazol-4-yl)-2-((1- methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile; 4-(1-(2-chloro-4-((methylamino)methyl)phenyl)-2-methyl-1H-imidazol-4-yl)-2-((1- methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile; 4-(1-(4-cyano-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-2-((1- methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile; 2-methoxy-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)nicotinonitrile ; 3-methyl-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile; 2-methyl-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)nicotinonitrile; 3-fluoro-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 4-(1-(3-chloro-2-methoxypyridin-4-yl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(3-chloro-2-methylpyridin-4-yl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methoxynicotinonitrile; N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(3-fluoropyridin-4-yl)-2- methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 3-fluoro-4-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-2-methyl-1H-imidazol-1-yl)benzonitrile; 4-(1-(3-chloro-2-methoxypyridin-4-yl)-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(3-chloro-2-methylpyridin-4-yl)-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-3-methylpicolinonitrile; 3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 2-fluoro-3-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 2-fluoro-3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-2-methyl-1H-imidazol-1-yl)benzonitrile; 3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-2-methyl-1H-imidazol-1-yl)-2-methylbenzonitrile; 3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile; 3-chloro-4-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile; 3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinonitrile; 3-fluoro-4-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-2-methyl-1H-imidazol-1-yl)picolinonitrile; N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(3-fluoro-2- methoxypyridin-4-yl)-2-methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-methoxy-3-methylpyridin-4-yl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(3-fluoro-2- methylpyridin-4-yl)-2-methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(3-fluoro-2-methoxypyridin-4-yl)-2-methyl-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 2-(4-ethylpiperazin-1-yl)-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)nicotinonitrile; 2-(4-methylpiperazin-1-yl)-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)nicotinonitrile; 4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-imidazol-1-yl)-2-morpholinonicotinonitrile; 4-(1-(3-chloro-2-(4-ethylpiperazin-1-yl)pyridin-4-yl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(3-chloro-2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(3-chloro-2-morpholinopyridin-4-yl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(3-chloro-2-(dimethylamino)pyridin-4-yl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(3-chloro-2-(methylamino)pyridin-4-yl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 1-(4-(2-(((3R,4S)-1-(cyclopropylsulfonyl)-3-fluoropiperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol; 1-(4-(2-((1-(ethylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-imidazol-1-yl)-2-methylpropan-2-ol; 1-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol; 1-(4-(2-(((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol; 2-methyl-1-(4-(2-(((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)propan-2-ol; 4-(1-(2,2-difluoroethyl)-1H-imidazol-4-yl)-N-(1-(ethylsulfonyl)piperidin-4-yl)-5- trifluoromethyl)pyrimidin-2-amine; N-((3R,4S)-1-(cyclopropylsulfonyl)-3-fluoropiperidin-4-yl)-4-(1-(2,2-difluoroethyl)- 1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2,2-difluoroethyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2,2-difluoroethyl)-1H-imidazol-4-yl)-N-((3R,4R)-3-fluoro-1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 1-(4-(2-(((3R,4S)-1-(cyclopropylsulfonyl)-3-methylpiperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol; 1-(4-(2-(((3R,4R)-1-(cyclopropylsulfonyl)-3-fluoropiperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol; 4-(1-(2,2-difluoroethyl)-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-pyrazol-4- yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 1-(4-(2-(((3R,4R)-3-fluoro-1-((1-methyl-1H-pyrazol-3-yl)sulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol; 1-(4-(2-(((3R,4R)-3-fluoro-1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol; 4-(1-(2,2-difluoroethyl)-1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1-((1-methyl-1H-midazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 2-methyl-1-(4-(2-((1-(pyridin-2-ylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)propan-2-ol; 5-((4-ethylpiperazin-1-yl)methyl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 5-((isopropylamino)methyl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 5-((ethylamino)methyl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; (R)-5-((3-hydroxypyrrolidin-1-yl)methyl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 5-((cyclopropylamino)methyl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 5-((4-methylpiperazin-1-yl)methyl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-imidazol-1-yl)-5-(piperidin-1-ylmethyl)benzonitrile; 2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-imidazol-1-yl)-5-(pyrrolidin-1-ylmethyl)benzonitrile; 4-(1-(4-((cyclopropylamino)methyl)-2,6-difluorophenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2,6-difluoro-4-((isopropylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((ethylamino)methyl)-2,6-difluorophenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2,6-difluoro-4-((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((4-ethylpiperazin-1-yl)methyl)-2,6-difluorophenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2,6-difluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N- 1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-fluoro-4-((3-methoxyazetidin-1-yl)methyl)phenyl)-2-methyl-1H-imidazol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 1-(3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylazetidin-3-ol; 1-(3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)azetidin-3-ol; 4-(1-(4-((cyclopropylamino)methyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N- 1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((diethylamino)methyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((ethyl(methyl)amino)methyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((ethylamino)methyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-3-((isopropylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-3-((ethylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 1-(2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylazetidin-3-ol; (R)-1-(2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylpyrrolidin-3-ol; (R)-1-(2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)pyrrolidin-3-ol; (S)-1-(2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)pyrrolidin-3-ol; 4-(1-(3-(azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-3-(((tetrahydrofuran-3-yl)amino)methyl)phenyl)-1H-imidazol-4-yl)-N- 1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-3-(((tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)-1H-imidazol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-3-(2-morpholinoethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-3-(2-(dimethylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-3-(2-(cyclopropylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 1-(2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenethyl)-3-methylazetidin-3-ol; 4-(1-(3-(2-(azetidin-1-yl)ethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; (R)-1-(2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenethyl)-3-methylpyrrolidin-3-ol; 4-(1-(2-chloro-3-(1-(ethylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-3-(1-(dimethylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-3-(1-(methylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(3-((methylamino)methyl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 3-methyl-1-(3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-(trifluoromethyl)benzyl)azetidin-3-ol; 4-(1-(3-(azetidin-1-ylmethyl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; (R)-3-methyl-1-(3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-(trifluoromethyl)benzyl)pyrrolidin-3- ol; 4-(1-(2-methyl-6-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(5-bromo-1-methyl-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-pyrazol-4- yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 2-chloro-3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-2-methyl-1H-imidazol-1-yl)benzonitrile; 4-(1-(2-fluoro-4-((isopropylamino)methyl)-6-methylphenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2,6-difluoro-4-((isopropylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4S)- 3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(2-fluoro-4-((4- methylpiperazin-1-yl)methyl)phenyl)-2-methyl-1H-imidazol-4-yl)-5- trifluoromethyl)pyrimidin-2-amine; N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(2-fluoro-4- (isopropylamino)methyl)phenyl)-2-methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin- 2-amine; 4-(1-(4-((ethylamino)methyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N- (3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((ethylamino)methyl)-2,6-difluorophenyl)-1H-imidazol-4-yl)-N-((3R,4R)-3- luoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2,6-difluoro-4-((isopropylamino)methyl)phenyl)-1H-imidazol-4-yl)-N- (3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((4-ethylpiperazin-1-yl)methyl)-2,6-difluorophenyl)-1H-imidazol-4-yl)-N- (3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-((ethylamino)methyl)-6-fluorophenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-6-fluoro-4-((isopropylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-(azetidin-1-ylmethyl)-2-chloro-6-fluorophenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-((4-ethylpiperazin-1-yl)methyl)-6-fluorophenyl)-1H-imidazol-4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; (R)-1-(3-chloro-4-(4-(2-(((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylpyrrolidin-3-ol; 4-(1-(2-chloro-4-((4-ethylpiperazin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N- (3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-(azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-((3R,4R)-3- luoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-((isopropylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4R)-3- luoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-((ethylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-((3R,4R)-3- luoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; (R)-1-(3-chloro-5-fluoro-4-(4-(2-(((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylpyrrolidin- 3-ol; 4-(1-(2-chloro-4-((4-ethylpiperazin-1-yl)methyl)-6-fluorophenyl)-1H-imidazol-4-yl)- N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2- amine; 4-(1-(4-(azetidin-1-ylmethyl)-2-chloro-6-fluorophenyl)-1H-imidazol-4-yl)-N- (3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-6-fluoro-4-((isopropylamino)methyl)phenyl)-1H-imidazol-4-yl)-N- (3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-((ethylamino)methyl)-6-fluorophenyl)-1H-imidazol-4-yl)-N- (3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-(2-fluoro-4-(pyrrolidin-1- ylmethyl)phenyl)-2-methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((cyclopropylamino)methyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N- (3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(3,5-difluoro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-1-methylpiperazin-2-one; (S)-1-(3-chloro-4-(4-(2-(((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylpyrrolidin-3-ol; (R)-1-(3-chloro-4-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylpyrrolidin-3-ol; (S)-1-(3-chloro-4-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylpyrrolidin-3-ol; 4-(1-(4-(4-(diethylamino)piperidin-1-yl)-2-fluorophenyl)-2-methyl-1H-imidazol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-fluoro-4-(4-methyl-4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-2-methyl-1H-midazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-2-methyl-1H-midazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-(2-(azetidin-1-yl)ethyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-fluoro-4-(1-methylazetidin-3-yl)phenyl)-2-methyl-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-(1-ethylazetidin-3-yl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; (S)-1-(3-(3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)azetidin-1-yl)propan-2-ol; 2-(3-(3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)azetidin-1-yl)ethan-1-ol; (R)-1-(3-(3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)azetidin-1-yl)propan-2-ol; 1-((3-(3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)azetidin-1-yl)methyl)cyclopropan- 1-ol; 4-(1-(4-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N- 1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine ; 4-(1-(2-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-2-methyl-1H-imidazol-4-yl)-N- 1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; (S)-4-(1-(2-fluoro-4-((1-methylpyrrolidin-2-yl)methoxy)phenyl)-2-methyl-1H-midazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; (R)-4-(1-(2-fluoro-4-((1-methylpyrrolidin-2-yl)methoxy)phenyl)-2-methyl-1H-midazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 5-(1-isopropylazetidin-3-yl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 5-(1-methylazetidin-3-yl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 5-(1-ethylazetidin-3-yl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 5-(4-methylpiperazin-1-yl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 5-(methyl(2-(methylamino)ethyl)amino)-2-(4-(2-((1-(methylsulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 5-((2-(dimethylamino)ethyl)amino)-2-(4-(2-((1-(methylsulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 5-(2-(dimethylamino)ethyl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-imidazol-1-yl)-5-(2-(pyrrolidin-1-yl)ethyl)benzonitrile; 5-(2-(dimethylamino)ethoxy)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 5-ethoxy-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-imidazol-1-yl)-5-(2-(pyrrolidin-1-yl)ethoxy)benzonitrile; 4-(1-(2-chloro-4-(1-ethylpiperidin-4-yl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-(1-methylpiperidin-4-yl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-4-(1-methylazetidin-3-yl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 3-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)oxazolidin-2-one; 4-(1-(2-bromophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- trifluoromethyl)pyrimidin-2-amine; 4-(1-(2,6-difluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)-N- (3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((ethylamino)methyl)-2,6-difluorophenyl)-1H-imidazol-4-yl)-N-((3R,4S)-3- luoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-((4-ethylpiperazin-1-yl)methyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)- N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2- amine; 1-(3-fluoro-4-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-2-methyl-1H-imidazol-1-yl)benzyl)-4-methylpiperidin-4-ol; 4-(1-(4-((4-ethylpiperazin-1-yl)methyl)-2,6-difluorophenyl)-1H-imidazol-4-yl)-N- (3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-(((2,2-difluoroethyl)amino)methyl)-2-(trifluoromethyl)phenyl)-1H-imidazol- 4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 3-methyl-1-(4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-3-(trifluoromethyl)benzyl)azetidin-3-ol; 4-(1-(4-(((2,2-difluoroethyl)amino)methyl)-2-methylphenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-4-methylpiperazin-2-one; 1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)azetidin-2-one; 1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-3-methylimidazolidin-2-one; 1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)pyrrolidin-2-one; 1-(1-(3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)piperidin-4-yl)pyrrolidin-3-ol; 1-(3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)-3-methylazetidin-3-ol; 5-(2-(4-methylpiperazin-1-yl)ethyl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; 2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-imidazol-1-yl)-5-(2-(piperidin-1-yl)ethyl)benzonitrile; 4-(1-(4-(3-(azetidin-1-yl)propyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(4-(3-(ethyl(methyl)amino)propyl)-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(2-bromo-1-(2-fluorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4- yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-3-(((methyl-d3)amino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 1-(2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)azetidine-3-carbonitrile; 4-(1-(2-chloro-3-(2-(4-methylpiperazin-1-yl)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-3-(2-(isopropylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-3-(2-(ethylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-3-(2-(methylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(2-chloro-3-(1-(isopropylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 4-(1-(3-(1-(azetidin-1-yl)ethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1- methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine; 1-(3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-1H-imidazol-1-yl)-2-(trifluoromethyl)benzyl)azetidine-3-carbonitrile; (S)-1-(3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-(trifluoromethyl)benzyl)pyrrolidine-3- carbonitrile; and 2-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)amino)-5- trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitrile; or a pharmaceutically acceptable salt thereof. 34. A pharmaceutical composition comprising a compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 35. A method of inhibiting CDK2, comprising contacting the CDK2 with a compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof. 36. A method of inhibiting CDK2 in a patient, comprising administering to the patient a compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof. 37. A method of treating a disease or disorder associated with CDK2 in a patient, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-33, or pharmaceutically acceptable salt thereof, wherein the disease or disorder is associated with an amplification of the cyclin E1 (CCNE1) gene and/or overexpression of CCNE1. 38. A method of treating a disease or disorder associated with CDK2 in a patient, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-33, or pharmaceutically acceptable salt thereof 39. 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 1-33, or a pharmaceutically acceptable salt thereof, whereinhe human subject has been previously determined to: (i) (a) have a nucleotide sequence encoding a p16 protein comprising the amino acid equence of SEQ ID NO:1; and/or (b) have a cyclin dependent kinase inhibitor 2A (CDKN2A) gene lacking one or morenactivating 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. 40. 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 1-33, or a pharmaceutically acceptable salt thereof, to the human subject. 41. The method of claim 40, 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. 42. 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 1-33, or a pharmaceutically acceptable salt thereof, comprising: (a) administering the compound or the salt, to the human subject, wherein the human ubject 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 erine 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 athe 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. 43. The method of any one of claims 37-42, 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 1, 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 1.4-Chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine In a flask with a stir bar, a mixture of 2,4-dichloro-5- (trifluoromethyl)pyrimidine (9.18 g, 42.3 mmol) in tert-butanol (81 mL) and 1,2- dichloroethane (81 mL) was cooled to 0 °C in an ice bath before a 1 molar (M) solution of zinc chloride (60 mL, 60 mmol) in diethyl ether was added and the resulting mixture was stirred at 0 °C for 1 hour. To the reaction mixture was then added 1-(methylsulfonyl)piperidin-4-amine (7.18 g, 40.3 mmol), followed by dropwise addition of a solution of triethylamine (6.74 mL, 48.3 mmol) in a 1:1 mixture of 1,2-dichloroethane/tert-butanol (7 mL). The ice bath was then removed and the reaction mixture was allowed to warm to r.t. before heating to 60 °C overnight. The reaction mixture was then concentrated to approximately 1/3 volume and diluted with water. An off-white precipitate formed and the mixture was slurried for 2 hours. The precipitate was then collected via filtration, washed with water, and dried under air. The crude product obtained was used directly without further purification. LCMS calculated for C11H15ClF3N4O2S (M+H) + : m/z = 359.1; Found: 359.0. Intermediate 2.4-(1H-Imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)- 5- (trifluoromethyl)pyrimidin-2-amine To a vial containing 4-chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 1, 0.30 g, 0.836 mmol), tetrakis(triphenylphosphine)palladium (0) (0.048 g, 0.042 mmol), and 4- (tributylstannyl)-1-trityl-1H-imidazole (0.501 g, 0.836 mmol) was added DMF (3.4 mL). The vial was flushed with nitrogen and a fresh cap applied, then the reaction heated to 100 °C for 18 hours. After cooling to room temperature, the solution was filtered, washing with MeOH (3.4 mL). Aqueous HCl (1 M aq, 3.4mL) was added and the solution heated to 80 °C for 1 hour. The reaction was cooled to room temperature and MeOH evaporated on rotovap. Additional aqueous HCl (1 M, 3.4 mL) was added. The aqueous layer was extracted with EtOAc (3x) to remove unwanted organic byproducts. The aqueous layer was basified by addition of NaOH to pH 13. This was extracted with DCM (5x). The combined organics were dried over sodium sulfate and evaporated to deliver the desired product which was used without further purification. LCMS calculated for C14H18F3N6O2S (M+H) + : m/z = 391.1; Found: 391.2. Intermediate 3. tert-Butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidine-1-carboxylate A mixture of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (11.4 g, 52.5 mmol) in tert-butanol (100 mL) and 1,2-dichloroethane (100 mL) was cooled to 0 °C in an ice bath before a 1 M solution of zinc chloride (75 mL, 75 mmol) in diethyl ether was added and the resulting mixture was purged with nitrogen and stirred at 0 °C for 1 hour. To the reaction mixture was then added tert-butyl 4-aminopiperidine-1- carboxylate (10.0 g, 49.9 mmol), followed by dropwise addition of a solution of triethylamine (8.35 mL, 59.9 mmol) in a 1:1 mixture of 1,2-dichloroethane/tert- butanol (15 mL). The ice bath was then removed and the reaction mixture was allowed to warm to r.t. before heating to 60 °C overnight. After cooling to r.t., the reaction mixture was then concentrated to approximately 1/3 volume and diluted with water. Upon stirring an off-white precipitate formed and the mixture was slurried for 1 hour. The precipitate was then collected via filtration, washed with water and hexanes, and dried under air. The crude product obtained was used directly without further purification. LCMS calculated for C11H13ClF3N4O2 (M-C4H8+H) + : m/z = 325.1; Found 325.0. Intermediate 4.4-Chloro-N-(1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperid in-4- yl)-5-(trifluoromethyl)pyrimidin-2-amine A mixture of tert-butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidine-1-carboxylate (Intermediate 3, 3.00 g, 7.88 mmol) in THF (39.4 mL) was purged with nitrogen and stirred at 80 °C for 10 minutes before a 4 M solution of HCl in 1,4-dioxane (7.88 mL, 31.5 mmol) was added and the reaction mixture was stirred at 80 °C for 2 hours. After cooling to r.t., the reaction mixture was sparged with nitrogen for 5 minutes before 1-methyl-1H-imidazole-4-sulfonyl chloride (1.71 g, 9.47 mmol) was added followed by dropwise addition of triethylamine (6.59 mL, 47.3 mmol), and the mixture was stirred at r.t. for 1 hour. The reaction mixture was then diluted with water and extracted with EtOAc and CH2Cl2. The combined organic phases were then dried over MgSO4 and concentrated. The crude material obtained was used directly without further purification. LCMS calculated for C14H17ClF3N6O2S (M+H) + : m/z = 425.1; Found 425.1. Intermediate 5.4-(1H-Imidazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-a mine Step 1: N,N-Dimethyl-4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)p iperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazole-1- sulfonamide In a microwave vial with a stir bar, a mixture of 4-chloro-N-(1-((1-methyl-1H- imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)py rimidin-2-amine (Intermediate 4, 250 mg, 0.588 mmol), N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-imidazole-1-sulfonamide (177 mg, 0.588 mmol), Pd(dppf)Cl2 ^CH2Cl2 (96.0 mg, 0.118 mmol), sodium carbonate (187 mg, 1.77 mmol), acetonitrile (8 mL), and water (1.6 mL) was sparged with nitrogen and heated at 80 °C for 16 hours. After cooling to r.t., the solution was filtered through a pad of SiliaMetS Thiol ® , and concentrated. The residue was purified by flash column chromatography (Agela Flash Column Silica-CS (24 g), eluting with a gradient of 0 to 20% CH2Cl2/methanol) to afford N,N-dimethyl-4-(2-((1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-1H-imidazole-1- sulfonamide, which was used in the next reaction without further purification. LCMS calculated for C19H25F3N9O4S2 (M+H) + : m/z = 564.1; Found 564.2. Step 2: 4-(1H-Imidazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfon yl)piperidin-4- yl)-5-(trifluoromethyl)pyrimidin-2-amine The N,N-dimethyl-4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl)p iperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazole-1- sulfonamide from Step 1 was dissolved in EtOH (10 mL) and a 12 M aqueous solution of HCl (1 mL). The solution was irradiated in a microwave reactor at 80 °C for 1 hour. After cooling to room temperature, the solution was washed with Et2O (10 mL). The resultant aqueous solution was then basified with a 1 M aqueous solution of NaOH. The solution was extracted with CH2Cl2 (10 mL x 3), and washed with brine (10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to afford 4-(1H-imidazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl)sulfon yl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (226 mg, 0.470 mmol, 80 % yield over 2 steps). LCMS calculated for C17H20F3N8O2S (M+H) + : m/z = 457.1; Found 457.4. Intermediate 6. tert-Butyl 4-((4-chloro-5-cyanopyrimidin-2-yl)amino)piperidine- 1-carboxylate A mixture of 2,4-dichloropyrimidine-5-carbonitrile (23.89 g, 137 mmol) in tert-butanol (156 mL) and 1,2-dichloroethane (156 mL) was cooled to 0 °C in an ice bath before a 1 M solution of zinc chloride (25.5 g, 187 mmol) in diethyl ether was added and the resulting mixture was purged with nitrogen and stirred at 0 °C for 1 hour. To the reaction mixture was then added tert-butyl 4-aminopiperidine-1- carboxylate (25 g, 125 mmol), followed by slow addition of a solution of Hunig’s base (32.7 mL, 187 mmol) in a 1:1 mixture of 1,2-dichloroethane/tert-butanol (15 mL). The ice bath was then removed and the reaction mixture was allowed to warm to r.t. before heating to 60 °C overnight. After cooling to r.t., the reaction mixture was then concentrated to approximately 1/3 volume and poured into rapidly stirred water. Upon stirring, a precipitate formed and the mixture was slurried for 1 hour. The precipitate was then collected via filtration, washed with water and hexanes, and dried under air. The crude product obtained was used directly without further purification. LCMS calculated for C11H13ClN5O2 (M-C4H8+H) + : m/z = 282.1; found 282.0. Intermediate 7. tert-Butyl 4-((4,5-dichloropyrimidin-2-yl)amino)piperidine-1- carboxylate This compound was prepared according to the procedures described in Intermediate 6, using 2,4,5-trichloropyrimidine instead of 2,4-dichloropyrimidine-5- carbonitrile as starting material. LCMS calculated for C10H13Cl2N4O2 (M-C4H8+H) + : m/z = 291.0; Found: 291.0. Intermediate 8: N-(4-Chloro-3-methylpyridin-2-yl)acetamide In a vial with a stir bar, a mixture of 4-chloro-3-methylpyridin-2-amine (62.5 mg, 0.438 mmol), acetic anhydride (0.50 mL, 5.3 mmol), and triethylamine (1.0 mL, 7.2 mmol) was stirred at room temperature for 12 hours. The resultant solution was concentrated. The crude product obtained was used directly without further purification. LCMS calculated for C8H10ClN2O (M+H) + : m/z = 185.0; Found 185.2. Intermediate 9.4-Chloro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimi dine- 5-carbonitrile This compound was prepared according to the procedures described in Intermediate 4, using tert-butyl 4-((4-chloro-5-cyanopyrimidin-2- yl)amino)piperidine-1-carboxylate (Intermediate 6) and methanesulfonyl chloride instead of tert-butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperid ine- 1-carboxylate and 1-methyl-1H-imidazole-4-sulfonyl chloride as starting material. LCMS calculated for C11H15ClN5O2S (M+H) + : m/z = 316.1; Found: 316.0. Intermediate 10.4-(1H-Imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4- yl)amino)pyrimidine-5-carbonitrile This compound was prepared according to the procedures described in Intermediate 2, using 4-chloro-2-((1-(methylsulfonyl)piperidin-4- yl)amino)pyrimidine-5-carbonitrile (Intermediate 6) instead of 4-chloro-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine as starting material. LCMS calculated for C14H18N7O2S (M+H) + : m/z = 348.1; Found: 348.1. Intermediate 11.4-Chloro-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Intermediate 4, using cyclopropanesulfonyl chloride instead of 1-methyl-1H- imidazole-4-sulfonyl chloride as starting material. LCMS calculated for C13H17ClF3N4O2S (M+H) + : m/z = 385.1; Found: 385.1. Intermediate 12. N-(1-(Cyclopropylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-y l)- 5-(trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Intermediate 2, using 4-chloro-N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 11) instead of 4-chloro-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine as starting material. LCMS calculated for C16H20F3N6O2S (M+H) + : m/z = 417.1; Found: 417.2. Intermediate 13.4-(1H-Imidazol-4-yl)-N-(piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Intermediate 5, using tert-butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidine-1-carboxylate (Intermediate 3) instead of 4-chloro-N-(1-((1- methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluor omethyl)pyrimidin-2- amine as starting material in Step 1. LCMS calculated for C13H16F3N6 (M+H) + : m/z = 313.1; Found 313.2. Intermediate 14. tert-Butyl 4-((4-(1H-imidazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxyla te To a vial containing 4-(1H-imidazol-4-yl)-N-(piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 13, 1.079 g, 3.46 mmol) and di- tert-butyl dicarbonate (0.795 mL, 3.46 mmol) was added DCM (34.6 mL). The mixture was stirred vigorously until full dissolution was achieved (about 10 minutes) then triethylamine (1.441 mL, 10.37 mmol) was added dropwise at room temperature. The reaction was stirred for 30 minutes, at which point in time LCMS indicated completion. The crude reaction mixture was concentrated and purified by flash column chromatography (Agela Flash Column Silica-CS (24 g), eluting with a gradient of 0 to 20% CH2Cl2/methanol) to afford tert-butyl 4-((4-(1H-imidazol-4-yl)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxy late, which was used in the next reaction without further purification. LCMS calculated for C18H24F3N6O2 (M+H) + : m/z = 413.2; Found 413.3. Intermediate 15. tert-Butyl (3R,4S)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)-3-fluoropiperidine-1-carboxylate This compound was prepared according to the procedures described in Intermediate 3, using tert-butyl (3R,4S)-4-amino-3-fluoropiperidine-1-carboxylate instead of tert-butyl 4-aminopiperidine-1-carboxylate as starting material. LCMS calculated for C15H20ClF4N4O2 (M+H) + : m/z = 399.1; Found 399.2. Intermediate 16.4-Chloro-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin- 4-yl)- 5-(trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Intermediate 4, using tert-butyl (3R,4S)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)-3-fluoropiperidine-1-carboxylate (Intermediate 15) and methanesulfonyl chloride instead of tert-butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidine-1-carboxylate and 1-methyl-1H-imidazole-4-sulfonyl chloride as starting material. LCMS calculated for C11H14ClF4N4O2S (M+H) + : m/z = 377.1; Found 376.9. Intermediate 17. N-((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H- imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Intermediate 5, using 4-chloro-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-y l)- 5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 16) instead of 4-chloro-N-(1-((1- methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluor omethyl)pyrimidin-2- amine as starting material. LCMS calculated for C14H17F4N6O2S (M+H) + : m/z = 409.1; Found 409.2. Intermediate 18. N-((3R,4S)-3-Fluoropiperidin-4-yl)-4-(1H-imidazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Intermediate 5, using tert-butyl (3R,4S)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)-3-fluoropiperidine-1-carboxylate (Intermediate 15) instead of 4-chloro-N- (1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine as starting material. LCMS calculated for C13H15F4N6 (M+H) + : m/z = 331.1; Found 331.0. Intermediate 19. tert-Butyl (3R,4S)-4-((4-(1H-imidazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3-fluoropiperidine-1- carboxylate This compound was prepared according to the procedures described in Intermediate 4, using N-((3R,4S)-3-fluoropiperidin-4-yl)-4-(1H-imidazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 18) instead of 4-(1H-imidazol-4- yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine as starting material. LCMS calculated for C18H23F4N6O2 (M+H) + : m/z = 431.2; Found 431.1. Intermediate 20. tert-Butyl (3R,4S)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)-3-methylpiperidine-1-carboxylate This compound was prepared according to the procedures described in Intermediate 3, using tert-butyl (3R,4S)-4-amino-3-methylpiperidine-1- carboxylateinstead of tert-butyl 4-aminopiperidine-1-carboxylate as starting material. LCMS calculated for C16H23ClF3N4O2 (M+H) + : m/z = 395.2; Found 395.2. Intermediate 21.4-Chloro-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin- 4- yl)-5-(trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Intermediate 4, using tert-butyl (3R,4S)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)-3-methylpiperidine-1-carboxylate (Intermediate 20) and methanesulfonyl chloride instead of tert-butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidine-1-carboxylate and 1-methyl-1H-imidazole-4-sulfonyl chloride as starting material. LCMS calculated for C12H17ClF3N4O2S (M+H) + : m/z = 373.1; Found 373.1. Intermediate 22.4-(1H-Imidazol-4-yl)-N-((3R,4S)-3-methyl-1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine This compound was prepared according to the procedures described in Intermediate 5, using 4-chloro-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4- yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 21) instead of 4-chloro-N-(1- ((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trif luoromethyl)pyrimidin-2- amine as starting material. LCMS calculated for C15H20F3N6O2S (M+H) + : m/z = 405.1; Found 405.2. Intermediate 23.4-(1H-Imidazol-4-yl)-N-((3R,4S)-3-methylpiperidin-4-yl)-5 - (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Intermediate 5, using tert-butyl (3R,4S)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)-3-methylpiperidine-1-carboxylate (Intermediate 20) instead of 4-chloro-N- (1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine as starting material. LCMS calculated for C14H18F3N6 (M+H) + : m/z = 327.2; Found 327.3. Intermediate 24. tert-Butyl (3R,4S)-4-((4-(1H-imidazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3-methylpiperidine-1- carboxylate This compound was prepared according to the procedures described in Intermediate 4, using 4-(1H-imidazol-4-yl)-N-((3R,4S)-3-methylpiperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 23) instead of 4-(1H-imidazol-4- yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine as starting material. LCMS calculated for C19H26F3N6O2 (M+H) + : m/z = 427.2; Found 427.3.
Intermediate 25.6-Chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino )-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinoni trile To a vial containing 6-chloro-3-fluoropicolinonitrile (0.38 g, 2.46 mmol) and cesium carbonate (2.00 g, 6.15 mmol) was added a solution of 4-(1H-imidazol-4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyri midin-2-amine (Intermediate 2, 0.80 g, 2.05 mmol) in acetonitrile (30 mL). The reaction was stirred at 80 °C for 2 hours. Upon cooling to room temperature the reaction was filtered and washed with acetonitrile. The filtrate was concentrated and then purified by flash column chromatography (Agela Flash Column Silica-CS (24 g), eluting with a gradient of 0 to 100% ethyl acetate/hexanes) to afford 6-chloro-3-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)picolinonitrile, which was used in the next reaction without further purification. LCMS calculated for C20H19ClF3N8O2S (M+H) + : m/z = 527.1; Found 527.2. Intermediate 26.4-(1-(6-Chloro-2-(trifluoromethyl)pyridin-3-yl)-1H-imidaz ol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine This compound was prepared according to the procedures described in Intermediate 25, using 6-chloro-3-fluoro-2-(trifluoromethyl)pyridine instead of 6- chloro-3-fluoropicolinonitrile as the starting material. LCMS calculated for C20H19ClF6N7O2S (M+H) + : m/z = 570.1; Found 570.0. Intermediate 27.4-(1-(6-Chloro-2-(difluoromethyl)pyridin-3-yl)-1H-imidazo l-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine This compound was prepared according to the procedures described in Intermediate 25, using 6-chloro-2-(difluoromethyl)-3-fluoropyridine instead of 6- chloro-3-fluoropicolinonitrile as the starting material. LCMS calculated for C20H20ClF5N7O2S (M+H) + : m/z = 552.1; Found 552.0. Intermediate 28.6-Methyl-5-(4-(2-(piperidin-4-ylamino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinoni trile Step 1: tert-Butyl 4-((4-(1-(6-cyano-2-methylpyridin-3-yl)-1H-imidazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxyla te To a vial containing 5-fluoro-6-methylpicolinonitrile (0.051 g, 0.378 mmol) and cesium carbonate (0.308 g, 0.946 mmol) was added a solution of tert-butyl 4-((4- (1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)p iperidine-1-carboxylate (Intermediate 14, 0.130 g, 0.315 mmol) in acetonitrile (3.94 mL). The reaction was stirred at 80 °C for 1 hour, then the reaction was cooled to room temperature and filtered, washing with excess acetonitrile and DCM. The filtrate was concentrated and advanced to step 2 without further purification. LCMS calculated for C25H28F3N8O2 (M+H) + : m/z = 529.2; Found 529.3. Step 2: 6-Methyl-5-(4-(2-(piperidin-4-ylamino)-5-(trifluoromethyl)py rimidin-4-yl)- 1H-imidazol-1-yl)picolinonitrile The crude tert-butyl 4-((4-(1-(6-cyano-2-methylpyridin-3-yl)-1H-imidazol-4- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-car boxylate from step 1 was reconstituted in DCM (4 mL). Trifluoroacetic acid (0.483 mlL, 6.30 mmol) was added and the reaction stirred at room temp for 1.5 hours. LCMS indicated full conversion to desired product. The reaction was concentrated on rotovap, dried on high vacuum and advanced to the next step without further purification. LCMS calculated for C20H20F3N8 (M+H) + : m/z = 429.2; Found 429.2. Intermediate 29.4-(1-(2-(Difluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N - (piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Intermediate 28, using 2-(difluoromethyl)-3-fluoropyridine instead of 5-fluoro-6- methylpicolinonitrile as the starting material for step 1. LCMS calculated for C19H19F5N7 (M+H) + : m/z = 440.2; Found 440.0. Intermediate 30.3-(4-(2-(Piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidi n-4- yl)-1H-imidazol-1-yl)picolinonitrile This compound was prepared according to the procedures described in Intermediate 28, using 3-fluoropicolinonitrile instead of 5-fluoro-6- methylpicolinonitrile as the starting material for step 1. LCMS calculated for C19H18F3N8 (M+H) + : m/z = 415.2; Found 415.1.
Intermediate 31.6-Methyl-3-(4-(2-(piperidin-4-ylamino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinoni trile This compound was prepared according to the procedures described in Intermediate 28, using 3-fluoro-6-methylpicolinonitrile instead of 5-fluoro-6- methylpicolinonitrile as the starting material for step 1. LCMS calculated for C20H20F3N8 (M+H) + : m/z = 429.2; Found 429.2. Intermediate 32. N-(Piperidin-4-yl)-5-(trifluoromethyl)-4-(1-(2- (trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)pyrimid in-2-amine This compound was prepared according to the procedures described in Intermediate 28, using 3-fluoro-2-(trifluoromethyl)pyridine instead of 5-fluoro-6- methylpicolinonitrile as the starting material for step 1. LCMS calculated for C19H18F6N7 (M+H) + : m/z = 458.2; Found 458.0.
Intermediate 33.3-(4-(2-(Piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidi n-4- yl)-1H-imidazol-1-yl)-2-(trifluoromethyl)benzonitrile This compound was prepared according to the procedures described in Intermediate 28, using 3-fluoro-2-(trifluoromethyl)benzonitrile instead of 5-fluoro-6- methylpicolinonitrile as the starting material for step 1. LCMS calculated for C21H18F6N7 (M+H) + : m/z = 482.2; Found 482.0. Intermediate 34.4-(1-(3-Bromo-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine This compound was prepared according to the procedures described in Example 1, using 1-bromo-2-chloro-3-fluorobenzene instead of 3-chloro-4- fluorobenzonitrile as starting material. LCMS calculated for C20H20BrClF3N6O2S (M+H) + : m/z = 579.0; Found 579.1.
Intermediate 35.2-Chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino )-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehy de Step 1: 4-(1-(2-Chloro-3-vinylphenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine To a solution of 4-(1-(3-bromo-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (Intermediate 34, 0.411 g, 0.709 mmol), potassium carbonate (0.294 g, 2.127 mmol), and XPhos Pd G3 (0.030 g, 0.035 mmol) in dioxane (2.95 mL) and water (0.591 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.364 mL, 2.127 mmol). The headspace was purged with nitrogen and heated to 50 °C for 18 hours. Upon cooling to room temperature the reaction solution was purified by flash column chromatography (Agela Flash Column Silica-CS (12 g), eluting with a gradient of 0 to 100% ethyl acetate/hexanes) to afford 4-(1-(2-chloro-3-vinylphenyl)-1H-imidazol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine, which was used in the next reaction without further purification. LCMS calculated for C22H23ClF3N6O2S (M+H) + : m/z = 527.1; Found 527.1. Step 2: 2-Chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5 - (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehy de To a solution of 4-(1-(2-chloro-3-vinylphenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (0.192 g, 0.364 mmol) and sodium meta periodate (0.234 g, 1.093 mmol) in THF (4.86 mL) and water (2.429 mL) was added an osmium tetroxide (0.223 mL, 0.036 mmol) solution (4% in water). The reaction was stirred vigorously for 4 hours. LCMS indicated full conversion to desired product. The reaction was quenched by addition of water and extracted into DCM (3x). The combined organics were dried over sodium sulfate, concentrated on rotovap, and advanced to the next step without further purification. LCMS calculated for C21H21ClF3N6O3S (M+H) + : m/z = 529.1; Found 529.1. Intermediate 36. N-((3R,4R)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H- imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine Step 1: tert-Butyl (3R,4R)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino )-3- fluoropiperidine-1-carboxylate This compound was prepared according to the procedures described in Intermediate 3, using tert-butyl (3R,4R)-4-amino-3-fluoropiperidine-1-carboxylate instead of tert-butyl 4-aminopiperidine-1-carboxylate as starting material. LCMS calculated for C11H12ClF4N4O2 (M+H-C4H8) + : m/z = 343.1; Found: 343.0. Step 2: 4-Chloro-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4-y l)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Intermediate 4, using tert-butyl (3R,4R)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)-3-fluoropiperidine-1-carboxylate and methanesulfonyl chloride instead of tert-butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperid ine-1- carboxylate (Intermediate 3) and 1-methyl-1H-imidazole-4-sulfonyl chloride as starting material. LCMS calculated for C11H14ClF4N4O2S (M+H) + : m/z = 377.0; Found: 377.1. Step 3: N-((3R,4R)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H- imidazol-4-yl)- 5-(trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Intermediate 5, using 4-chloro-N-((3R,4R)-3-fluoro-1-(methylsulfonyl)piperidin-4- yl)-5-(trifluoromethyl)pyrimidin-2-amine instead of 4-chloro-N-(1-((1-methyl-1H- imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)py rimidin-2-amine (Intermediate 4) as starting material. LCMS calculated for C14H17F4N6O2S (M+H) + : m/z = 409.1; Found: 409.2. Intermediate 37. N,N,2-Trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-imidazole-1-sulfonamide Step 1: N,N,2-Trimethyl-1H-imidazole-1-sulfonamide A mixture of 2-methyl-1H-imidazole (28.6 g, 348 mmol) and triethyl amine (48 mL, 350 mmol) was dissolved in DCM (1.6 L). Dimethylsulfamoyl chloride (18.7 mL, 174 mmol) was added dropwise to the solution at 0 °C. After stirring for 2 hours, the solution was stirred at room temperature for another 24 hours. The resultant mixture was concentrated under reduced pressure, and an off-white precipitate was formed. The precipitate was removed via filtration. The filtrate was distilled (0.5 Torr, 110 °C) to give N,N,2-trimethyl-1H-imidazole-1-sulfonamide (20 g, 106 mmol). LCMS calculated for C6H12N3O2S (M+H) + : m/z = 190.1; Found: 190.1. Step 2: N,N,2-Trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H- imidazole-1-sulfonamide In a 100 mL air free schlenk storage vessel with a stir bar, a mixture of N,N,2- trimethyl-1H-imidazole-1-sulfonamide (3.61 g, 19.1 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (9.69 g, 38.2 mmol), 4,4'-di-tert-butyl-2,2'- bipyridine (1.6 g, 6.0 mmol), and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (2.0 g, 3.0 mmol) in diethyl ether (25 mL) was purged with nitrogen. The mixture was shaken several times, and then stirred for 3 days in a water bath (23 °C). The resultant solid mixture in the vessel was transferred into 1 L round bottom flask by using hexanes (800 mL). After the slurry washed for 30 minutes, the dark red color suspension was filtered, and washed with hexanes (100 mL). The residue was dissolved in EtOAc (400 mL). The dark red color solution was filtered through a pad of silica gel (100 g), and washed with extra EtOAc (1600 mL). The solution was concentrated under reduced pressure. The obtained brown solid was attached to a vacuum line over 24 hours to afford N,N,2-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-imidazole-1-sulfonamide (3.0 g, 9.5 mmol). LCMS calculated for C12H23BN3O4S (M+H) + : m/z = 316.1; Found: 316.1. Intermediate 38.4-(2-Methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperi din- 4-yl)-5-(trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Intermediate 5, using N,N,2-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-imidazole-1-sulfonamide (Intermediate 37) and 4-chloro-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (Intermediate 1) instead of N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H- imidazole-1-sulfonamide and 4-chloro-N-(1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-a mine (Intermediate 4) as starting material. LCMS calculated for C15H20F3N6O2S (M+H) + : m/z = 405.1; Found: 405.2. Intermediate 39. N-((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(2- methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amin e This compound was prepared according to the procedures described in Intermediate 5, using N,N,2-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-imidazole-1-sulfonamide (Intermediate 37) and 4-chloro-N-((3R,4S)-3-fluoro- 1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimid in-2-amine (Intermediate 16) instead of N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-imidazole-1-sulfonamide and 4-chloro-N-(1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-a mine (Intermediate 4) as starting material. LCMS calculated for C15H19F4N6O2S (M+H) + : m/z = 423.1; Found: 423.1. Intermediate 40.4-(2-Methyl-1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piper idin- 4-yl)amino)pyrimidine-5-carbonitrile This compound was prepared according to the procedures described in Intermediate 5, using N,N,2-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-imidazole-1-sulfonamide (Intermediate 37) and 4-chloro-2-((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitri le (Intermediate 9) instead of N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H- imidazole-1-sulfonamide and 4-chloro-N-(1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-a mine (Intermediate 4) as starting material. LCMS calculated for C15H20N7O2S (M+H) + : m/z = 362.1; Found: 362.1. Intermediate 41.4-(1-(2-Fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)-N -(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine Step 1: 4-(1-(2-Fluoro-4-nitrophenyl)-2-methyl-1H-imidazol-4-yl)-N-( 1- (methylsulfonyl) piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine In a vial with a stir bar, a mixture of 1,2-difluoro-4-nitrobenzene (203 mg, 1.28 mmol), 4-(2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin -4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 38, 431 mg, 1.06 mmol), cesium carbonate (1041 mg, 3.20 mmol), and acetonitrile (7.1 mL) was sparged with nitrogen. The mixture was heated at 90 °C for 1 hour. After cooling to r.t., the resultant mixture was filtered and washed with acetonitrile. The filtrate was concentrated and the residue was used directly without further purification. LCMS calculated for C21H22ClF4N7O4S (M+H) + : m/z = 544.1; Found 544.1. Step 2: 4-(1-(4-Amino-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-( 1- (methylsulfonyl) piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine To a mixture of 4-(1-(2-fluoro-4-nitrophenyl)-2-methyl-1H-imidazol-4-yl)-N- (1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimi din-2-amine (1.42 g, 2.61 mmol) and iron (730 mg, 13.1 mmol) in water (2.90 mL) and EtOH (5.8 mL) was added ammonium chloride (14.0 mg, 0.26 mmol). The mixture was refluxed for 1 h. After cooling to room temperature, the mixture was filtered through a pad of celite and washed by MeOH. The filtrate was concentrated and the residue was used directly without further purification. LCMS calculated for C21H24F4N7O2S (M+H) + : m/z = 514.2; Found 514.3. Step 3: 4-(1-(2-Fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1 - (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine To 4-(1-(4-amino-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-( 1- (methylsulfonyl) piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (from Step 2) was added HCl (1.0M aq. solution, 4.0 mL) and sodium nitrite (361 mg, 5.23 mmol) at 0 o C. After stirring for 5 min, potassium iodide (867 mg, 5.23 mmol) was added and the mixture was stirred at room temperature for 30 min. The reaction was quenched by sodium bicarbonate solution and Na2S2O3 solution and extracted with DCM three times. The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography eluting with DCM/MeOH (0-10%) to give the titled compound. LCMS calculated for C21H22IF4N6O2S (M+H) + : m/z = 625.1; Found 625.1. Intermediate 42.4-(1-(2-Chloro-4-iodophenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine In a vial with a stir bar, a mixture of 2-chloro-1-fluoro-4-iodobenzene (199 mg, 0.778 mmol), 4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl) pyrimidin-2-amine (Intermediate 2, 276 mg, 0.707 mmol), cesium carbonate (691 mg, 2.121 mmol), and N,N-dimethylacetamide (2.4 mL) was sparged with nitrogen. The mixture was heated at 150 °C under microwave irradiation for 80 minutes. After cooling to room temperature, the resultant mixture was filtered and the filtrate was diluted with DCM (20 mL). The mixture was then washed with water five times. The organic phase was concentrated and purified by column chromatography on silica gel. LCMS calculated for C20H20ClF3IN6O2S (M+H) + : m/z = 627.0; Found 627.0. Intermediate 43.5-Chloro-4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperi din- 4-yl)pyrimidin-2-amine Step 1: 4,5-Dichloro-N-(1-(methylsulfonyl)piperidin-4-yl)pyrimidin-2 -amine This compound was prepared according to the procedures described in Intermediate 4, using tert-butyl 4-((4,5-dichloropyrimidin-2-yl)amino)piperidine-1- carboxylate (Intermediate 7) and methanesulfonyl chloride instead of tert-butyl 4-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1- carboxylate (Intermediate 3) and 1-methyl-1H-imidazole-4-sulfonyl chloride as starting material. LCMS calculated for C10H15Cl2N4O2S (M+H) + : m/z = 325.0; Found 325.0. Step 2: 5-Chloro-4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin -4-yl)pyrimidin- 2-amine This compound was prepared according to the procedures described in Intermediate 5, using 4,5-dichloro-N-(1-(methylsulfonyl)piperidin-4-yl)pyrimidin-2 - amine (Step 1) instead of 4-chloro-N-(1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-a mine (Intermediate 4) as starting material. 1 H NMR (TFA salt, 500 MHz, DMSO-d6) d 9.29 (s, 1H), 8.51 (s, 2H), 7.81-7.64 (m, 1H), 4.38-4.14 (m, 1H), 3.64-3.49 (m, 2H), 3.00-2.80 (m, 5H), 2.03-1.88 (m, 2H), 1.69-1.47 (m, 2H). LCMS calculated for C13H18ClN6O2S (M+H) + : m/z = 357.1; Found 357.1. Example 1.3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino) -5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitri le In a vial with a stir bar, a mixture of 3-chloro-4-fluorobenzonitrile (35.5 mg, 0.228 mmol), 4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 2, 50 mg, 0.128 mmol), cesium carbonate (94 mg, 0.289 mmol), and acetonitrile (6 mL) was sparged with nitrogen. The mixture was heated at 80 °C for 1 hour. After cooling to r.t., the resultant mixture was filtered and concentrated. The residue was purified by flash column chromatography (Agela Flash Column Silica-CS (12 g), eluting with a gradient of 0 to 20% CH2Cl2/methanol). Fractions containing the desired product were then concentrated, and the material obtained was dissolved in acetonitrile and purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford 3-chloro-4-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)benzonitrile. 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 343 K) d 8.60 (s, 1H), 8.31 (d, J = 1.6 Hz, 1H), 8.10 (s, 1H), 8.08 (brs, 1H), 8.02 (dd, J = 8.2, 1.6 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.69 (m, 1H), 4.02 (m, 1H), 3.57 (m, 2H), 2.92 (td, J = 12.2, 2.7 Hz, 2H), 2.85 (s, 3H), 1.99 (m, 2H), 1.63 (m, 2H). LCMS calculated for C21H20ClF3N7O2S (M+H) + : m/z = 526.1; Found 526.1. Example 2.3-Chloro-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino) -5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitri le This compound was prepared according to the procedures described in Example 1, using 3-chloro-2-fluorobenzonitrile instead of 3-chloro-4- fluorobenzonitrile as starting material. LCMS calculated for C21H20ClF3N7O2S (M+H) + : m/z = 526.1; Found 526.1. Example 3.4-(1-(2-Chloro-4-((methylamino)methyl)phenyl)-1H-imidazol- 4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyri midin-2-amine Step 1: 3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5 - (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehy de This compound was prepared according to the procedures described in Example 1, using 3-chloro-4-fluorobenzaldehyde instead of 3-chloro-4- fluorobenzonitrile as starting material. LCMS calculated for C21H21ClF3N6O3S (M+H) + : m/z = 529.1; Found 529.1. Step 2: 4-(1-(2-Chloro-4-((methylamino)methyl)phenyl)-1H-imidazol-4- yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine In a vial with a stir bar, a mixture of 3-chloro-4-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)benzaldehyde from Step 1 (60 mg, 0.113 mmol), methanamine (170 µL, 0.340 mmol), acetic acid (60 µL, 1.05 mmol), and THF (3 mL) was stirred at room temperature for 12 hours. NaCNBH3 (21.4 mg, 0.340 mmol) was then added to the resultant mixture, followed by the addition of MeOH (3 mL). After the solution was stirred for 12 hours, the mixture was concentrated. The material obtained was dissolved in methanol and purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 1:1 rotamers) d 8.96 (brs, 2H), 8.65 (s, 0.5H), 8.59 (s, 0.5H), 8.19 (s, 0.5H), 8.10 (d, J = 1.0 Hz, 1H), 8.00 (s, 0.5H), 7.94-7.85 (m, 2H), 7.81-7.72 (m, 1H), 7.65-7.59 (m, 1H), 4.24 (t, J = 5.8 Hz, 2H), 4.07-3.93 (m, 1H), 3.60-3.45 (m, 2H), 2.93-2.81 (m, 5H), 2.64-2.57 (m, 3H), 2.00-1.91 (m, 2H), 1.64-1.53 (m, 2H). LCMS calculated for C22H26ClF3N7O2S (M+H) + : m/z = 544.2; Found 544.1. Example 4.3-Chloro-4-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl) piperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1 -yl)benzonitrile In a microwave vial with a stir bar, a mixture of 4-(1H-imidazol-4-yl)-N-(1- ((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trif luoromethyl)pyrimidin-2- amine (Intermediate 5, 10 mg, 0.022 mmol), 3-chloro-4-fluorobenzonitrile (10 mg, 0.066 mmol), cesium carbonate (21 mg, 0.066 mmol), and DMSO (2 mL) was sparged with nitrogen and irradiated in the microwave at 100 °C for 30 minutes. After cooling to r.t., the resultant mixture was diluted with acetonitrile, and filtered. The solution containing the desired product was then purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford 3-chloro-4-(4-(2-((1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-1H-imidazol-1- yl)benzonitrile. LCMS calculated for C24H22ClF3N9O2S (M+H) + : m/z = 592.1; Found 592.3. Example 5.3-Chloro-2-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl) piperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1 -yl)benzonitrile This compound was prepared according to the procedures described in Example 4, using 3-chloro-2-fluorobenzonitrile instead of 3-chloro-4- fluorobenzonitrile as starting material. LCMS calculated for C24H22ClF3N9O2S (M+H) + : m/z = 592.1; Found 592.3. Example 6.4-(1-(2-Amino-5-fluoropyridin-4-yl)-1H-imidazol-4-yl)-N-(1 -((1- methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluor omethyl)pyrimidin- 2-amine This compound was prepared according to the procedures described in Example 4, using 4,5-difluoropyridin-2-amine instead of 3-chloro-4- fluorobenzonitrile as starting material. LCMS calculated for C22H23F4N10O2S (M+H) + : m/z = 567.2; Found 567.4. Example 7.3-Methyl-4-(4-(2-((1-((1-methyl-1H-imidazol-4-yl)sulfonyl) piperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1 -yl)picolinonitrile This compound was prepared according to the procedures described in Example 4, using 4-chloro-3-methylpicolinonitrile instead of 3-chloro-4- fluorobenzonitrile as starting material. LCMS calculated for C24H24F3N10O2S (M+H) + : m/z = 573.2; Found 573.4. Example 8. N-(3-Methyl-4-(4-(2-((1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-1H- imidazol-1-yl)pyridin-2-yl)acetamide This compound was prepared according to the procedures described in Example 4, using N-(4-chloro-3-methylpyridin-2-yl)acetamide (Intermediate 8) instead of 3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated for C25H28F3N10O3S (M+H) + : m/z = 605.2; Found 605.4. Example 9.4-(1-(2-Amino-3-methylpyridin-4-yl)-1H-imidazol-4-yl)-N-(1 -((1- methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluor omethyl)pyrimidin- 2-amine This compound was prepared according to the procedures described in Example 4, using N-(4-chloro-3-methylpyridin-2-yl)acetamide (Intermediate 8) instead of 3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated for C23H26F3N10O2S (M+H) + : m/z = 563.2; Found 563.4. Example 10.4-(1-Methyl-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-imidazol -4- yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-a mine To a vial containing 4-chloro-N-(1-((1-methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-a mine (Intermediate 4, 0.273 g, 0.643 mmol), 1-methyl-4-(tributylstannyl)-1H-imidazole (0.276 g, 0.707 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.037 g, 0.032 mmol) was added DMF (2.57 mL). The vial was flushed with nitrogen and a fresh cap applied, then the reaction heated to 100 °C for 18 hours. Based on LCMS the starting material was fully consumed and converted to the desired product. The reaction was cooled, diluted with ethyl acetate, and filtered over celite, washing with additional ethyl acetate. The filtrate was concentrated then purified by flash column chromatography (Agela Flash Column Silica-CS (12 g), eluting with a gradient of 0 to 20% CH2Cl2/methanol). LCMS calculated for C18H22F3N8O2S (M+H) + : m/z = 471.2; Found 471.2. Example 11.4-(1-Methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperi din-4-yl)- 5-(trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 10, using 4-chloro-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 1) instead of 4-chloro-N-(1-((1- methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluor omethyl)pyrimidin-2- amine as starting material. LCMS calculated for C 15 H 20 F 3 N 6 O 2 S (M+H) + : m/z = 405.1; Found 405.3. Example 12.4-(2,5-Dichloro-1-methyl-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine To a room temperature solution of 4-(1-methyl-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (Example 11, 0.292 g, 0.722 mmol) in DCM (7.22 mL) was added N-chlorosuccinimide (0.216 g, 1.588 mmol) in a single portion. The reaction was warmed to 40 °C for 18 hours. After cooling to room temperature the reaction was quenched with sodium bicarbonate and extracted with DCM. The combined organics were dried over sodium sulfate, filtered, and concentrated, then purified by flash column chromatography (Agela Flash Column Silica-CS (12 g), eluting with a gradient of 0 to 20% CH2Cl2/methanol). LCMS calculated for C15H18Cl2F3N6O2S (M+H) + : m/z = 473.1; Found 473.1. Example 13.4-(5-Bromo-1-methyl-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine To a room temperature solution of 4-(1-methyl-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (Example 11, 0.186 g, 0.460 mmol) in MeCN (4.60 mL) was added N-bromosuccinimide (0.087 g, 0.483 mmol) in a single portion. The reaction was stirred at room temperature for 2 hours then heated to 50 °C and stirred for an additional hour. The reaction was concentrated then purified by flash column chromatography (Agela Flash Column Silica-CS (12 g), eluting with a gradient of 0 to 20% CH2Cl2/methanol). LCMS calculated for C15H19BrF3N6O2S (M+H) + : m/z = 483.0; Found 483.0. Example 14.4-(5-Chloro-1-methyl-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine This compound was prepared according to the procedures described in Example 13, using N-chlorosuccinimide instead of N-bromosuccinimide as starting material. LCMS calculated for C15H19ClF3N6O2S (M+H) + : m/z = 439.1; Found 439.2. Example 15.4-(1,5-Dimethyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)pi peridin- 4-yl)-5-(trifluoromethyl)pyrimidin-2-amine To a vial containing 4-(5-bromo-1-methyl-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (Example 13, 0.027 g, 0.056 mmol), tri-o-tolylphosphine (3.40 mg, 0.011 mmol), and palladium(II) acetate (1.254 mg, 5.59 µmol) in DMF (0.559 mL) was added tetramethyltin (0.077 mL, 0.559 mmol). The reaction was heated to 110 °C for 20 minutes. LCMS indicated full consumption of the starting material and clean conversion to the desired product. After cooling to r.t., the resultant mixture was diluted with acetonitrile, and filtered. The solution containing the desired product was then purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford 4-(1,5-dimethyl-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine. LCMS calculated for C16H22F3N6O2S (M+H) + : m/z = 419.2; Found 419.1. Example 16.1-Methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5 - (trifluoromethyl)pyrimidin-4-yl)-1H-imidazole-5-carbonitrile To a vial containing 4-(5-bromo-1-methyl-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (Example 13, 0.027 g, 0.056 mmol), zinc cyanide (0.033 g, 0.279 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.016 g, 0.014 mmol) was added DMF (0.372 mL). The reaction was heated to 110 °C for 18 hours. LCMS indicated full consumption of the starting material and clean conversion to the desired product. After cooling to r.t., the resultant mixture was diluted with acetonitrile and filtered. The solution containing the desired product was then purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford 1-methyl-4-(2-((1-(methylsulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazole-5- carbonitrile. LCMS calculated for C16H19F3N7O2S (M+H) + : m/z = 430.1; Found 430.1. Example 17. (1-Methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-2-yl)methanol To a -78 °C solution of 4-(1-methyl-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (Example 11, 0.031 g, 0.077 mmol) in THF (0.767 mL) was added butyllithium (0.184 mL, 0.460 mmol) dropwise. The resulting orange solution was stirred at -78 °C for 30 minutes, then paraformaldehyde (2.302 mg, 0.077 mmol) was added. The reaction was stirred at -78 °C for 45 minutes then allowed to slowly warm to room temperature and stir overnight. The resultant mixture was diluted with acetonitrile and filtered. The solution containing the desired product was then purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford (1-methyl-4-(2-((1-(methylsulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-2-y l)methanol. LCMS calculated for C16H22F3N7O3S (M+H) + : m/z = 435.1; Found 435.1. Example 18.2-Methyl-1-(1-methyl-4-(2-((1-(methylsulfonyl)piperidin-4 - yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-2-y l)propan-2-ol This compound was prepared according to the procedures described in Example 17, using 2,2-dimethyloxirane instead of paraformaldehyde as electrophile. LCMS calculated for C19H28F3N6O3S (M+H) + : m/z = 477.2; Found 477.3. Example 19.4-(1,2-Dimethyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)pi peridin- 4-yl)-5-(trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 17, using iodomethane instead of paraformaldehyde as electrophile. LCMS calculated for C16H22F3N6O3S (M+H) + : m/z = 419.2; Found 419.2. Example 20.4-(5-Chloro-1-methyl-1H-imidazol-4-yl)-N-(1-((1-methyl-1H - imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)py rimidin-2-amine This compound was prepared according to the procedures described in Example 13, using N-chlorosuccinimide instead of N-bromosuccinimide and using 4- (1-methyl-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-imidazol-4-yl )sulfonyl)piperidin-4- yl)-5-(trifluoromethyl)pyrimidin-2-amine (Example 10) instead of 4-(1-methyl-1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifl uoromethyl)pyrimidin-2- amine as starting material. 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 343 K) d 8.57 (s, 1H), 7.83 (s, 1H), 7.77 (s, 1H), 7.73 (s, 1H), 7.71 (d, J = 6.2 Hz, 1H), 3.88 (s, 1H), 3.74 (s, 3H), 3.66 (s, 3H), 3.63 (d, J = 12.4 Hz, 1H), 2.72 (td, J = 12.0, 2.8 Hz, 2H), 1.97 (d, J = 12.8 Hz, 2H), 1.62 (ddd, J = 23.7, 11.0, 3.9 Hz, 2H). LCMS calculated for C18H21ClF3N8O2S (M+H) + : m/z = 505.1; Found 505.1. Example 21.4-(1-(2,2-Difluoroethyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine A mixture of 4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 2, 10 mg, 0.026 mmol), 1,1- difluoro-2-iodoethane (9.8 mg, 0.051 mmol) and cesium carbonate (25 mg, 0.077 mmol) in acetonitrile (1 mL) was stirred at 80 °C for 3 h. After cooling to r.t., the resultant mixture was diluted with acetonitrile and filtered. The solution containing the desired product was then purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford 4-(1-(2,2-difluoroethyl)-1H-imidazol-4-yl)-N-(1-(methylsulfo nyl)piperidin-4- yl)-5-(trifluoromethyl)pyrimidin-2-amine. LCMS calculated for C16H20F5N6O2S (M+H) + : m/z = 455.1; Found 455.1. Example 22.2-Methyl-1-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino )-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)propan-2-o l This compound was prepared according to the procedures described in Example 21, using 2,2-dimethyloxirane instead of 1,1-difluoro-2-iodoethane as starting material. 1 H NMR (TFA salt, 500 MHz, DMSO-d6) d 8.64 (s, 1H), 8.12 (br, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 4.10 (s, 1H), 4.05 (br, 3H), 4.02 (s, 1H), 3.56 (d, J = 11.8 Hz, 2H), 2.89 (d, J = 6.8 Hz, 3H), 1.97 (br, 2H), 1.61 (m, 2H), 1.10 (d, J = 13.3 Hz, 6H). LCMS calculated for C18H26F3N6O3S (M+H) + : m/z = 463.2; Found 463.4. Example 23. N-(1-(Methylsulfonyl)piperidin-4-yl)-4-(1-(2,2,2-trifluoroet hyl)-1H- imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 21, using 2,2,2-trifluoroethyl 4-methylbenzenesulfonate instead of 1,1- difluoro-2-iodoethane as starting material. LCMS calculated for C16H19F6N6O2S (M+H) + : m/z = 473.1; Found 473.0. Example 24. N-(1-(Methylsulfonyl)piperidin-4-yl)-4-(1-(tetrahydro-2H-pyr an-4- yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 21, using tetrahydro-2H-pyran-4-yl methanesulfonate instead of 1,1-difluoro-2- iodoethane as starting material. LCMS calculated for C19H26F3N6O3S (M+H) + : m/z = 475.2; Found 475.1. Example 25.3-Cyclopropyl-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)propanenit rile This compound was prepared according to the procedures described in Example 21, using (E)-3-cyclopropylacrylonitrile and 1,8-diazabicyclo[5.4.0]undec- 7-ene instead of 1,1-difluoro-2-iodoethane and cesium carbonate as starting material. LCMS calculated for C20H25F3N7O2S (M+H) + : m/z = 484.2; Found 484.1. Example 26.4-(1-(2,2-Difluoroethyl)-1H-imidazol-4-yl)-2-((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitri le This compound was prepared according to the procedures described in Example 21, using 4-(1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4- yl)amino)pyrimidine-5-carbonitrile (Intermediate 10) instead of 4-(1H-imidazol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine as starting material. LCMS calculated for C16H20F2N7O2S (M+H) + : m/z = 412.1; Found 412.1. Example 27.4-(1-(2-Hydroxy-2-methylpropyl)-1H-imidazol-4-yl)-2-((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitri le This compound was prepared according to the procedures described in Example 21, using 4-(1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4- yl)amino)pyrimidine-5-carbonitrile (Intermediate 10) and 2,2-dimethyloxirane instead of 4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine and 1,1-difluoro-2-iodoethane as starting material. LCMS calculated for C18H26N7O3S (M+H) + : m/z = 420.2; Found 420.1. Example 28.4-(1-(2-Chloro-4-cyanophenyl)-1H-imidazol-4-yl)-2-((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitri le This compound was prepared according to the procedures described in Example 21, using 4-(1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4- yl)amino)pyrimidine-5-carbonitrile (Intermediate 10) and 3-chloro-4- fluorobenzonitrile instead of 4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4- yl)-5-(trifluoromethyl)pyrimidin-2-amine and 1,1-difluoro-2-iodoethane as starting material. LCMS calculated for C21H20ClN8O2S (M+H) + : m/z = 483.1; Found 483.1. Example 29. N-(1-(Cyclopropylsulfonyl)piperidin-4-yl)-4-(1-(2,2-difluoro ethyl)- 1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 21, using N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-y l)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 12) instead of 4-(1H-imidazol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine as starting material. LCMS calculated for C18H22F5N6O2S (M+H) + : m/z = 481.1; Found 481.1. 1 H NMR (500 MHz, DMSO-d6) d 8.55 (d, 1H), 7.83 (m, 2H), 7.69 (s, 1H), 4.79 (s, 1H), 3.99 (m, 1H), 3.95 (s, 2H), 3.62 (d, J = 12.3 Hz, 2H), 3.00 (d, J = 10.5 Hz, 2H), 2.59 (m, 1H), 1.98 (m, 2H), 1.62 (m, 2H), 1.08 (s, 6H), 1.00 (m, 2H), 0.95 (m, 2H). Example 30.1-(4-(2-((1-(Cyclopropylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylp ropan-2-ol This compound was prepared according to the procedures described in Example 21, using N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-y l)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 12) and 2,2-dimethyloxirane instead of 4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine and 1,1-difluoro-2-iodoethane as starting material. LCMS calculated for C20H28F3N6O3S (M+H) + : m/z = 489.2; Found 489.2. 1 H NMR (TFA salt, 500 MHz, DMSO-d6) d 8.64 (m, 1H), 8.45 – 7.76 (m, 6H), 7.72 (td, J = 7.6, 1.2 Hz, 1H), 4.06 – 3.99 (m, 2H), 3.54 (d, J = 11.7 Hz, 2H), 2.97 – 2.82 (m, 5H), 1.99 (t, J = 13.0 Hz, 2H), 1.59 (dt, J = 20.1, 9.7 Hz, 2H). Example 31.2-(4-(2-((1-(Methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitri le This compound was prepared according to the procedures described in Example 4, using 2-fluorobenzonitrile instead of 3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated for C21H21F3N7O2S (M+H) + : m/z = 492.1; Found 492.1. 1 H NMR (TFA salt, 500 MHz, DMSO-d6) d 8.64 (m, 1H), 8.45 – 7.76 (m, 6H), 7.72 (td, J = 7.6, 1.2 Hz, 1H), 4.06 – 3.99 (m, 2H), 3.54 (d, J = 11.7 Hz, 2H), 2.97 – 2.82 (m, 5H), 1.99 (t, J = 13.0 Hz, 2H), 1.59 (dt, J = 20.1, 9.7 Hz, 2H). Example 32. N-(1-(Methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)-4-( 1-(2- (trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)pyrimidin-2- amine This compound was prepared according to the procedures described in Example 4, using 3-fluoro-2-(trifluoromethyl)pyridine instead of 3-chloro-4- fluorobenzonitrile as starting material. LCMS calculated for C20H20F6N7O2S (M+H) + : m/z = 536.1; Found 536.1. 1 H NMR (TFA salt, 500 MHz, DMSO-d6) d 8.93 (d, J = 4.7 Hz, 1H), 8.63 (m, 1H), 8.34 – 7.90 (m, 5H), 3.99 (s, 1H), 3.54 (t, J = 13.4 Hz, 2H), 2.94 – 2.79 (m, 5H), 2.03 – 1.89 (m, 2H), 1.59 (t, J = 11.6 Hz, 2H). Example 33.6-Methyl-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino )-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinoni trile This compound was prepared according to the procedures described in Example 4, using 5-fluoro-6-methylpicolinonitrile instead of 3-chloro-4- fluorobenzonitrile as starting material. LCMS calculated for C21H22F3N8O2S (M+H) + : m/z = 507.2; Found 507.1. 1 H NMR (TFA salt, 500 MHz, DMSO-d6) d 8.66 (d, J = 30.4 Hz, 1H), 8.37 – 8.08 (m, 4H), 7.96 (t, J = 6.5 Hz, 1H), 4.03 (s, 1H), 3.55 (d, J = 11.5 Hz, 2H), 2.90 (m, 5H), 2.52 (m, 5H), 1.99 (d, J = 12.7 Hz, 2H), 1.62 (t, J = 10.7 Hz, 2H). Example 34.3-(4-(2-((1-(Methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinoni trile This compound was prepared according to the procedures described in Example 4, using 3-fluoropicolinonitrile instead of 3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated for C20H20F3N8O2S (M+H) + : m/z = 493.1; Found 493.1. 1 H NMR (TFA salt, 500 MHz, DMSO-d6) d 8.87 (d, J = 4.7 Hz, 1H), 8.73 – 8.23 (m, 4H), 8.05 – 7.92 (m, 2H), 4.02 (s, 1H), 3.55 (d, J = 10.7 Hz, 2H), 2.89 (m, 5H), 2.01 (m, 2H), 1.60 (p, J = 10.9, 8.7 Hz, 2H). Example 35.3-Methyl-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino )-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitri le This compound was prepared according to the procedures described in Example 4, using 4-fluoro-3-methylbenzonitrile instead of 3-chloro-4- fluorobenzonitrile as starting material. LCMS calculated for C22H23F3N7O2S (M+H) + : m/z = 506.2; Found 506.2. Example 36.6-Methyl-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino )-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinoni trile This compound was prepared according to the procedures described in Example 1, using 3-fluoro-6-methylpicolinonitrile instead of 3-chloro-4- fluorobenzonitrile as starting material. LCMS calculated for C21H22F3N8O2S (M+H) + : m/z = 507.2; Found 507.1. 1 H NMR (TFA salt, 500 MHz, DMSO-d6) d 8.65 (m, 1H), 8.47 – 8.16 (m, 3H), 7.97 (m, 1H), 7.84 (m, 1H), 4.01 (s, 1H), 3.55 (d, J = 11.6 Hz, 2H), 2.95 – 2.83 (m, 5H), 2.63 (s, 3H), 1.99 (t, J = 15.5 Hz, 2H), 1.67 – 1.53 (m, 2H). Example 37.4-(1-(2-(Difluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N -(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine This compound was prepared according to the procedures described in Example 1, using 3-fluoro-6-methylpicolinonitrile instead of 3-chloro-4- fluorobenzonitrile as starting material. LCMS calculated for C20H21F5N7O2S (M+H) + : m/z = 518.1; Found 518.2. 1 H NMR (TFA salt, 500 MHz, DMSO-d6) d 8.86 (d, J = 4.6 Hz, 1H), 8.64 (m, 1H), 8.28 – 7.99 (m, 3H), 7.94 (d, J = 7.7 Hz, 1H), 7.85 (td, J = 8.3, 4.6 Hz, 1H), 6.95 (m, 1H), 4.00 (s, 1H), 3.54 (t, J = 13.6 Hz, 2H), 2.96 – 2.78 (m, 5H), 1.98 (m, 2H), 1.59 (t, J = 12.5 Hz, 2H). Example 38.3-(4-(2-((1-(Methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2- (trifluoromethyl)benzonitrile This compound was prepared according to the procedures described in Example 1, using 3-fluoro-6-methylpicolinonitrile instead of 3-chloro-4- fluorobenzonitrile as starting material. LCMS calculated for C22H20F6N7O2S (M+H) + : m/z = 560.1; Found 560.2. 1 H NMR (TFA salt, 500 MHz, DMSO-d6) d 8.63 (m, 1H), 8.42 – 7.97 (m, 5H), 7.95 (t, J = 8.5 Hz, 1H), 4.00 (m, 1H), 3.60 – 3.47 (m, 2H), 2.87 (m, 5H), 1.96 (dq, J = 12.2, 3.6 Hz, 2H), 1.59 (h, J = 11.6, 10.9 Hz, 2H). Example 39.6-Methoxy-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinoni trile To a vial containing 6-chloro-3-fluoropicolinonitrile (0.038 g, 0.246 mmol) and cesium carbonate (0.200 g, 0.615 mmol) was added a solution of 4-(1H-imidazol- 4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethy l)pyrimidin-2-amine (Intermediate 2, 0.08 g, 0.205 mmol) in acetonitrile (3 mL). The reaction was stirred at 80 °C for 1 hour then cooled to room temperature and methanol (3 mL, 74.1 mmol) was added. The reaction was heated to 60 °C for 40 minutes at which point LCMS indicated reaction completion. Upon cooling to room temperature the reaction was diluted to 10 mL with 1:1 acetonitrile:H2O plus TFA (0.3 mL) and purified by prep- LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford 6-methoxy-3-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)picolinonitrile. LCMS calculated for C21H22F3N8O3S (M+H) + : m/z = 523.2; Found 523.1. 1 H NMR (TFA salt, 500 MHz, DMSO-d6) d 8.64 (m, 1H), 8.44 – 8.12 (m, 3H), 7.97 (m, 1H), 7.42 (dd, J = 13.3, 8.9 Hz, 1H), 4.07 – 3.94 (m, 4H), 3.54 (m, 2H), 2.94 – 2.83 (m, 5H), 2.05 – 1.92 (m, 2H), 1.68 – 1.53 (m, 2H). Example 40.6-(2-(Dimethylamino)ethoxy)-3-(4-(2-((1-(methylsulfonyl)p iperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1 -yl)picolinonitrile This compound was prepared according to the procedures described in Example 39 using 2-(dimethylamino)ethan-1-ol instead of methanol as starting material. LCMS calculated for C24H29F3N9O3S (M+H) + : m/z = 580.2; Found 580.1. 1 H NMR (TFA salt, 500 MHz, DMSO-d6) d 9.72 (s, 1H), 8.65 (m, 1H), 8.43 – 8.13 (m, 3H), 7.96 (m, 1H), 7.44 (t, J = 8.4 Hz, 1H), 4.72 – 4.63 (m, 2H), 4.01 (s, 1H), 3.62 – 3.50 (m, 4H), 2.95 – 2.83 (m, 10H), 2.00 (m, 2H), 1.60 (m, 2H).
Example 41.6-Ethyl-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino) -5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinoni trile To a vial containing potassium carbonate (0.030 g, 0.216 mmol) and XPhos Pd G3 (6.10 mg, 7.21 µmol) was added 6-chloro-3-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)picolinonitrile (Intermediate 25, 0.038 g, 0.072 mmol) in dioxane (0.401 mL). 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.026 mL, 0.144 mmol) was added followed by water (0.080 mL) and the solution heated to 50 °C for 40 minutes. LCMS indicated full consumption of starting material and conversion to the vinyl intermediate. The crude reaction was cooled to room temperature and filtered through a pad of SiliaMetS Thiol ® , rinsing with MeOH (1 mL). To the filtrate was added palladium on carbon (one scoop) and the reaction was stirred under a hydrogen balloon for 2 hours. LCMS indicated that hydrogenation was complete. The reaction was filtered over celite, diluted to 5 mL with 1:1 acetonitrile:H2O and purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C22H24F3N8O2S (M+H) + : m/z = 521.2; Found 521.2.
Example 42.3-(4-(2-(((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4- yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methy lbenzonitrile Step 1: 2-Bromo-3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperid in-4-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonit rile To a vial containing 2-bromo-3-fluorobenzonitrile (0.024 g, 0.122 mmol) and cesium carbonate (0.060 g, 0.184 mmol) was added a solution of N-((3R,4S)-3-fluoro- 1-(methylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(tr ifluoromethyl)pyrimidin- 2-amine (Intermediate 17, 0.025 g, 0.061 mmol) in acetonitrile (1 mL). The reaction was stirred at 80 °C for 1.5 hours. Upon cooling to room temperature the reaction was filtered and washed with acetonitrile. The filtrate was concentrated and advanced to step 2 without further purification. LCMS calculated for C21H19BrF4N7O2S (M+H) + : m/z = 588.0; Found 588.1. Step 2: 3-(4-(2-(((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylb enzonitrile To a vial containing crude 2-bromo-3-(4-(2-(((3R,4S)-3-fluoro-1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)benzonitrile from step 1 was added tri-o-tolylphosphane (7.45 mg, 0.024 mmol), palladium(II) acetate (2.75 mg, 0.012 mmol), and tetramethylstannane (0.085 mL, 0.612 mmol) followed by DMF (0.8 mL). The reaction was stirred at 110 °C for 6 hours. Upon cooling to room temperature the reaction filtered through a pad of SiliaMetS Thiol ® , rinsing with acetonitirle (2 mL) then was diluted to 5 mL with 1:1 acetonitrile:H2O and purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C22H22F4N7O2S (M+H) + : m/z = 524.2; Found 524.3. Example 43.2-Methyl-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino )-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitri le This compound was prepared according to the procedures described in Example 42, using 4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 2) instead of N-((3R,4S)-3-fluoro- 1-(methylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5-(tr ifluoromethyl)pyrimidin- 2-amine as starting material for step 1. LCMS calculated for C22H23F3N7O2S (M+H) + : m/z = 506.2; Found 506.2. 1 H NMR (TFA salt, 500 MHz, DMSO-d6) d 8.63 (m, 1H), 8.27 – 7.87 (m, 4H), 7.81 (dd, J = 30.6, 8.0 Hz, 1H), 7.61 (q, J = 7.6 Hz, 1H), 4.01 (dd, J = 25.9, 9.9 Hz, 1H), 3.53 (m, 2H), 2.94 – 2.78 (m, 5H), 2.35 (d, J = 6.2 Hz, 3H), 1.96 (dt, J = 12.2, 3.7 Hz, 2H), 1.60 (h, J = 11.2, 10.0 Hz, 2H).
Example 44.4-(1-(6-Methyl-2-(trifluoromethyl)pyridin-3-yl)-1H-imidaz ol-4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyri midin-2-amine To a vial containing 4-(1-(6-chloro-2-(trifluoromethyl)pyridin-3-yl)-1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifl uoromethyl)pyrimidin-2- amine (Intermediate 25, 0.265 g, 0.465 mmol), tri-o-tolylphosphine (0.028 g, 0.093 mmol), and palladium(II) acetate (10.44 mg, 0.046 mmol) in DMF (4.65 mL) was added tetramethyltin (0.515 mL, 3.72 mmol). The headspace was flushed with nitrogen, then the vial was capped and the reaction was heated to 110 °C for 40 minutes. Upon cooling to room temperature the reaction filtered through a pad of SiliaMetS Thiol ® , rinsing with acetonitrile (5 mL) then was diluted to 20 mL with 1:1 acetonitrile:H2O and purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C21H22F6N7O2S (M+H) + : m/z = 550.2; Found 550.2. 1 H NMR (TFA salt, 500 MHz, DMSO-d6) d 8.63 (m, 1H), 8.21 – 7.89 (m, 4H), 7.83 (t, J = 7.8 Hz, 1H), 3.99 (s, 1H), 3.58 – 3.48 (m, 2H), 2.87 (m, 5H), 2.66 (s, 3H), 1.97 (d, J = 12.6 Hz, 2H), 1.65 – 1.51 (m, 2H). Example 45.2-Chloro-3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)pip eridin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-y l)benzonitrile This compound was prepared according to the procedures described in Example 1, using 2-chloro-3-fluorobenzonitrile instead of 3-chloro-4- fluorobenzonitrile and N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H- imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 17) instead of 4- (1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine as starting materials. LCMS calculated for C21H19ClF4N7O2S (M+H) + : m/z = 544.1; Found 544.1. 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 4:6 rotamers) d 8.66 (m, 1H), 8.38 – 7.96 (m, 5H), 7.78 (t, J = 8.0 Hz, 1H), 4.96 (m, 1H), 4.21 (m, 1H), 3.83 (s, 1H), 3.72 – 3.60 (m, 1H), 3.30 – 3.13 (m, 1H), 3.00 (t, J = 12.1 Hz, 1H), 2.91 (s, 3H), 1.96 (m, 1H), 1.84 – 1.74 (m, 1H). Example 46. N-((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-( 6- methyl-2-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 42, using using 6-chloro-3-fluoro-2-(trifluoromethyl)pyridine instead of 2- bromo-3-fluorobenzonitrile as starting material for step 1. LCMS calculated for C21H21F7N7O2S (M+H) + : m/z = 568.1; Found 568.1.
Example 47.3-(4-(2-(((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4- yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolino nitrile This compound was prepared according to the procedures described in Example 1, using 3-fluoropicolinonitrile instead of 3-chloro-4-fluorobenzonitrile and N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H- imidazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 17) instead of 4-(1H-imidazol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine as starting materials. LCMS calculated for C20H19F4N8O2S (M+H) + : m/z = 511.1; Found 511.2. 1 H NMR (TFA salt, 500 MHz, DMSO-d6) d 8.88 (m, 1H), 8.73 – 8.28 (m, 4H), 8.10 (m, 1H), 8.00 (m, 1H), 4.99 (m, 1H), 4.28 – 4.10 (m, 1H), 3.91 – 3.78 (m, 1H), 3.68 (d, J = 13.3 Hz, 1H), 3.23 (m, 1H), 3.09 – 2.95 (m, 1H), 2.92 (s, 3H), 1.98 (qt, J = 12.2, 6.8 Hz, 1H), 1.88 – 1.76 (m, 1H). Example 48. N-((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)-4-(1-(2-(trifluoromethyl)pyridin-3-yl)-1H- imidazol-4- yl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 1, using 3-fluoro-2-(trifluoromethyl)pyridine instead of 3-chloro-4- fluorobenzonitrile and N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H- imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 17) instead of 4- (1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine as starting materials. LCMS calculated for C20H19F7N7O2S (M+H) + : m/z = 554.1; Found 554.1. 1 H NMR (TFA salt, 500 MHz, DMSO-d6) d 8.94 (m, 1H), 8.66 (m, 1H), 8.35 – 8.10 (m, 3H), 8.05 (m, 1H), 7.99 (m, 1H), 4.95 (m, 1H), 4.19 (d, J = 29.3 Hz, 1H), 3.83 (q, J = 13.8 Hz, 1H), 3.71 – 3.60 (m, 1H), 3.19 (m, 1H), 3.07 – 2.94 (m, 1H), 2.91 (m, 3H), 1.95 (dt, J = 16.7, 13.0 Hz, 1H), 1.85 – 1.73 (m, 1H). Example 49.5-(4-(2-(((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4- yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-methy lpicolinonitrile This compound was prepared according to the procedures described in Example 1, using 5-fluoro-6-methylpicolinonitrile instead of 3-chloro-4- fluorobenzonitrile and N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H- imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 17) instead of 4- (1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine as starting materials. LCMS calculated for C21H21F4N8O2S (M+H) + : m/z = 525.1; Found 525.1. 1 H NMR (TFA salt, 500 MHz, DMSO-d6) d 8.67 (d, J = 13.7 Hz, 1H), 8.36 (s, 1H), 8.27 – 8.11 (m, 3H), 8.03 (m, 1H), 4.96 (m, 1H), 4.29 – 4.11 (m, 1H), 3.82 (d, J = 13.0 Hz, 1H), 3.66 (d, J = 12.4 Hz, 1H), 3.21 (m, 1H), 2.99 (t, J = 11.4 Hz, 1H), 2.91 (s, 3H), 2.50 (s, 3H), 1.96 (d, J = 11.8 Hz, 1H), 1.80 (dd, J = 13.7, 3.9 Hz, 1H). Example 50.4-(1-(2-(Difluoromethyl)pyridin-3-yl)-1H-imidazol-4-yl)-N -((3R,4S)- 3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethy l)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 1, using 2-(difluoromethyl)-3-fluoropyridine instead of 3-chloro-4- fluorobenzonitrile and N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H- imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 17) instead of 4- (1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine as starting materials. LCMS calculated for C20H20F6N7O2S (M+H) + : m/z = 536.1; Found 536.1. 1 H NMR (TFA salt, 500 MHz, DMSO-d6) d 8.87 (m, 1H), 8.66 (m, 1H), 8.34 – 7.97 (m, 3H), 7.86 (t, J = 5.4 Hz, 1H), 6.96 (m, 1H), 4.96 (m, 1H), 4.29 – 4.11 (m, 1H), 3.90 – 3.76 (m, 1H), 3.71 – 3.61 (m, 1H), 3.20 (m, 1H), 3.09 – 2.94 (m, 1H), 2.91 (m, 3H), 2.03 – 1.91 (m, 1H), 1.80 (dd, J = 13.4, 4.0 Hz, 1H). Example 51.3-(4-(2-(((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4- yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-methy lpicolinonitrile This compound was prepared according to the procedures described in Example 1, using 3-fluoro-6-methylpicolinonitrile instead of 3-chloro-4- fluorobenzonitrile and N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H- imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 17) instead of 4- (1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine as starting materials. LCMS calculated for C21H21F4N8O2S (M+H) + : m/z = 525.2; Found 525.3. Example 52.3-(4-(2-(((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4- yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-metho xypicolinonitrile This compound was prepared according to the procedures described in Example 39, using N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H- imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 17) instead of 4- (1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine as starting material. LCMS calculated for C21H21F4N8O3S (M+H) + : m/z = 541.1; Found 541.1. Example 53.6-(2-(Dimethylamino)ethoxy)-3-(4-(2-(((3R,4S)-3-fluoro-1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)picolinonitrile This compound was prepared according to the procedures described in Example 39, using N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H- imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 17) instead of 4- (1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine and using 2-(dimethylamino)ethan-1-ol instead of methanol as starting materials. LCMS calculated for C24H28F4N9O3S (M+H) + : m/z = 598.2; Found 598.2. Table 2. The compounds in Table 2 were prepared in accordance with the synthetic protocols set forth in Example 1 using the appropriate starting materials.
Table 3. The compounds in Table 3 were prepared in accordance with the synthetic protocols set forth in Example 39 using the appropriate starting materials.
Example 77.4-(1-(2-Chloro-3-((dimethylamino)methyl)phenyl)-1H-imidaz ol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine To a room temperature solution of 2-chloro-3-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)benzaldehyde (Intermediate 35, 0.020 g, 0.038 mmol) and dimethylamine (0.023 mL, 0.045 mmol) in DCE (0.5 mL) was added sodium triacetoxyborohydride (0.012 g, 0.057 mmol) in a single portion. The reaction was stirred at room temperature for 1 hour at which point LCMS indicated full consumption of the aldehyde and conversion to desired product. The reaction was diluted to 5 mL with 1:1 acetonitrile:MeOH and purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C23H28ClF3N7O2S (M+H) + : m/z = 558.2; Found 558.1. Table 4. The compounds in Table 4 were prepared in accordance with the synthetic protocols set forth in Example 77 using the appropriate amine starting material.
Example 83.1-(2-Chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)am ino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)eth an-1-ol To a solution of 2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5 - (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehy de (Intermediate 35, 0.015 g, 0.028 mmol) in THF (0.5 mL) was added methylmagnesium bromide (0.047 mL, 0.142 mmol). The reaction was stirred for 10 minutes at room temperature at which point LCMS indicated full consumption of starting material and conversion to the desired product. The reaction was quenched with H2O (0.5 mL) and diluted to 5 mL with 1:1 acetonitrile:MeOH then purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C22H25ClF3N6O3S (M+H) + : m/z = 545.1; Found 545.1. Table 5. The compounds in Table 5 were prepared in accordance with the synthetic protocols set forth in Example 83 using the appropriate reductant. Example 87.3-(4-(2-((1-(Ethylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-methylp icolinonitrile To a solution of 6-methyl-3-(4-(2-(piperidin-4-ylamino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinoni trile (Intermediate 31, 0.019 g, 0.045 mmol) in THF (0.450 mL) was added ethanesulfonyl chloride (6.4 µL, 0.068 mmol) followed by dropwise addition of triethylamine (0.063 mL, 0.450 mmol). The reaction was stirred at room temperature for 1 hour at which point LCMS showed full conversion to the desired product. The reaction was diluted to 5 mL with 1:1 acetonitrile:H2O then purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C22H24F3N8O2S (M+H) + : m/z = 521.2; Found 521.1. Table 6. The compounds in Table 6 were prepared in accordance with the synthetic protocols set forth in Example 87 using the appropriate starting materials.
Table 7. The compounds in Table 7 were prepared in accordance with the synthetic protocols set forth in Example 41 using the appropriate starting materials.
Example 96.4-(1-(3-(2-Aminopyridin-4-yl)-2-chlorophenyl)-1H-imidazol -4-yl)-N- (1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimi din-2-amine To a vial containing 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2- amine (0.019 g, 0.086 mmol), potassium carbonate (0.018 g, 0.129 mmol), and XPhos Pd G3 (3.65 mg, 4.31 µmol) was added a solution of 4-(1-(3-bromo-2-chlorophenyl)- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 34, 0.025 g, 0.043 mmol) in dioxane (0.180 mL) followed by water (0.036 mL). The headspace was purged with nitrogen then the vial capped and heated to 80 °C for 2 hours. The crude reaction was cooled to room temperature and filtered through a pad of SiliaMetS Thiol ® , rinsing with MeOH (1 mL). The solution was then diluted to 5 mL with 1:1 acetonitrile:H2O and purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C25H25ClF3N8O2S (M+H) + : m/z = 593.2; Found 593.0. Table 8. The compounds in Table 8 were prepared in accordance with the synthetic protocols set forth in Example 96 using the appropriate starting materials. Example 99.5-(4-(2-((1-(Methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6- (trifluoromethyl)picolinonitrile To a vial containing 4-(1-(6-chloro-2-(trifluoromethyl)pyridin-3-yl)-1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifl uoromethyl)pyrimidin-2- amine (Intermediate 26, 0.044 g, 0.077 mmol), zinc cyanide (0.027 g, 0.231 mmol), and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.013 g, 0.015 mmol) was added DMF (0.5 mL). The vial was purged with nitrogen then heated to 110 °C for 16 hours. The crude reaction was cooled to room temperature and filtered through a pad of SiliaMetS Thiol ® , rinsing with MeOH (1 mL). The solution was then diluted to 5 mL with 1:1 acetonitrile:H2O and purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C21H19F6N8O2S (M+H) + : m/z = 561.1; Found 561.2. Table 9. The compounds in Table 9 were prepared in accordance with the synthetic protocols set forth in Example 99 using the appropriate starting materials. Example 101.4-(1-(4-(4-(Dimethylamino)piperidin-1-yl)-2-fluorophenyl )-2- methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl )-5- (trifluoromethyl)pyrimidin-2-amine To a mixture of 4-(1-(2-fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)-N- (1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimi din-2-amine (Intermediate 41, 25 mg, 0.040 mmol) and N,N-dimethylpiperidin-4-amine (15.4 mg, 0.120 mmol) in toluene (0.27 mL) and dioxane (0.13 mL) was added tris(dibenzylideneacetone)dipalladium (0):BINAP:sodium tert-butoxide (0.05:0.15:2 molar ratio) (13.3 mg). The mixture was degassed with N2 and then stirred in a sealed vial at 100 o C for 1 h. After cooling to room temperature, the reaction mixture was concentrated. The residue was then diluted with MeOH, filtered and the filtrate was 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). 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 1:1 rotamers) d 9.51 (s, 1H), 8.61 (s, 0.5H), 8.55 (s, 0.5H), 7.89 (s, 0.5H), 7.86 (d, J = 7.6 Hz, 1H), 7.68 (s, 0.5H), 7.43 (t, J = 8.9 Hz, 1H), 7.13 – 7.04 (m, 1H), 6.93 (d, J = 7.5 Hz, 1H), 4.07-3.98 (m, 2H), 3.95 (m, 1H), 3.52 (m, 2H), 3.36 (m, 1H), 2.90-2.81 (m, 7H), 2.78 (s, 3H), 2.77 (s, 3H), 2.20 (s, 3H), 2.06 (m, 2H), 1.95 (m, 2H), 1.63 (m, 2H), 1.57 (m, 2H). LCMS calculated for C28H37F4N8O2S (M+H) + : m/z = 625.3; Found 625.4. Example 102.4-(1-(2-Fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1- (methylsulfonyl) piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine This compound is a major side-product from deiodination of 4-(1-(2-fluoro-4- iodophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl) piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 41) under the C-N coupling reaction condition (the same procedure described in Example 101). This compound was 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). LCMS calculated for C21H23F4N6O2S (M+H) + : m/z = 499.2; Found 499.2. Example 103.4-(1-(2-Fluoro-4-(4-methylpiperazin-1-yl)phenyl)-2-methy l-1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 101, using 1-methylpiperazine instead of N,N-dimethylpiperidin-4-amine as starting material. 1 H NMR (TFA salt, 400 MHz, DMSO-d6, 4:6 rotamers) d 10.31 (s, 1H), 8.65 (s, 0.4H), 8.60 (s, 0.6H), 8.02 (m, 1H), 7.98 (s, 0.6H), 7.82 (s, 4H), 7.63 – 7.45 (m, 1H), 7.16 (d, J = 7.4 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 4.01 (m, 3H), 3.53 (m, 6H), 3.13 (m, 4H), 2.89 (m, 6H), 2.30 (d, J = 8.0 Hz, 3H), 1.95 (m, 2H), 1.58 (m, 2H). LCMS calculated for C26H33F4N8O2S (M+H) + : m/z = 597.2; Found 597.2.
Table 10. The compounds in Table 10 were prepared in accordance with the synthetic protocols set forth in Example 101 using the appropriate starting materials. Example 118.4-(1-(4-(4-(Dimethylamino)piperidin-1-yl)-2-fluorophenyl )-2- methyl-1H-imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfon yl)piperidin-4-yl)- 5-(trifluoromethyl)pyrimidin-2-amine Step 1: N-((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-( 2-fluoro-4- iodophenyl)-2-methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)py rimidin-2-amine This compound was prepared according to the procedures described in Intermediate 41, using N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(2- methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amin e (Intermediate 39) instead of 4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 38) as starting material. LCMS calculated for C21H21F5IN6O2S (M+H) + : m/z = 643.0; Found 643.0. Step 2: 4-(1-(4-(4-(Dimethylamino)piperidin-1-yl)-2-fluorophenyl)-2- methyl-1H- imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperid in-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 101, using N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-( 2- fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)-5-(trifluoro methyl)pyrimidin-2- amine (Step 1) instead of 4-(1-(2-fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyri midin-2-amine (Intermediate 41) as starting material. LCMS calculated for C28H36F5N8O2S (M+H) + : m/z = 643.3; Found 643.3. Example 119.4-(1-(2-Chloro-4-(1-methyl-1H-pyrazol-5-yl)phenyl)-1H-im idazol- 4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethy l)pyrimidin-2-amine Step 1: 4-(1-(4-Bromo-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine This compound was prepared according to the procedures described in Intermediate 42, using 2-chloro-1-fluoro-4-bromobenzene instead of 2-chloro-1- fluoro-4-iodobenzene as starting material. LCMS calculated for C20H20BrClF3N6O2S (M+H) + : m/z = 579.0; Found 579.0. Step 2: 4-(1-(2-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y l)phenyl)-1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifl uoromethyl)pyrimidin-2- amine To a mixture of 4-(1-(4-bromo-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl) piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (100 mg, 0.172 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (52.6 mg, 0.207 mmol) and potassium acetate (42.3 mg, 0.431 mmol) in dioxane (0.575 mL) was added dichloro[1,1'-bis(diphenylphosphino)ferrocene] palladium (II) dichloromethane adduct (14.08 mg, 0.017 mmol). The mixture was purged with N2, sealed and stirred at 100 °C for 2 h. After completion, the reaction was cooled to room temperature. The mixture was concentrated and the residue was purified by column chromatography eluting with a gradient of hexanes/EtOAc (0 - 90%) on silica gel. LCMS calculated for C26H32BClF3N6O4S (M+H) + : m/z = 627.2; Found 627.2. Step 3: 4-(1-(2-Chloro-4-(1-methyl-1H-pyrazol-5-yl)phenyl)-1H-imidaz ol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine To a mixture of 4-(1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin- 4-yl)-5- (trifluoromethyl) pyrimidin-2-amine (15 mg, 0.024 mmol), 5-iodo-1-methyl-1H- pyrazole (14.93 mg, 0.072 mmol) and potassium phosphate (15.24 mg, 0.072 mmol) in water (0.04 mL) and dioxane (0.20 mL) was added chloro(2- dicyclohexylphosphino-2¢,4¢,6¢-triisopropyl-1,1¢-bipheny l)[2-(2¢-amino-1,1¢- biphenyl)]palladium(II) (2.82 mg, 3.59 µmol). The mixture was purged with N2, sealed and stirred at 110 °C for 2 h. After completion, the reaction was cooled to room temperature. The mixture was diluted with MeOH, filtered and purified by prep HPLC (pH=2). LCMS calculated for C24H25ClF3N8O2S (M+H) + : m/z = 581.2; Found 581.2. Table 11. The compounds in Table 11 were prepared in accordance with the synthetic protocols set forth in Example 119 using the appropriate halides for Suzuki coupling in the last step.
Example 125.5-(1-Methyl-1H-1,2,4-triazol-5-yl)-2-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)benzonitrile Step 1: 5-Bromo-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitri le To a solution of 4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (112 mg, 0.287 mmol) in acetonitrile (1.434 mL) was added 5-bromo-2-fluorobenzonitrile (57.4 mg, 0.287 mmol) and cesium carbonate (280 mg, 0.861 mmol). The mixture was stirred at 80 °C for 4 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated and used directly in the next step. LCMS calculated for C21H20BrF3N7O2S (M+H) + : m/z = 570.0; Found 570.0. Step 2: 2-(4-(2-((1-(Methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-5-(4,4,5, 5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzonitrile This compound was prepared according to the procedures described in Example 119, Step 2, using 5-bromo-2-(4-(2-((1-(methylsulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-y l)benzonitrile instead of 4-(1-(4-bromo-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1-(methyl sulfonyl)piperidin- 4-yl)-5-(trifluoromethyl)pyrimidin-2-amine as starting material. LCMS calculated for C27H32BF3N7O4S (M+H) + : m/z = 618.2; Found 618.2. Step 3: 5-(1-Methyl-1H-1,2,4-triazol-5-yl)-2-(4-(2-((1-(methylsulfon yl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-y l)benzonitrile This compound was prepared according to the procedures described in Example 119, using 2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-5-(4,4,5, 5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzonitrile and 5-bromo-1-methyl-1H-1,2,4-triazole instead of 4- (1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl)-1H-imidazol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine and 5-iodo-1-methyl-1H-pyrazole as starting materials for the Suzuki coupling reaction. LCMS calculated for C24H24F3N10O2S (M+H) + : m/z = 573.2; Found 573.2. Example 126.5-(Difluoromethoxy)-2-(4-(2-((1-(methylsulfonyl)piperidi n-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-y l)benzonitrile To a solution of 2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-5-(4,4,5, 5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzonitrile (Example 125, Step 2, 14.8 mg, 0.024 mmol) in THF (0.24 mL) was added sodium hydroxide (4.0 M aq. solution, 12.0 µL) and hydrogen peroxide (35% in water, 5 µL). The reaction was stirred at room temperature for 1 h. Then to the mixture was added potassium hydroxide (26.8 mg, 0.479 mmol) and diethyl (bromodifluoromethyl)phosphonate (8.50 µL, 0.048 mmol). The reaction mixture was further stirred at room temperature for 1 h. Then the reaction was diluted and filtered and purified by prep HPLC (pH=2). LCMS calculated for C22H21F5N7O3S (M+H) + : m/z = 558.1; Found 558.2. Example 127.4-(1-(4-(1,3-Dimethyl-1H-pyrazol-4-yl)-2-fluorophenyl)-2 -methyl- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine A mixture of 4-(1-(2-fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1 - (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (12 mg, 0.019 mmol), 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (8.54 mg, 0.038 mmol)), sodium carbonate (6.11 mg, 0.058 mmol) and dichloro[1,1'- bis(diphenylphosphino)ferrocene] palladium (II) dichloromethane adduct (3.5 mg) in water (0.032 mL) and dioxane (0.16 mL) was purged with N2 and then stirred at 100 °C overnight. The reaction was cooled to room temperature. After cooling, the reaction mixture was then diluted with MeOH, filtered and the filtrate was 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). LCMS calculated for C26H29F4N8O2S (M+H) + : m/z = 593.2; Found 593.2.
Example 128.4-(1-(2-Fluoro-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl) -2-methyl- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine Step 1: (3-Fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-y l)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)bor onic acid This compound was prepared according to the procedures described in Example 119, Step 2, using 4-(1-(2-fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine instead of 4-(1-(4-bromo-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine as starting material. LCMS calculated for C21H24BF4N6O4S (M+H) + : m/z = 543.3; Found 543.3. Step 2: 4-(1-(2-Fluoro-4-(1-methyl-1H-1,2,3-triazol-5-yl)phenyl)-2-m ethyl-1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifl uoromethyl)pyrimidin-2- amine This compound was prepared according to the procedures described in Example 119, Step 3, using (3-fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1 -yl)phenyl)boronic acid and 4-bromo-1-methyl-1H-1,2,3-triazole instead of 4-(1-(2-chloro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-4-yl )-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine and 5-iodo-1- methyl-1H-pyrazole as starting materials for the Suzuki coupling reaction. LCMS calculated for C24H26F4N9O2S (M+H) + : m/z = 580.2; Found 580.2. Table 12. The compound in Table 12 was prepared in accordance with the synthetic protocols set forth in Example 128, using the appropriate heteroaryl halide for Suzuki coupling in the last step. Example 130.6-Methyl-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinami de To a solution of 6-methyl-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolino nitrile (Example 33, 14 mg, 0.028 mmol) in ethanol (200 µL) and water (30 µL) was added hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphinito- kP)]platinum(II) (0.3 mg). The mixture was refluxed at 100 °C in a sealed vial for 2 h. After cooling to room temperature, the reaction mixture was diluted with MeOH, filtered and the filtrate was 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). LCMS calculated for C21H24F3N8O3S (M+H) + : m/z = 525.2; Found 525.2. Example 131.6-Methyl-N-(methyl-d 3 )-5-(4-(2-((1-(methylsulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-y l)picolinamide Step 1: 5-Fluoro-6-methyl-N-(methyl-d3)picolinamide A mixture of 5-fluoro-6-methylpicolinic acid (20 mg, 0.129 mmol), Hunig’s base (90 µL, 0.516 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (63.7 mg, 0.168 mmol) in DCM (0.5 mL) was stirred at room temperature for 20 min, then the methan-d3-amine hydrochloride (9.09 mg, 0.129 mmol) was added and the solution was stirred for 1 h. After completion, the reaction was quenched with water. The organic layer was separated using a phase separator and the filtrate was concentrated. The residue was used directly without further purification. LCMS calculated for C8H7D3FN2O (M+H) + : m/z = 172.1; Found 172.1. Step 2: 6-Methyl-N-(methyl-d3)-5-(4-(2-((1-(methylsulfonyl)piperidin -4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinami de A mixture of 4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (8 mg, 0.020 mmol), 5-fluoro-6-methyl-N- (methyl-d3)picolinamide (3.51 mg, 0.020 mmol) and cesium carbonate (26.7 mg, 0.082 mmol) in anhydrous DMF (0.068 mL) was heated at 110 °C for 1 h. After cooling, the reaction mixture was dissolved in MeOH, filtered and purified by prep HPLC (pH =2). LCMS calculated for C22H23D3F3N8O3S (M+H) + : m/z = 542.2; Found 542.2. Table 13. The compounds in Table 13 were prepared in accordance with the synthetic protocols set forth in Example 131, using the appropriate amines for amide coupling in step 1.
Example 135.3-Chloro-N,N-dimethyl-4-(4-(2-((1-(methylsulfonyl)piperi din-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-y l)benzamide This compound was prepared according to the procedures described in Example 131, using 3-chloro-4-fluorobenzoic acid and dimethylamine instead of 5- fluoro-6-methylpicolinic acid and methan-d3-amine hydrochloride as starting material for step 1. LCMS calculated for C 23 H 26 ClF 3 N 7 O 3 S (M+H) + : m/z = 572.2; Found 572.2.
Example 136.3-Chloro-2-fluoro-N,N-dimethyl-4-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)benzamide This compound was prepared according to the procedures described in Example 131, using 3-chloro-2,4-difluorobenzoic acid and dimethylamine instead of 5-fluoro-6-methylpicolinic acid and methan-d3-amine hydrochloride as starting material for step 1. LCMS calculated for C23H25ClF4N7O3S (M+H) + : m/z = 590.1; Found 590.1. Example 137.2,3-Dichloro-N-methyl-4-(4-(2-((1-(methylsulfonyl)piperi din-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-y l)benzamide This compound was prepared according to the procedures described in Example 131, using 2,3-dichloro-4-difluorobenzoic acid and methylamine instead of 5-fluoro-6-methylpicolinic acid and methan-d3-amine hydrochloride as starting material for step 1. LCMS calculated for C22H23Cl2F3N7O3S (M+H) + : m/z = 592.1; Found 592.1. Example 138. (R)-1-(3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)a mino)- 5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)p yrrolidin-3-ol This compound was prepared according to the procedures described in Example 101, using 4-(1-(2-chloro-4-iodophenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (Intermediate 42) instead of 4-(1-(2-fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1 - (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (Intermediate 41) as starting material. LCMS calculated for C24H28ClF3N7O3S (M+H) + : m/z = 586.2; Found 586.2. Table 14. The compounds in Table 14 were prepared in accordance with the synthetic protocols set forth in Example 138, using the appropriate amine as starting material. Example 151.4-(1-(2-Chloro-4-methoxyphenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine To a mixture of 4-(1-(2-chloro-4-iodophenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (15 mg, 0.024 mmol), cesium carbonate (11.70 mg, 0.036 mmol),3,4,7,8-tetramethyl-1,10- phenanthroline (0.566 mg, 2.393 µmol) and copper(I) iodide (0.228 mg, 1.197 µmol) in toluene (0.120 mL) was added methanol (7.67 mg, 0.239 mmol). The mixture was degassed with N2 and then sealed, and stirred at 100 o C overnight. After completion, the reaction was cooled to room temperature. The mixture was diluted with MeOH, 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). LCMS calculated for C21H23ClF3N6O3S (M+H) + : m/z = 531.1; Found 531.1. Example 152.6-Methyl-3-(4-(2-(((3R,4S)-3-methyl-1-((1-methyl-1H-imid azol-4- yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-1H- imidazol-1-yl)picolinonitrile Step 1: tert-Butyl (3R,4S)-4-((4-(1-(2-cyano-6-methylpyridin-3-yl)-1H-imidazol- 4-yl)- To a solution of tert-butyl (3R,4S)-4-((4-(1H-imidazol-4-yl)-5- (trifluoromethyl) pyrimidin-2-yl)amino)-3-methylpiperidine-1-carboxylate (Intermediate 24, 0.225 g, 0.528 mmol) in acetonitrile (5.28 mL) was added 3-fluoro- 6-methylpicolinonitrile (0.086 g, 0.633 mmol) and cesium carbonate (0.516 g, 1.583 mmol). The mixture was stirred at 80 °C for 1 h. After cooling to room temperature, the reaction was diluted with acetonitrile and filtered through a short pad of celite. The filtrate was concentrated and the residue was used directly without further purification. LCMS calculated for C26H30F3N8O2 (M+H) + : m/z = 543.2; Found 543.2. Step 2: 6-Methyl-3-(4-(2-(((3R,4S)-3-methylpiperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinoni trile To a solution of tert-butyl (3R,4S)-4-((4-(1-(2-cyano-6-methylpyridin-3-yl)- 1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3 -methylpiperidine-1- carboxylate (the residue in Step 1) in THF (5.0 mL) was added HCl (4M in dixoane, 0.40 mL). The mixture was stirred at 90 o C for 1 h. After cooling to room temperature, the mixture was diluted with water (15 mL) and then washed by Et2O three times. The aqueous layer was separated and neutralized by addition of sodium hydroxide pellets until pH = 6-7. The neutralized aqueous layer was then extracted with DCM three times. The organic layers were combined and dried over MgSO4. After filtration, the filtrate was concentrated and the residue was used directly without further purification. LCMS calculated for C21H22F3N8 (M+H) + : m/z = 443.2; Found 443.2. Step 3: 6-Methyl-3-(4-(2-(((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol -4- yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-1H-imidazol-1- yl)picolinonitrile To a solution of 6-methyl-3-(4-(2-(((3R,4S)-3-methylpiperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinoni trile hydrochloride (10 mg, 0.021 mmol) in CH2Cl2 (0.20 mL) was added triethylamine (15 µL) and 1- methyl-1H-imidazole-4-sulfonyl chloride (4.5 mg, 0.025 mmol) at 0 o C. The mixture was stirred at room temperature for 1 h. Then the reaction was concentrated and diluted with MeOH, which was 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). LCMS calculated for C25H26F3N10O2S (M+H) + : m/z = 587.2; Found 587.2. Table 15. The compounds in Table 15 were prepared in accordance with the synthetic protocols set forth in Example 152, using the appropriate sulfonyl chlorides in step 3.
Example 155.2-Chloro-3-(4-(2-(((3R,4S)-3-methyl-1-((1-methyl-1H-imid azol-4- yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-1H- imidazol-1-yl)benzonitrile Step 1: N,N-Dimethyl-4-(2-(((3R,4S)-3-methylpiperidin-4-yl)amino)-5- (trifluoromethyl) pyrimidin-4-yl)-1H-imidazole-1-sulfonamide This compound was prepared from Boc deprotection (according to the procedure described in Example 152, step 2) of tert-butyl (3R,4S)-4-((4-(1-(N,N- dimethylsulfamoyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyri midin-2-yl)amino)-3- methylpiperidine-1-carboxylate, which is the Suzuki coupling product described in the Intermediate 23 procedure. LCMS calculated for C16H23F3N7O2S (M+H) + : m/z = 434.2; Found 434.2. Step 2: N,N-Dimethyl-4-(2-(((3R,4S)-3-methyl-1-((1-methyl-1H-imidazo l-4- yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-1H-imidazole-1- sulfonamide To a solution of N,N-dimethyl-4-(2-(((3R,4S)-3-methylpiperidin-4-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazole-1-sulfonamid e (180 mg, 0.415 mmol) in DCM (2.1 mL) was added 1-methyl-1H-imidazole-4-sulfonyl chloride (75 mg, 0.415 mmol) and triethylamine (180 µL, 1.25 mmol) at 0 o C. The mixture was stirred at room temperature for 1 h. Then the reaction was concentrated and the residue was purified by column chromatography on silica gel to afford N,N-dimethyl- 4-(2-(((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfon yl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazole-1- sulfonamide. LCMS calculated for C20H27F3N9O4S2 (M+H) + : m/z = 578.2; Found 578.3. Step 3: 4-(1H-Imidazol-4-yl)-N-((3R,4S)-3-methyl-1-((1-methyl-1H-imi dazol-4- yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-a mine In a vial with a stir bar, N,N-dimethyl-4-(2-(((3R,4S)-3-methyl-1-((1-methyl- 1H-imidazol-4-yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoro methyl)pyrimidin-4-yl)- 1H-imidazole-1-sulfonamide (200 mg) was dissolved in EtOH (2 mL). Concentrated HCl (0.2 mL) was added to the mixture at room temperature, then the solution was heated at 70 o C for 2 hours. After the completion, the mixture was cooled to room temperature, then water was added (15 mL). The resultant solution was washed with Et2O. The aqueous phase was neutralized by NaOH (solid) and adjusted to pH 6-7. The product in the aqueous phase was extracted by DCM/MeOH (10/1 ratio) three times. The filtrate was dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel to afford 4-(1H-imidazol-4-yl)-N-((3R,4S)-3- methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-yl )-5- (trifluoromethyl)pyrimidin-2-amine. LCMS calculated for C18H22F3N8O2S (M+H) + : m/z = 471.1; Found 471.1. Step 4: 2-Chloro-3-(4-(2-(((3R,4S)-3-methyl-1-((1-methyl-1H-imidazol -4- yl)sulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-1H-imidazol-1- yl)benzonitrile To a mixture of 4-(1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1-((1-methyl-1H- imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)py rimidin-2-amine (10 mg, 0.021 mmol) and triethylamine (14.81 µL, 0.106 mmol) in DCM (0.21 mL) was added 2-chloro-3-fluorobenzonitrile (3.31 mg, 0.021 mmol). The mixture was stirred at room temperature for 30 min. Then the reaction was concentrated and diluted with MeOH, which was 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). LCMS calculated for C25H24ClF3N9O2S (M+H) + : m/z = 606.1; Found 606.1. Example 156.4-(1-(5-Bromoquinoxalin-6-yl)-1H-imidazol-4-yl)-N-((3R,4 S)-3- methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine To a mixture of 4-(1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (Intermediate 22, 12 mg, 0.030 mmol), 5-bromo-6-fluoroquinoxaline (20.2 mg, 0.089 mmol) and cesium carbonate (48.3 mg, 0.148 mmol) was added DMF (0.15 mL). The mixture was stirred at 110 °C for 2 h. After cooling to room temperature, the resultant mixture was diluted with MeOH, and then filtered. The filtrate was 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). LCMS calculated for C23H23BrF3N8O2S (M+H) + : m/z = 611.1; Found 611.1. Example 157.4-(1-(2-Chloro-4-(2-(dimethylamino)ethyl)phenyl)-1H-imid azol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine Step 1: 4-(1-(4-Allyl-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine A mixture of 4-(1-(2-chloro-4-iodophenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (Intermediate 42, 250 mg, 0.40 mmol), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (335 mg, 2.0 mmol), cesium fluoride (182 mg, 1.2 mmol) and dichloro[1,1'- bis(diphenylphosphino)ferrocene] palladium (II) dichloromethane adduct (32.6 mg, 0.04 mmol) in water (0.57 mL) and dioxane (2.85 mL) was purged with N2 and then stirred at 100 °C for 2 h. The reaction was cooled to room temperature. The reaction mixture was diluted with dichloromethane and then washed with H2O and brine solution. The organic layer was dried MgSO4, filtered and the filtrate was concentrated to give a crude residue, which was purified by flash chromatography eluting with a gradient of hexanes/EtOAc (0 to 80%) on a silica gel column. LCMS calculated for C23H25ClF3N6O2S (M+H) + : m/z = 541.1; Found 541.1. Step 2: 2-(3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino )-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)ace taldehyde To a vial was added sodium periodate (427 mg, 1.994 mmol), potassium osmate dihydrate (7.35 mg, 0.020 mmol) and 4-(1-(4-allyl-2-chlorophenyl)-1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifl uoromethyl)pyrimidin-2- amine (from Step 1) in THF (2.85 mL) and water (0.570 mL). The mixture was stirred at room temperature for 1 h. Then the mixture was diluted with water and extracted with DCM three times. The organic layers were combined and dried over MgSO4. After filtration, the filtrate was concentrated and the residue was purified by column chromatography with a gradient of DCM/MeOH (0 to 15%) on silica gel. LCMS calculated for C22H23ClF3N6O3S (M+H) + : m/z = 543.2; Found 543.2. Step 3: 4-(1-(2-Chloro-4-(2-(dimethylamino)ethyl)phenyl)-1H-imidazol -4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine A mixture of 2-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino )-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)ace taldehyde (13 mg, 0.024 mmol), dimethylamine (35.9 µL, 0.072 mmol, 2.0M in THF) and acetic acid (2.74 µL, 0.048 mmol) in DCM (0.160 mL) was stirred at room temperature for 30 min. Then sodium triacetoxyborohydride (10.15 mg, 0.048 mmol) was added. The mixture was further stirred at room temperature for 1 h. The reaction was concentrated. The residue was then diluted with MeOH, filtered and the filtrate was 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). LC-MS calculated for C24H30ClF3N7O2S (M+H) + : m/z = 572.2; found 572.2. Table 16. The compounds in Table 16 were prepared in accordance with the synthetic protocols set forth in Example 157, using the appropriate amines for reductive amination in the last step. Example 160.4-(1-(4-(Azetidin-3-yl)-2-fluorophenyl)-2-methyl-1H-imid azol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine To a mixture of zinc dust (3.15 mg, 0.048 mmol), 1,2-dibromoethane (0.277 µL, 3.21 µmol) and TMSCl (0.408 µL, 3.21 µmol) was added THF (0.161 mL). The mixture was sparged with N2 and then stirred at 60 o C in a sealed vial. After 15 minutes, to the mixture was added tert-butyl 3-iodoazetidine-1-carboxylate (9.10 mg, 0.032 mmol) in N,N-dimethylacetamide (0.16 mL). The mixture continued to stir at 60 o C for an additional 15 minutes. Then after the reaction was cooled to room temperature, to the mixture was added 4-(1-(2-fluoro-4-iodophenyl)-2-methyl-1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifl uoromethyl)pyrimidin-2- amine (20.07 mg, 0.032 mmol), [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (1:1) (1.312 mg, 1.607 µmol) and CuI (0.306 mg, 1.607 µmol). The mixture was purged with N2 and stirred at 80 °C overnight. After cooling to room temperature, the mixture was filtered through a short pad of celite and the filtrate was concentrated. The residue was then dissolved in DCM (0.20 mL) and treated with trifluoroacetic acid (0.40 mL). The mixture was stirred at room temperature for 30 min. The reaction was concentrated and diluted with MeOH, then was 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). LCMS calculated for C24H28F4N7O2S (M+H) + : m/z = 554.2; Found 554.2. Table 17. The compound in Table 17 was prepared in accordance with the synthetic protocols set forth in Example 160, using the appropriate alkyl iodides for the coupling reaction in the last step. Example 162.4-(1-(5-Bromoquinoxalin-6-yl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine A mixture of 4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 2, 8 mg, 0.020 mmol), 5-bromo-6- fluoroquinoxaline (6.98 mg, 0.031 mmol) and cesium carbonate (26.7 mg, 0.082 mmol) in anhydrous DMF (0.068 mL) was heated at 120 °C for 2 h. After cooling, the reaction mixture was then diluted with MeOH, filtered and the filtrate was 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). LCMS calculated for C22H21BrF3N8O2S (M+H) + : m/z = 597.1; Found 597.1. Table 18. The compounds in Table 18 were prepared in accordance with the synthetic protocols set forth in Example 162, using the appropriate heteroaryl halides for the SNAr reaction.
Example 166.4-(1-(5-Methylquinoxalin-6-yl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine A mixture of 4-(1-(5-bromoquinoxalin-6-yl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (Intermediate 162, 28 mg, 0.046 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (23.15 mg, 0.184 mmol), potassium carbonate (15.93 mg, 0.115 mmol) and dichloro[1,1'- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (7.53 mg, 9.22 µmol) in water (0.05 mL) and dioxane (0.25 mL) was purged with N2 and then stirred at 100 °C overnight. The reaction was cooled to room temperature. After cooling, the reaction mixture was then diluted with MeOH, filtered and the filtrate was 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). LCMS calculated for C23H24F3N8O2S (M+H) + : m/z = 533.2; Found 533.2. Example 167.6-(4-(2-((1-(Methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)quinoxalin e-5-carbonitrile To a mixture of 4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 2, 15 mg, 0.038 mmol), 5-bromo-6- fluoroquinoxaline (13.1 mg, 0.058 mmol) and cesium carbonate (37.6 mg, 0.115 mmol) was added DMF (0.4 mL). The mixture was heated at 100 °C for 1 h. The reaction was then cooled to room temperature and filtered to remove insolubles. To the filtrate was added zinc cyanide (4.5 mg, 0.038 mmol) and tetrakis(triphenylphosphine)palladium(0) (9 mg, 7.68 µmol). The mixture was sparged with N2 and stirred at 120 o C in a sealed vial overnight. After cooling to room temperature, the reaction mixture was diluted with MeOH, filtered and the filtrate was 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). LCMS calculated for C23H21F3N9O2S (M+H) + : m/z = 544.2; Found 544.2. Example 168.4-Methyl-5-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinoni trile To a mixture of 4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 2, 15 mg, 0.038 mmol), 5-chloro-4- methylpicolinonitrile (17.59 mg, 0.115 mmol) and cesium carbonate (62.6 mg, 0.192 mmol) was added DMF (0.128 mL). The mixture was stirred at 100 °C for 2 hrs. The crude solution was diluted with MeCN and MeOH after cooling to room temperature. The diluted solution was filtered and purified by prep HPLC (pH=2). LCMS calculated for C21H22F3N8O2S (M+H) + : m/z = 507.2; Found 507.3. Example 169.4-(1-(1,3-Dimethyl-1H-pyrazol-4-yl)-1H-imidazol-4-yl)-N- (1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine To a mixture of 4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (15 mg, 0.038 mmol), 4-iodo-1,3-dimethyl-1H- pyrazole (25.6 mg, 0.115 mmol), cesium carbonate (37.6 mg, 0.115 mmol), copper(I) oxide (0.550 mg, 3.84 µmol), and salicylaldoxime (1.054 mg, 7.68 µmol) in a vial was added DMF (0.20 mL). The mixture was degassed by N2. Then the sealed vial was stirred at 150 °C overnight. After cooling to room temperature, the mixture was diluted with MeOH and MeCN, and filtered. The filtrate was purified by prep HPLC (pH=2). LCMS calculated for C19H24F3N8O2S (M+H) + : m/z = 485.2; Found 485.2. Example 170.3-Chloro-4-(5-chloro-4-(2-((1-(methylsulfonyl)piperidin- 4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-y l)benzonitrile In a vial with a stir bar, a mixture of 3-chloro-4-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)benzonitrile (Example 1, 16 mg, 0.030 mmol) and N-chlorosuccinimide (8.1 mg, 0.060 mmol) was stirred at room temperature for 16 hours. After the resultant mixture was concentrated under reduced pressure, the material obtained was dissolved in methanol and purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). 1 H NMR (TFA salt, 500 MHz, DMSO-d6) d 8.71 (s, 0.33H), 8.65 (s, 0.67H), 8.47 (s, 1H), 8.20 (s, 0.67H), 8.18 (s, 0.33H), 8.15-8.05 (m, 2H), 8.02 (d, J = 8.2 Hz, 0.67H), 7.94 (d, J = 8.2 Hz, 0.33H), 4.03-3.93 (m, 1H), 3.58-3.47 (m, 2H), 2.91-2.73 (m, 5H), 2.03-1.92 (m, 2H), 1.64-1.49 (m, 2H). LCMS calculated for C21H19Cl2F3N7O2S (M+H) + : m/z = 560.1; Found 560.1. Table 19. The compounds in Table 19 were prepared in accordance with the synthetic protocols set forth in Example 1 using the appropriate starting materials.
Example 174. N-(3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino )-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)-N- methylacetamide In a vial with a stir bar, a mixture of 4-(1-(2-chloro-4- ((methylamino)methyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methyls ulfonyl)piperidin-4- yl)-5-(trifluoromethyl)pyrimidin-2-amine (Example 3, 10 mg, 0.018 mmol), acetic acid (0.50 mL, 8.7 mmol), and triethylamine (1.50 mL, 10.8 mmol) was stirred at room temperature for 6 hours. After the resultant mixture was concentrated under reduced pressure, the material obtained was dissolved in methanol and purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C24H28ClF3N7O3S (M+H) + : m/z = 586.2; Found 586.1. Example 175.4-(1-(2-Chloro-4-((dimethylamino)methyl)phenyl)-1H-imida zol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine In a vial with a stir bar, a mixture of 3-chloro-4-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)benzaldehyde (Step 1 in Example 3, 140 mg, 0.260 mmol), dimethylamine (2 M in THF, 1.3 mL, 2.6 mmol), acetic acid (0.10 mL, 1.7 mmol), triethylamine (0.10 mL, 0.72 mmol), MeOH (10 mL), and THF (10 mL) was stirred at 70 °C for 1 hour. After the solution was cooled to room temperature, NaCNBH3 (200 mg, 3.2 mmol) was added to the resultant mixture. The solution was stirred at room temperature for 30 minutes, and then at 60 °C for 30 minutes. The resultant mixture was concentrated under reduced pressure. The residue was dissolved in MeOH and purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). 1 H NMR (TFA salt, 600 MHz, DMSO-d6, 1:1 rotamers) d 10.1 (brs, 1H), 8.66 (s, 0.5H), 8.60 (s, 0.5H), 8.20 (s, 0.5H), 8.11 (s, 1H), 8.01 (s, 0.5H), 7.97-7.87 (m, 2H), 7.85-7.73 (m, 1H), 7.70-7.61 (m, 1H), 4.39 (s, 2H), 4.09-3.91 (m, 1H), 3.59-3.45 (m, 2H), 2.97-2.82 (m, 5H), 2.78 (s, 6H), 2.00-1.91 (m, 2H), 1.63-1.54 (m, 2H). LCMS calculated for C23H28ClF3N7O2S (M+H) + : m/z = 558.2; Found 558.3.
Example 176.4-(1-(4-(Azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazo l-4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyri midin-2-amine This compound was prepared according to the procedures described in Example 175, using azetidine hydrochloride instead of dimethylamine (2 M in THF) as starting material. 1 H NMR (TFA salt, 600 MHz, DMSO-d6, 1:1 rotamers) d 10.4 (brs, 1H), 8.65 (s, 0.5H), 8.59 (s, 0.5H), 8.20 (s, 0.5H), 8.11-8.09 (m, 1H), 7.99 (s, 0.5H), 7.96-7.82 (m, 2H), 7.82-7.71 (m, 1H), 7.66-7.57 (m, 1H), 4.46 (s, 2H), 4.19- 3.92 (m, 5H), 3.60-3.45 (m, 2H), 2.94-2.80 (m, 5H), 2.47-2.27 (m, 2H), 2.00-1.91 (m, 2H), 1.64-1.52 (m, 2H). LCMS calculated for C24H28ClF3N7O2S (M+H) + : m/z = 570.2; Found 570.2. Example 177.4-(1-(2-Chloro-4-((3-methylazetidin-1-yl)methyl)phenyl)- 1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 175, using 3-methylazetidine hydrochloride instead of dimethylamine (2 M in THF) as starting material. 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 4:6 rotamers) d 10.1 (brs, 1H), 8.66 (s, 0.4H), 8.59 (s, 0.6H), 8.19 (s, 0.6H), 8.09 (s, 1H), 7.99 (s, 0.4H), 7.96-7.83 (m, 2H), 7.83-7.72 (m, 1H), 7.67-7.58 (m, 1H), 4.48 (d, J = 5.9 Hz, 0.8H), 4.43 (d, J = 5.6 Hz, 1.2H), 4.23-4.14 (m, 0.8H), 4.12-3.92 (m, 2.2H), 3.84 (dd, J = 9.1, 9.1 Hz, 1.2H), 3.77-3.68 (m, 0.8H), 3.60-3.46 (m, 2H), 2.95-2.76 (m, 6H), 2.01-1.90 (m, 2H), 1.65-1.52 (m, 2H), 1.24 (d, J = 7.0 Hz, 1.2H), 1.18 (d, J = 6.7 Hz, 1.8H). LCMS calculated for C25H30ClF3N7O2S (M+H) + : m/z = 584.2; Found 584.2. Example 178.4-(1-(2-Chloro-4-(pyrrolidin-1-ylmethyl)phenyl)-1H-imida zol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine This compound was prepared according to the procedures described in Example 175, using pyrrolidine instead of dimethylamine (2 M in THF) as starting material. 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 1:1 rotamers) d 9.92 (brs, 1H), 8.66 (s, 0.5H), 8.60 (s, 0.5H), 8.19 (s, 0.5H), 8.14-8.06 (m, 1H), 8.00 (s, 0.5H), 7.97- 7.86 (m, 2H), 7.85-7.74 (m, 1H), 7.72-7.63 (m, 1H), 4.53-4.38 (m, 2H), 4.08-3.91 (m, 1H), 3.61-3.47 (m, 2H), 3.47-3.35 (m, 2H), 3.20-3.07 (m, 2H), 2.95-2.79 (m, 5H), 2.12-2.00 (m, 2H), 2.00-1.93 (m, 2H), 1.93-1.82 (m, 2H), 1.65-1.53 (m, 2H). LCMS calculated for C25H30ClF3N7O2S (M+H) + : m/z = 584.2; Found 584.2.
Example 179.4-(1-(4-((2-Azabicyclo[2.2.2]octan-2-yl)methyl)-2-chloro phenyl)- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 175, using 2-azabicyclo[2.2.2]octane instead of dimethylamine (2 M in THF) as starting material. LCMS calculated for C28H34ClF3N7O2S (M+H) + : m/z = 624.2; Found 624.2. Example 180.4-(1-(4-((2-Azabicyclo[2.2.1]heptan-2-yl)methyl)-2-chlor ophenyl)- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 175, using 2-aza-bicyclo[2.2.1]heptane instead of dimethylamine (2 M in THF) as starting material. LCMS calculated for C27H32ClF3N7O2S (M+H) + : m/z = 610.2; Found 610.2. Example 181. (R)-1-(3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)a mino)- 5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)- 3-methylpyrrolidin- 3-ol This compound was prepared according to the procedures described in Example 175, using (R)-3-methylpyrrolidin-3-ol hydrochloride instead of dimethylamine (2 M in THF) as starting material. 1 H NMR (TFA salt, 600 MHz, DMSO-d6, 6:4 rotamers) d 10.4 (brs, 0.6H), 10.3 (brs, 0.4H), 8.66 (s, 0.4H), 8.60 (s, 0.6H), 8.20 (s, 0.6H), 8.10 (s, 1H), 8.00 (s, 0.4H), 7.98-7.86 (m, 2H), 7.84-7.73 (m, 1H), 7.73-7.67 (m, 1H), 5.34 (brs, 1H), 4.58-4.35 (m, 2H), 4.08-3.92 (m, 1H), 3.65- 3.06 (m, 6H), 2.96-2.80 (m, 5H), 2.17-1.81 (m, 4H), 1.64-1.52 (m, 2H), 1.40-1.28 (m, 3H). LCMS calculated for C26H32ClF3N7O3S (M+H) + : m/z = 614.2; Found 614.2. Example 182.4-(1-(2-Chloro-4-((methylamino)methyl)phenyl)-1H-imidazo l-4- yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 3, using 4-(1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (Intermediate 22) instead of 4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 2) as starting material for Step 1. LCMS calculated for C23H28ClF3N7O2S (M+H) + : m/z = 558.2; Found 558.1. Example 183.4-(1-(2-Chloro-4-((dimethylamino)methyl)phenyl)-1H-imida zol-4- yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine Step 1: 3-Chloro-4-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperi din-4-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzalde hyde This compound was prepared according to the procedures described in Example 3, using N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H- imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 17) instead of 4- (1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 2) as starting material for Step 1. LCMS calculated for C21H20ClF4N6O3S (M+H) + : m/z = 547.1; Found 547.1. Step 2: 4-(1-(2-Chloro-4-((dimethylamino)methyl)phenyl)-1H-imidazol- 4-yl)-N- ((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5-(trifl uoromethyl)pyrimidin-2- amine This compound was prepared according to the procedures described in Example 175, using 3-chloro-4-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)piperi din- 4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1 -yl)benzaldehyde instead of 3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5 - (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehy de (Step 1 in Example 3) as starting material. LCMS calculated for C23H27ClF4N7O2S (M+H) + : m/z = 576.2; Found 576.1. Example 184.4-(1-(4-(Azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazo l-4-yl)- N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 183, using azetidine hydrochloride instead of dimethylamine as starting material for Step 2. LCMS calculated for C24H27ClF4N7O2S (M+H) + : m/z = 588.2; Found 588.2.
Example 185. N-(3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino )-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)ace tamide Step 1: 4-(1-(4-(Aminomethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1 - (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine This compound was prepared according to the procedures described in Example 175, using ammonia (0.4M in dioxane) instead of dimethylamine as starting material. LCMS calculated for C21H24ClF3N7O2S (M+H) + : m/z = 530.1; Found 530.1. Step 2: N-(3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino )-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)ace tamide This compound was prepared according to the procedures described in Example 174, using 4-(1-(4-(aminomethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1 - (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (Step 1) instead of 4-(1-(2-chloro-4-((methylamino)methyl)phenyl)-1H-imidazol-4- yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (Example 3) as starting material. LCMS calculated for C23H26ClF3N7O3S (M+H) + : m/z = 572.1; Found 572.1. Table 20. The compounds in Table 20 were prepared in accordance with the synthetic protocols set forth in Example 175 using the appropriate starting materials.
Example 228.4-(1-(4-(Azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazo l-4-yl)- N-(1-(cyclopropylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl )pyrimidin-2-amine Step 1: tert-Butyl 4-((4-(1-(2-chloro-4-formylphenyl)-1H-imidazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxyla te
A mixture of tert-butyl 4-((4-(1H-imidazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxyla te (113 mg, 0.274 mmol), 3-chloro-4-fluorobenzaldehyde (217 mg, 1.37 mmol), cesium carbonate (890 mg, 2.74 mmol), and MeCN (10 mL) was sparged with nitrogen. The reaction mixture was heated at 80 °C for 30 minutes. After filtration of the resultant mixture at room temperature, the filtrate was purified by flash column chromatography (Agela Flash Column Silica-CS (40 g), eluting with a gradient of 0 to 10% CH2Cl2/methanol) to afford the desired product, which was used in the next reaction without further purification. LCMS calculated for C25H27ClF3N6O3 (M+H) + : m/z = 551.2; Found 551.2. Step 2: tert-Butyl 4-((4-(1-(4-(azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazo l-4- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-car boxylate In a vial with a stir bar, a mixture of tert-butyl 4-((4-(1-(2-chloro-4- formylphenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin -2- yl)amino)piperidine-1-carboxylate, azetidine hydrochloride (256 mg, 2.74 mmol), triethylamine (0.57 mL, 4.1 mmol), acetic acid (0.40 mL, 7.0 mmol), THF (5 mL), and MeOH (5 mL) was stirred at 70 °C for 1 hour. NaBH3CN (200 mg, 3.2 mmol) was added to the resultant solution at room temperature. The mixture was heated at 60 °C for 30 minutes and the solution was then concentrated in vacuo. The residue was dissolved in MeOH and purified by prep-LCMS (XBridge column, eluting with a gradient of acetonitrile/water containing 0.1% NH4OH, at flow rate of 60 mL/min) to afford the desired product, which was used in the next reaction without further purification. LCMS calculated for C28H34ClF3N7O2 (M+H) + : m/z = 592.2; Found 592.4. Step 3: 4-(1-(4-(Azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4- yl)-N- (piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine The tert-butyl 4-((4-(1-(4-(azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazo l- 4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-c arboxylate was treated with TFA (5 mL) at room temperature for 2 days. The resultant solution was concentrated under reduced pressure to afford the desired product, which was used in the next reaction without further purification. LCMS calculated for C23H26ClF3N7 (M+H) + : m/z = 492.2; Found 492.2. Step 4: 4-(1-(4-(Azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazol-4- yl)-N-(1- (cyclopropylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyri midin-2-amine In a vial with stir bar, a solution of 4-(1-(4-(azetidin-1-ylmethyl)-2- chlorophenyl)-1H-imidazol-4-yl)-N-(piperidin-4-yl)-5-(triflu oromethyl)pyrimidin-2- amine, triethylamine (0.10 mL, 0.72 mmol) was dissolved in DCM (1 mL). Cyclopropanesulfonyl chloride (14.3 mg, 0.102 mmol) was added into reaction mixture. After stirring at room temperature for 1 hour, the mixture was quenched by saturated aqueous NaHCO3 solution, and the mixture was then concentrated under reduced pressure. The material obtained was dissolved in MeOH and purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/in). LCMS calculated for C26H30ClF3N7O2S (M+H) + : m/z = 596.2; Found 596.1. Example 229.4-(1-(4-(Azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imidazo l-4-yl)- N-(1-(ethylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrim idin-2-amine This compound was prepared according to the procedures described in Example 228, using ethanesulfonyl chloride instead of cyclopropanesulfonyl chloride as starting material for Step 4. LCMS calculated for C25H30ClF3N7O2S (M+H) + : m/z = 584.2; Found 584.2. Example 230.4-((4-(1-(4-(Azetidin-1-ylmethyl)-2-chlorophenyl)-1H-imi dazol-4- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-cyclopropylpi peridine-1- sulfonamide This compound was prepared according to the procedures described in Example 228, using cyclopropylsulfamoyl chloride instead of cyclopropanesulfonyl chloride as starting material for Step 4. LCMS calculated for C26H31ClF3N8O2S (M+H) + : m/z = 611.2; Found 611.2. Example 231. (3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)- 5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)met hanol A mixture of 4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (100 mg, 0.256 mmol), 3-chloro-4- fluorobenzaldehyde (122 mg, 0.768 mmol), cesium carbonate (584 mg, 1.79 mmol) and acetonitrile (3 mL) was sparged with nitrogen. The reaction mixture was heated at 80 °C for 30 minutes. After filtration of the resultant mixture, the filtrate was concentrated. The residue was dissolved in MeOH (3 mL), followed by the addition of sodium borohydride (48.5 mg, 1.28 mmol). After stirring at room temperature for 2 hours, the solution was concentrated under reduced pressure. The residue was dissolved in MeOH and purified by prep-LCMS (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. LCMS calculated for C21H23ClF3N6O3S (M+H) + : m/z = 531.1; Found 531.2. Example 232.2-(Hydroxymethyl)-3-(4-(2-((1-(methylsulfonyl)piperidin- 4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-y l)benzonitrile A mixture of 4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (20 mg, 0.051 mmol), methyl 2-cyano-6- fluorobenzoate (45.9 mg, 0.256 mmol), cesium carbonate (167 mg, 0.512 mmol) and acetonitrile (3 mL) was sparged with nitrogen. The reaction mixture was heated at 80 °C for 1 hour. After filteration of the resultant mixture, the filtrate was concentrated. The residue was dissolved in MeOH (3 mL), followed by the addition of sodium borohydride (19.4 mg, 0.512 mmol). After stirring at room temperature for 2 hours, the solution was concentrated under reduced pressure. The residue was dissolved in MeOH and purified by prep-LCMS (XBridge column, eluting with a gradient of acetonitrile/water containing 0.1% NH4OH, at flow rate of 60 mL/min) to afford the desired product. LCMS calculated for C22H23F3N7O3S (M+H) + : m/z = 522.2; Found 522.2. Example 233.4-(4-(2-((1-(Methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)isobenzofu ran-1(3H)-one In a vial with stir bar, 2-(hydroxymethyl)-3-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)benzonitrile (10 mg, 0.019 mmol) was dissolved in TFA (3 mL), and stirred at room temperature for 12 hours. The solution was quenched by water, and the resultant solution was concentrated under reduced pressure. The residue was dissolved in MeOH and purified by prep-LCMS (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. LCMS calculated for C22H22F3N6O4S (M+H) + : m/z = 523.1; Found 523.1. Table 21. The compounds in Table 21 were prepared in accordance with the synthetic protocols set forth in Example 231 using the appropriate starting materials. Example 238.4-(1-(4-((1H-Imidazol-1-yl)methyl)-2-chlorophenyl)-1H-im idazol- 4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethy l)pyrimidin-2-amine In a vial with stir bar, to a solution of N,N-diisopropyl ethylamine (68 µL, 0.39 mmol), (3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)- 5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)met hanol (Example 231, 68.6 mg, 0.129 mmol) in DCM (5 mL) was added methanesulfonyl chloride (10 µL, 0.13 mmol). After the reaction mixture was stirred at room temperature for 1 hour, the mixture was concentrated under reduced pressure. The residue was mixed with imidazole (18 mg, 0.26 mmol) and DMF (1 mL), and the solution was then heated at 100 °C for 2 hours. The resultant solution was diluted in MeOH and purified by prep- LCMS (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. LCMS calculated for C24H25ClF3N8O2S (M+H)+: m/z = 581.1; Found 581.1. Table 22. The compounds in Table 22 were prepared in accordance with the synthetic protocols set forth in Example 238 using the appropriate starting materials.
Example 245.4-(1-(2-(Difluoromethyl)-6-((methylamino)methyl)pyridin- 3-yl)- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine Step 1: Methyl 6-(difluoromethyl)-5-fluoropicolinate In a vial with stir bar, (trimethylsilyl)diazomethane (2.0 M in hexanes, 0.45 mL, 0.90 mmol) was added dropwise to a solution of 6-(difluoromethyl)-5- fluoropicolinic acid (115 mg, 0.602 mmol) in MeOH (10 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched with AcOH and concentrated in vacuo to afford the desired product, which was used in the next reaction without further purification. LCMS calculated for C 8 H 7 F 3 NO 2 (M+H) + : m/z = 206.0; Found 206.2. Step 2: (6-(Difluoromethyl)-5-(4-(2-((1-(methylsulfonyl)piperidin-4- yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)pyridin-2- yl)methanol A mixture of 4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 2, 37.8 mg, 0.0970 mmol), methyl 6-(difluoromethyl)-5-fluoropicolinate (59.6 mg, 0.290 mmol), cesium carbonate (189 mg, 0.581 mmol) and acetonitrile (5 mL) was sparged with nitrogen. The reaction mixture was heated at 80 °C for 30 minutes. After filtration of the resultant mixture, the filtrate was concentrated. The residue was dissolved in MeOH (3 mL), followed by the addition of sodium borohydride (48.5 mg, 1.28 mmol). After stirring at room temperature for 2 hours, the solution was purified by prep-LCMS (XBridge column, eluting with a gradient of acetonitrile/water containing 0.1% NH4OH, at flow rate of 60 mL/min) to afford the desired product. LCMS calculated for C21H23F5N7O3S (M+H) + : m/z = 548.1; Found 548.3. Step 3: 4-(1-(2-(Difluoromethyl)-6-((methylamino)methyl)pyridin-3-yl )-1H-imidazol- In a microwave vial with a stir bar, to a solution of N,N-diisopropyl ethylamine (68 µL, 0.39 mmol), (6-(difluoromethyl)-5-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)pyridin-2-yl)methanol (10.6 mg, 0.019 mmol) in DCM (5 mL) was added methanesulfonyl chloride (6 µL, 0.08 mmol). After the reaction mixture was stirred at room temperature for 1 hour, the mixture was concentrated under reduced pressure. The residue was mixed with methylamine (2 M in THF, 0.100 mL, 0.200 mmol) and DMF (1 mL), and the solution was then heated at 100 °C for 2 hours. The resultant solution was diluted in MeOH and purified by prep-LCMS (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. LCMS calculated for C22H26F5N8O2S (M+H) + : m/z = 561.2; Found 561.2. Example 246.4-(1-(6-((Dimethylamino)methyl)-2-(trifluoromethyl)pyrid in-3-yl)- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine Step 1: (5-(4-(2-((1-(Methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-6-(triflu oromethyl)pyridin-2- yl)methanol This compound was prepared according to the procedures described in Example 245, using 5-fluoro-6-(trifluoromethyl)picolinic acid instead of 6- (difluoromethyl)-5-fluoropicolinic acid as starting material for Step 1, and methyl 5- fluoro-6-(trifluoromethyl)picolinate instead of methyl 6-(difluoromethyl)-5- fluoropicolinate for Step 2. LCMS calculated for C21H22F6N7O3S (M+H) + : m/z = 566.1; Found 566.2. Step 2: 4-(1-(6-((Dimethylamino)methyl)-2-(trifluoromethyl)pyridin-3 -yl)-1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifl uoromethyl)pyrimidin-2- amine This compound was prepared according to the procedures described in Example 245, using dimethylamine instead of methylamine as starting material for Step 3. LCMS calculated for C23H27F6N8O2S (M+H) + : m/z = 593.2; Found 593.2. Example 247.4-(1-(6-(Azetidin-1-ylmethyl)-2-(trifluoromethyl)pyridin -3-yl)-1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 246, using azetidine instead of dimethylamine as starting material for Step 2. LCMS calculated for C24H27F6N8O2S (M+H) + : m/z = 605.2; Found 605.1.
Example 248.1-(3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)a mino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)eth an-1-ol In a vial with stir bar, to a solution of 3-chloro-4-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)benzaldehyde (Step 1 in Example 3, 10 mg, 0.019 mmol) in THF (2 mL) was added methylmagnesium bromide (1.0 M in dibutyl ether, 0.10 mL, 0.10 mmol). After stirring at room temperature for 1 hour, the mixture was filtered and then the filtrate was concentrated under reduced pressure. The residue was dissolved in MeOH and purified by prep-LCMS (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. LCMS calculated for C22H25ClF3N6O3S (M+H) + : m/z = 545.1; Found 545.2. Example 249.5-((Methylamino)methyl)-2-(4-(2-((1-(methylsulfonyl)pipe ridin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-y l)benzonitrile This compound was prepared according to the procedures described in Example 3, using 2-fluoro-5-formylbenzonitrile instead of 3-chloro-4- fluorobenzaldehyde as starting material. LCMS calculated for C23H26F3N8O2S (M+H) + : m/z = 535.2; Found 535.2. Example 250.4-(1-(4-((Dimethylamino)methyl)-2-(trifluoromethyl)pheny l)-1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine Step 1: 4-(4-(2-((1-(Methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-3-(triflu oromethyl)benzaldehyde In a vial with a stir bar, a mixture of 4-(1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (280 mg, 0.717 mmol), 4-fluoro-3-(trifluoromethyl)benzaldehyde (490 µL, 3.6 mmol), cesium carbonate (2.3 g, 7.2 mmol), and acetonitrile (10 mL) was sparged with N2, and the mixture was stirred at 70 °C for 30 minutes. After filtration of the resultant mixture at room temperature, the filtrate was purified by flash column chromatography (Agela Flash Column Silica-CS (40 g), eluting with a gradient of 0 to 10% CH2Cl2/methanol) to afford the desired product. LCMS calculated for C 22 H 21 F 6 N 6 O 3 S (M+H) + : m/z = 563.1; Found 563.1. Step 2: 4-(1-(4-((Dimethylamino)methyl)-2-(trifluoromethyl)phenyl)-1 H-imidazol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine In a vial with a stir bar, a mixture of 3-chloro-4-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)benzaldehyde, dimethylamine (2 M in THF, 3.0 mL, 6.0 mmol), triethylamine (0.10 mL, 0.72 mmol), acetic acid (0.5 mL, 8.7 mmol), THF (10 mL), and MeOH(10 mL) was stirred at 70 °C for 1 hour. NaBH3CN (200 mg, 3.2 mmol) was added to the resultant solution at room temperature. The mixture was heated at 60 °C for 30 minutes and the solution was then concentrated in vacuo. The residue was dissolved in MeOH and purified by prep-LCMS (XBridge column, eluting with a gradient of acetonitrile/water containing 0.1% NH4OH, at flow rate of 60 mL/min). Fractions containing the desired product were then concentrated, and the material obtained was dissolved in acetonitrile and purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 1:1 rotamers) d 9.96 (brs, 1H), 8.65 (s, 0.5H), 8.60 (s, 0.5H), 8.17 (s, 1H), 8.13 (s, 0.5H), 8.03 (s, 1H), 8.00-7.76 (m, 3.5H), 4.48 (s, 2H), 4.04-3.90 (m, 1H), 3.60-3.45 (m, 2H), 2.91-2.82 (m, 5H), 2.79 (s, 6H), 2.01-1.89 (m, 2H), 1.66-1.50 (m, 2H). LCMS calculated for C24H28F6N7O2S (M+H) + : m/z = 592.2; Found 592.2. Example 251.4-(1-(4-(Azetidin-1-ylmethyl)-2-(trifluoromethyl)phenyl) -1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine In a vial with a stir bar, a mixture of 4-(4-(2-((1-(methylsulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-y l)-3- (trifluoromethyl)benzaldehyde (Step 1 in Example 250, 60 mg, 0.11 mmol), azetidine hydrochloride (50 mg, 0.53 mmol), acetic acid (0.20 mL, 3.5 mmol), triethylamine (0.20 mL, 1.4 mmol), MeOH (10 mL), and THF (10 mL) was stirred at 70 °C for 1 hour. After the solution was cooled to room temperature, NaCNBH3 (200 mg, 3.2 mmol) was added to the resultant mixture. The solution was stirred at room temperature for 30 minute, and then 60 °C for 30 minutes. The resultant mixture was concentrated under reduced pressure. The residue was dissolved in MeOH and purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 1:1 rotamers) d 10.54 (s, 1H), 8.65 (s, 0.5H), 8.59 (s, 0.5H), 8.12 (s, 1.5H), 8.03 (s, 1H), 8.00-7.76 (m, 3.5H), 4.56 (s, 2H), 4.24-3.91 (m, 5H), 3.62-3.43 (m, 2H), 2.95-2.76 (m, 5H), 2.46-2.27 (m, 2H), 2.03-1.88 (m, 2H), 1.66-1.51 (m, 2H). LCMS calculated for C25H28F6N7O2S (M+H) + : m/z = 604.2; Found 604.3. Example 252.4-(1-(6-(Azetidin-1-ylmethyl)-2-methylpyridin-3-yl)-1H-i midazol- 4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethy l)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 250, using 5-fluoro-6-methylpicolinaldehyde instead of 4-fluoro-3- (trifluoromethyl)benzaldehyde as starting material for Step 1, and azetidine hydrochloride instead of dimethylamine as starting material for Step 2. LCMS calculated for C24H30F3N8O2S (M+H) + : m/z = 551.2; Found 551.2. Example 253.4-(1-(2-Chloro-4-((dimethylamino)methyl)-3-fluorophenyl) -1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 250, using 3-chloro-2,4-difluorobenzaldehyde instead of 4-fluoro-3- (trifluoromethyl)benzaldehyde as starting material. 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 1:1 rotamers) d 10.1 (brs, 1H), 8.66 (s, 0.5H), 8.60 (s, 0.5H), 8.22 (s, 0.5H), 8.14 (s, 1H), 8.04 (s, 0.5H), 7.98-7.87 (m, 1H), 7.80-7.64 (m, 2H), 4.48 (s, 2H), 4.08-3.91 (m, 1H), 3.59-3.47 (m, 2H), 2.94-2.76 (m, 11H), 2.00-1.91 (m, 2H), 1.65-1.53 (m, 2H). LCMS calculated for C23H27ClF4N7O2S (M+H) + : m/z = 576.2; Found 576.3. Table 23. The compounds in Table 23 were prepared in accordance with the synthetic protocols set forth in Example 250 using the appropriate starting materials. Example 271.4-(1-(4-((Dimethylamino)methyl)-2-methylphenyl)-1H-imida zol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine Step 1: 3-Methyl-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5 - (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehy de In a vial with a stir bar, a mixture of 4-fluoro-3-methylbenzaldehyde (270 µL, 2.2 mmol), 4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 2, 170 mg, 0.435 mmol), cesium carbonate (1.4 g, 4.4 mmol), and DMF (10 mL) was sparged with nitrogen. The mixture was heated at 100 °C for 1 hour. After cooling to room temperature, the resultant mixture was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Agela Flash Column Silica-CS (40 g), eluting with a gradient of 0 to 10% CH 2 Cl 2 /methanol) to afford the desired product. LCMS calculated for C22H24F3N6O3S (M+H) + : m/z = 509.2; Found 509.2. Step 2: 4-(1-(4-((Dimethylamino)methyl)-2-methylphenyl)-1H-imidazol- 4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine In a vial with a stir bar, a mixture of 3-methyl-4-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)benzaldehyde (110 mg, 0.216 mmol), dimethylamine (2 M in THF, 2.0 mL, 4.0 mmol), acetic acid (0.30 mL, 5.2 mmol), triethylamine (0.30 mL, 2.2 mmol), MeOH (5 mL), and THF (5 mL) was stirred at 70 °C for 1 hour. After the solution was cooled to room temperature, NaCNBH3 (200 mg, 3.2 mmol) was added to the resultant mixture. The solution was stirred at room temperature for 30 minutes, and then 60 °C for 30 minutes. The resultant mixture was concentrated under reduced pressure. The residue was dissolved in MeOH and purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 4:6 rotamers) d 9.83 (brs, 1H), 8.65 (s, 0.4H), 8.59 (s, 0.6H), 8.15 (s, 0.6H), 8.04 (s, 1H), 7.95-7.82 (m, 1.4H), 7.61-7.45 (m, 3H), 4.38-4.27 (m, 2H), 4.11-3.92 (m, 1H), 3.60-3.45 (m, 2H), 2.94-2.81 (m, 5H), 2.81-2.66 (m, 6H), 2.24 (s, 3H), 2.02-1.89 (m, 2H), 1.65-1.51 (m, 2H). LCMS calculated for C24H31F3N7O2S (M+H) + : m/z = 538.2; Found 538.3. Example 272.4-(1-(2-Methyl-4-((methylamino)methyl)phenyl)-1H-imidazo l-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine This compound was prepared according to the procedures described in Example 271, using methanamine instead of dimethylamine as starting material. LCMS calculated for C23H29F3N7O2S (M+H) + : m/z = 524.2; Found 524.2.
Example 273.4-(1-(2-Chloro-4-(1-(ethylamino)ethyl)phenyl)-1H-imidazo l-4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyri midin-2-amine Step 1: 1-(3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino )-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)eth an-1-one This compound was prepared according to the procedures described in Example 250, using 1-(3-chloro-4-fluorophenyl)ethan-1-one instead of 4-fluoro-3- (trifluoromethyl)benzaldehyde as starting material for Step 1. LCMS calculated for C22H23ClF3N6O3S (M+H) + : m/z = 543.1; Found 543.1. Step 2: 4-(1-(2-Chloro-4-(1-(ethylamino)ethyl)phenyl)-1H-imidazol-4- yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine In a vial with a stir bar, a mixture of 1-(3-chloro-4-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)phenyl)ethan-1-one (250 mg, 0.46 mmol), ethylamine (2 M in THF, 1.0 mL, 2.0 mmol), acetic acid (0.20 mL, 3.5 mmol), triethylamine (0.20 mL, 1.4 mmol), MeOH (5 mL), and THF (5 mL) was stirred at 70 °C for 1 hour. After the solution was cooled to room temperature, NaCNBH3 (200 mg, 3.2 mmol) was added to the resultant mixture. The solution was stirred at room temperature for 30 minutes, and then 60 °C for 30 minutes. The resultant mixture was concentrated under reduced pressure. The residue was dissolved in MeOH and purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 4:6 rotamers) d 9.09 (brs, 1H), 8.94 (brs, 1H), 8.65 (s, 0.4H), 8.59 (s, 0.6H), 8.20 (s, 0.6H), 8.09 (s, 1H), 7.99 (s, 0.4H), 7.95-7.85 (m, 2H), 7.84-7.74 (m, 1H), 7.67 (d, J = 8.2 Hz, 1H), 4.58-4.47 (m, 1H), 4.08-3.93 (m, 1H), 3.59-3.47 (m, 2H), 3.01-2.70 (m, 7H), 2.01- 1.90 (m, 2H), 1.65-1.52 (m, 5H), 1.18 (t, J = 7.2 Hz, 3H). LCMS calculated for C24H30ClF3N7O2S (M+H) + : m/z = 572.2; Found 572.3. Example 274.4-(1-(4-(1-(Azetidin-1-yl)ethyl)-2-chlorophenyl)-1H-imid azol-4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyri midin-2-amine This compound was prepared according to the procedures described in Example 273, using azetidine hydrochloride instead of ethylamine as starting material. LCMS calculated for C25H30ClF3N7O2S (M+H) + : m/z = 584.2; Found 584.1.
Example 275.4-(1-(2-Chloro-4-(1-(methylamino)ethyl)phenyl)-1H-imidaz ol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine Step 1: 4-(1-(2-Chloro-4-(1-(methylamino)ethyl)phenyl)-1H-imidazol-4 -yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine This compound was prepared according to the procedures described in Example 273, using methanamine instead of ethylamine as starting material. LCMS calculated for C23H28ClF3N7O2S (M+H) + : m/z = 558.2; Found 558.2.
Step 2: tert-Butyl (1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)eth yl)(methyl)carbamate In a vial with a stir bar, a mixture of 4-(1-(2-chloro-4-(1- (methylamino)ethyl)phenyl)-1H-imidazol-4-yl)-N-(1-(methylsul fonyl)piperidin-4-yl)- 5-(trifluoromethyl)pyrimidin-2-amine (12.8 mg, 0.023 mmol), triethylamine (14 µL, 0.10 mmol), di-tert-butyl dicarbonate (11 mg, 0.051 mmol), and DCM (3 mL) was stirred at room temperature for 4 hours. After concentration of the resultant mixture, the residue was purified by flash column chromatography (Agela Flash Column Silica-CS (24 g), eluting with a gradient of 0 to 10% CH2Cl2/methanol) to afford the desired product. Then, the two enantiomers were separated with chiral prep-HPLC (Phenomenex Lux Cellulose-1, 21.2x250 mm, 5 micron, eluting with 45% EtOH in hexanes, at flow rate of 20 mL/min, tR, peak 1 = 6.9 min, tR, peak 2 = 10.7 min). Peak 1: LCMS calculated for C28H36ClF3N7O4S (M+H) + : m/z = 658.2; Found 658.4. Peak 2: LCMS calculated for C28H36ClF3N7O4S (M+H) + : m/z = 658.2; Found 658.4.
Step 3: 4-(1-(2-Chloro-4-(1-(methylamino)ethyl)phenyl)-1H-imidazol-4 -yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine In a vial with a stir bar, tert-butyl (1-(3-chloro-4-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)phenyl)ethyl)(methyl)carbamate (Peak 1, 7.0 mg, 10 µmol) was dissolved in TFA (3 mL), and stirred at room temperature for 3 hours. After the resultant mixture was concentrated under reduced pressure, the residue was dissolved in MeOH. The solution was purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C23H28ClF3N7O2S (M+H) + : m/z = 558.2; Found 558.2. Example 276.4-(1-(2-Chloro-4-(1-(methylamino)ethyl)phenyl)-1H-imidaz ol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine In a vial with a stir bar, tert-butyl (1-(3-chloro-4-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)phenyl)ethyl)(methyl)carbamate (Example 275 in Step 2, Peak 2, 7.0 mg, 10 µmol) was dissolved in TFA (3 mL), and stirred at room temperature for 3 hours. After the resultant mixture was concentrated under reduced pressure, the residue was dissolved in MeOH. The solution was purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C23H28ClF3N7O2S (M+H) + : m/z = 558.2; Found 558.1. Example 277.4-(1-(2-Chloro-4-(piperidin-2-yl)phenyl)-1H-imidazol-4-y l)-N- ((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine Step 1: tert-Butyl 6-(3-chloro-4-(4-(2-(((3R,4S)-3-methyl-1-(methylsulfonyl)pip eridin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1 -yl)phenyl)-3,4- dihydropyridine-1(2H)-carboxylate In a microwave vial with a stir bar, a mixture of 4-(1-(2-chloro-4-iodophenyl)- 1H-imidazol-4-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)pipe ridin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 42, 51 mg, 0.080 mmol), tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrop yridine-1(2H)- carboxylate (73.8 mg, 0.239 mmol), Pd(dppf)Cl2 ^CH2Cl2 (65.0 mg, 0.080 mmol), sodium carbonate (25.3 mg, 0.239 mmol), acetonitrile (3 mL), and water (0.6 mL) was sparged with nitrogen and heated at 80 °C for 10 hours. After cooling to room temperature, the solution was filtered through a pad of SiliaMetS Thiol ® , and concentrated. The residue was purified by flash column chromatography (Agela Flash Column Silica-CS (24 g), eluting with a gradient of 0 to 20% CH2Cl2/methanol) to afford the desired product, which was used in the next reaction without further purification. LCMS calculated for C31H38ClF3N7O4S (M+H) + : m/z = 696.2; Found 696.3. Step 2: 4-(1-(2-Chloro-4-(piperidin-2-yl)phenyl)-1H-imidazol-4-yl)-N -((3R,4S)-3- methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine In a vial with a stir bar, tert-butyl 6-(3-chloro-4-(4-(2-(((3R,4S)-3-methyl-1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)phenyl)-3,4-dihydropyridine-1(2H)-carboxylate was dissolved in TFA (3 mL), and stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and then dissolved in THF (5 mL). To this solution was added triethylamine (300 µL, 2.15 mmol) and acetic acid (100 µL, 1.75 mmol), followed by sodium triacetoxyborohydride (84 mg, 0.40 mmol). The mixture was stirred at room temperature for 16 hours. The resultant solution was quenched by saturated aqueous NaHCO3 solution, and the mixture was then concentrated under reduced pressure. The material obtained was dissolved in MeOH and purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/in) to afford the desired product, which was used in the next reaction without further purification. LCMS calculated for C26H32ClF3N7O2S (M+H) + : m/z = 598.2; Found 598.2. Step 3: tert-Butyl 2-(3-chloro-4-(4-(2-(((3R,4S)-3-methyl-1-(methylsulfonyl)pip eridin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1 -yl)phenyl)piperidine-1- carboxylate This compound was prepared according to the procedures described in Example 275, using 4-(1-(2-chloro-4-(piperidin-2-yl)phenyl)-1H-imidazol-4-yl)-N - ((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifl uoromethyl)pyrimidin-2- amine instead of 4-(1-(2-chloro-4-(1-(methylamino)ethyl)phenyl)-1H-imidazol-4 -yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyri midin-2-amine as starting material for Step 2. Separation conditions of chiral prep-HPLC (Phenomenex Lux Cellulose-1, 21.2x250 mm, 5 micron, eluting with 30% EtOH in hexanes, at flow rate of 20 mL/min, tR, peak 1 = 7.7 min, tR, peak 2 = 10.2 min). Peak 1: LCMS calculated for C31H40ClF3N7O4S (M+H) + : m/z = 698.2; Found 698.2; Found 698.2. Peak 2: LCMS calculated for C31H40ClF3N7O4S (M+H) + : m/z = 698.2; Found 698.2. Step 4: 4-(1-(2-Chloro-4-(piperidin-2-yl)phenyl)-1H-imidazol-4-yl)-N -((3R,4S)-3- methyl-1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine This compound was prepared according to the procedures described in Example 275, using tert-butyl 2-(3-chloro-4-(4-(2-(((3R,4S)-3-methyl-1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)phenyl)piperidine-1-carboxylate (Example 277 in Step 3, Peak 1) instead of tert-butyl (1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amin o)- 5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)e thyl)(methyl)carbamate as starting material for Step 3. LCMS calculated for C26H32ClF3N7O2S (M+H) + : m/z = 598.2; Found 598.2.
Example 278.4-(1-(2-Chloro-4-(piperidin-2-yl)phenyl)-1H-imidazol-4-y l)-N- ((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 276, using tert-butyl 2-(3-chloro-4-(4-(2-(((3R,4S)-3-methyl-1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)phenyl)piperidine-1-carboxylate (Example 277 in Step 3, Peak 2) instead of tert-butyl (1-(3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amin o)- 5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)e thyl)(methyl)carbamate as starting material. LCMS calculated for C26H32ClF3N7O2S (M+H) + : m/z = 598.2; Found 598.2. Example 279.4-(1-(4-((Dimethylamino)methyl)-2-fluorophenyl)-2-methyl -1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine Step 1: 3-Fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl )amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehy de In a vial with a stir bar, a mixture of 4-(2-methyl-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (Intermediate 38, 200 mg, 0.50 mmol), 3,4-difluorobenzaldehyde (0.27 mL, 2.5 mmol), cesium carbonate (1.6 g, 5.0 mmol), and MeCN (10 mL) was sparged with N2, and the mixture was stirred at room temperature for 5 hours. After filtration of the resultant mixture, the filtrate was purified by flash column chromatography (Agela Flash Column Silica-CS (40 g), eluting with a gradient of 0 to 10% CH2Cl2/methanol) to afford the desired product. LCMS calculated for C22H23F4N6O3S (M+H) + : m/z = 527.1; Found 527.3. Step 2: 4-(1-(4-((Dimethylamino)methyl)-2-fluorophenyl)-2-methyl-1H- imidazol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine In a vial with a stir bar, a mixture of 3-fluoro-4-(2-methyl-4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)benzaldehyde (0.23 g, 0.44 mmol), dimethylamine (2 M in THF, 2.0 mL, 4.0 mmol), triethylamine (0.20 mL, 1.4 mmol), acetic acid (0.20 mL, 3.5 mmol), THF (10 mL), and MeOH (10 mL) was stirred at 70 °C for 1 hour. NaBH3CN (200 mg, 3.2 mmol) was added to the resultant solution at room temperature. The mixture was heated at 60 °C for 30 minutes and the solution was then concentrated in vacuo. The residue was dissolved in MeOH and purified by prep-LCMS (XBridge column, eluting with a gradient of acetonitrile/water containing 0.1% NH4OH, at flow rate of 60 mL/min). Fractions containing the desired product were then concentrated, and the material obtained was dissolved in acetonitrile and purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 1:1 rotamers) d 9.95 (brs, 1H), 8.63 (s, 0.5H), 8.58 (s, 0.5H), 8.01 (s, 0.5H), 7.95-7.85 (m, 1H), 7.85- 7.73 (m, 1.5H), 7.69 (d, J = 10.5 Hz, 1H), 7.52 (d, J = 7.5 Hz, 1H), 4.39 (s, 2H), 4.08- 3.91 (m, 1H), 3.59-3.43 (m, 2H), 2.95-2.82 (m, 5H), 2.79 (s, 6H), 2.27 (s, 3H), 2.00- 1.88 (m, 2H), 1.64-1.51 (m, 2H). LCMS calculated for C24H30F4N7O2S (M+H) + : m/z = 556.2; Found 556.2. Example 280.4-(1-(4-((Bis(methyl-d 3 )amino)methyl)-2-fluorophenyl)-2-methyl- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 279, using dimethyl-d6-amine hydrochloride instead of dimethylamine (2 M in THF) as starting material. 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 1:1 rotamers) d 9.82 (brs, 1H), 8.63 (s, 0.5H), 8.57 (s, 0.5H), 8.02 (s, 0.5H), 7.93-7.86 (m, 1H), 7.85-7.75 (m, 1.5H), 7.69 (d, J = 10.7 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 4.38 (s, 2H), 4.07-3.90 (m, 1H), 3.59-3.44 (m, 2H), 2.94-2.79 (m, 5H), 2.26 (s, 3H), 2.01-1.89 (m, 2H), 1.64-1.52 (m, 2H). LCMS calculated for C24H24D6F4N7O2S (M+H) + : m/z = 562.2; Found 562.3.
Example 281.4-(1-(4-(Azetidin-1-ylmethyl)-2-fluorophenyl)-2-methyl-1 H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 279, using azetidine hydrochloride instead of dimethylamine (2 M in THF) as starting material. 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 1:1 rotamers) d 10.4 (brs, 1H), 8.63 (s, 0.5H), 8.57 (s, 0.5H), 8.03 (s, 0.5H), 7.95-7.87 (m, 1H), 7.85-7.72 (m, 1.5H), 7.65 (d, J = 10.7 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 4.48 (s, 2H), 4.19-3.91 (m, 5H), 3.58-3.46 (m, 2H), 2.93-2.80 (m, 5H), 2.46-2.29 (m, 2H), 2.25 (s, 3H), 1.99- 1.89 (m, 2H), 1.63-1.53 (m, 2H). LCMS calculated for C25H30F4N7O2S (M+H) + : m/z = 568.2; Found 568.3. Example 282.2-(1-(3-Fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)pipe ridin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-y l)benzyl)azetidin- 3-yl)propan-2-ol This compound was prepared according to the procedures described in Example 279, using 2-(azetidin-3-yl)propan-2-ol hydrochloride instead of dimethylamine as starting material. LCMS calculated for C28H36F4N7O3S (M+H) + : m/z = 626.3; Found 626.3. Example 283.4-(1-(2-Fluoro-4-((3-methylazetidin-1-yl)methyl)phenyl)- 2-methyl- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 279, using 3-methylazetidine hydrochloride instead of dimethylamine as starting material. LCMS calculated for C26H32F4N7O2S (M+H) + : m/z = 582.2; Found 582.2. Example 284.4-(1-(4-(Azetidin-1-ylmethyl)-2-chlorophenyl)-2-methyl-1 H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine
Step 1: 3-Chloro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl )amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehy de In a vial with a stir bar, a mixture of 4-(2-methyl-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (Intermediate 38, 70 mg, 0.17 mmol), 3-chloro-4-fluorobenzaldehyde (140 mg, 0.87 mmol), cesium carbonate (560 mg, 1.7 mmol), and acetonitrile (3 mL) was sparged with N2, and the mixture was stirred at 70 °C for 30 minutes. After filtration of the resultant mixture, the filtrate was purified by flash column chromatography (Agela Flash Column Silica- CS (40 g), eluting with a gradient of 0 to 10% CH2Cl2/methanol) to afford the desired product. LCMS calculated for C22H23ClF3N6O3S (M+H) + : m/z = 543.1; Found 543.3. Step 2: 4-(1-(4-(Azetidin-1-ylmethyl)-2-chlorophenyl)-2-methyl-1H-im idazol-4-yl)-N- (1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimi din-2-amine In a vial with a stir bar, a mixture of 3-chloro-4-(2-methyl-4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)benzaldehyde (80 mg, 0.15 mmol), azetidine hydrochloride (160 mg, 1.7 mmol), triethylamine (0.40 mL, 2.9 mmol), acetic acid (0.40 mL, 7.0 mmol), THF (3 mL), and MeOH (3 mL) was stirred at 70 °C for 1 hour. NaBH3CN (200 mg, 3.2 mmol) was added to the resultant solution at room temperature. The mixture was heated at 60 °C for 30 minutes and the solution was then concentrated in vacuo. The residue was dissolved in MeOH and purified by prep-LCMS (XBridge column, eluting with a gradient of acetonitrile/water containing 0.1% NH4OH, at flow rate of 60 mL/min). Fractions containing the desired product were then concentrated, and the material obtained was dissolved in acetonitrile and purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). 1 H NMR (TFA salt, 600 MHz, DMSO-d6, 1:1 rotamers) d 10.4 (s, 1H), 8.63 (s, 0.5H), 8.57 (s, 0.5H), 8.00 (s, 0.5H), 7.94-7.85 (m, 2H), 7.83- 7.71 (m, 1.5H), 7.63 (d, J = 7.0 Hz, 1H), 4.47 (s, 2H), 4.20-3.91 (m, 5H), 3.58-3.45 (m, 2H), 2.93-2.81 (m, 5H), 2.46-2.29 (m, 2H), 2.16 (s, 3H), 2.01-1.88 (m, 2H), 1.63- 1.51 (m, 2H). LCMS calculated for C25H30ClF3N7O2S (M+H) + : m/z = 584.2; Found 584.3. Example 285.4-(1-(4-(Azetidin-1-ylmethyl)-2-methylphenyl)-2-methyl-1 H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 271, using 4-(2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin - 4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 38) and azetidine hydrochloride instead of 4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)- 5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 2) and dimethylamine as starting material. LCMS calculated for C26H33F3N7O2S (M+H) + : m/z = 564.2; Found 564.3.
Example 286.4-(1-(4-((Dimethylamino)methyl)-2-fluorophenyl)-2-methyl -1H- imidazol-4-yl)-N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperid in-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 279, using N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(2- methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amin e (Intermediate 39) instead of 4-(2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin -4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 38) as starting material. LCMS calculated for C24H29F5N7O2S (M+H) + : m/z = 574.2; Found 574.2. Example 287. N-((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-( 2- fluoro-4-((methylamino)methyl)phenyl)-2-methyl-1H-imidazol-4 -yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 279, using N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(2- methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amin e (Intermediate 39) and methanamine instead of 4-(2-methyl-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (Intermediate 38) and dimethylamine as starting material. LCMS calculated for C23H27F5N7O2S (M+H) + : m/z = 560.2; Found 560.1. Example 288.4-(1-(2-Chloro-4-((dimethylamino)methyl)phenyl)-2-methyl -1H- imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)py rimidine-5- carbonitrile Step 1: 4-(1-(2-Chloro-4-formylphenyl)-2-methyl-1H-imidazol-4-yl)-2- ((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitri le In a vial with a stir bar, a mixture of 4-(2-methyl-1H-imidazol-4-yl)-2-((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitri le (60.0 mg, 0.166 mmol), 3-chloro-4-fluorobenzaldehyde (132 mg, 0.830 mmol), cesium carbonate (540 mg, 1.66 mmol), and MeCN (3 mL) was sparged with N2, and the mixture was stirred at 70 °C for 30 minutes. After filtration of the resultant solution, the filtrate was purified by flash column chromatography (Agela Flash Column Silica-CS (40 g), eluting with a gradient of 0 to 10% CH2Cl2/methanol) to afford the desired product. LCMS calculated for C22H23ClN7O3S (M+H) + : m/z = 500.1; Found 500.3. Step 2: 4-(1-(2-Chloro-4-((dimethylamino)methyl)phenyl)-2-methyl-1H- imidazol-4- yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5- carbonitrile In a vial with a stir bar, a mixture of 4-(1-(2-chloro-4-formylphenyl)-2- methyl-1H-imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-y l)amino)pyrimidine-5- carbonitrile (20 mg, 0.040 mmol), dimethylamine (2 M in THF, 0.42 mL, 0.84 mmol), triethylamine (0.10 mL, 0.72 mmol), acetic acid (0.10 mL, 1.7 mmol), THF (1 mL), and MeOH (2 mL) was stirred at 70 °C for 1 hour. NaBH3CN (200 mg, 3.2 mmol) was added to the resultant solution at room temperature. The mixture was heated at 60 °C for 30 minutes and the solution was then concentrated under reduced pressure. The residue was dissolved in MeOH and purified by prep-LCMS (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. LCMS calculated for C24H30ClN8O2S (M+H) + : m/z = 529.2; Found 529.2. Example 289.4-(1-(2-Chloro-4-((methylamino)methyl)phenyl)-2-methyl-1 H- imidazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)py rimidine-5- carbonitrile This compound was prepared according to the procedures described in Example 288, using methanamine instead of dimethylamine as starting material for Step 2. LCMS calculated for C23H28ClN8O2S (M+H) + : m/z = 515.2; Found 515.1.
Example 290.4-(1-(4-Cyano-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl) -2-((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitri le In a vial with a stir bar, a mixture of 4-(2-methyl-1H-imidazol-4-yl)-2-((1- (methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitri le (10 mg, 0.028 mmol), 3,4-difluorobenzonitrile (19.2 mg, 0.138 mmol), cesium carbonate (90 mg, 0.277 mmol), and acetonitrile (3 mL) was sparged with N2. After the mixture was stirred at 70 °C for 1 hour, the reaction mixture was filtered. The filtrate was then purified by prep-LCMS (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. LCMS calculated for C22H22FN8O2S (M+H) + : m/z = 481.2; Found 481.1. Example 291.2-Methoxy-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)ami no)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)nicotinoni trile This compound was prepared according to the procedures described in Example 1, using 4-chloro-2-methoxynicotinonitrile instead of 3-chloro-4- fluorobenzonitrile as starting material. LCMS calculated for C 21 H 22 F 3 N 8 O 3 S (M+H) + : m/z = 523.1; Found 523.1. 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 1:1 rotamers) d 8.69 (s, 0.5H), 8.63 (m, 1.5H), 8.55 (s, 0.5H), 8.45 (s, 1H), 8.30 (s, 0.5H), 8.02 (m, 1H), 7.58 (d, J = 5.5 Hz, 0.5H), 7.52 (d, J = 5.4 Hz, 0.5H), 4.10 (s, 3H), 4.01 (br, 1H), 3.56 (d, J = 12.2 Hz, 2H), 2.91 (m, 2H), 2.88 (s, 3H), 2.00 (m, 2H), 1.59 (m, 2H). Example 292.3-Methyl-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinoni trile This compound was prepared according to the procedures described in Example 1, using 4-chloro-3-methylpicolinonitrile instead of 3-chloro-4- fluorobenzonitrile as starting material. LCMS calculated for C21H22F3N8O2S (M+H) + : m/z = 507.2; Found 507.2. 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 1:1 rotamers) d 8.79 (m, 1H), 8.68 (s, 0.5H), 8.62 (s, 0.5H), 8.31 (s, 0.5H), 8.23 (s, 1H), 8.10 (s, 0.5H), 7.95 (m, 2H), 4.01 (br, 1H), 3.55 (m, 2H), 2.89 (m, 5H), 2.47 (s, 3H), 1.97 (m, 2H), 1.60 (m, 2H). Example 293.2-Methyl-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)nicotinoni trile This compound was prepared according to the procedures described in Example 1, using 4-chloro-2-methylnicotinonitrile instead of 3-chloro-4- fluorobenzonitrile as starting material. LCMS calculated for C21H22F3N8O2S (M+H) + : m/z = 507.2; Found 507.2. 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 1:1 rotamers) d 8.90 (m, 1H), 8.67 (m, 1H), 8.53 (s, 0.5H), 8.42 (s, 1H), 8.29 (s, 0.5H), 8.02 (m, 1H), 7.77 (m, 1H), 4.02 (br, 1H), 3.56 (m, 2H), 2.88 (m, 5H), 2.80 (s, 3H), 2.02 (m, 2H), 1.60 (m, 2H). Table 24. The compounds in Table 24 were prepared in accordance with the synthetic protocols set forth in Example 1 using the appropriate starting materials. Example 300.4-(1-(3-Chloro-2-methoxypyridin-4-yl)-1H-imidazol-4-yl)- N- ((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 1, using N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H- imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 17) instead of 4- (1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine and 3,4-dichloro-2-methoxypyridine instead of 3- chloro-4-fluorobenzonitrile as starting material. LCMS calculated for C20H21ClF4N7O3S (M+H) + : m/z = 550.1; Found 550.1. 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 1:1 rotamers) d 8.67 (d, J = 16.3 Hz, 1H), 8.34 (m, 1.5H), 8.24 (d, J = 7.4 Hz, 1H), 8.18 (s, 0.5H), 8.62 (s, 0.5H), 8.07 (m, 1H), 7.38 (m, 1H), 4.95 (m, 1H), 4.21 (m, 1H), 4.04 (s, 3H), 3.85 (m, 1H), 3.67 (d, J = 12.0 Hz, 1H), 3.22 (m, 1H), 3.01 (t, J = 11.4 Hz, 1H), 2.92 (s, 3H), 1.98 (m, 1H), 1.81 (m, 1H).
Example 301.4-(1-(3-Chloro-2-methylpyridin-4-yl)-1H-imidazol-4-yl)-N - ((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 1, using N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H- imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 17) instead of 4- (1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine and 3,4-dichloro-2-methylpyridine instead of 3- chloro-4-fluorobenzonitrile as starting material. LCMS calculated for C20H21ClF4N7O2S (M+H) + : m/z = 534.1; Found 534.1. 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 1:1 rotamers) d 8.64 (m, 2H), 8.36 (s, 0.5H), 8.22 (t, J = 6.9 Hz, 1H), 8.16 (s, 0.5H), 8.07 (m, 1H), 7.63 (m, 1H), 4.96 (m, 1H), 4.23 (m, 1H), 3.84 (m, 1H), 3.66 (d, J = 12.9 Hz, 1H), 3.22 (m, 1H), 3.01 (t, J = 11.5 Hz, 1H), 2.92 (s, 3H), 2.70 (s, 3H), 1.98 (m, 1H), 1.80 (m, 1H).
Example 302.4-(4-(2-(((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4 - yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-y l)-3- methylpicolinonitrile This compound was prepared according to the procedures described in Example 1, using N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H- imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 17) instead of 4- (1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine and 4-chloro-3-methylpicolinonitrile instead of 3- chloro-4-fluorobenzonitrile as starting material. LCMS calculated for C21H21F4N8O2S (M+H) + : m/z = 525.1; Found 525.2. 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 1:1 rotamers) d 8.80 (m, 1H), 8.68 (m, 1H), 8.36 (s, 0.5H), 8.23 (s, 1H), 8.12 (m, 1H), 8.03 (m, 0.5H), 7.93 (m, 1H), 4.99 (m, 1H), 4.21 (m, 1H), 3.85 (m, 1H), 3.68 (m, 1H), 3.22 (m, 1H), 3.01 (m, 1H), 2.93 (s, 3H), 2.50 (s, 3H), 1.98 (m, 1H), 1.81 (m, 1H). Example 303.3-Fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin- 4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-y l)benzonitrile This compound was prepared according to the procedures described in Example 1, using 4-(2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin -4- yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 38) instead of 4-(1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifl uoromethyl)pyrimidin-2- amine and 3,4-difluorobenzonitrile instead of 3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated for C22H22F4N7O2S (M+H) + : m/z = 524.1; Found 524.1. 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 1:1 rotamers) d 8.66 (s, 0.5H), 8.61 (s, 0.5H), 8.27 (m, 1H), 8.14 (s, 0.5H), 7.96 (m, 2.5H), 4.02 (m, 1H), 3.55 (m, 2H), 2.88 (m, 5H), 2.31 (s, 3H), 1.97 (m, 2H), 1.60 (m, 2H). Example 304.2-Fluoro-3-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin- 4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-y l)benzonitrile Step 1: 4-(1-(3-Bromo-2-fluoro-4-nitrophenyl)-2-methyl-1H-imidazol-4 -yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine This compound was prepared according to the procedures described in Example 1, using 4-(2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin -4- yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 38) instead of 4-(1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifl uoromethyl)pyrimidin-2- amine and 2-bromo-3,4-difluoro-1-nitrobenzene instead of 3-chloro-4- fluorobenzonitrile as starting material. LCMS calculated for C21H21BrF4N7O4S (M+H) + : m/z = 622.0; Found 622.0. Step 2: 4-(1-(4-Amino-3-bromo-2-fluorophenyl)-2-methyl-1H-imidazol-4 -yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine A mixture of 4-(1-(3-bromo-2-fluoro-4-nitrophenyl)-2-methyl-1H-imidazol-4 - yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine (130 mg, 0.21 mmol), iron powder (58.3 mg, 1.04 mmol), ammonium chloride (112 mg, 2.09 mmol) in tetrahydrofuran (4 mL), water (1 mL) and methanol (2 mL) was stirred at 55 °C for 3 hours. Upon cooling to room temperature, to the reaction was added dichloromethane (20 mL), then was filtered and washed with dichloromethane. The filtrate was concentrated and then purified by flash column chromatography (methanol/ dichloromethane) to afford the desired product. LCMS calculated for C21H23BrF4N7O2S (M+H) + : m/z = 592.1; Found 592.1. Step 3: 4-(1-(3-Bromo-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-( 1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine A solution of 4-(1-(4-amino-3-bromo-2-fluorophenyl)-2-methyl-1H-imidazol- 4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethy l)pyrimidin-2-amine (100 mg, 0.17 mmol) and tert-butyl nitrite (30.1 µL, 0.25 mmol) in THF (3 mL) was stirred at 65 °C for 4 hours. Upon cooling to room temperature, the reaction was concentrated and then purified by flash column chromatography (methanol/ dichloromethane) to afford the desired product. LCMS calculated for C21H22BrF4N6O2S (M+H) + : m/z = 577.1; Found 576.9. Step 4: 2-Fluoro-3-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4-yl )amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitri le A mixture of 4-(1-(3-bromo-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N- (1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimi din-2-amine (163 mg, 0.282 mmol), Zn(CN)2 (66.3 mg, 0.565 mmol) and tBuXPhos Pd G3 (44.8 mg, 0.056 mmol) in DMF (4 mL) was stirred at 80 °C for 3 h. After cooling to r.t., the resultant mixture was diluted with acetonitrile and filtered. The solution containing the desired product was then purified by prep-LCMS (Sunfire C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford the product. LCMS calculated for C22H22F4N7O2S (M+H) + : m/z = 524.1; Found 524.1. 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 1:1 rotamers) d 8.63 (m, 1H), 8.12 (m, 2.5H), 7.94 (m, 1.5H), 7.63 (m, 1H), 4.02 (m, 1H), 3.54 (m, 2H), 2.87 (m, 5H), 2.30 (s, 3H), 1.96 (m, 2H), 1.60 (m, 2H). Example 305.2-Fluoro-3-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)pi peridin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-2-methyl-1H-imi dazol-1- yl)benzonitrile This compound was prepared according to the procedures described in Example 304, using N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(2- methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amin e (Intermediate 39) instead of 4-(2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin -4-yl)-5- (trifluoromethyl)pyrimidin-2-amine as starting material. LCMS calculated for C22H21F5N7O2S (M+H) + : m/z = 542.1; Found 542.1. 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 4:6 rotamers) d 8.66 (m, 1H), 8.30 – 7.90 (m, 4H), 7.65 (m, 1H), 4.95 (d, J = 48.8 Hz, 1H), 4.22 (m, 1H), 3.84 (m, 1H), 3.66 (d, J = 12.5 Hz, 1H), 3.21 (m, 1H), 3.01 (t, J = 12.0 Hz, 1H), 2.92 (s, 3H), 2.30 (s, 3H), 1.96 (m, 1H), 1.80 (m, 1H). Example 306.3-(4-(2-(((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4 - yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-2-methyl-1H-imi dazol-1-yl)-2- methylbenzonitrile This compound was prepared according to the procedures described in Example 42, using N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(2- methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amin e (Intermediate 39) instead of N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H- imidazol-4- yl)-5-(trifluoromethyl)pyrimidin-2-amine as starting material. LCMS calculated for C23H24F4N7O2S (M+H) + : m/z = 538.2; Found 538.1. 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 1:1 rotamers) d 8.66 (m, 1H), 8.13 (s, 0.5H), 8.03 (m, 2H), 7.85 (m, 1.5H), 7.64 (m, 1H), 4.95 (m, 1H), 4.22 (m, 1H), 3.82 (m, 1H), 3.65 (m, 1H), 3.21 (m, 1H), 3.00 (m, 1H), 2.92 (d, J = 6.9 Hz, 3H), 2.20 (m, 6H), 1.96 (m, 1H), 1.80 (m, 1H).
Example 307.3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinoni trile Step 1: 4-(1-(2,3-Dichloropyridin-4-yl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine This compound was prepared according to the procedures described in Example 1, using 2,3,4-trichloropyridine instead of 3-chloro-4-fluorobenzonitrile as starting material. LCMS calculated for C19H19Cl2F3N7O2S (M+H) + : m/z = 536.1; Found 536.0. Step 2: 3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5 - (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)picolinoni trile This compound was prepared according to the procedures described in Example 304, Step 4, using 4-(1-(2,3-dichloropyridin-4-yl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine instead of 4-(1- (3-bromo-2-fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine as starting material. LCMS calculated for C20H19ClF3N8O2S (M+H) + : m/z = 527.1; Found 527.0. 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 1:1 rotamers) d 8.90 (m, 1H), 8.69 (s, 0.5H), 8.63 (s, 0.5H), 8.36 (s, 0.5H), 8.28 (d, J = 1.3 Hz, 1H), 8.18 (m, 1.5H), 8.13 (m, 1H), 8.00 (d, J = 6.8 Hz, 1H), 4.01 (br, 1H), 3.56 (br, 2H), 2.89 (m, 5H), 1.98 (br, 2H), 1.61 (br, 2H). Example 308.3-Chloro-4-(4-(2-(((3R,4S)-3-fluoro-1-(methylsulfonyl)pi peridin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-y l)picolinonitrile This compound was prepared according to the procedures described in Example 307, using N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1H- imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 17) instead of 4- (1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine as starting material. LCMS calculated for C20H18ClF4N8O2S (M+H) + : m/z = 545.1; Found 545.1. 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 1:1 rotamers) d 8.91 (m, 1H), 8.69 (m, 1H), 8.41 (s, 0.5H), 8.29 (s, 1H), 8.24 (s, 0.5H), 8.16 (m, 2H), 8.08 (m, 1H), 4.98 (m, 1H), 4.21 (m, 1H), 3.86 (m, 1H), 3.67 (m, 1H), 3.23 (m, 1H), 3.02 (m, 1H), 2.93 (s, 3H), 1.98 (m, 1H), 1.81 (m, 1H). Table 25. The compounds in Table 25 were prepared in accordance with the synthetic protocols set forth in Example 307 using the appropriate starting materials.
Example 311. N-((3R,4S)-3-Fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(1-( 3- fluoro-2-methoxypyridin-4-yl)-2-methyl-1H-imidazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 39, using N-((3R,4S)-3-fluoro-1-(methylsulfonyl)piperidin-4-yl)-4-(2- methyl-1H-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amin e (Intermediate 39) instead of 4-(1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine and 2,3,4-trifluoropyridine instead of 6-chloro-3- fluoropicolinonitrile as starting material. LCMS calculated for C21H23F5N7O3S (M+H) + : m/z = 548.2; Found 548.1. 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 1:1 rotamers) d 8.66 (m, 1H), 8.18 (m, 2H), 8.06 (m, 1H), 7.98 (s, 1H), 7.37 (m, 1H), 4.99 (s, 0.5H), 4.91 (s, 0.5H), 4.21 (m, 1H), 4.04 (s, 3H), 3.83 (m, 1H), 3.66 (m, 1H), 3.21 (m, 1H), 3.01 (m, 1H), 2.92 (s, 3H), 2.35 (s, 3H), 1.97 (m, 1H), 1.80 (m, 1H). Table 26. The compounds in Table 26 were prepared in accordance with the synthetic protocols set forth in Example 42 using the appropriate starting materials. Table 27. The compounds in Table 27 were prepared in accordance with the synthetic protocols set forth in Example 39 using the appropriate starting materials.
Example 323.1-(4-(2-(((3R,4S)-1-(Cyclopropylsulfonyl)-3-fluoropiperi din-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-y l)-2-methylpropan- 2-ol Step 1: N-((3R,4S)-1-(Cyclopropylsulfonyl)-3-fluoropiperidin-4-yl)-4 -(1H-imidazol-4- yl)-5-(trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Intermediate 17, using cyclopropanesulfonyl chloride instead of methanesulfonyl chloride as starting material. LCMS calculated for C16H19F4N6O2S (M+H) + : m/z = 435.1; Found 435.1. Step 2: 1-(4-(2-(((3R,4S)-1-(Cyclopropylsulfonyl)-3-fluoropiperidin- 4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylp ropan-2-ol This compound was prepared according to the procedures described in Example 21, using N-((3R,4S)-1-(cyclopropylsulfonyl)-3-fluoropiperidin-4-yl)-4 -(1H- imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine instead of 4-(1H-imidazol-4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyri midin-2-amine and 2,2- dimethyloxirane instead of 1,1-difluoro-2-iodoethane as starting material. LCMS calculated for C20H27F4N6O3S (M+H) + : m/z = 507.2; Found 507.2. 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 1:1 rotamers) d 8.69 (m, 1H), 8.34 (br, 0.5H), 8.19 (br, 0.5H), 8.04 (m, 1.5H), 7.92 (s, 0.5H), 4.97 (m, 1H), 4.30 (m, 1H), 4.15 (s, 1H), 4.05 (s, 1H), 3.91 (br, 1H), 3.71 (m, 1H), 3.26 (m, 1H), 3.07 (m, 1H), 2.62 (m, 1H), 2.00 (m, 1H), 1.81 (br, 1H), 1.12 (s, 3H), 1.09 (s, 3H), 1.00 (m, 4H). Example 324.1-(4-(2-((1-(Ethylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)-2-methylp ropan-2-ol Step 1: N-(1-(Ethylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Intermediate 2, using ethanesulfonyl chloride instead of methanesulfonyl chloride as starting material. LCMS calculated for C15H20F3N6O2S (M+H) + : m/z = 405.1; Found 405.1. Step 2: 1-(4-(2-((1-(Ethylsulfonyl)piperidin-4-yl)amino)-5-(trifluor omethyl)pyrimidin- 4-yl)-1H-imidazol-1-yl)-2-methylpropan-2-ol This compound was prepared according to the procedures described in Example 21, using N-(1-(ethylsulfonyl)piperidin-4-yl)-4-(1H-imidazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine instead of 4-(1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine and 2,2- dimethyloxirane instead of 1,1-difluoro-2-iodoethane as starting material. LCMS calculated for C19H28F3N6O3S (M+H) + : m/z = 477.2; Found 477.3. 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 1:1 rotamers) d 8.65 (br, 2H), 8.18 (br, 0.5H), 8.01 (m, 1H), 7.88 (s, 0.5H), 4.11 (m, 3H), 3.62 (d, J = 12.2 Hz, 2H), 3.07 (m 2H), 2.98 (d, J = 6.7 Hz, 2H), 1.94 (m, 2H), 1.58 (m, 2H), 1.23 (t, J = 7.3 Hz, 3H), 1.12 (s, 3H), 1.09 (s, 3H). Table 28. The compounds in Table 28 were prepared in accordance with the synthetic protocols set forth in Example 21 using the appropriate starting materials.
Table 29. The compounds in Table 29 were prepared in accordance with the synthetic protocols set forth in Example 87 using the appropriate starting materials.
Example 339.5-((4-Ethylpiperazin-1-yl)methyl)-2-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)benzonitrile
Step 1: 5-Formyl-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5 - (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitri le This compound was prepared according to the procedures described in Example 250, Step 1, using 2-fluoro-5-formylbenzonitrile instead of 4-fluoro-3- (trifluoromethyl)benzaldehyde as starting material. LCMS calculated for C22H21F3N7O3S (M+H) + : m/z = 520.1; Found 520.1. Step 2: 5-((4-Ethylpiperazin-1-yl)methyl)-2-(4-(2-((1-(methylsulfony l)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-y l)benzonitrile This compound was prepared according to the procedures described in Example 175, using 5-formyl-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5 - (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitri le instead of 3-chloro-4- (4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoro methyl)pyrimidin-4-yl)- 1H-imidazol-1-yl)benzaldehyde and 1-ethylpiperazine instead of dimethylamine as starting material. LCMS calculated for C28H35F3N9O2S (M+H) + : m/z = 618.3; Found 618.3. 1 H NMR (TFA salt, 500 MHz, DMSO-d6, 1:1 rotamers) d 8.69 (s, 0.5H), 8.63 (s, 0.5H), 8.41 (s, 0.5H), 8.28 (s, 1H), 8.16 (s, 0.5H), 8.06 (s, 1H), 7.98 (m, 1H), 7.86 (br, 1.5H), 7.81 (m, 0.5H), 4.02 (br, 1H), 3.74 (s, 2H), 3.56 (br, 2H), 3.48 (d, J = 11.7 Hz, 2H), 3.15 (d, J = 7.1 Hz, 2H), 2.96 (m, 6H), 2.87 (s, 3H), 2.43 (m, 2H), 2.01 (m, 2H), 1.60 (m, 2H), 1.22 (t, J = 7.2 Hz, 3H). Example 340.5-((Isopropylamino)methyl)-2-(4-(2-((1-(methylsulfonyl)p iperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1 -yl)benzonitrile This compound was prepared according to the procedures described in Example 339, using propan-2-amine instead of 1-ethylpiperazine as starting material. LCMS calculated for C25H30F3N8O2S (M+H) + : m/z = 563.2; Found 563.1. 1 H NMR (TFA salt, 600 MHz, DMSO-d6, 1:1 rotamers) d 8.83 (s, 1H), 8.69 (s, 0.5H), 8.64 (s, 0.5H), 8.45 (s, 0.5H), 8.34 (s, 1H), 8.25 (s, 1H), 8.21 (s, 0.5H), 7.98 (m, 3H), 4.33 (s, 2H), 4.02 (br, 1H), 3.56 (br, 2H), 3.37 (m, 1H), 2.90 (m, 2H), 2.87 (s, 3H), 1.99 (m, 2H), 1.61 (m, 2H), 1.31 (d, J = 6.5 Hz, 6H). Table 30. The compounds in Table 30 were prepared in accordance with the synthetic protocols set forth in Example 175 using the appropriate starting materials.
Table 31. The compounds in Table 31 were prepared in accordance with the synthetic protocols set forth in Example 77 using the appropriate amine starting material. Example 369.4-(1-(2-Chloro-3-(2-morpholinoethyl)phenyl)-1H-imidazol- 4-yl)-N- (1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimi din-2-amine This compound was prepared according to the procedures described in Intermediate 35, using 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane as starting material for Step 1. LCMS calculated for C22H23ClF3N6O3S (M+H) + : m/z = 543.1; Found 543.1. Step 2: 4-(1-(2-Chloro-3-(2-morpholinoethyl)phenyl)-1H-imidazol-4-yl )-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine This compound was prepared according to the procedures described in Example 77, using 2-(2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino )-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)ace taldehyde and morpholine instead of 2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5 - (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehy de and dimethylamine as starting materials. LCMS calculated for C26H32ClF3N7O3S (M+H) + : m/z = 614.2; Found 614.2. Table 32. The compounds in Table 32 were prepared in accordance with the synthetic protocols set forth in Example 369 using the appropriate amine starting material.
Example 375.4-(1-(2-Chloro-3-(1-(ethylamino)ethyl)phenyl)-1H-imidazo l-4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyri midin-2-amine
Step 1: 1-(2-Chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino )-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)eth an-1-one This compound was prepared according to the procedures described in Intermediate 35, using 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane instead of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane as starting material for Step 1. LCMS calculated for C22H23ClF3N6O3S (M+H) + : m/z = 543.1; Found 543.0. Step 2: 4-(1-(2-Chloro-3-(1-(ethylamino)ethyl)phenyl)-1H-imidazol-4- yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine This compound was prepared according to the procedures described in Example 175, using 1-(2-chloro-3-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino )-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)eth an-1-one and ethanamine instead of 3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5 - (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzaldehy de and dimethylamine as starting materials. LCMS calculated for C24H30ClF3N7O2S (M+H) + : m/z = 572.2; Found 572.3.
Table 33. The compounds in Table 33 were prepared in accordance with the synthetic protocols set forth in Example 375 using the appropriate amine starting material. Example 378.4-(1-(3-((Methylamino)methyl)-2-(trifluoromethyl)phenyl) -1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 3, using 3-fluoro-2-(trifluoromethyl)benzaldehyde instead of 3-chloro-4- fluorobenzaldehyde as the starting material for Step 1. LCMS calculated for C23H26F6N7O2S (M+H) + : m/z = 578.2; Found 578.4. Table 34. The compounds in Table 34 were prepared in accordance with the synthetic protocols set forth in Example 378 using the appropriate amine starting material.
Example 382.4-(1-(2-Methyl-6-(piperidin-1-ylmethyl)pyridin-3-yl)-1H- imidazol- 4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethy l)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 250, using 5-fluoro-6-methylpicolinaldehyde instead of 4-fluoro-3- (trifluoromethyl)benzaldehyde for Step 1 and piperidine instead of dimethylamine as the starting material for Step 2. LCMS calculated for C26H34F3N8O2S (M+H) + : m/z = 579.3; Found 579.4. Example 383.4-(5-Bromo-1-methyl-1H-imidazol-4-yl)-N-(1-((1-methyl-1H - pyrazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyr imidin-2-amine Step 1: 4-Chloro-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin- 4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Intermediate 4, using 1-methyl-1H-pyrazole-4-sulfonyl chloride instead of 1-methyl- 1H-imidazole-4-sulfonyl chloride as starting material. LCMS calculated for C14H17ClF3N6O2S (M+H) + : m/z = 425.1; Found 425.2. Step 2: 4-(1-Methyl-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-pyrazol-4- yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-a mine This compound was prepared according to the procedures described in Example 10, using 4-chloro-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin- 4- yl)-5-(trifluoromethyl)pyrimidin-2-amine instead of 4-chloro-N-(1-((1-methyl-1H- imidazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)py rimidin-2-amine as starting material. LCMS calculated for C18H22F3N8O2S (M+H) + : m/z = 471.2; Found 471.2. Step 3: 4-(5-Bromo-1-methyl-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-pyr azol-4- yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-a mine This compound was prepared according to the procedures described in Example 13, using 4-(1-methyl-1H-imidazol-4-yl)-N-(1-((1-methyl-1H-pyrazol-4- yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-a mine instead of 4-(1- methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl )-5- (trifluoromethyl)pyrimidin-2-amine as starting material. LCMS calculated for C18H21BrF3N8O2S (M+H) + : m/z = 549.1; Found 549.1.
Table 35. The compounds in Table 35 were prepared in accordance with the synthetic protocols set forth in Example 1 using the appropriate starting materials. Table 36. The compounds in Table 36 were prepared in accordance with the synthetic protocols set forth in Example 175 using the appropriate starting materials.
Table 37. The compounds in Table 37 were prepared in accordance with the synthetic protocols set forth in Example 101 using the appropriate starting materials. Example 416.4-(1-(4-(2-(Azetidin-1-yl)ethyl)-2-fluorophenyl)-2-methy l-1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 157, using 4-(1-(2-fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1 - (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (Intermediate 41) and azetidine instead of 4-(1-(2-chloro-4-iodophenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine and dimethylamine as starting material. LCMS calculated for C26H32F4N7O2S (M+H) + : m/z = 582.2; Found 582.2. Example 417.4-(1-(2-Fluoro-4-(1-methylazetidin-3-yl)phenyl)-2-methyl -1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine A mixture of 4-(1-(4-(azetidin-3-yl)-2-fluorophenyl)-2-methyl-1H-imidazol -4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine (Example 160, 19.2 mg, 0.035 mmol), formaldehyde (5.2 mg, 0.17 mmol) and acetic acid (2.0 µL, 0.035 mmol) in DCM (0.2 mL) was stirred at room temperature for 30 min. Then sodium triacetoxyborohydride (11 mg, 0.052 mmol) was added. The mixture was further stirred at room temperature for 1 h. The reaction was concentrated. The residue was then diluted with MeOH and filtered and the filtrate was 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). 1 H NMR (600 MHz, DMSO-d6, 1:1 rotamers) d 10.28 – 9.72 (m, 1H), 8.62 (m, 1H), 8.01– 7.81 (m, 1H), 7.93 (d, J = 7.5 Hz, 1H), 7.79 – 7.64 (m, 2H), 7.48 (d, J = 7.5 Hz, 1H), 4.56 – 4.39 (m, 2H), 4.36 – 4.26 (m, 1H), 4.24 – 4.15 (m, 2H), 4.02 (m, 1H), 3.62 – 3.47 (m, 2H), 3.02– 2.87 (m, 5H), 2.86 (s, 3H), 2.27 (d, J = 3.6 Hz, 3H), 2.01 – 1.92 (m, 2H), 1.59 (s, 2H). LCMS calculated for C25H30F4N7O2S (M+H) + : m/z = 568.2; Found 568.2. Example 418.4-(1-(4-(1-Ethylazetidin-3-yl)-2-fluorophenyl)-2-methyl- 1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 157, using acetaldehyde instead of formaldehyde as starting material. LCMS calculated for C26H32F4N7O2S (M+H) + : m/z = 582.2; Found 582.2. Example 419. (S)-1-(3-(3-Fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)pipe ridin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1 - yl)phenyl)azetidin-1-yl)propan-2-ol Step 1: (S)-4-(1-(4-(1-(2-((tert-Butyldimethylsilyl)oxy)propyl)azeti din-3-yl)-2- fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfony l)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 417, using (S)-2-((tert-butyldimethylsilyl)oxy)propanal instead of formaldehyde as starting material. After completion, the reaction was concentration and purified by column chromatography (DCM/MeOH 0-10% gradient). LCMS calculated for C33H48F4N7O3SSi (M+H) + : m/z = 726.3; Found 726.3. Step 2: (S)-1-(3-(3-Fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)pipe ridin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-y l)phenyl)azetidin-1- yl)propan-2-ol (S)-4-(1-(4-(1-(2-((tert-butyldimethylsilyl)oxy)propyl)azeti din-3-yl)-2- fluorophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfony l)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (20 mg, 0.027 mmol) in THF (0.14 mL) was treated with TBAF (0.05 mL, 1.0 M in THF). The mixture was further stirred at room temperature for 1 h. The reaction was concentrated. The residue was then diluted with MeOH and was 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). LCMS calculated for C27H34F4N7O3S (M+H) + : m/z = 612.2; Found 612.2. Table 38. The compounds in Table 38 were prepared in accordance with the synthetic protocols set forth in Example 419 using the appropriate starting materials.
Example 423.4-(1-(4-(2-(Dimethylamino)ethoxy)-2-fluorophenyl)-2-meth yl-1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine To a mixture of 4-(1-(2-fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)-N- (1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimi din-2-amine (Intermediate 41, 20 mg, 0.032 mmol) and 2-(dimethylamino)ethan-1-ol (5.7 mg, 0.064 mmol) in 1,4-dioxane (0.12 mL) was added [(2-di-tert-butylphosphino-3,6- dimethoxy-2¢,4¢,6¢-triisopropyl-1,1¢-biphenyl)-2-(2¢-am ino-1,1¢- biphenyl)]palladium(II) methanesulfonate (1.4 mg, 1.6 µmol) and sodium tert- butoxide (7.7 mg, 0.080 mmol). The mixture was degassed with N2 and then stirred in a sealed vial at 70 o C for 6 h. After cooling to room temperature, the reaction mixture was concentrated. The residue was then diluted with MeOH, filtered to remove Pd residues and the filtrate was 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). LCMS calculated for C25H32F4N7O3S (M+H) + : m/z = 586.2; Found 586.2. Table 39. The compounds in Table 39 were prepared in accordance with the synthetic protocols set forth in Example 423 using the appropriate starting materials. Example 427.5-(1-Isopropylazetidin-3-yl)-2-(4-(2-((1-(methylsulfonyl )piperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1 -yl)benzonitrile Step 1: 5-(Azetidin-3-yl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl )amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitri le To a mixture of zinc dust (17.20 mg, 0.263 mmol) in THF (1 mL) was added 1,2-dibromoethane (1.511 µL, 0.018 mmol) and TMSCl (2.225 µL, 0.018 mmol). The mixture was sparged with N2 and then stirred at 60 o C in a sealed vial. After 15 minutes, to the mixture was added tert-butyl 3-iodoazetidine-1-carboxylate (49.6 mg, 0.175 mmol) in N,N-dimethylacetamide (1 mL). The mixture continued to stir at 60 o C for an additional 15 minutes. After the reaction was cooled to room temperature, to the mixture was added 5-bromo-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitri le (Example 125, step 1, 100 mg, 0.175 mmol), [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (1:1) (7.2 mg, 8.8 µmol) and CuI (1.7 mg, 8.8 µmol). The mixture was purged with N2 and stirred at 80 °C overnight. After cooling to room temperature, the mixture was filtered through a short pad of celite and the filtrate was concentrated. The residue was then dissolved in DCM (0.20 mL) and treated with trifluoroacetic acid (0.40 mL). The mixture was stirred at room temperature for 30 min. The reaction was concentrated and diluted with MeOH, then was purified by prep HPLC. LCMS calculated for C24H26F3N8O2S (M+H) + : m/z = 547.2; Found 547.2. Step 2: 5-(1-isopropylazetidin-3-yl)-2-(4-(2-((1-(methylsulfonyl)pip eridin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-y l)benzonitrile A mixture of 5-(azetidin-3-yl)-2-(4-(2-((1-(methylsulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-y l)benzonitrile (10 mg, 0.018 mmol), propan-2-one (10.18 mg, 0.175 mmol) and acetic acid (2.74 µL, 0.048 mmol) in DCM (0.180 mL) was stirred at room temperature for 30 min. Then sodium triacetoxyborohydride (10.2 mg, 0.048 mmol) was added. The mixture was further stirred at room temperature for 1 h. The reaction was concentrated. The residue was then diluted with MeOH, filtered and the filtrate was 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). LCMS calculated for C27H32F3N8O2S (M+H) + : m/z = 589.2; Found 589.2. Table 40. The compounds in Table 40 were prepared in accordance with the synthetic protocols set forth in Example 427 using the appropriate starting materials.
Example 430.5-(4-Methylpiperazin-1-yl)-2-(4-(2-((1-(methylsulfonyl)p iperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-y l)benzonitrile To a mixture of 5-bromo-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitri le (Example 125, Step 1, 15 mg, 0.026 mmol) and 1-methylpiperazine (7.90 mg, 0.079 mmol) in 1,4-dioxane (0.1 mL) was added tris(dibenzylideneacetone)dipalladium(0):BINAP:sodium tert- butoxide (0.05:0.15:2 molar ratio) (13 mg). The mixture was degassed with N2 and then stirred in a sealed vial at 100 o C for 1 h. After cooling to room temperature, the reaction mixture was concentrated. The residue was then diluted with MeOH, filtered to remove Pd residue and the filtrate was 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). LCMS calculated for C26H31F3N9O2S (M+H) + : m/z = 590.2; Found 590.2. Table 41. The compounds in Table 41 were prepared in accordance with the synthetic protocols set forth in Example 430 using the appropriate starting materials. Example 433.5-(2-(Dimethylamino)ethyl)-2-(4-(2-((1-(methylsulfonyl)p iperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1 -yl)benzonitrile This compound was prepared according to the procedures described in Example 157, using 5-bromo-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitri le (Example 125, step 1) instead of 4-(1-(2-chloro-4-iodophenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine as starting material. LCMS calculated for C25H30F3N8O2S (M+H) + : m/z = 563.2; Found 563.2. Table 42. The compounds in Table 42 were prepared in accordance with the synthetic protocols set forth in Example 433 using the appropriate starting materials. Example 435.5-(2-(Dimethylamino)ethoxy)-2-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)benzonitrile This compound was prepared according to the procedures described in Example 423, using 5-bromo-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitri le (Example 125, step 1) instead of 4-(1-(2-fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)-N-(1 - (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine as starting material. LCMS calculated for C25H30F3N8O3S (M+H) + : m/z = 579.2; Found 579.2. Table 43. The compounds in Table 43 were prepared in accordance with the synthetic protocols set forth in Example 435 using the appropriate starting materials.
Example 438.4-(1-(2-Chloro-4-(1-ethylpiperidin-4-yl)phenyl)-1H-imida zol-4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyri midin-2-amine This compound was prepared according to the procedures described in Example 427, using 4-(1-(2-chloro-4-iodophenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (Intermediate 42) instead of 5-bromo-2-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzonitri le (Example 125, step 1), tert-butyl 4-iodopiperidine-1-carboxylate instead of tert-butyl 3-iodoazetidine-1- carboxylate, and acetaldehyde instead of acetone as starting material. LCMS calculated for C27H34ClF3N7O2S (M+H) + : m/z = 612.2; Found 612.2. Table 44. The compounds in Table 44 were prepared in accordance with the synthetic protocols set forth in Example 438 using the appropriate starting materials.
Example 441.3-(3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)a mino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)oxa zolidin-2-one Step 1: 4-(1-(4-(Bromomethyl)-2-chlorophenyl)-1H-imidazol-4-yl)-N-(1 - (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine To a solution of (3-chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)m ethanol (Example 231, 226 mg, 0.425 mmol) in DCM (2 mL) was added carbon tetrabromide (155 mg, 0.468 mmol) and triphenylphosphine (123 mg, 0.468 mmol) at 0 o C. The reaction was stirred at room temperature for 2 h. After concentration, the residue was purified by column chromatography (DCM/EtOAc 0-100% gradient). LCMS calculated for C21H22BrClF3N6O2S (M+H) + : m/z = 593.0; Found 593.0. Step 2: 3-(3-Chloro-4-(4-(2-((1-(methylsulfonyl)piperidin-4-yl)amino )-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)benzyl)oxa zolidin-2-one To a solution of oxazolidin-2-one (6.60 mg, 0.076 mmol) in THF (0.253 mL) was added sodium hydride (2.425 mg, 0.101 mmol). The mixture was stirred at room temperature for 5 min before 4-(1-(4-(bromomethyl)-2-chlorophenyl)-1H-imidazol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine (15 mg, 0.025 mmol) was added. The mixture was further stirred at the same temperature for 1 h. After completion, the reaction mixture was concentrated. The residue was then diluted with MeOH 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). LCMS calculated for C24H26ClF3N7O4S (M+H) + : m/z = 600.1; Found 600.1. Example 442.4-(1-(2-Bromophenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine
Step 1: 4-(1-(4-Amino-2-bromophenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine This compound was prepared according to the procedures described in Intermediate 41 using 4-(2-methyl-1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin - 4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 2) instead of 4-(2-methyl- 1H-imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Intermediate 38) and 1-fluoro-2-bromo-4- nitrobenzene instead of 1,2-difluoro-4-nitrobenzene as starting material. LCMS calculated for C20H22BrF3N7O2S (M+H) + : m/z = 560.1; Found 560.1. Step 2: 4-(1-(2-Bromophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl) piperidin-4- yl)-5-(trifluoromethyl)pyrimidin-2-amine To 4-(1-(4-amino-2-bromophenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine (359 mg, 0.64 mmol) was added HCl (2.0M aq. solution, 4.0 mL) and sodium nitrite (221 mg, 3.20 mmol) at 0 o C. After stirring for 5 min, sodium hypophosphite monohydrate (200 mg, 1.921 mmol) was added and the mixture was stirred at room temperature for 30 min. The reaction was quenched by sodium bicarbonate solution and Na2S2O3 solution and extracted with DCM three times. The combined organic layers were dried over MgSO4, filtered, and concentrated. A small fraction of residue was then diluted with MeOH 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). LCMS calculated for C 20 H 21 BrF 3 N 6 O 2 S (M+H) + : m/z = 545.1; Found 545.1. Table 45. The compounds in Table 45 were prepared in accordance with the synthetic protocols set forth in Example 175 using the appropriate amine starting material.
Table 46. The compounds in Table 46 were prepared in accordance with the synthetic protocols set forth in Example 441 using the appropriate starting materials.
Table 47. The compounds in Table 47 were prepared in accordance with the synthetic protocols set forth in Example 101 using the appropriate starting materials.
Table 48. The compounds in Table 48 were prepared in accordance with the synthetic protocols set forth in Example 433 using the appropriate starting materials. Example 459.4-(1-(4-(3-(Azetidin-1-yl)propyl)-2-fluorophenyl)-2-meth yl-1H- imidazol-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine
Step 1: 3-(3-Fluoro-4-(2-methyl-4-(2-((1-(methylsulfonyl)piperidin-4 -yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1H-imidazol-1-yl)phenyl)pro panal To a mixture of 4-(1-(2-fluoro-4-iodophenyl)-2-methyl-1H-imidazol-4-yl)-N- (1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimi din-2-amine (106 mg, 0.170 mmol) and prop-2-en-1-ol (14.8 mg, 0.255 mmol) in DMF (0.42 ml) was added benzyltriethylammonium chloride (38.7 mg, 0.170 mmol), sodium bicarbonate (35.7 mg, 0.424 mmol) and palladium(II) acetate (1.9 mg, 8.5 µmol). The mixture was degassed with N2 and then stirred in a sealed vial at 55 °C overnight. After cooling to room temperature, the reaction mixture was concentrated. The product was purified by column chromatography (eluting with DCM/EtOAc, 0-100% followed by DCM/MeOH, 0-10%). LCMS calculated for C24H27F4N6O3S (M+H) + : m/z = 555.2; Found 555.2. Step 2: 4-(1-(4-(3-(Azetidin-1-yl)propyl)-2-fluorophenyl)-2-methyl-1 H-imidazol-4-yl)- N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyri midin-2-amine This compound was prepared according to the procedures described in Example 157, Step 3, using 3-(3-fluoro-4-(2-methyl-4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)phenyl)propanal instead of 2-(3-chloro-4-(4-(2-((1- (methylsulfonyl)piperidin-4-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-1H- imidazol-1-yl)phenyl)acetaldehyde (Example 157, step 2) and azetidine instead of dimethylamine as starting material. LCMS calculated for C27H34F4N7O2S (M+H) + : m/z = 596.2; Found 596.2. Table 49. The compound in Table 49 was prepared in accordance with the synthetic protocols set forth in Example 423 using the appropriate starting materials. Example 461.4-(2-Bromo-1-(2-fluorophenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine Step 1: 4-(1-(2-Fluorophenyl)-1H-imidazol-4-yl)-N-(1-(methylsulfonyl )piperidin-4- yl)-5-(trifluoromethyl)pyrimidin-2-amine This compound was prepared according to the procedures described in Example 442 using 1,2-difluoro-4-nitrobenzene instead of 1-fluoro-2-bromo-4- nitrobenzene as starting material. LCMS calculated for C20H21F4N6O2S (M+H) + : m/z = 485.1; Found 485.1. Step 2: 4-(2-Bromo-1-(2-fluorophenyl)-1H-imidazol-4-yl)-N-(1- (methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin -2-amine To a solution of diisopropylamine (0.17 mL, 1.2 mmol) in 3 mL THF at -78 °C was added n-BuLi in hexanes (0.69 mL,1.6 M, 1.1 mmol) and the mixture stirred 1 min at -78 °C. To the LDA solution was added 4-(1-(2-fluorophenyl)-1H-imidazol-4- yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine (219 mg, 0.452 mmol) in THF (3 mL) at -78 o C and the mixture was stirred at -78 o C for more than 30 min. To the mixture was then added carbon tetrabromide (600 mg, 1.808 mmol) in THF (4 mL) and the mixture was slowly warmed up to room temperature. Then the reaction mixture was concentrated. A small fraction of residue was then diluted with MeOH 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). LCMS calculated for C20H20BrF4N6O2S (M+H) + : m/z = 563.0; Found 563.0. Table 50. The compounds in Table 50 were prepared in accordance with the synthetic protocols set forth in Example 77 using the appropriate amine starting material. Table 51. The compounds in Table 51 were prepared in accordance with the synthetic protocols set forth in Example 369 using the appropriate amine starting material.
Table 52. The compounds in Table 52 were prepared in accordance with the synthetic protocols set forth in Example 375 using the appropriate amine starting material.
Table 53. The compounds in Table 53 were prepared in accordance with the synthetic protocols set forth in Example 378 using the appropriate amine starting material. Table 54. The compounds in Table 54 were prepared in accordance with the synthetic protocols set forth in Example 1 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 MgCl2, 2 mM DTT, 0.05mg/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 IC 50 for each compound. The IC 50 data as measured for the compounds of the Examples at 1 mM ATP in the assay of Example A is shown in Table 55. Table 55
+ refers to £ 50 nM ++ refers to >50 nM to 200 nM +++ refers to >200 nM to 500 nM ++++ refers to >500 nM to 1000 nM Example B1. Characterization of cyclin E1 in ovarian and endometrial cancer cell lines The cyclin E1 (“CCNE1”) gene was evaluated in various ovarian and endometrial cancer cell lines (FIGs.1A and 1B). CCNE1 was amplified in COV318, OVCAR3 OVARY, Fu-OV1, and KLE cells, each of which displayed a CCNE1 gain of function by copy number (copy number (“CN”) > 2) (FIG.1A). In contrast, CCNE1 was not amplified in COV504, OV56, or Igrov1 cells, each of which displayed copy neutral (2) or loss of function of the gene (CN £ 2). CN was obtained from the Broad Institute Cancer Cell Line Encyclopedia (“CCLE”) database (Barretina, et al., Nature, 2012, 483(7391):603-7, which is incorporated herein by reference in its entirety). Western blot analysis was performed on protein samples from COV318, OVCAR3_OVARY, Fu-OV1, KLE, COV504, OV56, and Igrov1 cells to evaluate CCNE1 protein levels. CCNE1 protein levels were higher in cell lines with CCNE1 gain of function by copy number (CN > 2; i.e., COV318, OVCAR3 OVARY, Fu- OV1, and KLE cells) compared to cell lines with copy neutral or loss of function of the gene (CN £ 2; i.e., COV504, OV56, and Igrov1 cells). Example B2. CDK2-knockdown by siRNA inhibits proliferation in CCNE1- amplified, but not CCNE1-non-amplified human cancer cell lines The effect of CDK2-knockdown in CCNE1-amplified versus CCNE1-non- amplified cell lines was evaluated. CCNE1-amplified cell lines (Fu-OV1 and KLE) or CCNE1-non-amplified cell lines (COV504 and Igrov1) were treated with a control (“ctrl”) or CDK2-specific small interfering RNAs (“siRNAs”) (“CDK2 siRNA-1” and “CDK2 siRNA-2”) (FIGs.2A and 2B and 3A and 3B). Seventy-two hours after transfection with the siRNAs, the cells were harvested and subjected to cell cycle analysis by fluorescence activated cell sorting (“FACS”) (FIGs.2A and 3A). Knockdown of CDK2 was confirmed by western blot (FIGs.2B and 3B). CDK2- knockdown inhibited proliferation in CCNE1-amplified cell lines, but not in CCNE1- non-amplified cell lines (FIGs.2A and 3A). A similar experiment was performed in additional CCNE1-amplified cell lines (COV318, OVCAR3, Fu-OV1, and KLE) and CCNE1-non-amplified cell lines (COV504, OV56, and Igrov1) (FIG.4). The percentage of cells at the S phase three days after treatment with CDK2-specific siRNAs was significantly decreased in CCNE1-amplified cell lines as compared to treatment with control siRNA (FIG.4). Consistent with the results of FIGs.2A and 3A, the percentage of cells at the S phase three days after treatment with CDK2-specific siRNAs was not significantly different in CCNE1-non-amplified cell lines as compared to treatment with control siRNA (FIG.4). Example B3. Proliferation in CCNE1 amplified and CCNE-non-amplified cell lines upon CDK4/6 inhibition The effect of CDK4/6-inhibition in CCNE1-amplified versus CCNE1-non- amplified cell lines was evaluated. CCNE1-amplified cells (OVCAR3) or CCNE1- non-amplified cells (COV504) were treated with dimethyl sulfoxide (“DMSO”) control or increasing concentrations of CDK4/6 inhibitor palbociclib (FIG.5). Sixteen hours after treatment with DMSO or palbociclib, the cells were harvested and subjected to cell cycle analysis by FACS (FIG.5). CDK4/6-inhibition resulted in dose-dependent inhibition of the proliferation in CCNE1-non-amplified cells, but not in CCNE1-amplified cells (FIG.5). A similar experiment was performed in a larger set of CCNE1-amplified cell lines (COV318 and OVCAR3) and CCNE1-non-amplified cell lines (COV504, OV56, and Igrov1) (FIG.6). The percentage of cells at the S phase 16 hours after treatment with palbociclib was decreased in CCNE1-non-amplified cell lines in a dose-dependent fashion as compared to treatment with DMSO (FIG.6). Consistent with the results of FIG.5, the percentage of cells at the S phase 16 hours after treatment with palbociclib was not significantly different in CCNE1-amplified cell lines as compared to treatment with DMSO (FIG.6). Example B4. CDK2-knockdown blocks Rb phosphorylation at S780 in CCNE1- amplified, but not in CCNE1-non-amplified, cell lines The effect of CDK2-knockdown on Rb phosphorylation at Ser-780 of SEQ ID NO:3 (“S780”) in CCNE1-amplified versus CCNE1-non-amplified cell lines was evaluated. CCNE1-amplified cell lines (COV318, Fu-OV1 and KLE) or CCNE1- non-amplified cell lines (COV504, OV56 and Igrov1) were treated with ctrl or CDK2-specific siRNAs (FIGs.7A and 7B). 72 hours after transfection with the siRNAs, the cells were harvested and total protein was extracted and analyzed by western blot. Knockdown of CDK2 was confirmed by western blot. CDK2- knockdown blocked Rb phosphorylation at S780 in CCNE1-amplified cell lines (FIG. 7A), but not in CCNE1-non-amplified cell lines (FIG.7B). Example B5. Palbociclib blocks Rb phosphorylation at S780 in CCNE1 non- amplified, but not in CCNE1-amplified, cell lines The effect of CDK4/6-inhibition on Rb phosphorylation at S780 in CCNE1- amplified versus CCNE1-non-amplified cell lines was evaluated. CCNE1-amplified cell lines (OVCAR3 and COV318) or CCNE1-non-amplified cell lines (COV504 and OV56) were treated with DMSO or various doses of palbociclib (FIGs.8A and 8B). One or 15 hours after treatment, the cells were harvested and total protein was extracted and analyzed by western blot (FIG.8). Palbociclib treatment blocked Rb phosphorylation at S780 in CCNE1-non-amplified cell lines (FIG.8B), but not in CCNE1-amplified cell lines (FIG.8A). Example B6. CDK2 degradation by dTAG decreases Rb phosphorylation at S780 To further confirm that CDK2 knockdown decreases Rb phosphorylation at S780 in CCNE1-amplified cells (see Example B4), the dTAG system was used to degrade CDK2 and the level of S780-phosphorylated Rb was evaluated (Erb et al., Nature, 2017, 543(7644):270-274, which is incorporated herein by reference in its entirety). Briefly, OVCAR3 cells were engineered to express Cas9 by lentiviral transduction of Cas9 construct. The OVCAR3-Cas9 cells were then engineered to express CDK2-FKBP12F36V-HA fusion protein by lentiviral transduction of CDK2- FKBP12F36V-HA expression construct. Next, to engineer the line to have endogenous CDK2 inactivated, OVCAR3 (Cas9, CDK2-FKBP12F36V-HA) cells were transduced with CDK2 sgRNA (“CDK2-gRNA”); OVCAR3 (Cas9, CDK2- FKBP12F36V-HA) cells transduced with non-targeting sgRNA (“Ctl-gRNA”; Cellecta) served as a control cell line. To degrade CDK2-FKBP12F36V-HA protein by dTAG (FIG.9A), cells were treated with DMSO or with a titration of concentrations of dTAG for 14 hours. Cells were collected and processed for Western blot (FIG.9B). A dose-responsive degradation of CDK2-FKBP12(F36V) was detected by western blot after treatment with dTAG in both control- and CDK2-gRNA treated cells (FIG.9B). Degradation was further confirmed by western blot for HA-Tag. Endogenous CDK2 protein was detected in OVCAR3 cells treated with control gRNA, but not with CDK2-gRNA (FIG.9B). CDK2-FKBP12(F36V) degradation inhibited Rb phosphorylation at S780 in CDK2 knockout OVCAR3 cells, but not in OVCAR3 cells with endogenous CDK2 expression. Example B7. p-Rb S780 HTRF cellular Assay for identification of CDK2 inhibitors An in vitro CDK2/CCNE1 enzyme activity assay was used to measure phosphorylation of a peptide substrate using homogenous time-resolved energy transfer (“HTRF”). First, the specificity of 8-((1R,2R)-2-hydroxy-2- methylcyclopentyl)-2-((1-(methylsulfonyl)piperidin-4-yl)amin o)pyrido[2,3- d]pyrimidin-7(8H)-one (Compound A; see US Patent Application Publication No. 2018/0044344 at page 51, paragraph [0987], which is incorporated by reference herein in its entirety) for CDK2 inhibition was confirmed via a kinase activity assay (FIG.10A). To this end, the LANCE® Ultra kinase assay was used with a ULight™- labeled EIF4E-binding protein 1 (Thr37/46) peptide (PerkinElmer, TRF0128-M) as substrate and an Europium-labeled anti-phospho-EIF4E binding protein1 (Thr37/46) antibody (PerkinElmer, TRF0216-M). A ratio of fluorescence transferred to the labeled substrate (665 nm) relative to fluorescence of the Europium donor (620 nm) represents the extent of phosphorylation. The IC 50 for Compound A was determined to be 1.1 nM (FIG.10A). In contrast, the IC 50 for the CDK4/6 inhibitor palbociclib was 10,000 nM (FIG.10A). Next, a CDK2 pRb (S780) HTRF cellular assay was performed, enabling the quantitative detection of Rb phosphorylated on serine 780 in CCNE1 amplified COV318 cells upon treatment with Compound A or palbociclib (FIG.10B). Treatment with Compound A, but not palbociclib, inhibited Rb phosphorylation on serine 780 in CCNE1 amplified cells (FIG.10B). The IC 50 for Compound A in this assay was 37 nM, while the IC 50 for palbociclib was > 3,000 nM (FIG.10B). Compound A Example B8. Bioinformatics analysis of CCLE dataset reveals the sensitivity to CDK2 inhibition in CCNE1 amplified cells relies on functional p16 In an attempt to identify a biomarker for predicting sensitivity to CDK2- inhibition in CCNE1-amplified cells, 460 cell lines from CCLE were analyzed (Barretina, supra). First, the cell lines were filtered based on CCNE1 copy number and expression and CDK2 sensitive score based on shRNA knockdown data. A total of 41 cell lines were identified as having CCNE1 copy number of > 3 and CCNE1 expression score (CCLE: > 3). Of these 41 cell lines, 18 (44%) were sensitive to CDK2 inhibition (CDK2 sensitive score £-3), while 23 (56%) were insensitive to CDK2 inhibition (CDK2 sensitive score >-3). Next, the p16 status was evaluated in the CDK2-sensitive and CDK2- insensitive cell lines (FIG.11). Of the 18 cell lines that were sensitive to CDK2- inhibition, 100% expressed normal p16 gene (FIG.11). In contrast, only 4 of the 23 CDK2-insensitive cell lines expressed normal p16 gene (FIG.11). The majority of the 23 CDK2-insensitive cell lines displayed dysfunctional p16 gene expression: the p16 gene was deleted in 10 of 23 cell lines; the p16 gene was silenced in 5 of the 23 cell lines, and the p16 gene was mutated in 4 of the 23 cell lines (FIG.11). A summary of CDK2 sensitivity and CDKN2A/p16 status in CCNE1 amplified cell lines is provided in Table 56, below.
Table 56. Cell lines with CDK2 sensitive Score £ 3 counted as CDK2 Sensitive lines; ³3 as CDK2 insensitive line. Cell lines verified in experiments are in bold. NCIN87_STOMACH showed no CDKN2A/P16 protein expression in western blot. CCNE1 and CDKN2A/P16 copy number were calculated based on CCLE dataset. Expression Score <0 counted as gene silencing.
Example B9. CCNE1 amplified cells with dysfunctional p16 do not respond to CDK2 inhibition To further evaluate the role of p16 in CDK2-sensitivity in CCNE1-amplified cells, p16 protein expression in three gastric cell lines with CCNE1-amplification was evaluated by western blot. AGS and NCI-N87 cells displayed absent or dramatically reduced levels of p16 (FIG.12A). In contrast, p16 protein was detected in MKN1 cellular protein extracts (FIG.12A). Next, the impact of CDK2-knockdown in these cells was evaluated. Mkn1, Ags, and NCI-N87 cells were treated with control or CDK2-specific siRNA. Three days-post-siRNA transfection, cell cycle phase distribution of the cells was evaluated by FACS. The percentage of cells at the S phase in the Mkn1 cells (CCNE1- amplified, p16 protein detected) was significantly decreased in the CDK2 siRNA- treated cells as compared to control (FIG.12B). In contrast, the percentage of cells at the S phase was not significantly decreased in Ags and NCI-N87 cells (CCNE1- amplified, dysfunctional p16 protein levels) after treatment with CDK2 siRNA as compared to control (FIG.12B). Example B10. p16 knockdown by siRNA abolishes CDK2 inhibition induced cell cycle suppression in CCNE1 amplified cells To confirm the role of p16 in CDK2-sensitivity of CCNE1-amplified cells, COV318 cells were treated with control or p16-specifict siRNA. Seventy-two hours after transfection, cells were treated with DMSO (control) or 100 nM of Compound A. Sixteen hours after treatment with DMSO or the CDK2-inhibitor, cells were harvested and subjected to cell cycle analysis by FACS. Consistent with the results described above, the percentage of S phase cells significantly decreased in the control siRNA-treated cells treated with CDK2-inhibitor (Compound A), but not with the DMSO control (FIG.13). In contrast, the percentage of S phase cells was not significantly decreased after treatment with the CDK2-inhibitor (Compound A) in p16 knocked down cells as compared to DMSO control (FIG.13). Materials and Methods used in Examples B1-B10 Cell culture and transfection Human cyclin E1 (CCNE1) amplified ovarian cell lines OVCAR3, COV318, Fu-OV1, endometrial cell line KLE, gastric cell lines MKN1, AGS, NCIN87, and CCNE1 non-amplified ovarian cell lines COV504, OV56, Igrov1 were cultured in RPMI 1640 medium. The complete growth medium was supplemented with 10% FBS, 0.1 mM non-essential amino acids, 2 mM L-glutamine, 100 units/mL penicillin G and 100 mg/mL streptomycin in 37° C humidified incubator and an atmosphere of 5% CO2 in air. Fu-OV1 line was purchased from Leibniz-Institute DSMZ –German Collection of Microorganisms and Cell Cultures; MKN1 was purchased from Japanese Cancer Research Resources Bank; and the rest of cell lines were purchased from American Type Culture Collection. For transfection, cells were seeded into 6- well for 24 hours and transiently transfected by Lipofectamine 2000 Reagent (Thermo Fisher, 11668027). ON-TARGETplus Human CKD2 siRNAs (GE Healthcare Dharmacon, J-003236-11-0002 and J-003236-12-0002) and ON-TARGETplus Human CDKN2A/p16 siRNAs (GE Healthcare Dharmacon, J-011007-08-0002) were used to knockdown the endogenous CDK2 and CDKN2A/p16. ON-TARGETplus Non-targeting Pool (GE Healthcare Dharmacon, D-001810-10-20) was used as a negative control. Western blot analysis Whole cell extracts were prepared using RIPA buffer (Thermo Scientific, 89900) with a Halt Protease and Phosphatase Inhibitor Cocktail (Thermo Scientific, 78440). Protein concentration was quantified with a BCA Protein Assay Kit (Thermo Scientific, 23225) and 40 mg of protein lysates were loaded for SDS–PAGE using precast gradient gels (Bio-Rad, Hercules, No.456-1094). Samples were diluted in 5X Laemmli buffer (300 mM Tris-HCl pH 6.8, 10% SDS (w/v), 5% 2-mercaptoethanol, 25% glycerol (v/v),0.1% bromophenol blue w/v) and boiled for 5 minutes.35 mg of proteins were separated by 8–15%SDS-PAGE and transferred onto polyvinylidene fluoride (PVDF) membranes. Unspecific binding sites on the PVDF membranes were blocked with 5% non-fat milk in TBST (20 mM Tris-HCl, pH 7.6, 137 mM NaCl, 1% Tween-20). Membranes were hybridized with antibodies against anti-CDKN2A/p16 (Cell Signaling Technology, 92803S), anti-Cas9 (Cell Signaling Technology, 97982S), anti-HA (Cell Signaling Technology, 3724S), anti-Rb (Cell Signaling Technology, 9309S), anti-phospho-Rb (Ser780) (Cell Signaling Technology, 8180S), anti-CDK2 (Cell Signaling Technology, 2546S), anti-CCNE1 (Cell Signaling Technology, 20808S) and anti-GAPDH (Cell Signaling Technology, 8884S) for overnight at 4° C, followed by incubation with horseradish peroxidase(HRP)-conjugated secondary antibodies for 1 hour at room temperature. The membranes were then developed using Immobilon Western chemiluminescence HRP substrates (Millipore, WBKLS0500). Images were captured by Luminescence/Fluorescence Imaging System Odyssey CLx Imager (LI-COR). Cell cycle analysis Cells were seeded in six-well tissue culture plates and 24 hours later were treated with a titration of concentrations of Palbociclib or Compound A. After overnight treatment, cells exposed to 10 mM EdU for 3 hours before detection of EdU-DNA by Click-iT AlexaFluor® 647 azide kit (Life Technology, C10424) following the manufacturer's instructions. Bulk DNA was stained with DAPI. Compound-treated and DMSO treated control cells were acquired with CytoFlex (Beckman Coulter) and were analyzed using the FlowJo software. For cell cycle analysis of cells with siRNA knockdown, 72 hours after siRNA transfection, cells exposed to 10 mM EdU for 3 hours before detection of Click-iT Alexa Fluor® 647 azide kit. Plasmids LentiCas9 plasmid pRCCH-CMV-Cas9-2A (Cellecta, SVC9-PS) was used for Cas9 expression. sgRNA-CDK2 lentiviral construct, designed to target AAGCAGAGATCTCTCGGA (SEQ ID NO:8) of CDK2, was cloned into sgRNA expression vector pRSG-U6 and purchased from Cellecta (93661). For CDK2- FKBP12F36V-HA expression, a 1306 base pair DNA fragment encoding CDK2 and FKBP12F36V-2xHA tag at the C-terminus was synthesized and cloned into EcoRI and BamHI digested pCDH-EF1a-MCS-T2A-Puro lentivector (Systembio, CD527A- 1). Sequence of 1306 bp DNA fragment: GAATTC (SEQ ID NO:5; EcoRI), GGATCC (SEQ ID NO:6; BamHI) and TTCGAA (SEQ ID NO:7; BstBI) restriction enzyme sites were underlined. Sequence encoding CDK2 is in bold and sequence of FKBP12F36V-HA is in italics. Three nucleic acids underlined within the CDK2 sequence indicated modifications that abolished PAM sites to avoided CRISPR knockout effect. These changes did not change amino acids encoded. Lentivirus production Production of lentivirus was performed in 293T cells by co-transfection of Lentiviral Packaging Mix (Sigma, SHP001), and a given lentiviral expression plasmid using Lipofectamine 2000. Viral supernatants were collected 48 and 72 hours after transfection, filtered through a 0.22 µm membrane. All cells lines were transduced by spinoculation at 2000 revolutions per minute (rpm) for 1 hour at room temperature with 8 µg/mL polybrene (Santa Cruz, sc-134220). CDK2-dTAG cells OVCAR3 cells were first engineered to express Cas9 by lentiviral transduction of Cas9 construct. Cells were selected and maintained in 100 µg/mL hygromycin (Life Technologies, 10687010) and verified to express Cas9 by immunoblot. OVCAR3-Cas9 cells were then engineered to express CDK2-FKBP12F36V-HA fusion protein by lentiviral transduction of CDK2- FKBP12F36V-HA expression construct and selection with 2 µg/mL puromycin dihydrochloride (Life Technologies, A1113803). Expression of CDK2- FKBP12F36V-HA was verified by immunoblot using anti-CDK2 and anti-HA antibodies. Next, to engineer the line to have endogenous CDK2 inactivated, OVCAR3 (Cas9, CDK2-FKBP12F36V-HA) cells were transduced with CDK2 sgRNA and selected by 50 µg/mL Zeocin (Life Technologies, R25001). Inactivated expression of endogenous CDK2 in the expanded clones was tested by immunoblotting. OVCAR3 (Cas9, CDK2-FKBP12F36V-HA) cells transduced with non-targeting sgRNA (Cellecta) were served as a control cell line. To degrade CDK2-FKBP12F36V-HA protein by dTAG, 200,000 cells were seeded in 1 mL media in triplicate in a 24-well plate and treated with dimethyl sulfoxide (DMSO) or with a titration of concentrations of dTAG for 14 hours. Cells were collected and processed for Western blot. CDK2 / CCNE1 enzymatic assay In vitro CDK2/CCNE1 enzyme activity assay measures phosphorylation of a peptide substrate using homogeneous time-resolved energy transfer (HTRF). The LANCE® Ultra kinase assay used a ULight™-labeled EIF4E-binding protein 1 (Thr37/46) peptide (PerkinElmer, TRF0128-M) as substrate and an Europium-labeled anti-phospho-EIF4E binding protein1 (Thr37/46) antibody (PerkinElmer, TRF0216- M). A ratio of fluorescence transferred to the labeled substrate (665 nm) relative to fluorescence of the Europium donor (620 nm) represents the extent of phosphorylation. Ratios for treated wells are normalized to DMSO only (100% activity) and no enzyme (0% activity) controls. Normalized data is analyzed using a four parameter dose response curve to determine IC 50 for each compound. CDK2 pRb (S780) HTRF cellular Assay CDK2 pRb (S780) HTRF cellular assay enables the quantitative detection of Rb phosphorylated on serine 780 in CCNE1 amplified COV318 cells. The assay comprised two antibodies: Europium cryptate labeled anti-Phospho-Rb S780 antibody (donor) and d2 labeled anti-Rb antibody (acceptor). In brief, COV318 cells were seeded into the wells of 96-well plate at a density of 25,000 per well with 9-point, 3- fold serial diluted compounds and cultured overnight at 37 degree with 5% CO2. The final concentrations of compounds start from 3 µM. The next day cells were lysed in 70 µL 1X Phospho-total protein lysis buffer #2 (Cisbio), supplemented with 0.7 µL blocking buffer (Cisbio) and 1.4 µL protease inhibitor cocktail set III, EDTA-free (Calbiochem, 539134).16 µL of cell lysates were mixed with 4 µL of the fluorophore-conjugated antibodies to a final concentration of 0.188 nM cryptate- labeled anti-Phospho-Rb S780 antibody and 0.14 nM d2 labeled anti-Rb antibody. After 2h of incubation at room temperature, HTRF signals were measured on the PHERAstar microplate reader (BMG Labtech), using 340 nm as excitation wavelength, a 620 nm filter for the Europium donor fluorescence, and a 665-nm filter for the acceptor fluorescence detection. HTRF signals were calculated as the HTRF ratio (ratio of fluorescence measured at 665 nm and 620 nm) × 10000. 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.