Compositions comprising USP1 inhibitors and methods of using the same

Abstract

The subject matter described herein relates to compositions comprising Ubiquitin- Specific Protease 1 (USP1) inhibitors and methods of using the same.

Description

x xOMPOSITIONS COMPRISING USP1 INHIBITORS AND METHODS OF USING THE SAME CROSS-REFERENCE TO RELATED APPLICATION This application claims priority to U.S. Provisional Application No.63 / 610,860 filed December 15, 2023, the contents of which are incorporated herein by reference in their entirety. TECHNICAL FIELD The subject matter described herein relates to compositions comprising Ubiquitin- Specific Protease 1 (USP1) inhibitors and methods of using the same. BACKGROUND The USP1 gene encodes a deubiquitinase that is directly involved in DNA damage repair by regulating the ubiquitination of key regulators like PCNA and FANCD2. Overexpression of USP1 is commonly observed in osteosarcoma, colorectal, non-small cell lung, and gastric cancers, and blockade of USP1 induces apoptosis in many cancers. Moreover, several USP1 inhibitors sensitize cancer cells to platinum-, DNA-damaging-, and radiation-induced death. Given the well-established role USP1 as a selective anti-cancer target for inhibition, there remains a need in the art for new USP1 inhibitors for use in the treatment of such cancers. SUMMARY OF THE INVENTION In certain aspects, the compositions and methods described herein relate to compositions comprising USP1 inhibitors and methods of their use in treating disease, e.g., cancer. In certain embodiments, the compositions and methods described herein relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof:wherein:R1is selected from C3-C8 cycloalkyl ring, C6-C10aryl, or 4-, 5-, 6-, or 7- membered heterocyclyl ring, and C6-C10aryl fused with 3-8 membered heterocyclic group; wherein R1is optionally substituted with one or more groups selected from - OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, -OCD3, C1-6haloalkoxy, C1-6hydroxyalkyl, C6-10aryl, 5-8 membered heteroaryl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, -O-C1-6alkyl, -O-C1-6alkylene, -O-C1-6haloalkyl, -NH-C1-6alkyl, and -NH-C3-8cycloalkyl, wherein the C6-10aryl, 5-8 membered heteroaryl, C3-8 cycloalkyl, and 3-8 membered heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of -OH, - COOH, -NH2, -CN, halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6hydroxyalkyl; R2is selected from:, , , and ; R3is selected from H, D, -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6hydroxyalkyl; Z, U, V, W, P, Q, S, and T are independently selected from C, O, N, and S; wherein Z, U, V, W, P, Q, S, and T are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8cycloalkyl ring; wherein when R2is , the phenyl ring is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8cycloalkyl ring;wherein when R2is , the 5- or 6-membered ring is saturated or unsaturated;wherein when R2is , the 5-membered ring is saturated or unsaturated;wherein when R2is , is saturated or unsaturated; X1is selected from C and N; X2is selected from C and N; wherein when X2is C, the said C is optionally substituted with hydrogen, halogen, -CN, -OR4, -SR4, -N(R5)2, C1-6alkyl, C1-6haloalkyl, wherein R4and R5are independently selected from C1-C6alkyl; and Ring A is a C6-C8 cycloalkyl ring, C6-C10aryl, or 4-, 5-, 6-, or 7- membered heterocyclyl ring; wherein the said ring A is optionally substituted with one or more groups selected from -OH, -COOH, -C(O)-, -NH2, -(NH)-, =O, =NH, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and -C1-6alkyl-epoxide; wherein the said -C(O)- is optionally substituted with H, -OH, NH2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl; wherein the said –(NH)- is optionally substituted with one or more groups selected from H, C1-6alkyl, C1-6nitrile, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, and C1-6alkyl-epoxide; wherein the said C1-6alkyl-epoxide is optionally substituted with one or more C1-6alkyl.wherein when ring A contains ring carbon atoms and one or more heteroatoms, the heteroatoms are selected from N and S; wherein when ring A is a 5-membered heterocyclyl ring and contains one heteroatomselected from N, ring A is selected from , , and ;wherein when ring A is and R2is , V and W are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl and C3-C8cycloalkyl ring;wherein when ring A is and Z is O, ring A is optionally substituted with one or more groups selected from -OH, -COOH, -C(O)-, -NH2, -(NH)-, =O, =NH, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and -C1-6alkyl-epoxide; wherein the said -C(O)- is optionally substituted with H, -OH, NH2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl; wherein the said –(NH)- is optionally substituted with one or more groups selected from H, C1-6alkyl, C1-6nitrile, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, and C1-6alkyl-epoxide; wherein the said C1-6alkyl-epoxide is optionally substituted with one or more C1-6alkyl. wherein when ring A is a 5-membered heteroc cl l rin and at least one heteroatom is S, ring A is selected from, , or , where Z is N;wherein when ring A is selected from or , Z is N, and R2iswhere S and P are N, wherein:(i) when S or P are substituted with C1 alkyl then R1is C6-C10aryl; (ii) S or P are substituted with one or more groups selected from -OH, -COOH, - NH2, -CN, -CD(CD3)2, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl; or (iii) V or W are substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6h droxyalkyl, and C3-C8 cycloalkyl ring;wherein when ring A is and Z is N, R1is selected from C3-C8 cycloalkyl ring, 4-, 5-, 6-, or 7- membered heterocyclyl ring, and C6-C10aryl fused with 3-8 membered heterocyclic group; wherein when ring A is a 5-membered heterocyclyl ring and contains twoheteroatoms selected from N, ring A is selected from , , , andwherein when ring A isor , Z is O, and R2iswhere S and P are N, S and P are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring;wherein when ring A is or , Z is O, and R2iswhere Q and P are N, S is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6haloalkoxy C1-6hydroxyalkyl, and C3-C8cycloalkyl ring;wherein when ring A is and Z is O, S and P are optionally substituted with one or more groups selected from OH COOH NH2CN CD(CD3)2halogenC3-6alkyl, C2-6alkynyl, C1-6haloalkyl, C2-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C4-C8 cycloalkyl ring; wherein when ring A is a 6-membered heterocyclyl ring and contains one or twoheteroatoms selected from N, ring A is selected from , , ,, , , , and ; wherein when ring A is, or , Z is O; wherein when ring A is, , or , Z is O and R2is, P and S are substituted with one or more groups selected from - OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C3-6 alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C4-C8 cycloalkyl ring; wherein when ring A is, Z is N and ring A is optionally substituted with one or more groups selected from -COOH, -NH2, -(NH)-, =O, =NH, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and -C1-6alkyl-epoxide. In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R1is selected from C3-C8cycloalkyl ring, C6-C10aryl, or 4-, 5-, 6-, or 7- membered heterocyclyl ring, and C6-C10aryl fused with 3-8 membered heterocyclic group; and wherein R1is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, -OCD3, C1-6haloalkoxy, C1-6hydroxyalkyl, C6-10aryl, 5-8 membered heteroaryl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, -O-C1-6alkyl, -O- C1-6alkylene, -O-C1-6haloalkyl, -NH-C1-6alkyl, and -NH-C3-8cycloalkyl, wherein the C6-10aryl, 5-8 membered heteroaryl, C3-8cycloalkyl, and 3-8 membered heterocyclyl are eachindependently optionally substituted with one or more substituents selected from the group consisting of -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6hydroxyalkyl. In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R1is selected from C6aryl, 5- or 6-memered heterocyclic ring and C6aryl fused with 5-membered heterocyclic group; and wherein R1is optionally substituted with one or more groups selected from -OH, -COOH, - NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, -OCD3, C1-6haloalkoxy, C1-6hydroxyalkyl, C6-10aryl, 5-8 membered heteroaryl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, -O-C1-6alkyl, -O-C1-6alkylene, -O-C1-6haloalkyl, -NH-C1-6alkyl, and -NH-C3-8cycloalkyl, wherein the C6-10aryl, 5-8 membered heteroaryl, C3-8cycloalkyl, and 3-8 membered heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6hydroxyalkyl. In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R1is selected from:In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein when R2is, , , and ; and R3is selected from H, D, -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6hydroxyalkyl; Z, U, V, W, P, Q, S, and T are independently selected from C, O, N, and S, wherein Z, U, V, W, P, Q, S, and T are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C1- 6 alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8cycloalkyl ring; wherein when R2is , the phenyl ring is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring; wherein when R2is , the 5- or 6-membered ring issaturated or unsaturated; wherein when R2is , the 5-membered ring issaturated or unsaturated; wherein when R2is , wherein is saturated or unsaturated. In certain embodiments, the present disclosure is directed to a compound of formula(I), or a pharmaceutically acceptable salt thereof:wherein R2is , Z is selected from C, O, N, and S; and R3is selected from H, D, -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6hydroxyalkyl; wherein the phenyl ring is optionally substituted with one or more groups selected from - OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8cycloalkyl ring. In certain embodiments, the present disclosure is directed to a compound of formula(I), or a pharmaceutically acceptable salt thereof: wherein R2is selected from: ,, and . In certain embodiments, the present disclosure is directed to a compound of formula(I), or a pharmaceutically acceptable salt thereof: wherein R2is and the 5 or 6 membered ring is saturated or unsaturated; R3 is selected from H, D, -OH, -COOH, - NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6hydroxyalkyl; and Z, U, V, W, P, Q, S, and T are independently selected from C, O, N, and S; wherein Z, U, V, W, P, Q, S and T are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring. In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R2is selected from:In certain embodiments, the present disclosure is directed to a compound of formula(I), or a pharmaceutically acceptable salt thereof: wherein R2is , and the 5-membered ring is saturated or unsaturated; R3 is selected from H, D, -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6hydroxyalkyl; and Z, P, Q, and S are independently selected from C, O, N, and S; wherein Z, P, Q, and S are optionally substituted with one or more groups selected from -OH, - COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8cycloalkyl ring. In certain embodiments, the present disclosure is directed to a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein R2is selected from:, , , and . In certain embodiments, the present disclosure is directed to a compound of formula(I), or a pharmaceutically acceptable salt thereof: wherein R2is , and issaturated or unsaturated; Z, P, Q, and S are independently selected from C, O, N, and S, wherein Z, P, Q, and S are optionally substituted with one or more groups selected from - OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8cycloalkyl ring. In certain embodiments, the present disclosure is directed to a compound of formula(I), or a pharmaceutically acceptable salt thereof: wherein R2is selected from: ,, and . In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein X1is selected from C and N. In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein X2is selected from C and N; wherein when X2is C, the said C is optionally substituted with hydrogen, halogen, -CN, - OR4, -SR4, -N(R5)2, C1-6alkyl, C1-6haloalkyl, wherein R4and R5 are independently selected from C1-C6alkyl. In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein ring A is a C6-C8 cycloalkyl ring, C6-C10aryl, or 4-, 5-, 6-, or 7- membered heterocyclyl ring wherein the said ring A is optionally substituted with one or more groups selected from -OH, -COOH, -C(O)-, -NH2, -(NH)-, =O, =NH, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and C1-6alkyl-epoxide; wherein the said -C(O)- is optionally substituted with H, -OH, NH2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl; wherein the said –(NH)- is optionally substituted with one or more groups selected from H, C1-6alkyl, C1-6nitrile, C2-6alkynyl,C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, and C1-6alkyl-epoxide; wherein the said C1-6alkyl-epoxide is optionally substituted with one or more C1-6alkyl. In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein when ring A contains ring carbon atoms and one or more heteroatoms, the heteroatoms are selected from N and S wherein when ring A is a 5-membered heterocyclyl ring and contains one heteroatom selected fromN, ring A is selected from , , and ; wherein when ring A isand R2is , V and W are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8cycloalkyl ring; wherein whenring A is and Z is O, ring A is optionally substituted with one or more groups selected from -OH, -COOH, -C(O)-, -NH2, -(NH)-, =O, =NH, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and -C1- 6 alkyl-epoxide; wherein the said -C(O)- is optionally substituted with H, -OH, NH2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl; wherein the said –(NH)- is optionally substituted with one or more groups selected from H, C1-6alkyl, C1-6nitrile, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, and C1-6alkyl-epoxide; wherein the said C1-6alkyl-epoxide is optionally substituted with one or more C1-6alkyl. In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein when ring A is a 5-memberedheterocyclyl ring and at least one heteroatom is S, ring A is selected from ,, or , where Z is N; wherein when ring A is selected from or , Z isN, and R2is where S and P are N, wherein: (i) when S or P are substituted with C1 alkyl then R1is C6-C10aryl;(ii) S or P are substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl; or (iii) V or W are substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring; In certain embodiments, the present disclosure is directed to a compound of formula(I), or a pharmaceutically acceptable salt thereof: wherein when ring A is and Z is N, R1is selected from C3-C8 cycloalkyl ring or 4-, 5-, 6-, or 7- membered heterocyclyl ring, and C6-C10aryl fused with 3-8 membered heterocyclic group; wherein when ring A is a 5- membered heterocyclyl ring and contains two heteroatoms selected from N, ring A is selected from, , , and ; wherein when ring A is, Z is O, and R2is where S and P are N, S and P are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring; wherein when ring A is , Z is O, and R2is where Q and P are N, S is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring;wherein when ring A is and Z is O, S and P are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C3-6 alkyl, C2-6alkynyl, C1-6haloalkyl, C2-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C4-C8 cycloalkyl ring; wherein when ring A is a 6-membered heterocyclyl ring and contains one or twoheteroatoms selected from N ring A is selected from, , ,, , , , and ; wherein when ring A is or , Z isO; wherein when ring A is , or , Z is O and R2is, P and S, are substituted with one or more groups selected from -OH, - COOH, -NH2, -CN, -CD(CD3)2, halogen, C3-6 alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C4-C8cycloalkyl ring; wherein when ring A is, Z is N, ring A is optionally substituted with one or more groups selected from - COOH, -NH2, -(NH)-, =O, =NH, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and -C1-6alkyl-epoxide. In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein ring A is a 5-membered heterocyclyl ring; wherein the said ring A is optionally substituted with one or more groups selected from -OH, -COOH, -C(O)-, -NH2, -(NH)-, =O, =NH, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and -C1-6alkyl-epoxide; wherein the said -C(O)- is optionally substituted with H, -OH, NH2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl; wherein the said –(NH)- is optionally substituted with one or more groups selected from H, C1-6alkyl, C1-6nitrile, C2-6 alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, and C1-6alkyl- epoxide; wherein the said C1-6alkyl-epoxide is optionally substituted with one or more C1-6alkyl. In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein when ring A contains ring carbon atoms and one or more heteroatoms, the heteroatoms are selected from N and S; wherein when ring A is a 5-membered heterocyclyl ring and contains one heteroatom selected fromN, ring A is selected from , , and ; wherein when ring A isand R2is , V and W are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring; wherein whenring A is and Z is O, ring A is optionally substituted with one or more groups selected from -OH, -COOH, -C(O)-, -NH2, -(NH)-, =O, =NH, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and -C1- 6 alkyl-epoxide; wherein the said -C(O)- is optionally substituted with H, -OH, NH2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl; wherein the said –(NH)- is optionally substituted with one or more groups selected from H, C1-6alkyl, C1-6nitrile, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, and C1-6alkyl-epoxide; wherein the said C1-6alkyl-epoxide is optionally substituted with one or more C1-6alkyl. In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein when ring A is a 5-memberedheterocyclyl ring and at least one heteroatom is S, ring A is selected from ,, or , where Z is N; wherein when ring A is selected from or , Z isN, and R2is where S and P are N, wherein: (i) when S or P are substituted with C1 alkyl then R1is C6-C10aryl; (ii) S or P are substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl; or (iii) V or W are substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring;wherein when ring A is and Z is N, R1is selected from C3-C8 cycloalkyl ring or 4-, 5-, 6-, or 7- membered heterocyclyl ring, and C6-C10aryl fused with 3-8 membered heterocyclic group; wherein when ring A is a 5-membered heterocyclyl ring and contains two heteroatoms selected from N, ring A is selected from, , , and ; wherein when ring A is , Zis O, and R2is where S and P are N, S and P are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, - CD(CD3)2, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring; wherein when ring A is, Z is O, and R2is where Q and P are N, S is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, - CD(CD3)2, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring; wherein when ring A is and Z is O, S and P are optionally substituted with one or more groups selected from -OH, - COOH, -NH2, -CN, -CD(CD3)2, halogen, C3-6 alkyl, C2-6alkynyl, C1-6haloalkyl, C2- 6 alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C4-C8 cycloalkyl ring. In certain embodiments, the present disclosure is directed to a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein ring A is selected from:In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein ring A is a 6-membered heterocyclyl ring, wherein the said ring A is optionally substituted with one or more groups selected from -OH, -COOH, -C(O)-, -NH2, -(NH)-, =O, =NH, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and -C1-6alkyl-epoxide; wherein the said -C(O)- is optionally substituted with H, -OH, NH2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl; wherein the said –(NH)- is optionally substituted with one or more groups selected from H, C1-6alkyl, C1-6nitrile, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, and C1-6alkyl-epoxide; wherein the said C1-6alkyl-epoxide is optionally substituted with one or more C1-6alkyl; wherein when ring A contains ring carbon atoms and one or more heteroatoms, the heteroatoms are selected from N and S wherein when ring A is a 6 membered heterocyclyl ring and contains one or two heteroatoms selected from N, or , Z is O and R2is , P and S are substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C3- 6 alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C4- C8 cycloalkyl ring; wherein when ring A is , Z is N and ring A is optionally substituted with one or more groups selected from -COOH, -NH2, -(NH)-, =O, =NH,halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and -C1-6alkyl-epoxide. In certain embodiments, the present disclosure is directed to a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein ring A is selected from:In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein ring A is a C6-C10aryl; wherein the said ring A is optionally substituted with one or more groups selected from -OH, - COOH, -C(O)-, -NH2, -(NH)-, =O, =NH, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and C1-6alkyl-epoxide; wherein the said -C(O)- is optionally substituted with H, -OH, NH2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl; wherein the said –(NH)- is optionally substituted with one or more groups selected from H, C1-6alkyl, C1-6nitrile, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, and C1-6alkyl- epoxide; wherein the said C1-6alkyl-epoxide is optionally substituted with one or more C1-6alkyl. In certain embodiments, the present disclosure is directed to a compound of formula(I), or a pharmaceutically acceptable salt thereof: wherein ring A is . In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein the compound is selected from:In certain embodiments, the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof:wherein: X’ and X” are independently selected from N or C; R1iswherein Z is selected from O or N optionally substituted with R1a or -CH2R1a, wherein R1a is C3-C6cycloalkyl or 4-, 5-, or 6- membered heterocyclyl; wherein R2is selected from H or deuterium; R3 is selected from, , and , whereinW is selected from C or N, and wherein R3a, R3b, and R3c are independently selected from - H or halogen, R3aand R2optionally form a bond to form a 5- or 6-membered heterocyclyl,or R3and R3boptionally combine to form a bridge; R4is selected from, , , , , , and, wherein U and Y are independently selected from C or N, and wherein when U is N, Y is C, and when U is C, Y is N or C; wherein R5, R6, and R7are independently selected from -H, -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl ring is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, C3-C8 spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein whenR7is a 4-, 5-, or 6- membered heterocyclyl ring, R4is or ;and wherein R3c optionally forms a bond with R5 or R7 to form a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl or C5-C12 cycloalkyl, wherein the 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl or C5-C12 cycloalkyl is optionally substituted with one or more groups selected from C1-6alkyl, -OH, =O, C1-6alkoxy, and halogen; Ring A is a 5- or 6- membered heterocyclyl ring comprising one to three heteroatoms selected from N, O, or S; wherein when ring A is a 5-membered heterocyclyl ring and contains one heteroatom, ringA is selected from where X’ and X” are C and where X’ and X” are C;wherein when ring A is where X’ and X” are C, R4is , and Z is O, R7 is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C3-6 alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C4-C8 cycloalkyl ring, and 4-, 5- , or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, C3-C8 spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein whenring A is where X’ and X” are C and R4is , R7 is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, C3-C8 spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein when ring A is a 5- membered heterocyclyl ring and contains two heteroatoms, ring A is selected fromwhere X’ and X” are C, where X’ and X” are C, where X’ isN and X” is C, where X’ is C and X” is N, and where X’ is C and X” is N;wherein whenwhere X’ and X” are C or where X’ and X” are C, R4isor , and Z is O, R7 is selected from -H, -OH, -COOH, -NH2, - CN, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C2-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, C3-C8spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein when ring A is a 5-membered heterocyclyl ring andcontains three heteroatoms, ring A is where X’ is C and X” is N; wherein whenring A is 6-membered heterocyclyl ring, ring A is where X’ and X” are C and Z isN; wherein when ring A is where X’ and X” are C, Z is N, and R4is , R7 is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, and 4-, 5- , or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, C3-C8spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said ring A is optionally substituted with one or more groups selected from =O, C1-6alkyl, C2-C6alkenyl, and C2-6alkynyl; wherein when ring A is where X’ and X” are C, the compound of formula (II) or a pharmaceutically acceptable salt thereof comprises one or more of: Z is substituted with R1aor -CH2R1a, R3aand R3bare halogen, R5, R6, or R7is a 4-, 5-, or 6- membered heterocyclyl ring, R3 is , R4is ,, or where U and Y are C,where U is C and Y isN, or R3 is where U is N and Y is C, or a combination thereof; wherein whenring A is where X’ and X” are C , the compound of formula (II) or a pharmaceutically acceptable salt thereof comprises a ring A substituted with a C2-C6alkenyl; wherein when ring A iswhere X’ is N and X” is C, the compound of formula (II) or a pharmaceutically acceptable salt thereof comprises one or more of: R3a and R2form a bond to form a 5 or 6 membered heterocyclyl R3a and R3b combine to form a bridge, R3 is, R4is , , or , R5, R6, or R7 a 4-, 5-, or 6- membered heterocyclyl ring, R3c forms a bond with R5 to form a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl or C5-C12 cycloalkyl, or a combination thereof. In certain embodiments, the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein R1iswherein Z is selected from O or N optionally substituted with R1a or -CH2R1a, wherein R1ais C3-C6cycloalkyl or 4-, 5-, or 6- membered heterocyclyl; wherein R2is selected from H or deuterium; R3 is selected from, and, wherein W is selected from C or N, and wherein R3a, R3b, and R3c are independently selected from -H or halogen, R3aand R2optionally form a bond to form a 5- or 6-membered heterocyclyl, or R3a and R3b optionally combine to form a bridge; R4isselected from , , , , ,,,and , wherein U and Y are independently selected from C or N, and wherein when U is N, Y is C, and when U is C, Y is N or C; wherein R5, R6, and R7 are independently selected from -H, -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl ring is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, - CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, C3-C8 spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein when R7is a 4-, 5-, or 6- membered heterocyclyl ring, R4isor ;and wherein R3c optionally forms a bond with R5 or R7 to form a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl or C5-C12 cycloalkyl, wherein the 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl or C5-C12 cycloalkyl is optionally substituted with one or more groups selected from C1-6alkyl, -OH, =O, C1-6alkoxy, and halogen. In certain embodiments, the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein R3 is selected from , , and , wherein W is selected from N or C.In certain embodiments, the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein R3 isselected from , , , , and . In certain embodiments, the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3aand R2form a bond to form a 5- or 6-membered heterocyclyl, R3is . In certain embodiments, the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3aand R3b combine to form a bridge, R3 is . In certain embodiments, the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein R4is selected from , , , , ,,,and, wherein U and Y are independently selected from C or N, and wherein when U is N, Y is C, and when U is C, Y is N or C; wherein R5, R6, and R7 are independently selected from -H, -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, C3-C8 spiro-cycloalkyl, and 4-, 5-, or 6- memberedheterocyclyl ring; wherein when R7is a 4-, 5-, or 6- membered heterocyclyl ring, R4is or . In certain embodiments, the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein R4is , , , , and . In certain embodiments, the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3 is , R1is selected from:. In certain embodiments, the compositions and methods described herein relate to a compound of formula (II) or a pharmaceutically acceptable salt thereof: wherein when R3is , R1is . In certain embodiments, the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3is , R1is . In certain embodiments, the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3is , R1is . In certain embodiments, the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3is , R1is selected from and .In certain embodiments, the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3aand R2form a bond to form a 5- or 6-membered heterocyclyl, R1is . In certain embodiments, the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3aand R3bcombine to form a bridge, R1is . In certain embodiments, the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3c forms a bond with R5 or R7 to form a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl or C5-C12cycloalkyl, wherein the 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl or C5-C12 cycloalkyl is optionally substituted with one or more groups selected from C1-6alkyl, -OH, =O, C1-6alkoxy, and halogen, R1is selected from:, and . In certain embodiments, the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein ring A is a 5- or 6- membered heterocyclyl ring comprising one to three heteroatoms selected from N, O, or S; wherein when ring A is a 5-membered heterocyclyl ring and contains oneheteroatom, ring A is selected from where X’ and X” are C and where X’and X” are C; wherein when ring A is where X’ and X” are C, R4is , and Z is O, R7is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C3-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C4-C8cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, C3-C8spiro-cycloalkyl, and 4-, 5-, or 6- memberedheterocyclyl ring; wherein when ring A is where X’ and X” are C and R4is, R7 is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is areoptionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, C3-C8 spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein when ring A is a 5-membered heterocyclyl ring and contains twoheteroatoms, ring A is selected from where X’ and X” are C, where X’and X” are C, where X’ is N and X” is C, where X’ is C and X” is N, andwhere X’ is C and X” is N; wherein when where X’ and X” are C orwhere X’ and X” are C, R4isor , and Z is O, R7 is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C2-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C2-6alkyl, C1-6haloalkyl or C3-C8 cycloalkyl ring are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, C3-C8 spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein when ring A is a 5-membered heterocyclyl ring and contains three heteroatoms, ring A iswhere X’ is C and X” is N; wherein when R ring A is 6-membered heterocyclyl ring, ring A iswhere X’ and X” are C and Z is N; whereinwhen ring A is where X’ and X” are C and R4is, R7 is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, C3-C8spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said ring A is optionally substituted with one or more groups selected from =O, C1-6alkyl, C2-C6alkenyl, and C2-6alkynyl. In certain embodiments, the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein Ring A is a 5- membered heterocyclyl ring comprising one to three heteroatoms selected from N, O, or S; wherein when ring A is a 5-membered heterocyclyl ring and contains one heteroatom,ring A is selected from where X’ and X” are C and where X’ and X” areC; wherein when ring A is where X’ and X” are C, R4is , and Z is O, R7is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C3-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C4-C8 cycloalkyl ring, and 4-, 5- , or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, C3-C8 spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein whenring A is where X and X are C and R4is , R7 is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, C3-C8spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein when ring A is a 5- membered heterocyclyl ring and contains two heteroatoms, ring A is selected fromwhere X and X are C, where X and X are C, where X isN and X” is C,where X’ is C and X” is N, andwhere X’ is C and X” is N;wherein when where X’ and X” are C orwhere X’ and X” are C, R4 isor , and Z is O, R7 is selected from -H, -OH, -COOH, -NH2, - CN, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C2-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, C3-C8spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein when ring A is a 5-membered heterocyclyl ring and N contains three heteroatoms, ring A iswhere X’ is C and X” is N; wherein the said ring A is optionally substituted with one or more groups selected from =O, C1-6alkyl, C2- C6alkenyl, and C2-6alkynyl. In certain embodiments, the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein ring A is selected from:and . In certain embodiments, the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein Ring A is a 6- membered heterocyclyl ring comprising one to three heteroatoms selected from N, O, or S; wherein when R ring A is 6-membered heterocyclyl ring, ring A iswhere X’and X” are C and Z is N; wherein when ring A iswhere X’ and X” are C and R4is, R7 is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, C3-C8spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said ring A is optionally substituted with one or more groups selected from =O, C1-6alkyl, C2-C6alkenyl, and C2-6alkynyl. In certain embodiments, the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein ring A is. In certain embodiments, the compositions and methods described herein relate to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein the compound is selected from:In certain embodiments, the present disclosure is directed to a method of modulating USP1 activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure is directed to a method of inhibiting USP1 activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure is directed to a method of treating a disorder or disease with a USP1 inhibitor in a subject, comprising administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure is directed to a method of treating cancer with a USP1 inhibitor in a subject, comprising administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure is directed to a method of treating cancer with a USP1 inhibitor in a subject, comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the cancer is characterized by over expression of USP1. In certain embodiments, the present disclosure is directed to a method treating cancer with a USP1 inhibitor in a subject, comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the cancer characterized by overexpression of USP1 is selected from prostate, breast, ovarian, non-small cell lung cancer, mesothelioma, Merkel cell carcinoma, synovial sarcoma, renal cell carcinoma, and osteosarcoma. In certain embodiments, the present disclosure is directed to a use of a compound of formula (I), or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer. In certain embodiments, the present disclosure is directed to a use of a compound of formula (I), or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer, wherein the cancer is characterized by overexpression of USP1. In certain embodiments, the present disclosure is directed to a process to manufacture a compound of formula (I), or a pharmaceutically acceptable salt thereof.BRIEF DESCRIPTION OF THE DRAWINGS The subject matter of the application will be more readily understood from the following detailed description when read in conjunction with the accompanying drawings. FIG.1 shows the mean tumor volume over a period of time in mice treated with 30 mg / kg and 100 mg / kg of Compound 12. FIG.2 shows the mean tumor volume over a period of time in mice treated with 30 mg / kg and 100 mg / kg of Compound 21. FIG.3 shows the mean tumor volume over a period of time in mice treated with 30 mg / kg and 100 mg / kg of Compound 129. FIG.4 shows the mean tumor volume over a period of time in mice treated with 30 mg / kg and 100 mg / kg of Compound 133. DETAILED DESCRIPTION The presently disclosed subject matter relates to compositions comprising USP1 inhibitors and methods of their use in treating cancer. For purposes of clarity of disclosure and not by way of limitation, the detailed description is divided into the following subsections: 1. Definitions 2. Compositions of Matter 3. Methods of Use 4. Examples 1. Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the presently disclosed subject matter. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other instances “comprising,” “consisting of”, and “consisting essentially of,” the instances or elements presented herein, whether explicitly set forth or not. For the recitation of numeric ranges herein, each intervening number within the range is explicitly contemplated with the same degree of precision. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated. As used herein, the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value. As used herein, “modulate” or “modulating” refers to increasing or decreasing, e.g., modulation of the activity of an enzyme includes increasing the activity of the enzyme as well as decreasing the activity of the enzyme. As used herein, “treat” or “treating” refers to an effort to alter the natural course of a disease, including prophylaxis of the disease, alleviation of symptoms and / or ameliorating pathology associated with the disease. As used herein, “alkyl” includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and may be unsubstituted or substituted. Thus, C1-Cnas in “C1-Cnalkyl" is defined to include groups having 1, 2, ...., n-1 or n carbons in a linear or branched arrangement. For example, C1-C6, as in “C1-C6alkyl” is defined to include groups having 1, 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, pentyl, hexyl, and octyl.As used herein, “alkenyl” refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least 1 carbon to carbon double bond, and up to the maximum possible number of non-aromatic carbon-carbon double bonds may be present, and may be unsubstituted or substituted. For example, “C2-C6alkenyl” means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and up to 1, 2, 3, 4, or 5 carbon-carbon double bonds respectively. Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. The term “alkynyl” refers to a hydrocarbon radical straight or branched, containing at least 1 carbon to carbon triple bond, and up to the maximum possible number of non- aromatic carbon-carbon triple bonds may be present, and may be unsubstituted or substituted. Thus, “C2-C6alkynyl” means an alkynyl radical having 2 or 3 carbon atoms and 1 carbon-carbon triple bond, or having 4 or 5 carbon atoms and up to 2 carbon-carbon triple bonds, or having 6 carbon atoms and up to 3 carbon-carbon triple bonds. Alkynyl groups include ethynyl, propynyl and butynyl. As used herein, “heteroalkyl” includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and at least 1 heteroatom within the chain or branch. As used herein, “cycloalkyl” shall mean cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl). As used herein, the term “heterocyclyl” or “heterocyclic” refers to a mono- or poly- cyclic ring system which can be saturated or contains one or more degrees of unsaturation and contains one or more heteroatoms. Preferred heteroatoms include N, O, and / or S, including N-oxides, sulfur oxides, and dioxides. Preferably the ring is three to ten- membered and is either saturated or has one or more degrees of unsaturation. The heterocycle may be unsubstituted or substituted, with multiple degrees of substitution being allowed. Such rings may be optionally fused to one or more of another “heterocyclic” ring(s), heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s). Examples of heterocycles include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, 1,3- oxathiolane, and the like. The alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl substituents may be substituted or unsubstituted, unless specifically defined otherwise. As used herein, “aryl” is intended to mean any stable monocyclic, bicyclic or polycyclic carbon ring of up to 10 atoms in each ring, wherein at least one ring is aromatic,and may be unsubstituted or substituted. Examples of such aryl elements include phenyl, p- toluenyl (4-methylphenyl), naphthyl, tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. In cases where the aryl substituent is bicyclic and one ring is non- aromatic, it is understood that attachment is via the aromatic ring. As used herein, the term “halogen” refers to F, Cl, Br, and I. As used herein, the term “haloalkyl” means an alkyl group that is substituted with one or more fluorine, chlorine, bromine or iodine atoms. Examples of such haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl groups. As used herein, the term “alkoxy” means an -O-alkyl group in which alkyl is defined herein. Preferably the alkoxy is a C1-C6alkoxy. Examples include, but are not limited to, methoxy and ethoxy. The group may be a terminal group or a bridging group. The term “substitution,” “substituted” and “substituent” refers to a functional group as described above in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms, provided that normal valencies are maintained and that the substitution results in a stable compound. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Examples of substituent groups include the functional groups described herein, and halogens (i.e., F, Cl, Br, and I); alkyl groups, such as methyl, ethyl, n-propyl, and trifluorom ethyl; hydroxyl; alkoxy groups, such as methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure result. The compounds of the subject invention may have spontaneous tautomeric forms. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers,each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form. This invention also provides isotopic variants of the compounds disclosed herein, including wherein the isotopic atom is2H and / or wherein the isotopic atom13C. Accordingly, in the compounds provided herein hydrogen can be enriched in the deuterium isotope. It is to be understood that the invention encompasses all such isotopic forms. In the compound structures depicted herein, hydrogen atoms are not shown for carbon atoms having less than four bonds to non-hydrogen atoms. However, it is understood that enough hydrogen atoms exist on said carbon atoms to satisfy the octet rule. Except where otherwise specified, if the structure of a compound of this invention includes an asymmetric carbon atom, it is understood that the compound occurs as a racemate, racemic mixture, and isolated single enantiomer. All such isomeric forms of these compounds are expressly included in this invention. Except where otherwise specified, each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. The compounds of the present invention include all hydrates, solvates, and complexes of the compounds used by this invention. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein. Compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well- known techniques and an individual enantiomer may be used alone. The compounds described in the present invention are in racemic form or as individual enantiomers. In choosing the compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e., R1, R2, etc. are to be chosen in conformity with well-known principles of chemical structure connectivity. The compounds used in the method of the present invention may be in a salt form. As used herein, a “salt” is a salt of the instant compounds which has been modified by making acid or base salts of the compounds. In the case of compounds used to treat an infection or disease caused by a pathogen, the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acidsalts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols. The salts can be made using an organic or inorganic acid. Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like. Phenolate salts are the alkali earth metal salts, sodium, potassium or lithium. The term "pharmaceutically acceptable salt" in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. The compounds used in the method of the present invention can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or in carriers such as the novel programmable sustained-release multi-compartmental nanospheres (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral, nasal, rectal, topical, intravenous or direct injection or parenteral administration. The compounds can be administered alone or mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used. The active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow- inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents,preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavorants and coloring agents. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen. 2. Compositions of Matter The presently disclosed subject matter relates to compositions comprising USP1 inhibitors and methods of using the same. For example, but not by way of limitation, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof:In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R1is selected from C3-C8cycloalkyl ring, C6-C10 aryl, or 4-, 5-, 6-, or 7- membered heterocyclyl ring, and C6-C10 arylfused with 3-8 membered heterocyclic group; wherein R1is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, -OCD3, C1-6haloalkoxy, C1-6hydroxyalkyl, C6-10aryl, 5-8 membered heteroaryl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, -O-C1-6alkyl, -O-C1-6alkylene, -O-C1-6haloalkyl, -NH-C1-6alkyl, and -NH-C3-8cycloalkyl, wherein the C6-10aryl, 5-8 membered heteroaryl, C3-8cycloalkyl, and 3-8 membered heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of -OH, - COOH, -NH2, -CN, halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1- 6 haloalkoxy, and C1-6hydroxyalkyl; In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R1is selected from:In certain embodiments, the present disclosure is directed to a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein R2is selected from:, , , and ; R3 is selected from H, D, -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6hydroxyalkyl; Z, U, V, W, P, Q, S, and T are independently selected from C, O, N, and S; wherein Z, U, V, W, P, Q, S, and T are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring; wherein when R2is , the phenyl ring is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8cycloalkyl ring; wherein when R2is , the 5- or 6-membered ring issaturated or unsaturated; wherein when R2is , the 5-membered ring issaturated or unsaturated; wherein when R2is , is saturated or unsaturated. In certain embodiments, the present disclosure is directed to a compound of formula(I), or a pharmaceutically acceptable salt thereof: wherein R2is , Z is selected from C, O, N, and S; and R3 is selected from H, D, -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6hydroxyalkyl; wherein the phenyl ring is optionally substituted with one or more groups selected from - OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring. In certain embodiments, the present disclosure is directed to a compound of formula(I), or a pharmaceutically acceptable salt thereof: wherein R2is selected from: ,, and . In certain embodiments, the present disclosure is directed to a compound of formula(I), or a pharmaceutically acceptable salt thereof: wherein R2is , the 5 and 6 membered ring are saturated or unsaturated; R3 is selected from H, D, -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6hydroxyalkyl; and Z, U, V, W, P, Q, S, and T are independently selected from C, O, N, and S, wherein Z, U, V, W, P, Q, S and T are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8cycloalkyl ring. In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R2is selected from:In certain embodiments, the present disclosure is directed to a compound of formula(I), or a pharmaceutically acceptable salt thereof: wherein R2is ,the 5- membered ring is saturated or unsaturated; R3 is selected from H, D, -OH, -COOH, -NH2, - CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6hydroxyalkyl; and Z, P, Q, and S are independently selected from C, O, N, and S, wherein Z, P, Q, and S are optionally substituted with one or more groups selected from -OH, - COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8cycloalkyl ring. In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R2is selected from:, , , and . In certain embodiments, the present disclosure is directed to a compound of formula(I), or a pharmaceutically acceptable salt thereof: wherein R2is , and is saturated or unsaturated; Z, P, Q, and S are independently selected from C, O, N, and S, wherein Z, P, Q, and S are optionally substituted with one or more groups selected from - OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8cycloalkyl ring. In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R2is selected from:, , and . In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein X1is selected from C and N. In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein X2is selected from C and N; wherein when X2is C, the said C is optionally substituted with hydrogen, halogen, -CN, - OR4, -SR4, -N(R5)2, C1-6alkyl, C1-6haloalkyl, wherein R4and R5 are independently selected from C1-6alkyl. In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein ring A is a C6-C8cycloalkyl ring,C6-C10 aryl, or 4-, 5-, 6-, or 7- membered heterocyclyl ring; wherein the said ring A isoptionally substituted with one or more groups selected from -OH, -COOH, -C(O)-, -NH2, -(NH)-, =O, =NH, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and C1-6alkyl-epoxide; wherein the said -C(O)- is optionally substituted with H, -OH, NH2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl; wherein the said –(NH)- is optionally substituted with one or more groups selected from H, C1-6alkyl, C1-6nitrile, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, and C1-6alkyl-epoxide; wherein the said C1-6alkyl-epoxide is optionally substituted with one or more C1-6alkyl; wherein when ring A contains ring carbon atoms and one or more heteroatoms, the heteroatoms are selected from N and S wherein when ring A is a 5-membered heterocyclylring and contains one heteroatom selected from N, ring A is selected from ,, and ; wherein when ring A is and R2is , V and W are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, - CN, -CD(CD3)2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring; wherein when ring A is and Z is O, ring A is optionally substituted with one or more groups selected from -OH, -COOH, -C(O)-, - NH2, -(NH)-, =O, =NH, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and -C1-6alkyl-epoxide; wherein the said -C(O)- is optionally substituted with H, -OH, NH2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl; wherein the said –(NH)- is optionally substituted with one or more groups selected from H, C1-6alkyl, C1-6nitrile, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, and C1-6alkyl-epoxide; wherein the said C1-6alkyl-epoxide is optionally substituted with one or more C1-6alkyl; wherein when ring A is a 5-membered heterocyclylring and at least one heteroatom is S, ring A is selected from , , or, where Z is N; wherein when ring A is selected from or , Z is N, and R2iswhere S and P are N, wherein: (i) when S or P are substituted with C1 alkyl then R1is C6-C10aryl; (ii) S or P are substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl; or (iii) V or W are substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring;wherein when ring A is and Z is N, R1is selected from C3-C8 cycloalkyl ring or 4- , 5-, 6-, or 7- membered heterocyclyl ring, and C6-C10aryl fused with 3-8 membered heterocyclic group; wherein when ring A is a 5-membered heterocyclyl ring and containstwo heteroatoms selected from N, ring A is selected from , , ,and ;wherein when ring A is, Z is O, and R2iswhere S and P are N, S and P are optionally substituted with one or more groups selected from - OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring; wherein when ring Ais, Z is O, and R2is where Q and P are N, S is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl C16 haloalkoxy, C1-6hydroxyalkyl, and C3- C cycloalkyl ring; where8 in when ring A is and Z is O, S and P are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C3-6 alkyl, C2-6alkynyl, C1-6haloalkyl, C2-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C4-C8 cycloalkyl ring; wherein when ring A is a 6-membered heterocyclyl ring and contains one or two heteroatoms selected from N ring A is selected from, , , , , , , and ;wherein when ring A isor , Z is O; wherein when ring A is,or , Z is O and R2is, P and S, are substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C3-6alkyl, C2-6 alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C4-C8cycloalkyl ring; wherein when ring A is , Z is N, ring A is optionally substituted with one or more groups selected from -COOH, -NH2, -(NH)-, =O, =NH, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and -C1-6alkyl-epoxide.In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein the said ring A is optionally substituted with one or more groups selected from -OH, -COOH, -C(O)-, -NH2, -(NH)-, =O, =NH, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and -C1-6alkyl-epoxide; wherein the said -C(O)- is optionally substituted with H, -OH, NH2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl; wherein the said –(NH)- is optionally substituted with one or more groups selected from H, C1-6alkyl, C1-6nitrile, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, and C1-6alkyl-epoxide; wherein the said C1-6alkyl-epoxide is optionally substituted with one or more C1-6alkyl. wherein when ring A contains ring carbon atoms and one or more heteroatoms, the heteroatoms are selected from N and S; wherein when ring A is a 5-membered heterocyclyl ring and contains oneheteroatom selected from N, ring A is selected from , , and ;wherein when ring A is and R2is , V and W are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, andC3-C8 cycloalkyl ring; wherein when ring A is and Z is O, ring A is optionally substituted with one or more groups selected from -OH, -COOH, -C(O)-, -NH2, -(NH)-, =O, =NH, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and -C1-6alkyl-epoxide; wherein the said -C(O)- is optionally substituted with H, -OH, NH2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl; wherein the said –(NH)- is optionally substituted with one or more groups selected from H, C1-6alkyl, C1-6nitrile, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, and C1-6alkyl-epoxide; wherein the said C1-6alkyl-epoxide is optionally substituted with one or more C1-6alkyl; wherein when ring A is a 5-membered heterocyclyl ring and at least one heteroatom is S, ring A is selected from, , or , where Z is N; wherein when ring A is selected fromor , Z is N, and R2is where S and P are N, wherein: (i) when S or P are substituted with C1 alkyl then R1is C6-C10aryl; (ii) S or P are substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl; or (iii) V or W are substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring;wherein when ring A is and Z is N, R1is selected from C3-C8 cycloalkyl ring or 4- , 5-, 6-, or 7- membered heterocyclyl ring, and C6-C10aryl fused with 3-8 membered heterocyclic group; wherein when ring A is a 5-membered heterocyclyl ring and containstwo heteroatoms selected from N, ring A is selected from , , ,and ; wherein when ring A is , Z is O, and R2is where S and P are N, S and P are optionally substituted with one or more groups selected from - OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring; wherein when ring Ais , Z is O, and R2is where Q and P are N, S is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring; wherein when ring A is and Z is O, S and P are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2,halogen, C3-6alkyl, C2-6alkynyl, C1-6haloalkyl, C2-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C4-C8 cycloalkyl ring. In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein ring A is selected from:, and . In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein the said ring A is optionally substituted with one or more groups selected from -OH, -COOH, -C(O)-, -NH2, -(NH)-, =O, =NH, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and -C1-6alkyl-epoxide; wherein the said -C(O)- is optionally substituted with H, -OH, NH2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl; wherein the said –(NH)- is optionally substituted with one or more groups selected from H, C1-6alkyl, C1-6nitrile, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, and C1-6alkyl-epoxide; wherein the said C1-6alkyl-epoxide is optionally substituted with one or more C1-6alkyl wherein when ring A contains ring carbon atoms and one or more heteroatoms, the heteroatoms are selected from N and S wherein when ring A is a 6-membered heterocyclyl ring and contains one or two heteroatoms selected from N, ring A is selected from, , , and ; wherein when ring A isor , Z is O;wherein when ring A is , or , Z is O and R2is , P and S, are substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C3-6 alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1- 6 hydroxyalkyl, and C4-C8 cycloalkyl ring; wherein when ring A is, Z is N, ring A is optionally substituted with one or more groups selected from -COOH, -NH2, -(NH)-, =O, =NH, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and -C1-6alkyl-epoxide. In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein ring A is selected from:, , , , and . In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein ring A is a C6-C10aryl; wherein the said ring A is optionally substituted with one or more groups selected from -OH, - COOH, -C(O)-, -NH2, -(NH)-, =O, =NH, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and C1-6alkyl-epoxide; wherein the said -C(O)- is optionally substituted with H, -OH, NH2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl; wherein the said –(NH)- is optionally substituted with one or more groups selected from H, C1-6alkyl, C1-6nitrile, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, and C1-6alkyl- epoxide; wherein the said C1-6alkyl-epoxide is optionally substituted with one or more C1-6alkyl. In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein ring A isIn certain embodiments, the present disclosure is directed to a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein the compound is selected from:, and . In certain embodiments, the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof:In certain embodiments, the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: X’ and X” are independently selected from N or C. In certain embodiments, the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein R1iswherein Z is selected from O or N optionally substituted with R1a or -CH2R1a, wherein R1a is C3-C6cycloalkyl or 4-, 5-, or 6- membered heterocyclyl; wherein R2is selected from H or deuterium; R i3 s selected from , , and , wherein W is selected from C or N, and wherein R3a, R3b, and R3c are independently selected from - H or halogen, R3a and R2optionally form a bond to form a 5- or 6-membered heterocyclyl,or R3a and R3b optionally combine to form a bridge; R4is selected from ,, , , , , , and, wherein U and Y are independently selected from C or N, and wherein when U is N, Y is C, and when U is C, Y is N or C; wherein R5, R6, and R7 are independently selected from -H, -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl ring is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkylring, C3-C8spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein whenR7is a 4-, 5-, or 6- membered heterocyclyl ring, R4is or ;and wherein R3c optionally forms a bond with R5 or R7 to form a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl or C5-C12 cycloalkyl, wherein the 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl or C5-C12 cycloalkyl is optionally substituted with one or more groups selected from C1-6alkyl, -OH, =O, C1-6alkoxy, and halogen. In certain embodiments, the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein R3 is selected from, , and , wherein W is selected from N or C. In certain embodiments, the present disclosure is directed to a compound of formula(II), or a pharmaceutically acceptable salt thereof: wherein R3 is selected from, , , , and . In certain embodiments, the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3a and R2form a bond toform a 5- or 6-membered heterocyclyl, R3is . In certain embodiments, the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3a and R3b combine toform a bridge, R3 is . In certain embodiments, the present disclosure is directed to a compound of formula(II), or a pharmaceutically acceptable salt thereof: wherein R4is selected from, , , , , , , and, wherein U and Y are independently selected from C or N, and wherein when U is N, Y is C, and when U is C, Y is N or C; wherein R5, R6, and R7 are independently selected from -H, -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, C3-C8 spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein whenR7is a 4-, 5-, or 6- membered heterocyclyl ring, R4is or . In certain embodiments, the present disclosure is directed to a compound of formula(II), or a pharmaceutically acceptable salt thereof: wherein R4is selected from:, , and . In certain embodiments, the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3 is , R1is selected from:, and . In certain embodiments, the present disclosure is directed to a compound of formula(II) or a pharmaceutically acceptable salt thereof: wherein when R3 is , R1isIn certain embodiments, the present disclosure is directed to a compound of formula(II), or a pharmaceutically acceptable salt thereof: wherein when R3 is , R1is. In certain embodiments, the present disclosure is directed to a compound of formula(II), or a pharmaceutically acceptable salt thereof: wherein when R3 is , R1is, In certain embodiments, the present disclosure is directed to a compound of formula(II), or a pharmaceutically acceptable salt thereof: wherein when R3 is , R1isselected from and . In certain embodiments, the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3a and R2form a bond toform a 5- or 6-membered heterocyclyl, R1is . In certain embodiments, the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3a and R3b combine toform a bridge, R1is . In certain embodiments, the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when R3c forms a bond with R5or R7to form a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl or C5-C12cycloalkyl, wherein the 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl or C5-C12 cycloalkyl is optionally substituted with one or more groups selected from C1-6alkyl, -OH, =O, C1-6alkoxy, and halogen, R1is selected from:, and . In certain embodiments, the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein ring A is a 5- or 6- membered heterocyclyl ring comprising one to three heteroatoms selected from N, O, or S; wherein when ring A is a 5-membered heterocyclyl ring and contains one heteroatom, ring A isselected from where X’ and X” are C and where X’ and X” are C; whereinwhen ring A is where X’ and X” are C, R4is , and Z is O, R7 is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C3-6 alkyl, C2-6alkynyl, C1-6haloalkyl,C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C4-C8cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, C3-C8 spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein whenring A is where X’ and X” are C and R4is , R7is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, C3-C8 spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein when ring A is a 5- membered heterocyclyl ring and contains two heteroatoms ring A is selected fromN and X is C where X is C and X is N and where X is C and X is N;or , and Z is O, R7is selected from -H, -OH, -COOH, -NH2, - CN, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C2-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, C3-C8 spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein when ring A is a 5-membered heterocyclyl ring andcontains three heteroatoms, ring A is where X’ is C and X” is N; wherein when Rring A is 6-membered heterocyclyl ring, ring A is where X’ and X” are C and Z isN; wherein when ring A is where X’ and X” are C and R4is , R7 is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, C3-C8 spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said ring A is optionally substituted with one or more groups selected from =O, C1-6alkyl, C2- C6alkenyl, and C2-6alkynyl. In certain embodiments, the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein Ring A is a 5- membered heterocyclyl ring comprising one to three heteroatoms selected from N, O, or S; wherein when ring A is a 5-membered heterocyclyl ring and contains one heteroatom, ring A isselected from where X’ and X” are C and where X’ and X” are C; whereinwhen ring A is where X’ and X” are C, R4is , and Z is O, R7 is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C3-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C4-C8 cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, C3-C8 spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein whenring A is where X’ and X” are C and R4is , R7is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, and 4-, 5-, or 6- memberedheterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, C3-C8 spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein when ring A is a 5- membered heterocyclyl ring and contains two heteroatoms ring A is selected fromN and X is C, where X is C and X is N, and where X is C and X is N;or , and Z is O, R7is selected from -H, -OH, -COOH, -NH2, - CN, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C2-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, C3-C8 spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein when ring A is a 5-membered heterocyclyl ring andcontains three heteroatoms, ring A is where X’ is C and X” is N; wherein the said ring A is optionally substituted with one or more groups selected from =O, C1-6alkyl, C2- C6alkenyl, and C2-6alkynyl. In certain embodiments, the present disclosure is directed to a compound of formula (II) or a pharmaceutically acceptable salt thereof: wherein ring A is selected from:In certain embodiments, the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein Ring A is a 6- membered heterocyclyl ring comprising one to three heteroatoms selected from N, O, or S; whereinwhen R ring A is 6-membered heterocyclyl ring, ring A is where X’ and X” are Cand Z is N; wherein when ring A is where X’ and X” are C and R4is , R7 is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, and 4-, 5- , or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, C3-C8spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said ring A is optionally substituted with one or more groups selected from =O, C1-6alkyl, C2- C6alkenyl, and C2-6alkynyl. In certain embodiments, the present disclosure is directed to a compound of formula(II), or a pharmaceutically acceptable salt thereof: wherein ring A is . In certain embodiments, the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when ring A is where X’ and X” are C, the compound of formula (II) or a pharmaceutically acceptable salt thereof comprises one or more of: Z is substituted with R1a or -CH2R1a, R3a and R3b are halogen, R5,R6, or R7 is a 4-, 5-, or 6- membered heterocyclyl ring, R3 is , R4is, , or where U and Y are C, where Uis C and Y is N, or R3 is where U is N and Y is C, or a combination thereof. In certain embodiments, the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein when ring A is where X’ and X” are C , the compound of formula (II) or a pharmaceutically acceptable salt thereof comprises a ring A substituted with a C2-C6alkenyl. In certain embodiments, the present disclosure is directed to a compound of formula(II), or a pharmaceutically acceptable salt thereof: wherein when ring A is where X’ is N and X” is C, the compound of formula (II) or a pharmaceutically acceptable salt thereof comprises one or more of: R3a and R2form a bond to form a 5- or 6-membered heterocyclyl, R and R combine to f3a 3b orm a bridge, R3 is , R4is, , or , R5, R6, or R7 a 4-, 5-, or 6- membered heterocyclyl ring, R3c forms a bond with R5 to form a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl or C5-C12 cycloalkyl, or a combination thereof. In certain embodiments, the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof: wherein the compound is selected from:3. Methods of Use In certain embodiments, the present disclosure is directed to a method of modulating USP1 activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure is directed to a method of inhibiting USP1 activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure is directed to a method of treating a disorder or disease with a USP1 inhibitor in a subject, comprising administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure is directed to a method of treating cancer with a USP1 inhibitor in a subject, comprising administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure is directed to a method of treating cancer with a USP1 inhibitor in a subject, comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the cancer is characterized by over expression of USP1. In certain embodiments, the present disclosure is directed to a method treating cancer with a USP1 inhibitor in a subject, comprising administering a compound of formula (I), ora pharmaceutically acceptable salt thereof, wherein the cancer characterized by overexpression of USP1 is selected from prostate, breast, ovarian, non-small cell lung cancer, mesothelioma, Merkel cell carcinoma, synovial sarcoma, renal cell carcinoma, and osteosarcoma. In certain embodiments, the present disclosure is directed to a use of a compound of formula (I), or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer. In certain embodiments, the present disclosure is directed to a use of a compound of formula (I), or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer, wherein the cancer is characterized by overexpression of USP1. In certain embodiments, the present disclosure is directed to a process to manufacture a compound of formula (I), or a pharmaceutically acceptable salt thereof. 4. Examples The following Examples are presented by way of illustration, not limitation. One skilled in the art can modify the procedures set forth in the illustrative examples to arrive at the desired products.

[0001] Table 1: Exemplary compounds.Table 2: Abbreviations Used.Synthetic Examples General Procedures LCMS are recorded for the ion observed and could include M+H+, M+Na+, M+NH4+as well as common fragmentations like –Boc, –tBu, –NH3, –OH.1H NMRspectra is reported as observed, samples run in protic solvents or CDCl3may lack signals for exchangeable protons. General Procedure A Imidazole FormationTo a stirred suspension of dibromoketone (1.40 equiv.) in water (1.05 M) was added sodium acetate (1.60 equiv.) and the mixture was stirred at 100 °C for 1 h. The reaction was cooled to 23 °C and a solution of aldehyde (1.0 equiv.) in MeOH and 25% aqueous ammonia solution (1:1, 0.4 M ) was added. The reaction mixture was stirred at room temperature for 1 h and then stirred at 100 °C for 2 ^ 16 h. The reaction was cooled to 23 °C and the MeOH was removed under reduced pressure. The aqueous phase was extracted with EtOAc and the organics were washed with sat. sodium bicarbonate, brine, dried over magnesium or sodium sulfate, filtered and concentrated under reduced pressure. General Procedure B Imidazole AlkylationTo a stirred solution of imidazole in acetonitrile or N,N-dimethylformamide (0.4 M) was added Cs2CO3 (3.0 equiv.) at 0 °C followed by the alkyl halide (3.0 equiv.) and the mixture was heated at 90 °C for 24 h. The reaction was cooled to 23 °C and extracted with EtOAc. The organics were washed with sat. sodium bicarbonate, brine, dried over magnesium or sodium sulfate, filtered and concentrated under reduced pressure. The reaction mixture was^quenched with saturated ammonium chloride solution^and extracted with EtOAc.^The combined organic layers were washed with water, brine, dried over anhydrous sodium or magnesium sulfate, filtered, and concentrated under reduced pressure. General Procedure C Reduction of Nitriles or EstersTo a stirred solution of the benzonitrile (1.0 equiv.) in THF (0.3 M) was added LiAlH4 (1.2 equiv, 2.0 M in THF) or diisobutylaluminum hydride (1.0 M in hexane, 3.0 equiv.) at 0 ºC and the reaction mixture was warmed to 23 °C and stirred for 1 ^ 4 h. The reaction mixture was^quenched with saturated ammonium chloride solution^and extracted with EtOAc.^The combined organic layers were washed with water, brine, dried over anhydrous sodium or magnesium sulfate, filtered, and concentrated under reduced pressure. General Procedure D Raney Ni Reduction of NitrilesTo solution of the benzonitrile (1.0 equiv.) in EtOAc and 25% aq. ammonia solution (5:1, 0.3 M final concentration) stirring at 23 °C was added Raney nickel (85%, 5.0 equiv.) and the mixture was stirred under H2 (Parr reactor, 60 psi) for 16 h. The mixture was filtered through celite and the bed was thoroughly washed with ethanol followed by EtOAc. The filtrate was concentrated under reduced pressure. General Procedure E SNAr SubstitutionTo a stirred solution of amine (1.0 equiv.) dissolved in N,N-dimethylformamide (0.15 M) or acetonitrile (0.15 M) at 23 °C was added N,N-diisopropylethylamine (3.0 equiv) followed by the substituted pyrimidine (1.0 equiv.) and the reaction mixture was stirred at 50-100 °C for 16 h. Alternatively, to the alcohol (1.0 equiv.) dissolved in N,N- dimethylformamide was added sodium hydride (1.5 equiv.) and the mixture was stirred at 23 °C for 15 min. The substituted purine was added (1.0 equiv.) and the reaction was heated at 50-100 °C for 1 ^ 16 h. The reactions were concentrated under reduced pressure or extracted with EtOAc then washed with water, brine, dried over anhydrous sodium or magnesium sulfate, filtered, and concentrated under reduced pressure. General Procedure F Suzuki CouplingTo a stirred solution of the aryl halide (1.0 equiv.) and the boronic acid or ester (2.0 equiv.) in 1,2-dimethoxyethane / water (6:1, 0.1 M), or 1,4-dioxane / water (6:1, 0.1 M) was added potassium carbonate (2.5 equiv.) or Cs2CO3 (2.5 equiv.) at 23 °C. The reaction mixture was degassed with nitrogen gas for 10 min before adding the Pd catalyst (0.10 equiv.). The reaction mixture was further degassed with nitrogen gas for an additional 5 min and then heated at 100 °C for 1 ^ 16 h. The reactions were concentrated under reduced pressure or extracted with EtOAc then washed with water, brine, dried over anhydrous sodium or magnesium sulfate, filtered, and concentrated under reduced pressure. General Procedure G SNAr SubstitutionTo a stirred solution of heteroaryl^(1.0 equiv) in dimethylformamide (10.0 mL), was added Cs2CO3^(1.5 equiv) and ArylFluoride (1.0 equiv)^at 25 °C. The reaction mixture was stirred at 80^°C for 2^h.^ The reactions were concentrated under reduced pressure or extracted with EtOAc then washed with water, brine, dried over anhydrous sodium or magnesium sulfate, filtered, and concentrated under reduced pressure. Synthesis of Intermediates: Intermediate A Synthesis of (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine. Intermediate AStep 1: Preparation of 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile. Intermediate A.1To a stirred suspension of 3,3-dibromo-1,1,1-trifluoropropan-2-one (173 g, 641 mmol) in water (600 mL) was added sodium acetate (60.1 g, 732 mmol) and stirred at 100 °C for 1 h. The reaction mixture was cooled to 23 °C and a solution of 4-formylbenzonitrile (60.0 g, 457 mmol) in MeOH (600 mL) and 25% aqueous ammonia solution (600 mL) was added. The resulting reaction mixture was stirred at room temperature for 1 h and then stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature and the MeOH was removed under reduced pressure. The resulting solution was diluted with water (1000 mL) and extracted with EtOAc (2 x 1000 mL). The combined organic phases were washed with water (200 mL), brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and The crude product was purified by flash chromatography (30% EtOAc in petroleum ether) to afford 4-(4- (trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (51.0 g) as a pale yellow solid. LCMS observed m / z = 238.07 [M+H]+. Step 2: Preparation of 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzonitrile. Intermediate A.2To a stirred solution of 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (20 g, 84.32 mmol) in tetrahydrofuran (200 mL) was added sodium hydride (6.07 g, 252.97 mmol) at 0 °C and stirred for 15 minutes before adding methyl iodide (7.9 mL, 126.48 mmol). The reaction mixture was stirred at 0 °C for 5 h. After completion, the reaction mixture was quenched with cold water (50 mL), extracted with EtOAc (500 mL x 2). The combined organic layer was washed with water (200 mL), brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and The crude product was purified by flash chromatography (30% EtOAc in petroleum ether) to afford 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (15.5 g) as a pale yellow solid. LCMS observed m / z = 252.15 [M+H]+. Step 3: Preparation of (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)- methanamine.Intermediate ATo a solution of 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (15.5 g, 61.70 mmol) in EtOAc (150 mL) and 25% aq. ammonia solution (30 mL) stirring at 23 °C was added Raney nickel (85%, 15 g) and the mixture was stirred under H2 (Parr reactor, 60 psi) atmosphere for 16 h. Upon completion, the mixture was filtered through celite and the bed was thoroughly washed with ethanol followed by EtOAc. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (10% MeOH in dichloromethane eluent) to afford (4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)phenyl)-methanamine (9.60 g) as a pale yellow solid.1H NMR (DMSO-d6, 400 MHz) δ 7.92 (d, J = 0.8 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 3.82 (s, 2H), 3.77 (s, 3H). LCMS observed m / z = 256.06 [M+H]+. Intermediate B Synthesis of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine. Intermediate BThe title compound was prepared using a similar procedure as Intermediate A, replacing methyl iodide with 2-iodopropane and using general procedure C to reduce the nitrile.1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 1.2 Hz, 1H), 7.55 – 7.50 (m, 4H), 4.50 – 4.43 (m, 1H), 4.29 – 4.27 (m, 2H, D2O exchange protons), 3.88 (s, 2H), 1.40 (d, J = 6.8 Hz, 6H). LCMS observed m / z = 284.32 [M+H]+. Intermediate C Synthesis of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl). Intermediate CThe title compound was prepared using a similar procedure as Intermediate A, replacing 4-formylbenzonitrile with methyl 4-formylbenzoate and using General Procedure C (diisobutyl aluminum hydride) to reduce the ester.1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 0.8 Hz, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 5.31 (t, J = 5.8 Hz, 1H), 4.58 (d, J = 5.6 Hz, 2H), 4.51 – 4.44 (m, 1H), 1.40 (d, J = 6.8 Hz, 6H). LCMS observed m / z = 285.18 [M+H]+. Intermediate D Preparation of 2-(4-(chloromethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H- imidazole. Intermediate DTo a solution of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanol (7.00 g, 24.6 mmol, Intermediate C) in 1,2-dichloroethane (140 mL) was added thionyl chloride (5.35 mL, 73.9 mmol ) at 23 °C and reaction mixture was heated to 50 °C for 1 h. After completion, the reaction mixture was evaporated under vacuum and quenched with cold-water (100 mL) and extracted with dichloromethane (2 x 100 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and The crude product was purified by flash chromatography (silica gel, 10% EtOAc in petroleum ether) to afford 2-(4-(chloromethyl)phenyl)-1-isopropyl-4- (trifluoromethyl)-1H-imidazole (7.2 g) as an off-white solid.1H NMR (400 MHZ, DMSO- d6) δ 8.19 (d, J = 1.2 Hz, 1H), 7.59 (s, 4H), 4.86 (s, 2H), 4.52 – 4.45 (m, 1H), 1.41 (d, J = 6.4 Hz, 6H). LCMS observed m / z = 303.32 [M+H]+. Intermediate E Synthesis of 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-N- methyl-methanamine•HCl. Intermediate EStep 1: Preparation of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzaldehyde. Intermediate E.1To a stirred solution of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanol (1.80 g, 6.33 mmol, Intermediate C) in dichloromethane (25.0 mL) at 0 °C under a nitrogen atmosphere, Dess-Martin periodinane (0.990 g, 9.50 mmol) was added. The resulting reaction mixture was stirred at 23 °C for 2 h. After completion, the reaction mixture was quenched with a saturated ammonium bicarbonate solution (20 mL). The product was extracted with dichloromethane (50 mL x 2). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was triturated with pentane to afford 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (1.70 g) as an off-white solid. LCMS observed m / z = 283.24 [M+H]+. Step 2: Preparation of 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)-N-methyl-methanamine•HCl. Intermediate ETo a stirred solution of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzaldehyde (1.70 g, 6.02 mmol) and methylamine hydrochloride (0.810 g, 12.0 mmol) in MeOH (25.0 mL) at 0 °C and stirred for 30 min before adding sodium cyanoborohydride (1.14 g, 18.1 mmol). The resulting reaction mixture was stirred at 23 °C for 16 h. After completion, the reaction mixture was quenched with cold water (25 ml) and then the MeOH was concentrated under reduced pressure. The material was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in 4 M HCl in dioxane (5.0 ml) and the resulting reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was triturated with diethyl ether (5 mL)to afford 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-N- methylmethanamine•HCl (1.20 g) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.11 (br s, 2H), 8.21 (d, J = 0.8 Hz, 1H), 7.68 – 7.64 (m, 4H), 4.50 – 4.43 (m, 1H), 4.20 (t, J =5.8 Hz, 2H), 2.59 (t, J = 5.2 Hz, 3H), 1.42 (d, J = 6.8 Hz, 6H). LCMS observed m / z = 298.22 [M+H]+. Intermediate F Synthesis of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- methylphenyl)methanol. Intermediate FThe title compound was prepared using a similar procedure as Intermediate A, replacing 4-formylbenzonitrile with methyl 4-formyl-3-methylbenzoate and using General Procedure C to reduce the ester (NaBH4).1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 1.2 Hz, 1H), 7.32 (s, 1H), 7.25 (s, 2H), 5.27 (t, J = 5.4 Hz, 1H), 4.55 (d, J = 5.2 Hz, 2H), 4.03 – 3.97 (m, 1H), 2.09 (s, 3H), 1.32 (d, J = 6.8 Hz, 6H). LCMS observed m / z = 299.13 [M+H]+. Intermediate G Synthesis of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- methylphenyl)-methanamine•HCl. Intermediate GStep 1: Preparation of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzonitrile. Intermediate G.1To a stirred solution of 4-bromo-3-methylbenzonitrile (5.00 g, 25.5 mmol) in N,N- dimethylformamide (50.0 mL) was added bis(pinacolato)diboron (7.12 g, 28.1 mmol),followed by the addition of potassium acetate (5.00 g, 51.0 mmol) at 23 °C. The resultant suspension was purged with nitrogen gas for 20 min and subsequently [1,1'- bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (1.04 g, 1.27 mmol) was added. Then the reaction mixture was stirred at 100 °C for 16 h. The reaction was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (50 mL), brine (50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified using flash chromatography (silica gel, 10% EtOAc in petroleum ether) to afford 3- methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (3.50 g) as a light green solid.1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 3.0 Hz, 2H), 2.55 (s, 3H), 1.35 (s, 12H). Step 2: Preparation of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- methyl-benzonitrile. Intermediate G.2To a stirred ^solution of^ 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzonitrile (1.00 g, 4.11 mmol) in^1,4-dioxane^(10.0 mL) and water (1.00 mL) was added^ 2-bromo-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (1.16 g, 4.50 mmol), followed by^the addition of potassium carbonate (1.13 g, 8.22 mmol) at 23 °C. The reaction mixture was then purged with nitrogen gas for 20 min.^Subsequently [1,1'- bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (0.336 g, 0.411 mmol) was added and the resultant mixture was stirred at 90 °C for 6 h. The reaction mixture was quenched with cold-water (20^mL) and extracted with EtOAc^(3^x 20^mL).^The combined organic layer was washed with water (50^mL), brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 10–20% EtOAc in petroleum ether) to afford^4- (1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-methylbenzonitrile (1.10 g) as a brown solid. LCMS observed m / z = 294.26 [M+H]+. Step 3: Preparation of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- methylphenyl)-methanamine•HCl. Intermediate GTo a stirred solution of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- methylbenzonitrile (1.10 g, 3.75 mmol) in^tetrahydrofuran (17.0 mL) was added lithium aluminum hydride (15.0 mL, 1M solution in THF, 15 mmol) at 0 °C. Then the reaction mixture was brought to 25 °C and stirred for 2 h. On completion, the reaction mixture was^quenched with saturated NH4Cl solution^(10^mL) and extracted with EtOAc^(2^x 50^mL).^The combined organic layer was washed with water (20^mL), brine (20^mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in 4M hydrochloric acid solution in dioxane (10 mL). The mixture was stirred at 25 °C^for 1 h and^then concentrated under reduced pressure. Subsequently diethyl ether (5 mL) was added to the residue and the precipitated solid was filtered. The filtered residue was washed further with n-pentane (2 x 10 mL) and dried to afford^(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- methylphenyl)methanamine•HCl (0.87 g)^as an off-white solid.1H NMR (400 MHz, DMSO-d6,) δ^ 8.35 (br s, 3H), 8.18 (s, 1H), 7.50 (s, 1H), 7.45 – 7.40 (m, 2H), 4.08 (q, J = 5.7 Hz, 2H), 4.00 – 3.93 (m, 1H), 2.13 (s, 3H), 1.34 (d, J = 6.8 Hz, 6H). LCMS observed m / z = 298.18 [M+H]+. Intermediate H Synthesis of 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- methylphenyl)-N-methylmethanamine•TFA. Intermediate HStep 1: Preparation of tert-butyl (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)-3-methylbenzyl)carbamate. Intermediate H.1A stirred solution of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- methylphenyl)methanamine (1.80 g, 6.05 mmol) in tetrahydrofuran (36.0 mL) was prepared and cooled to 0 °C. Triethylamine (2.50 mL, 18.2 mmol) was added followed by 4- dimethylaminopyridine (0.0740 g, 0.600 mmol) to the reaction mixture. Then, di-tert-butyl dicarbonate (1.45 mL, 6.66 mmol) was added, and the mixture was stirred at 25 °C for 4 h. After completion of the reaction, the mixture was diluted with cold water (10 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl (4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)-3-methylbenzyl)carbamate (1.20 g) as a yellow liquid. LCMS observed m / z = 398.83 [M+H]+. Step 2: Preparation of tert-butyl (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)-3-methylbenzyl)(methyl)carbamate. Intermediate H.2To a solution of tert-butyl (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- methylbenzyl)carbamate (1.30 g, 3.27 mmol) in tetrahydrofuran (10.0 mL) was added sodium hydride (0.400 g, 9.82 mmol) at 0 °C, and the mixture was stirred for 20 min at the same temperature. Next, iodomethane (0.460 g, 3.27 mmol) was added to the reaction mixture, which was then stirred at room temperature for 16 h. After completion of the reaction, the mixture was quenched with a saturated ammonium chloride solution (5 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 15–20% EtOAc in petroleum ether) to afford tert-butyl (4-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-methylbenzyl)-(methyl)carbamate (1.12 g) as a brown solid. LCMS observed m / z = 412.86 [M+H]+. Step 3: Preparation of 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- methylphenyl)-N-methylmethanamine•TFA. Intermediate HA stirred solution of tert-butyl (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)-3-methylbenzyl)carbamate (1.12 g, 2.81 mmol) in dichloromethane (23.0 mL) was treated with trifluoroacetic acid (0.400 g, 5.63 mmol) at 0 °C. The mixture was then stirred at 23 °C for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was triturated with diethyl ether (10 mL). The solid precipitate was filtered and dried to afford 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-methylphenyl)-N-methylmethanamine (1.10 g) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ 8.86 (br s, 2H), 8.19 (s, 1H), 7.49 (s, 1H), 7.46 (s, 2H), 4.18 (t, J = 5.8 Hz, 2H), 4.01 – 3.95 (m, 1H), 2.61 (t, J = 5.4 Hz, 3H), 2.13 (s, 3H), 1.34 (d, J = 6.8 Hz, 6H). LCMS observed m / z = 312.34 [M+H]+. Intermediate I Synthesis of (2-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanol. Intermediate IThe title compound was prepared using a similar procedure as Intermediate A, replacing 4-formylbenzonitrile with methyl 2-fluoro-4-formylbenzoate and using General Procedure C to reduce the ester (LiAlH4).1H NMR (400 MHz, CD3OD) δ 7.95 (s, 1H), 7.70 – 7.66 (m, 1H), 7.41 – 7.38 (m, 1H), 7.34 – 7.31 (m, 1H), 4.76 (s, 2H), 4.58 (septet, J = 6.6 Hz, 1H), 1.48 (d, J = 6.6 Hz, 6H). LCMS observed m / z = 303.1 [M+H]+. Intermediate J Synthesis of (2-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)-methanamine. Intermediate JThe title compound was prepared using a similar procedure as Intermediate A, replacing 4-formylbenzonitrile with 2-fluoro-4-formylbenzonitrile and using General Procedure C to reduce the nitrile (LiAlH4).1H NMR (400 MHz, CD3OD) δ 7.94 (s, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.39 – 7.32 (m, 2H), 4.5 (septet., J = 6.6 Hz, 1H), 3.94 (s, 2H), 1.48 (d, J = 6.6 Hz, 6H). LCMS observed m / z = 302.2 [M+H]+. Intermediate K Synthesis of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanethiol. Intermediate KStep 1: Preparation of S-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl) ethanethioate. Intermediate K.1To a stirred solution of 2-(4-(chloromethyl)phenyl)-1-isopropyl-4- (trifluoromethyl)-1H-imidazole (80.0 mg, 0.264 mmol, Intermediate D) in dimethyl sulfoxide (1.00 mL) was added potassium iodide (46.0 mg, 0.281 mmol) followed by potassium thioacetate (35.0 mg, 0.310 mmol). The reaction mixture was stirred at 23 °C for 16 h. Upon completion, reaction mixture was quenched with cold water (3 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with water (10 mL), brine (5 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to afford S-(4-(1-isopropyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl) ethanethioate (0.600 g) as a tan solid. The material was used in the subsequent reaction. LCMS observed m / z = 343.4 [M+H]+.Step 2: Preparation of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanethiol. Intermediate KTo a solution of S-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl) ethane-thioate (60.0 mg, 0.175 mmol) in MeOH (2.0 mL) and water (1.0 mL) stirring at 23 °C was added potassium carbonate (72.0 mg, 0.526 mmol) and the reaction mixture was stirred for 16 h. Upon completion, reaction mixture was concentrated under reduce pressure and the residue was dissolved in EtOAc (30 mL) and washed with water (10 mL), brine (5 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 20–25% EtOAc in petroleum ether) to afford (4-(1-isopropyl-4-(trifluoromethyl)-1H- imidazol-2-yl)phenyl)methanethiol (30.0 mg) as a white solid. LCMS observed m / z = 301.3 [M+H]+. Intermediate L Synthesis of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1- yl)methanamine. Intermediate LStep 1: Preparation of 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-1- carboxamide. Intermediate L.1To a stirred solution of 3,3-dibromo-1,1,1-trifluoropropan-2-one (15.3 g, 56.8 mmol) in water (100 mL) was added sodium acetate (46.6 g, 56.8 mmol) at 0 °C. The reaction mixture was heated to 100°C for 1 h. The reaction was cooled to 0 °C and a solution of methyl 4-formylcubane-1-carboxylate (9.00 g, 47.3 mmol) in MeOH (180 mL)and ammonia (180 mL, 25% in water) was added. The reaction mixture was stirred at 23 °C for 16 h. After completion, the precipitated solid was filtered off and dried to 4-(4- (trifluoromethyl)-1H-imidazol-2-yl)cubane-1-carboxamide (4.50 g) as an off-white solid. The compound was used in the next step without further purification. LCMS observed m / z = 280.19 [M-H]-. Step 2: Preparation of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cubane- 1-carboxamide. Intermediate L.2To a stirred solution of 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-1- carboxamide (4.50 g, 16.0 mmol) in N,N-dimethylformamide (50.0 mL) stirring at 0 °C were added Cs2CO3 (7.82 g, 24.0 mmol) and 2-iodopropane (3.26 g, 19.2 mmol). The reaction mixture was warmed to 60 °C and stirred for 12 h. After completion, the reaction mixture was concentrated and the residue was diluted with water (100 mL) and the solids were collected via filtration. The solid was washed with n-pentane and dried to afford 4-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-1-carboxamide (2.80 g) as white solid. The material was used without further purification. LCMS observed m / z = 324.41 [M+H]+. Step 3: Synthesis of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1- yl)methanamine. Intermediate LTo a stirred solution of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)cubane-1-carboxamide (2.80 g, 8.66 mmol)^in dichloromethane (30.0 mL) was added chlorotrimethylsilane (1.66 mL, 13.0 mmol) at 0 °C and the mixture was stirred for 10 min. Lithium aluminium hydride (8.66 mL, 2.0 M solution in THF, 17.3 mmol) was added and the reaction mixture was warmed to 23 °C and stirred for 3 h. After completion, the reactionmixture was quenched with sat. aq. sodium sulfate solution (25 mL) and diluted withdichloromethane (100 mL). The resulting mixture was filtered through celite washingthoroughly with dichloromethane (2 x 50 mL).^The filtrate was concentrated under reduced pressure and the^residue was purified by reverse phase chromatography (mobile phase: 20- 100% acetonitrile in water w / 0.1% formic acid) to afford 4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)methanamine (0.900 g, formate salt) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.00 (s, 1H), 3.70 – 3.21 (br s, 2H), 4.20 – 4.17 (m, 3H), 4.06 – 3.99 (m, 4H), 3.04 (s, 2H), 1.43 – 1.41 (m, 6H). LCMS observed m / z = 310.321 [M+H]+. Intermediate M Synthesis of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1- yl)methanol. Intermediate MStep 1: Preparation of methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-1- carboxylate. Intermediate M.1A stirred solution of 3,3-dibromo-1,1,1-trifluoropropan-2-one (30.0 g, 110 mmol) in water (210 mL) was prepared and cooled to 0 °C. Sodium acetate (9.60 g, 118 mmol) was then added to the reaction mixture, which was subsequently stirred at 100 °C for 1 hour, then cooled to 0 °C. A solution of methyl 4-formylcubane-1-carboxylate (14.0 g, 73.6 mmol) in MeOH (210 mL) and 25% aqueous ammonia solution (210 mL) was added to the reaction and the mixture was stirred at 0 °C for 1 hour. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove MeOH. The material was then extracted with EtOAc (3 x 250 mL), and the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with n-pentane to afford methyl 4-(4- (trifluoromethyl)-1H-imidazol-2-yl)cubane-1-carboxylate (12.0 g) as an off-white solid. LCMS observed m / z = 296.97 [M+H]+. Step 2: Preparation of methyl 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)cubane-1-carboxylate.Intermediate M.2To a stirred solution of methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-1- carboxylate (12.0 g, 40.5 mmol) in N,N-dimethylformamide (120 mL) stirring at 0 °C were added Cs2CO3 (39.6 g, 122 mmol) and 2-iodopropane (34.4 g, 203 mmol). The reaction mixture was then heated at 90 °C for 16 h. After completion, the reaction mixture was quenched with cold water (250 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 10–20% EtOAc in petroleum ether) to afford methyl 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-1- carboxylate (5.50 g) as a pale brown solid. LCMS observed m / z = 339.62 [M+H]+. Step 3: Preparation of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban- 1-yl)methanol. Intermediate MA solution of methyl 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cubane- 1-carboxylate (2.00 g, 5.91 mmol) in tetrahydrofuran (20 mL) and MeOH (2.0 mL) was prepared at 0 °C. NaBH4(0.670 g, 17.7 mmol) was then added to the solution, and the reaction mixture was stirred at 23 °C for 16 h. After completion, the reaction mixture was diluted with cold water (25 mL) and concentrated under reduced pressure to remove MeOH. The mixture was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 35–50% EtOAc in petroleum ether) to afford (4-(1-isopropyl- 4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)methanol (1.10 g) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J = 1.2 Hz, 1H), 4.57 (t, J = 5.4 Hz, 1H), 4.16 (t, J = 5.0 Hz, 3H), 4.08 – 4.03 (m, 1H), 3.87 (t, J = 4.8 Hz, 3H), 3.57 (d, J = 5.2 Hz, 2H), 1.41 (d, J = 6.8 Hz, 6H). LCMS observed m / z = 311.22 [M+H]+.Intermediate N Synthesis of 1-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)-N- methylmethanamine•HCl. Intermediate NThe title compound was prepared using a similar procedure as Intermediate E, replacing (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (Intermediate C) with (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1- yl)methanol (Intermediate M).1H NMR (400 MHz, DMSO-d6) ^ 7.98 (d, J = 0.8 Hz, 1H), 4.26 – 4.16 (m, 3H), 4.09 – 4.02 (m, 1H), 3.89 – 3.87 (m, 3H), 2.74 (s, 2H), 2.33 (s, 3H), 1.41 (d, J = 6.8 Hz, 6H). LCMS observed m / z = 324.38 [M+H]+. Intermediate O Synthesis of 1-isopropyl-2-(4-(pyrrolidin-2-yl)phenyl)-4-(trifluoromethyl)-1H- imidazole•TFA. Intermediate OStep 1: Preparation of tert-butyl 2-(4-bromophenyl)pyrrolidine-1-carboxylate. Intermediate O.1To a stirred solution of 2-(4-bromophenyl) pyrrolidine (1.00 mg, 4.42 mmol) and N,N-diisopropylethylamine (1.54 mL, 8.84 mmol) in dichloromethane (40.0 mL) at 0 °C was added di-tert-butyl bicarbonate (1.21 mL, 5.30 mmol) and the mixture was warmed to 23 °C and stirred for 2 h. Upon completion, the reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (2 x 60 mL). The combined organic phases were washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The material was purified by flashchromatography (silica gel, 8–10% EtOAc in petroleum ether) to afford tert-butyl 2-(4- bromophenyl) pyrrolidine-1-carboxylate (1.10 g) as a white solid. LCMS observed m / z = 270.1 [M-56+H]+. Step 2: Preparation of tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)-pyrrolidine-1-carboxylate. Intermediate O.2A stirred solution of tert-butyl 2-(4-bromophenyl) pyrrolidine-1-carboxylate (900 mg, 2.75 mmol) in 1,4-dioxane (30 mL) was prepared at 23 °C. Bis(pinacolato)diboron (840 mg, 3.31 mmol) and potassium acetate (670 mg, 6.89 mmol) were added and the mixture was purged with nitrogen gas for 30 minutes. 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) (200 mg, 0.276 mmol) was added, and the reaction was heated at 90 °C in a sealed tube for 16 h. After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 90 mL). The combined organic phases were washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)pyrrolidine-1-carboxylate. (900 mg) as a brown solid. The material was used without further purification. LCMS observed m / z = 374.2 [M+H]+. Step 3: Preparation of tert-butyl 2-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol- 2-yl)phenyl)-pyrrolidine-1-carboxylate. Intermediate O.3To a solution of tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl) pyrrolidine-1-carboxylate (800 mg, 2.14 mmol) in dioxane (24.0 mL) and water (6.0 mL) stirring at 23 °C was added 2-bromo-1-isopropyl-4-(trifluoromethyl)-1H- imidazole (660 mg, 2.57 mmol) and Cs2CO3 (1.74 g, 5.35 mmol). The mixture was purged with nitrogen gas for 30 minutes, then tetrakis(triphenylphosphine)palladium(0) (284 mg,0.214 mmol) was added, and the reaction was heated in a sealed tube at 90 °C for 16 h. Upon completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 90 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford tert-butyl 2-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl) phenyl)pyrrolidine-1-carboxylate (700 mg) as a brown solid which was used without further purification. LCMS observed m / z = 424.7 [M+H]+. Step 4: Preparation of 1-isopropyl-2-(4-(pyrrolidin-2-yl)phenyl)-4- (trifluoromethyl)-1H-imidazole•TFA. Intermediate OTo a stirred solution of tert-butyl 2-(4-(1-isopropyl-4-(trifluoromethyl)-1H- imidazol-2-yl) phenyl)pyrrolidine-1-carboxylate (700 mg, 1.65 mmol) in dichloromethane (20 mL) at 0 °C was added trifluoroacetic acid (2.00 mL). The reaction mixture was warmed to 23 °C and stirred for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to afford 1-isopropyl-2-(4-(pyrrolidin-2-yl) phenyl)-4-(trifluoromethyl)- 1H-imidazole•TFA (510 mg) as a brown solid. The material was used without further purification. LCMS observed m / z = 324.65 [M+H]+. Intermediate P Synthesis of 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethan- 1-amine. Intermediate PStep 1: Preparation of 1-isopropyl-4-(trifluoromethyl)-1H-imidazole. Intermediate P.1To a stirred solution of 4-(trifluoromethyl)-1H-imidazole (12.5 g, 91.8 mmol) in N,N-dimethylformamide (125 mL) at 0 °C was added Cs2CO3 (119 g, 367 mmol) and 2- iodopropane (27.0 mL, 275 mmol). The reaction mixture was then stirred at 23 °C for 16 h. After completion, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the product. The material was further purified by flash chromatography (12–15% EtOAc / petroleum ether eluent) to afford 1-isopropyl-4-(trifluoromethyl)-1H-imidazole (11.3 g) as a yellow liquid. LCMS observed m / z = 179.2 [M+H]+. Step 2: Preparation of 2-bromo-1-isopropyl-4-(trifluoromethyl)-1H-imidazole. Intermediate P.2To a stirred solution of 1-isopropyl-4-(trifluoromethyl)-1H-imidazole (6.00 g, 33.6 mmol) in tetrahydrofuran (120 mL) at –78 °C, a 2.6M solution of n-butyllithium in THF (26.1 mL, 84.1 mmol) was carefully added. The reaction mixture was then gradually warmed to 0 °C and stirred for 1.5 h. Next, N-bromosuccinimide (6.59 g, 37.0 mmol) was added at -78 °C, and the reaction mixture was subsequently brought to 23 °C and stirred for 16 h. After completion, the reaction mixture was quenched with a saturated ammonium chloride solution (25 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The material was purified by flash chromatography (8–10% EtOAc / petroleum ether eluent) to afford 2-bromo-1-isopropyl-4- (trifluoromethyl)-1H-imidazole (2.10 g) as a yellow liquid. LCMS observed m / z = 257.0 [M+H]+. Step 3: Preparation of 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)ethan-1-one. Intermediate P.3A stirred solution of 2-bromo-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (700 mg, 2.72 mmol) and (4-acetylphenyl)boronic acid (535 mg, 3.26 mmol) in 1,4-dioxane (8.00 mL) and water (2.00 mL) was prepared. The solution was purged with nitrogen gas for 10 minutes, followed by the addition of Cs2CO3(2.04 g, 6.26 mmol). Tetrakis(triphenylphosphine)palladium(0) (346 mg, 0.300 mmol) was added to the reaction and the mixture was heated at 150 °C for 30 minutes in a microwave reactor. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The product was purified by flash chromatography (silica gel, 10–20% EtOAc in petroleum ether) to afford 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethan-1-one (690 mg) as a yellow solid. LCMS observed m / z = 297.05 [M+H]+. Step 4: Preparation of 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)ethan-1-amine. Intermediate PTo a stirred solution of 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl) ethan-1-one (1.40 g, 4.72 mmol) in MeOH (14.0 mL) was added ammonium acetate (3.60 g, 47.2 mmol) at 23 °C. The reaction mixture was stirred for 30 min at 23 °C, followed by the addition of sodium cyanoborohydride (1.48 g, 23.6 mmol). The reaction mixture was then heated to 60 °C and stirred for 4 h. After completion, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 25 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The material was purified by flash chromatography (silica gel, 5–10% MeOH in dichloromethane) to afford 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)ethan-1-amine (0.600 g) as a white solid.1H NMR (400 MHz, DMSO-d6) ^ 8.20 (s, 1H), 7.63 (br s, 2H), 7.60 (s, 4H), 4.46 – 4.38 (m, 2H), 1.47 (d, J = 6.4 Hz, 3H), 1.41 (d, J = 6.8 Hz, 6H). LCMS observed m / z = 298.37 [M+H]+. Intermediate QPreparation of 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)ethan-1-ol. Intermediate QA stirred solution of 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl) phenyl) ethan-1-one (1.20 g, 4.05 mmol, Intermediate P.3) in MeOH (25.0 mL) was prepared and cooled to 0 °C. NaBH4 (0.306 g, 8.10 mmol) was then carefully added to the reaction mixture, which was subsequently stirred for 1 h at 0 °C. Once the reaction was complete, it was quenched with a saturated ammonium chloride solution (20 mL) and concentrated under reduced pressure. The resulting residue was extracted with EtOAc (3 x 100 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The material was purified by flash chromatography (silica gel, 25–30% EtOAc in petroleum ether) to afford 1-(4-(1-isopropyl- 4-(trifluoromethyl)-1H-imidazol-2-yl) phenyl)ethan-1-ol (0.800 g) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 1.2 Hz, 1H), 7.52 – 7.50 (m, 4H), 5.28 (d, J = 4.0 Hz, 1H), 4.83 – 4.77 (m, 1H), 4.52 – 4.45 (m, 1H), 1.41 (d, J = 6.8 Hz, 6H), 1.37 (d, J = 6.4 Hz, 3H). LCMS observed m / z = 299.017 [M+H]+. Intermediate R Synthesis of (6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3- yl)methanamine•HCl.Preparation of 5-bromo-2-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)pyridine. Intermediate R.1The title compound was prepared using a similar procedure as Intermediate A, replacing 4-formylbenzonitrile with 5-bromo-2-pyridinecarboxaldehyde and following General Procedures A and B. LCMS observed m / z = 334.19 [M+H]+. Step 3: Preparation of tert-butyl ((6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol- 2-yl)pyridin-3-yl)methyl)carbamate. Intermediate R.2To a stirred^solution of 5-bromo-2-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)pyridine (2.90 g, 8.68 mmol) in^1,4-dioxane (26.0 mL) and water (3.0 mL) was added^ potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (2.47 g, 10.4 mmol), followed by the addition of Cs2CO3^(7.07 g, 21.7 mmol) at 23 °C. The reaction mixture was purged with nitrogen gas for 30 min. Then cataCXium A Pd G3 (0.63 g, 0.87 mmol) was added under nitrogen atmosphere and the resulting reaction mixture was heated at 100 °C for 16 h. After completion, the reaction mixture quenched with water^(10^mL)^and extracted with EtOAc (3 x 20^mL). The combined organic phases were washed with water (20^mL), brine (20^mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 60% EtOAc in petroleum ether) to afford^tert-butyl((6-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)methyl)carbamate (1.57 g) as a yellow solid. LCMS observed m / z = 385.5 [M+H]+. Step 4: Preparation of (6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)pyridin-3-yl)methanamine•HCl. Intermediate RTo a stirred solution of tert-butyl ((6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol- 2-yl)pyridin-3-yl)methyl)carbamate (1.57 g, 4.08 mmol) in dichloromethane (20 mL) was added 4M hydrochloric acid solution in 1,4-dioxane (2.0 mL, 8.00 mmol) at 0 °C. Subsequently the reaction mixture was brought to 23 °C and stirred for 2 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue wastriturated with pentane (5 mL) to afford (6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)pyridin-3-yl)methanamine hydrochloride (1.10 g) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 1.2 Hz, 1H), 8.45 (br s, 3H), 8.27 (d, J = 0.8 Hz, 1H), 8.13 – 8.06 (m, 2H), 5.77 – 5.71 (m, 1H), 4.17 – 4.13 (m, 2H), 1.46 (d, J = 6.8 Hz, 6H). LCMS observed m / z = 285.23 [M+H]+. Intermediate S Synthesis of 1-(6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)- N-methyl-methanamine•HCl. Intermediate SThe title compound was prepared using a similar procedure as Intermediate H, replacing (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- methylphenyl)methanamine with (6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)pyridin-3-yl)methanamine hydrochloride (Intermediate R).1H NMR (400 MHz, DMSO- d6) 9.42 (br s, 2H), 8.81 (s, 1H), 8.28 (s, 1H), 8.12 (d, J = 1.2 Hz, 2H), 5.80 – 5.70 (m, 1H), 4.21 (br s, 2H), 2.58 (t, J = 5.4 Hz, 3H), 1.47 (d, J = 6.8 Hz, 6H). LCMS observed m / z = 299.17 [M+H]+. Intermediate T Synthesis of (6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3- yl)methanol. Intermediate TStep 1: Preparation of 6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)nicotinaldehyde. Intermediate T.1To a stirred solution of 5-bromo-2-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)pyridine (2.10 g, 6.28 mmol, Intermediate R.1) in diethyl ether (21.0 mL) at -78 °C was added n-butyl lithium (11.7 mL, 1.6 M in hexanes, 18.8 mmol) drop wise and the mixture was stirred for 15 min. N,N-dimethylformamide (9.7 mL, 31.4 mmol) was added and the reaction mixture was stirred at –78 °C for 3 h. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with EtOAc (50 mL x 2). The combined organic phases were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and The crude product was purified by flash chromatography (silica gel, 10–20% EtOAc in petroleum ether) to afford 6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)nicotinaldehyde (1.40 g) as an off-white solid. LCMS observed m / z = 283.98 [M+H]+. Step 2: Preparation of (6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)pyridin-3-yl)methanol. Intermediate TTo a stirred solution of 6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)nicotinaldehyde (1.40 g, 4.94 mmol) in MeOH (14.0 mL) was added NaBH4 (0.380 g, 9.88 mmol) at 0 °C portion wise and the reaction mixture was warmed to 23 °C and stirred for 2 h. After completion, the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with EtOAc (50 mL x 2). The combined organic phases were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure and The crude product was purified by flash chromatography (silica gel, 10–20% EtOAc in petroleum ether) to afford (6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3- yl)methanol (1.05 g) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 1.6 Hz, 1H), 8.21 (d, J = 1.2 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.88 (dd, J = 8.2, 2.2 Hz, 1H), 5.78-5.71 (m, 1H), 5.42 (t, J = 5.6 Hz, 1H), 4.60 (d, J = 5.2 Hz, 2H), 1.45 (d, J = 6.8 Hz, 6H). LCMS observed m / z = 286.09 [M+H]+. Intermediate UPreparation of (2-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrimidin-5- yl)methanamine•TFA. Intermediate UThe title compound was prepared using a similar procedure as Intermediate R, replacing 5-bromo-2-pyridinecarboxaldehyde with 5-bromo-2-pyrimidinecarboxaldehyde. 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 2H), 8.34 (s, 1H), 8.26 (br s, 3H), 5.52 – 5.45 (m, 1H), 4.20 (q, J = 5.5 Hz, 2H), 1.47 (d, J = 6.8 Hz, 6H). LCMS observed m / z = 286.33 [M+H]+. Intermediate V Synthesis of (5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazin-2- yl)methanamine•HCl. Intermediate VStep 1: Preparation of tert-butyl ((5-(hydroxymethyl)pyrazin-2- yl)methyl)carbamate. Intermediate V.1To a stirred solution of (5-chloropyrazin-2-yl)methanol (2.00 g, 13.8 mmol) and tert- butyl ((trifluoro-l-boraneyl)methyl)carbamate, potassium salt (8.20 g, 34.6 mmol) in 1,4- dioxane (50.0 mL) and water (10.0 mL), Cs2CO3 (9.02 g, 27.7 mmol) was added. The reaction mixture was purged with nitrogen gas for 20 minutes, followed by the addition of palladium(II) acetate (0.310 g, 1.38 mmol) and cataXCium-A (0.990 g, 2.77 mmol). The reaction mixture was then heated at 105 °C for 16 h in a sealed tube. The reaction was filtered through a celite bed and washed with EtOAc (100 mL). The filtrate was further washed with water (50 mL) and brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 70–90% EtOAc in petroleum ether) to affordtert-butyl ((5-(hydroxymethyl)pyrazin-2-yl)methyl)carbamate (2.50 g) as an off-white solid. LCMS observed m / z = 240.31 [M+H]+. Step 2: Preparation of tert-butyl ((5-formylpyrazin-2-yl)methyl)carbamate. Intermediate V.2To a stirred solution of tert-butyl ((5-(hydroxymethyl)pyrazin-2- yl)methyl)carbamate (2.40 g, 10.0 mmol) in dichloromethane (25.0 mL) at 0 °C under a nitrogen atmosphere, Dess-Martin periodinane (1.57 g, 15.1 mmol) was added slowly. The resulting reaction mixture was then stirred for 3 h at 0 °C. After completion, the reaction mixture was diluted with saturated ammonium bicarbonate solution and extracted with dichloromethane (100 mL x 2). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was then triturated with pentane to afford tert-butyl ((5-formylpyrazin-2-yl)methyl)carbamate (2.00 g) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.09 (s, 1H), 8.76 (s, 1H), 5.43 (br s, 1H), 4.59 (s, 2H), 1.47 (s, 9H). Step 3: Preparation of tert-butyl ((5-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazin- 2-yl)methyl)carbamate. Intermediate V.3A stirred solution of 3,3-dibromo-1,1,1-trifluoropropan-2-one (2.73 g, 10.1 mmol) in water (50.0 mL) was prepared at 0 °C. Anhydrous sodium acetate (0.830 g, 10.1 mmol) was then added to the solution, and the mixture was stirred at 100 °C for 1 h. The mixture was cooled to 0 °C and tert-butyl ((5-formylpyrazin-2-yl)methyl)carbamate (2.00 g, 8.43 mmol) in MeOH (50 mL) and 25% aqueous ammonia solution (20 mL) was added to the reaction mixture. The mixture was then stirred at 25 °C for 16 h. After completion, the reaction mixture was concentrated under reduced pressure, and the residue was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 50– 70% EtOAc in petroleum ether) to afford tert-butyl ((5-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazin-2-yl)methyl)carbamate (2.30 g) as an off-white solid. LCMS observed m / z = 344.23 [M+H]+. Step 4: Preparation of tert-butyl ((5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol- 2-yl)pyrazin-2-yl)methyl)carbamate. Intermediate V.4To a stirred solution of tert-butyl ((5-(4-(trifluoromethyl)-1H-imidazol-2- yl)pyrazin-2-yl)methyl)carbamate (2.30 g, 6.70 mmol) in N,N-dimethylformamide (25.0 mL) were added Cs2CO3 (6.55 g, 20.1 mmol) and 2-iodopropane (3.42 g, 20.1 mmol) at 0 °C. The reaction mixture was then stirred at 80 °C for 16 h. After completion, the reaction mixture was quenched with cold water (30 mL) and extracted with EtOAc (2 x 100 mL). The combined organics were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 10–20% EtOAc in petroleum ether) to afford tert-butyl ((5-(1-isopropyl-4-(trifluoromethyl)-1H- imidazol-2-yl)pyrazin-2-yl)methyl)carbamate (2.10 g) as a pale brown solid. LCMS observed m / z = 386.80 [M+H]+. Step 5: Preparation of (5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)pyrazin-2-yl)methanamine•HCl. Intermediate VA stirred solution of tert-butyl ((5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)pyrazin-2-yl)methyl)carbamate (1.50 g, 3.89 mmol) in dichloromethane (15.0 mL) was treated with a 4.0 M solution of hydrochloric acid in dioxane (2.00 mL, 8.00 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 2 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was subsequently triturated with pentane (5 mL) to afford (5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)pyrazin-2-yl)methanamine•HCl (1.01 g) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 9.25 (d, J = 1.2 Hz, 1H), 8.86 (d, J = 1.2 Hz, 1H), 8.57 (br s, 3H), 8.38 (d, J = 0.8 Hz, 1H), 5.59 – 5.52 (m, 1H), 4.35 (q, J = 5.7 Hz, 2H), 1.48 (d, J = 6.8 Hz, 6H). LCMS observed m / z = 286.17 [M+H]+. Intermediate W Preparation of 1-(5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazin-2- yl)-N-methyl-methanamine•HCl. Intermediate WThe title compound was prepared using a similar procedure as Intermediate S, replacing tert-butyl ((6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3- yl)methyl)carbamate with tert-butyl ((5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)pyrazin-2-yl)methyl)carbamate.1H NMR (400 MHz, DMSO-d6) δ 9.27 (d, J = 1.2 Hz, 1H), 9.24 (br s, 2H), 8.85 (d, J = 1.2 Hz 1H), 8.39 (s, 1H), 5.60 – 5.53 (m, 1H), 4.44 (s, 2H), 2.67 (s, 3H), 1.48 (d, J = 6.4 Hz, 6H). LCMS observed m / z = 300.33 [M+H]+. Intermediate X Synthesis of (4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)methanamine. Intermediate XStep 1: Preparation of 4-(5-hydroxy-3-(trifluoromethyl)-1H-pyrazol-1- yl)benzonitrile. Intermediate X.1A solution of 4-hydrazineylbenzonitrile (4.0 g, 30 mmol) and sodium hydroxide (1.22 g, 30.0 mmol) in ethanol (60 mL) was stirred at 23 °C for 40 min. To this was added a solution of ethyl 4,4,4-trifluoro-3-oxobutanoate (6.64 g, 36.1 mmol) in ethanol (20 mL) was added and the reaction mixture was refluxed for 24 h. The reactionmixture was cooled to room temperature and filtered through celite, the filtrate was concentrated under reduced pressure and the residue was dissolved in toluene (200 mL) and para-toluenesulfonic acid (0.57 g, 3.0 mmol) was added. The reaction mixture was stirred at 120 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was triturated with pentane (100 mL x 3) to afford 4- (5-hydroxy-3-(trifluoromethyl)-1H-pyrazol-1-yl) benzonitrile (4.0 g) as an off-white solid. LCMS observed m / z = 254.05 [M+H]+. Step 2: Preparation of 4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1- yl)benzonitrile. Intermediate X.2To the stirred solution of 4-(5-hydroxy-3-(trifluoromethyl)-1H-pyrazol-1- yl)benzonitrile (3.0 g, 12 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (0.28 g dispersion in mineral oil, 12 mmol) at 0 °C and the mixture was stirred for 10 min. Iodomethane (0.89 mL, 14 mmol) was added and the reaction was warmed to 23 °C and stirred for 16 h. The reaction mixture was quenched with cold water (100 mL), extracted with EtOAc (100 mL x 2). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by flash chromatography (silica gel, 30% EtOAc in petroleum ether) to afford 4-(5-methoxy-3- (trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (1.5 g) as an off-white solid. LCMS observed m / z = 268.30 [M+H]+. Step 3: Preparation of (4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)-methanamine. Intermediate XTo a stirred solution of 4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1- yl)benzonitrile (5.3 g, 20 mmol) in THF (60 mL) was added LiAlH4(15 mL, 2.0 M in THF, 24 mmol) at 0 ºC. The reaction mixture was stirred at room temperature for 4 h. The reactionmixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate and filtered. Filtrate was concentrated under reduced pressure. The residue was triturated with diethyl ether (300 mL x 3) and concentrated under reduced pressure to afford (4-(5-methoxy-3-(trifluoromethyl)-1H- pyrazol-1-yl)phenyl)-methanamine (2.3 g).1H NMR (400 MHz, DMSO-d6) δ 7.57 – 7.55 (m, 2H), 7.48 – 7.46 (m, 2H), 6.45 (s, 1H), 3.99 (s, 3H), 3.77 (s, 2H). LCMS observed m / z = 272.10 [M+H]+. Intermediate Y Synthesis of (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)methanamine•HCl. Intermediate YThe title compound was prepared using a similar procedure as Intermediate X, replacing 4, 4, 4-trifluoro-3-oxobutanoate with 1,1,1-trifluoropentane-2,4-dione and using general procedure E to reduce the nitrile.1H NMR (400 MHz, DMSO-d6) δ 7.55 – 7.18 (m, 4H), 6.75 (s, 1H), 3.85 (s, 2H), 2.33 (s, 3H). LCMS observed m / z = 256.06 [M+H]+. Intermediate Z Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-methyl-6- (methylsulfonyl)-7H-purine. Intermediate ZStep 1: Preparation of 2-chloro-7-methyl-6-(methylthio)-7H-purine. Intermediate Z.1To a stirred solution of 2,6-dichloro-7-methyl-7H-purine (5.00 g, 24.6 mmol) in tetrahydrofuran (100 mL) at 0 °C was added sodium thiomethoxide (1.73 g, 24.6 mmol) andthe mixture was warmed to 23 °C and stirred for 16 h. The reaction mixture was diluted with cold water (100 mL) and extracted with EtOAc (2 x 250 mL). The combined organic phases were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford 2-chloro-7- methyl-6-(methylthio)-7H-purine (4.50 g) as a white solid. LCMS observed m / z = 215.11 [M+H]+. Step 2: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-methyl-6- (methylthio)-7H-purine. Intermediate Z.2A stirred solution of 2-chloro-7-methyl-6-(methylthio)-7H-purine (4.50 g, 9.31 mmol) in 1,2-dimethoxyethane (38.0 mL) and water (2.00 mL) was prepared at 23 °C. (4- cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (1.98 g, 10.2 mmol) and potassium carbonate (3.21 g, 23.2 mmol) were added and the reaction mixture was purged with nitrogen gas for 20 min. Tetrakis(triphenylphosphine)palladium(0) (1.08 g, 0.930 mmol) was added and the reaction mixture was heated at 110 °C for 16 h. The reaction was cooled to 23 °C and the solid precipitate was filtered, washed with water (2 x 50 mL), and concentrated under reduced pressure. to afford 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-methyl-6-(methylthio)- 7H-purine (3.5 g) as a grey solid. LCMS observed m / z = 329.33 [M+H]+. Step 3: 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-methyl-6-(methylsulfonyl)- 7H-purine. Intermediate ZA solution of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-methyl-6- (methylthio)-7H-purine (3.50 g, 10.6 mmol) in dichloromethane (70.0 mL) was prepared and cooled to 0 °C.3-chloroperbenzoic acid (5.52 g, 32.0 mmol) was slowly added and the mixture was maintained at 0 °C for 5 h. The mixture was diluted with a saturated sodiumbicarbonate solution (40.0 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography (silica gel, 50–70% EtOAc in petroleum ether) to afford 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-methyl-6-(methylsulfonyl)-7H-purine (2.14 g) as an off-white solid.1H NMR (400 MHz, DMSO-d6) 9.01 (s, 1H), 8.73 (s, 1H), 4.17 (s, 3H), 3.86 (s, 3H), 3.57 (s, 3H), 1.83-1.76 (m, 1H), 1.11-1.07 (m, 2H), 0.93-0.92 (m, 2H). LCMS observed m / z = 361.15 [M+H]+. Intermediate AA Preparation of 2,6-dichloro-7-(tetrahydro-2H-pyran-2-yl)-7H-purine. Intermediate AATo a stirred solution of 2,6-dichloro-7H-purine (3 g, 15.87 mmol) in EtOAc (30 mL) were added p-toluenesulfonic acid monohydrate (0.03 g, 0.16 mmol) and 3,4- dihydro-2H-pyran (2.0 g, 23.81 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 20% EtOAc in petroleum ether) to afford 2,6-dichloro-7- (tetrahydro-2H-pyran-2-yl)-7H-purine (2.5 g) as a white solid. LCMS observed m / z = 189.03 [M-THP+H]+. Intermediate AB Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-(methylsulfonyl)-7- (tetrahydro-2H-pyran-2-yl)-7H-purine. Intermediate ABThe title compound was prepared using a similar procedure as Intermediate Z, replacing 2,6-dichloro-7-methyl-7H-purine with 2,6-dichloro-7-(tetrahydro-2H-pyran-2-yl)-7H-purine (Intermediate AA).1H NMR (400 MHz, DMSO-d6) ^ 8.68 (s, 1H), 8.57 (s, 1H), 5.90 (dd, J = 10.4, 2.4 Hz, 1H), 4.22 – 4.20 (m, 1H), 3.91 (s, 3H), 3.80 – 3.79 (m, 1H), 3.50 (s, 3H), 2.23 – 2.21 (m, 1H), 2.20 – 2.02 (m, 2H), 1.83 – 1.80 (m, 2H), 1.79 – 1.65 (m, 2H), 1.26 – 1.24 (m, 2H), 0.93 – 0.90 (m, 2H). LCMS observed m / z = 431.25 [M+H]+. Intermediate AC Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-(methylsulfonyl)-7H- purine. Intermediate ACTo a solution of^2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-(methylsulfonyl)-7- (tetra-hydro-2H-pyran-2-yl)-7H-purine (4.00 g, 9.29^mmol, Intermediate AB)^in dichloromethane (50.0 mL) stirring at 0 °C was added trifluoroacetic acid (10.0 mL) and the resulting mixture was stirred at 0 °C for 2 h.^The reaction mixture was concentrated under reduced pressure at 10 °C and the residue was triturated with diethyl ether to afford^the desired product 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-(methylsulfonyl)-7H-purine (2.50 g) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 14.05 (br s, 1H), 8.97 (s, 1H), 8.73 (s, 1H), 3.86 (s, 3H), 3.54 (s, 3H), 1.76-1.70 (m, 1H), 1.09-1.07 (m, 2H), 0.90-0.87 (m, 2H). LCMS observed m / z = 347.18 [M+H]+. Intermediate AD Synthesis of tert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4- (methylsulfonyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate. Intermediate ADThe title compound was prepared using a similar procedure as Intermediate Z, replacing 2,6-dichloro-7-methyl-7H-purine with tert-butyl 2,4-dichloro-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidine-6-carboxylate.1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 4.94 (d, J = 9.6 Hz, 2H), 4.76 (d, J = 10.4 Hz, 2H), 3.88 (s, 3H), 3.37 (s, 3H), 1.79 – 1.76(m, 1H), 1.49 – 1.47 (m, 9H), 1.11 – 1.08 (m, 2H), 0.95 – 0.85 (m, 2H). LCMS observed m / z = 448.36 [M+H]+. Intermediate AE Synthesis of tert-butyl 2,4-dichloro-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidine-7- carboxylate. Intermediate AEStep 1: Preparation of 1,5,6,7-tetrahydro-2H-pyrrolo[2,3-d]pyrimidine-2,4(3H)- dione. Intermediate AE.1To the stirred solution of 1,7-dihydro-2H-pyrrolo[2,3-d]pyrimidine-2,4(3H)-dione (4.00 g, 26.5 mmol) dissolved in trifluoroacetic acid (80.0 mL) was added triethylsilane (12.7 mL, 79.4 mmol) at 0 °C and stirred the reaction mixture at room temperature for 16 h. After completion, the reaction mixture was concentrated and the residue was neutralized with sat. sodium bicarbonate solution. The precipitated solid was filtered off and the solid was dried under vacuum to afford 1,5,6,7-tetrahydro-2H-pyrrolo[2,3-d]pyrimidine-2,4(3H)- dione (4.00 g) as a brown solid. LCMS observed m / z = 154.03 [M+H]+. Step 2: Preparation of 2,4-dichloro-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine. Intermediate AE.2To the stirred solution of 1,5,6,7-tetrahydro-2H-pyrrolo[2,3-d]pyrimidine-2,4(3H)- dione (1.00 g, 6.53 mmol) in phosphorus(V)oxychloride (12.2 mL, 131 mmol) was added N,N-diisopropylethylamine (2.34 mL, 13.1 mmol) at 0 °C and the reaction mixture was stirred at 100 °C for 16 h. After completion, the reaction mixture was concentrated under reduced pressure and the residue was quenched with saturated sodium bicarbonate solution and extracted with EtOAc (30 mL x 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 2,4-dichloro-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidine (0.30 g). LCMS observed m / z = 190.01 [M+H]+.Step 3 : Preparation of tert-butyl 2,4-dichloro-5,6-dihydro-7H-pyrrolo[2,3- d]Jpyrimidine-7-carboxylate.Intermediate AEThe stirred solution of 2,4-dichloro-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (0.30 g, 1.58 mmol) in dichloromethane (10.0 mL) was added triethylamine (0.66 mL, 4.74 mmol) followed by di-tert-butyl dicarbonate (0.36 mL, 1.58 mmol) and the reaction mixture was stirred at 23 °C for 16 h. After completion, the reaction mixture was diluted with diluted with water (10 mL) and extracted with dichloromethane (30 mL x 2). The combined organic layer was washed with water (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and The crude product was purified by flash chromatography (silica gel, 10% EtOAc in petroleum ether) to afford tert-butyl 2,4- dichloro-5,6-dihydro-7H-pyrrolo[2,3-J]pyrimidine-7-carboxylate (0.20 g). LCMS observed m / z = 234.06 [M-56+H]+.Intermediate AFSynthesis of N-(4-(l-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)tetrahydro-2H-pyran-4-amine.Intermediate AFTo a stirred solution of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzaldehyde (1 g, 3.54 mmol Intermediate E. l) and tetrahydro-2H-pyran-4-amine (0.71 g, 7.08 mmol) inMeOH (20 mL) was added acetic acid (0.1 mL) at 0 °C and allowed to stir at room temperature for 2 h. Then sodium cyanoborohydride (0.44 g, 7.08 mmol) was added at 0 °C and allowed to stir at room temperature for 16 h. The progress of the reaction was monitored by LCMS and TLC. Upon completion, the reaction mixture was concentrated under reduced pressure. The crude product was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was washed by saturated sodium bicarbonate solution (100 mL x 2), dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The crude product was purified by flash chromatography using silica gel (devisil silica, 10% MeOH in dichloromethane) to afford N-(4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)tetrahydro-2H-pyran-4-amine (0.76 g) as yellow solid. LCMS observed m / z 368.32 [M+H]+. Intermediate AG Synthesis of (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol. Intermediate AGThe title compound was prepared using a similar procedure as Intermediate A, replacing 4-formylbenzonitrile with methyl 4-formylbenzoate and using General Procedure C (diisobutyl aluminum hydride) to reduce the ester. LCMS observed m / z = 257.125 [M+H]+. Intermediate AH Synthesis of N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)tetrahydro-2H-pyran-4-amine. Intermediate AHThe title compound was prepared using a similar procedure as Intermediate AF, replacing 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (Intermediate E.1) with (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (Intermediate AG). LCMS observed m / z 340.77 [M+H]+. Intermediate AI Synthesis of (4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol Intermediate AIThe title compound was prepared using a similar procedure as Intermediate A, replacing 4-formylbenzonitrile with methyl 4-formylbenzoate, methyl iodide with ethyl iodide, and using General Procedure C (diisobutyl aluminum hydride) to reduce the ester. LCMS observed m / z = 271.10 [M+H]+. Intermediate AJ Synthesis of N-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)tetrahydro-2H-pyran-4-amine. Intermediate AJThe title compound was prepared using a similar procedure as Intermediate AF, replacing 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (Intermediate E.1) with (4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (Intermediate AI). LCMS observed m / z = 354.33 [M+H]+. Intermediate AK Synthesis of 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde Intermediate AKThe title compound was prepared using a similar procedure as Intermediate E.1, replacing (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (intermediate C) with (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (Intermediate AG). LCMS observed m / z = 255.24 [M+H]+. Intermediate AL Synthesis of N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)cyclopropanamine Intermediate ALThe title compound was prepared using a similar procedure as Intermediate AF, using replacing 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (Intermediate E.1) with 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (Intermediate AK) and tetrahydro-2H-pyran-4-amine with cyclopropylamine. LCMS observed m / z = 296.23 [M+H]+. Intermediate AM Synthesis of 4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde Intermediate AMThe title compound was prepared using a similar procedure as Intermediate E.1, replacing (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (Intermediate C) with (4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (Intermediate AI). LCMS observed m / z = 269.61 [M+H]+. Intermediate AN Synthesis of N-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)cyclopropanamine Intermediate ANThe title compound was prepared using a similar procedure as Intermediate AF, replacing 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (Intermediate E.1) with 4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzaldehyde (Intermediate AM) and tetrahydro-2H-pyran-4-amine with cyclopropylamine. LCMS observed m / z = 310.27 [M+H]+. Intermediate AO Synthesis of (4-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)methanamine Intermediate AOStep 1: Preparation of tert-butyl (4-(4-(trifluoromethyl)-1H-1,2,3-triazol-1- yl)benzyl)carbamate Intermediate AO.1To a stirred solution of^4-(trifluoromethyl)-2H-1,2,3-triazole (0.85 g, 6.20 mmol) and (4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (2.33 g, 9.30 mmol) in 1,2-dichloroethane (50 mL) were added copper(II) acetate (1.69 g, 9.30 mmol) followed by pyridine (0.10 mL, 12.40 mmol) and molecular sieves 13 X, 4 to 8 mesh (2.73 g, 6.20 mmol) at 25° C. The reaction mixture was stirred at 25 °C for 12 h in presence of air. Upon completion of reaction, the reaction mixture was filtered through celite and diluted with cold water (20 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layer was washed with brine (10 mL), dried over Anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 20–30% EtOAc in petroleum ether) to afford tert-butyl (4-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)benzyl)carbamate (0.25 g) as an off-white solid. LCMS observed m / z 343.21 [M+H]+. Step 2: Preparation of (4-(4-(trifluoromethyl)-1H-1,2,3-triazol-1- yl)phenyl)methanamine Intermediate AOTo a stirred solution of tert-butyl (4-(4-(trifluoromethyl)-1H-1,2,3-triazol-1- yl)benzyl)carbamate (0.25 g, 0.730 mmol) in dichloromethane (5 mL) was added hydrogen chloride, 4M in 1,4-dioxane (5 mL) at 0 °C and the reaction mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue^was triturated with pentane (10 mL) to afford(4-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)methanamine (175 mg) as an off-white solid. LCMS observed m / z = 243.12 [M+H]+. Intermediate AP Synthesis of (4-(5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)methanamine Intermediate APThe title compound was prepared using a similar procedure as Intermediate AO, replacing tert-butyl (4-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)benzyl)carbamate with tert-butyl (4-(5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)benzyl)carbamate. LCMS observed m / z = 243.16 [M+H]+. Intermediate AQ Synthesis of (4-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl)methanamine Intermediate AQStep 1: Preparation of 4-(5-methyl-1H-1,2,3-triazol-1-yl)benzonitrile Intermediate AQ.1To a stirred solution of 5-methyl-1H-1,2,3-triazole (1.0 g, 12.0 mmol) in dimethylformamide (10.0 mL), was added Cs2CO3(5.89 g, 18.1 mmol) and 4- fluorobenzonitrile (1.46 g, 12.0 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 2 h. After completion (monitored by TLC, Rf: 0.50, mobile phase: 50% EtOAc in hexanes), the reaction mixture^was diluted with water (90.0 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by SFC prep to afford 4-(5-methyl-1H-1,2,3-triazol-1-yl)benzonitrile (3A) (120 mg) as an off-white solid, 4-(4-methyl-2H-1,2,3-triazol-2-yl)benzonitrile (3B) (1.0 g) as an off-white solid and 4-(4-methyl-1H-1,2,3-triazol-1-yl)benzonitrile (3C) (0.5 g) as an off-white solid.. LCMS observed m / z 185.20 [M+H]+.Step 2: Preparation of (4-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl)methanamine Intermediate AQTo a stirred solution of 4-(5-methyl-1H-1,2,3-triazol-1-yl)benzonitrile (110 mg, 0.597 mmol)^was added lithium aluminium hydride 1.0 M in THF (1.8^mL, 1.79^mmol) drop-wise^at 0 °C under nitrogen atmosphere and the reaction mixture was stirred at 25 °C for 3 h. After completion (monitored by TLC, Rf: 0.2, mobile phase: 10% MeOH in dichloromethane), the reaction mixture was quenched with aq.NH4Cl solution (20 mL) and extracted with EtOAc (2 x 30 mL). Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford (4-(5-methyl-1H-1,2,3- triazol-1-yl)phenyl)methanamine (0.1 g). The crude was material was forwarded to next step without any further purification. LCMS observed m / z = 188.97 [M+H]+. Intermediate AR Synthesis of (4-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl)methanamine Intermediate ARThe title compound was prepared using a similar procedure as Intermediate AQ, replacing 4-(5-methyl-1H-1,2,3-triazol-1-yl)benzonitrile with 4-(4-methyl-1H-1,2,3- triazol-1-yl)benzonitrile. LCMS observed m / z = 188.97 [M+H]+. Intermediate AS Synthesis of (4-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)methanamine Intermediate ASThe title compound was prepared using a similar procedure as Intermediate AQ, replacing 4-(5-methyl-1H-1,2,3-triazol-1-yl)benzonitrile with 4-(5-methyl-2H-1,2,3- triazol-2-yl)benzonitrile. LCMS observed m / z = 189.33 [M+H]+. Intermediate AT Synthesis of (4-(2H-1,2,3-triazol-2-yl)phenyl)methanamineIntermediate ATThe title compound was prepared using a similar procedure as Intermediate AQ, replacing 4-(5-methyl-1H-1,2,3-triazol-1-yl)benzonitrile with 4-(2H-1,2,3-triazol-2- yl)benzonitrile. LCMS observed m / z 175.3 [M+H]+. Intermediate AU Synthesis of (4-(1H-1,2,3-triazol-1-yl)phenyl)methanamine Intermediate AUThe title compound was prepared using a similar procedure as Intermediate AQ, replacing 4-(5-methyl-1H-1,2,3-triazol-1-yl)benzonitrile with 4-(1H-1,2,3-triazol-1- yl)benzonitrile. LCMS observed m / z = 175.2 [M+H]+. Intermediate AV Synthesis of (4-(1-isobutyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine. Intermediate AVThe title compound was prepared using a similar procedure as Intermediate A, replacing methyl iodide with 1-iodo-2-methylpropane and using general procedure C to reduce the nitrile. LCMS observed m / z = 298.27 [M+H]+. Intermediate AW Synthesis of (4-(1-(2,2-difluoroethyl)-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine. Intermediate AWThe title compound was prepared using a similar procedure as Intermediate A, replacing methyl iodide with 1,1-difluoro-2-iodoethane and using general procedure C to reduce the nitrile. LCMS observed m / z = 306.23 [M+H]+. Intermediate AX Synthesis of (4-(4-(trifluoromethyl)-1-((1-(trifluoromethyl)cyclopropyl)methyl)- 1H-imidazol-2-yl)phenyl)methanamine. Intermediate AXThe title compound was prepared using a similar procedure as Intermediate A, replacing methyl iodide with [1-(bromomethyl)cyclopropyl]trifluoromethane and using general procedure C to reduce the nitrile. LCMS observed m / z = 364.32 [M+H]+. Intermediate AY Synthesis of (4-(5-methyl-3-(trifluoromethyl)-1H-1,2,4-triazol-1- yl)phenyl)methanamine. Intermediate AYThe title compound was prepared using a similar procedure as Intermediate AO, replacing 4-(trifluoromethyl)-1H-1,2,3-triazole with 5-methyl-3-(trifluoromethyl)-1H- 1,2,4-triazole. LCMS observed m / z = 257.32 [M+H]+. Intermediate AZ Synthesis of (4-(5-(oxetan-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)methanamine Intermediate AZStep 1: Preparation of 5-(oxetan-3-yl)-3-(trifluoromethyl)-1H-pyrazole Intermediate AZ.1To a stirred solution of 2-bromo-3,3,3-trifluoroprop-1-ene (5 g, 28.58 mmol) and^oxetane-3-carbaldehyde (4.92 g, 57.16 mmol in toluene (100 mL) was added 1,8- diazabicyclo[5.4.0]undec-7-ene (13.05 g, 85.74 mmol) followed by p-toluenesulfonyl hydrazine (7.83 g, 34.30 mmol) at 25 °C. The reaction mixture was stirred at 60^°C for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure, diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine (20 mL), dried over Anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by normal phase flash chromatography (silica gel, 50–60% EtOAc in petroleum ether) to afford 5-(oxetan-3-yl)- 3-(trifluoromethyl)-1H-pyrazole (2 g) as a yellow solid. LCMS observed m / z 193.24 [M+H]+. Step 2: Preparation of tert-butyl (4-(5-(oxetan-3-yl)-3-(trifluoromethyl)-1H- pyrazol-1-yl)benzyl)carbamate Intermediate AZ.2To a stirred solution of 5-(oxetan-3-yl)-3-(trifluoromethyl)-1H-pyrazole (2.1 g, 10.93 mmol) and (4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (4.11 g, 16.39 mmol) in 1,2-dichloroethane ( 50 mL) were added copper(II) acetate (2.98 g, 16.394 mmol) followed by pyridine (1.76 mL, 21.86 mmol)^at 25° C. The reaction mixture was stirred at 25 °C for 6 h in air. Upon completion of reaction, the reaction mixture was filtered through celite and quenched with cold water (5 mL) and extracted with EtOAc (2 x 5 mL). The combined organic layer was washed with brine (20 mL), dried over Anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (Davisil silica gel & EtOAc: petroleum ether = 2:8) to afford tert- butyl (4-(5-(oxetan-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)carbamate (1.5 g) as an off-white solid. LCMS observed m / z = 398.24 [M+H]+. Step 3: Preparation of (4-(5-(oxetan-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)methanamine Intermediate AZTo a stirred solution of tert-butyl (4-(5-(oxetan-3-yl)-3-(trifluoromethyl)-lH- pyrazol-1-yl)benzyl)carbamate (1.5 g, 3.77 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (15 mL, 37.74 mmol) at 0 °C and the reaction mixture was stirred at 25 °C for 3 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was triturated with pentane (50 mL) to afford (4-(5-(oxetan-3-yl)-3- (trifluoromethyl)-lH-pyrazol-1-yl)phenyl)methanamine (1 g) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.21 (br s, 2H), 7.63 (d, J= 8.4 Hz, 2H), 7.51 (d, J= 8.4 Hz, 2H), 7.25 (s, 1H), 4.77-4.73 (m, 2H), 4.68-4.64 (m, 2H), 4.39-4.31 (m, 1H), 4.15 (s, 2H) LCMS observed m / z = 298.32 [M+H]+.Intermediate BASynthesis of (4-(1-isopropyl-3-(trifluoromethyl)-1H-1,2,4-triazol-5- yl)phenyl)methanamineIntermediate BAStep 1: Preparation of 5-bromo-1-isopropyl-3-(trifluoromethyl)-1H-1,2,4-triazoleIntermediate BA.1To a stirred solution of 5-bromo-3-(trifluoromethyl)-lH-l,2,4-triazole (1.0 g, 4.63 mmol) in N,N-dimethylformamide (DMF, 10 mL) was added sodium hydride, 60% dispersion in mineral oil (333 mg, 13.9 mmol) at 0 °C and stirred for 15 minutes. Then 2- iodopropane (2.36 g, 13.9 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was quenched with cold water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (Davisil silica gel, 10-20% EtOAc in petroleum ether) to afford 5-bromo-1-isopropyl-3-(trifluoromethyl)-1H-1,2,4-triazole (800 mg). Note: The isomeric mixture was used moving forward. LCMS observed m / z = 257.87 [M+H]+. Step 2: Preparation of 4-(1-isopropyl-3-(trifluoromethyl)-1H-1,2,4-triazol-5- yl)benzonitrile Intermediate BA.2To a stirred solution of 5-bromo-1-isopropyl-3-(trifluoromethyl)-1H-1,2,4-triazole (mixture of two regio-isomers) (800 mg, 3.10 mmol) in 1,4-dioxane (8 mL) and water (2 mL), (4-cyanophenyl) boronic acid (683 mg, 4.65 mmol) followed by potassium carbonate (1.28 g, 9.3 mmol) were added, and the mixture was purged with nitrogen gas for 30 min. Tetrakis(triphenylphosphine)palladium(0) (358 mg, 0.31 mmol) was added to the reaction mixture and stirred at 110 °C for 16 h. After completion, the reaction mixture was diluted with water (2 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (Davisil silica gel, 10–20% EtOAc in petroleum ether) to afford 4-(1-isopropyl-3-(trifluoromethyl)-1H-1,2,4-triazol-5- yl)benzonitrile (600 mg) as a white solid and 4-(1-isopropyl-5-(trifluoromethyl)-1H-1,2,4- triazol-3-yl) benzonitrile (200 mg). LCMS observed m / z = 281.31 [M+H]+. Step 3: Preparation of (4-(1-isopropyl-3-(trifluoromethyl)-1H-1,2,4-triazol-5- yl)phenyl)methanamine Intermediate BATo the stirred solution of 4-(1-isopropyl-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl) benzonitrile (800 mg, 2.85 mmol) in tetrahydrofuran (10 mL) was added LiAlH4powder (325 mg, 8.56 mmol) at 0 °C and stirred at room temperature for 16 h. After completion, the reaction mixture was quenched with saturated NH4Cl solution (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford (4-(1-isopropyl-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)phenyl) methanamine (600 mg).1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 3H), 7.75 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 4.69-4.75 (m, 1H), 4.15 (s, 2H), 1.48 (d, J = 12.0 Hz, 6H) LCMS observed m / z = 285.04 [M+H]+. Intermediate BBSynthesis of (4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine. Intermediate BBThe title compound was prepared using a similar procedure as Intermediate A, replacing methyl iodide with ethyl iodide and using general procedure C to reduce the nitrile.1H NMR (400 MHz, DMSO-d6) δ 8.42 (bs, 2H), 8.06 (d, J = 0.8 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 4.13-4.08 (m, 4H), 1.32 (t, J = 7.2 Hz, 3H). LCMS observed m / z = 271.3 [M+H]+. Intermediate BC Synthesis of (4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine. Intermediate BCThe title compound was prepared using a similar procedure as Intermediate A, replacing methyl iodide with iodocyclobutane and using general procedure C to reduce the nitrile.1H NMR (400 MHz, DMSO-d6) δ 8.42 (bs, 2H), 8.06 (d, J = 0.8 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 4.13-4.08 (m, 4H), 1.32 (t, J = 7.2 Hz, 3H). LCMS observed m / z = 298.19 [M+H]+. Intermediate BD Synthesis of (2-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)methanamine Intermediate BDThe title compound was prepared using a similar procedure as Intermediate X, replacing 4,4,4-trifluoro-3-oxobutanoate with 1,1,1-trifluoropentane-2,4-dione, 4- hydrazineylbenzonitrile with 2-fluoro-4-hydrazineylbenzonitrile, and using general procedure E to reduce the nitrile. LCMS observed m / z = 274.35 [M+H]+. Intermediate BE Synthesis of (3-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine Intermediate BEThe title compound was prepared using a similar procedure as Intermediate A, replacing 4-formylbenzonitrile with 3-fluoro-4-formylbenzonitrile and methyl iodide with isopropyl iodide. LCMS observed m / z = 302.2 [M+H]+. Intermediate BF Synthesis of (4-(5-isopropyl-3-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)methanamine. Intermediate BFStep 1: Preparation of 4-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1- yl)benzonitrile Intermediate BF.1To a stirred solution of (4-cyanophenyl)boronic acid^ (2.2 g, 14.97 mmol) and 5- bromo-3-(trifluoromethyl)-1H-pyrazole (3.86 g, 17.96 mmol) in 1,2-dichloroethane (44mL), copper(II) acetate (4.08 g, 22.46 mmol) was added, followed by pyridine (2.41 mL, 29.94 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 12 hours in air. Upon completion, the mixture was filtered through Celite, diluted with cold water (100 mL), and extracted with EtOAc (2 × 50 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 20– 30% EtOAc in hexanes) to afford 4-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1- yl)benzonitrile (2.7 g) as an off-white solid.1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 6.82 (s, 1H). LCMS observed m / z 315.9 [M+H]+. Step 2: Preparation of 4-(5-(prop-1-en-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1- yl)benzonitrile Intermediate BF.2To a stirred solution of 4-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1- yl)benzonitrile (2.5 g, 7.91 mmol) in 1,4-dioxane (50.0 mL) and water (5.0 mL), 4,4,5,5- tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (2.66 g, 15.82 mmol) and potassium carbonate (3.3 g, 23.73 mmol) were added. The reaction mixture was purged with nitrogen gas for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.91 g, 0.79 mmol) was then added, and the mixture was stirred at 110 °C for 16 hours. Upon completion, the reaction was quenched with cold water (25 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layer was washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (100-200 mesh silica gel, eluent: 4-6% EtOAc in hexanes) to afford 4-(5-(prop-1-en-2-yl)-3-(trifluoromethyl)-1H- pyrazol-1-yl)benzonitrile (1.8 g) as a pale brown solid. LCMS observed m / z = 278.15 [M+H]+. Step 3: Preparation of (4-(5-isopropyl-3-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)methanamine Intermediate BFTo a stirred solution of 4-(5-(prop-1-en-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1- yl)benzonitrile (1.8 g, 6.5 mmol) in EtOAc (50 mL), palladium on carbon (50% wet basis, 1.8 g), platinum(IV) oxide (0.2 g), and acetic acid (0.5 mL) were added. The reaction mixture was stirred in a Parr shaker under hydrogen atmosphere (85 psi) for 16 hours at 25 °C. Upon completion, as monitored by TLC (Rf: 0.6, mobile phase: 30% EtOAc in hexanes), the mixture was filtered through a Buchner funnel. The filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase chromatography (Mobile Phase A: 0.1% TFA in H2O; Mobile Phase B: Acetonitrile = 1:4) to afford (4-(5- isopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) phenyl) methanamine (0.75 g) as a pale brown solid. The compound is in the form of a TFA salt.1H NMR (400 MHz, DMSO-d6) δ 8.22 (br s, 3H), 7.67-7.61 (m, 4H), 6.85 (s, 1H), 4.16 (d, J = 5.6 Hz, 2H), 3.01-2.94 (m, 1H), 1.15 (d, J = 6.8 Hz, 6H). LCMS observed m / z = 284.38 [M+H]+. Intermediate BG Synthesis of (4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1- yl)phenyl)methanamine Intermediate BGThe title compound was prepared using a similar procedure as Intermediate AO, replacing 4-(trifluoromethyl)-2H-1,2,3-triazole with 3-(difluoromethyl)-5-methyl-1H- pyrazole.1H NMR (400 MHz, DMSO-d6) δ 8.39 (br s, 3H), 7.67-7.57 (m, 4H), 7.19-6.87 (m, 1H), 6.58 (s, 1H), 4.12 (d, J = 4.8 Hz, 2H), 2.35 (s, 3H). LCMS observed m / z = 238.33 [M+H]+. Intermediate BH Synthesis of (2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9- yl)methanamine Intermediate BHStep 1: Preparation of 3-bromo-4-(4-(trifluoromethyl)-1H-imidazol-2- yl)benzonitrile Intermediate BH.1To a mixture of 3,3-dibromo-1,1,1-trifluoro-2-propanone (619 µL, 1.1 eq., 5.02 mmol) in water (2.13 mL, 118 mmol) was added potassium acetate (497 mg, 1.1 eq., 5.07 mmol) and the mixture was heated to 100 °C for 1 h. The mixture was cooled to 23 °C, then a solution of 3-bromo-4-formylbenzonitrile (950 mg, 4.52 mmol) in MeOH (22.6 mL, 558 mmol) and ammonium hydroxide (5 mL, 128 mmol) (pre-stirred for 1 h) was added and stirred at 23 °C for 45 min, then warmed to 100 °C for 18 h. The reaction was cooled to 23 °C and diluted with water (75 mL) and EtOAc (50 mL). The mixture was filtered, and the phases were separated. The organic was dried over MgSO4, filtered and concentrated under reduced pressure to afford 3-bromo-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile as a yellow solid (1.43g). The material was used without purification. LCMS observed m / z = 316.0 [M+H]+. Step 2: Preparation of 4-(1-allyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- bromobenzonitrile Intermediate BH.2To a solution of 3-bromo-4-[4-(trifluoromethyl)-2-imidazolyl]benzonitrile (1.43 g, 4.52 mmol) in dimethylformamide (9.04 mL, 117 mmol) was added dipotassium carbonate (1.25 g, 2 eq., 9.04 mmol) followed by 3-bromopropene (586 µL, 1.5 eq., 6.78 mmol) and the mixture was stirred at 23 °C for 3 h. The reaction was poured into LiCl (20 mL, 10% aq) and extracted with EtOAc (2 x 15 mL). The combined organics were washed with water (15 mL), brine (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 10–25% EtOAc in hexanes eluent, 12 g Gold column) to afford 4-(1-allyl-4-(trifluoromethyl)-1H- imidazol-2-yl)-3-bromobenzonitrile (0.78 g) as an amber oil. LCMS observed m / z = 356.1 [M+H]+.Step 3: Preparation of 4-(1-allyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- vinylbenzonitrile. Intermediate BH.3To a suspension of 4-(1-allyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- bromobenzonitrile (356 mg, 1 mmol), Cs2CO3 (977 mg, 3 eq., 3 mmol), and 4,4,5,5- tetramethyl-2-vinyl-1,3,2-dioxaborolane (509 µL, 3 eq., 3 mmol) in 1,4-dioxane (4 mL, 46.9 mmol) and water (1 mL, 20 eq., 20 mmol) was added dichloro-palladamethane— dichloromethane—iron—1λ³,2λ³,3λ³,4λ³,5λ³-cyclopentyldiphenylphosphine (1 / 1 / 1 / 2) (81.7 mg, 0.1 eq., 0.1 mmol) and the mixture was degassed with N2 via vacuum / N2 backfill (5x). The vial was sealed and heated at 85 C for 16 h. The reaction was not complete at this time. An additional 2.0 equiv of the vinyl borane was added followed by Pd(dppf)Cl2 (100 mg) and the reaction was heated to 100 C for 24 h. At this point the starting material was consumed. The reaction was diluted with water (20 mL) and extracted with dichloromethane (2 x 20 mL). The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 10–20% EtOAc in hexanes eluent, 40 g Gold column) to afford the product 4-(1-allyl-4- (trifluoromethyl)-1H-imidazol-2-yl)-3-vinylbenzonitrile (0.56 g) as a pale yellow oil. LCMS observed m / z = 304.2 [M+H]+. Step 4: Preparation of 2-(trifluoromethyl)-5H-benzo[c]imidazo[1,2-a]azepine-9- carbonitrile. Intermediate BH.4To a solution of 4-(1-allyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- vinylbenzonitrile (716.6 mg, 2.33 mmol) in dichloromethane (3.22 mL, 50.3 mmol) was added ruthenium o-isopropoxymethanediidyltoluene 1,3-bis(mesityl)-2,2- imidazolidinediide dichloride (74.0 mg, 0.05 eq., 118.1 µmol) and the mixture was stirred at 23 °C for 16 h. The reaction was filtered through a plug of SiO2, washing with 50% EtOAc in hexanes (5 mL) and the resulting solution was concentrated under reducedpressure. The crude product was purified by flash chromatography (silica gel, 80–90% EtOAc in hexanes eluent, 24g column) to afford the product 2-(trifluoromethyl)-5H- benzo[c]imidazo[1,2-a]azepine-9-carbonitrile (0.48 g) as a yellow solid LCMS observed m / z = 276.1 [M+H]+. Step 5: Preparation of (2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2- a]azepin-9-yl)methanamine. Intermediate BHTo a solution of 4-(trifluoromethyl)-3,6-diazatricyclo[8.4.0.0²,⁶]tetradeca- 1(14),2,4,8,10,12-hexaene-12-carbonitrile (473 mg, 1.72 mmol) in tetrahydrofuran (10 mL, 123 mmol) and MeOH (10 mL, 247 mmol) at 0 °C was added nickel dichloride (81.8 mg, 0.2 eq., 344 µmol) followed by NaBH4(309 mg, 3 eq., 5.16 mmol). The mixture was warmed to 23 °C and stirred for 3 h at which point it was complete by LCMS. The reaction was quenched with water (10 mL) and stirred for 10 min. The mixture was extracted with EtOAc (2 x 10 mL) and the combined organics were washed with water (10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 0–10% MeOH in dichloromethane, 12 g column) to afford the product (2-(trifluoromethyl)-6,7-dihydro-5H- benzo[c]imidazo[1,2-a]azepin-9-yl)methanamine (243 mg) as an off-white solid. LCMS observed m / z = 282.1 [M+H]+. Intermediate BI Synthesis of ({4-[1-isopropyl-4-(trifluoromethyl)-2-imidazolyl]-2- oxabicyclo[2.2.2]oct-1-yl}methyl)amine—hydrogen chloride (1 / 1). Intermediate BIStep 1: Preparation of tert-butyl ((4-formyl-2-oxabicyclo[2.2.2]octan-1- yl)methyl)carbamate Intermediate BI.1To a solution of {4-(hydroxymethyl)-2-oxabicyclo[2.2.2]oct-1-yl}methyl 2-methyl- 2-propanecarbamate (407 mg, 1.5 mmol) in dichloromethane (15 mL, 234 mmol) stirring at 23 °C was added 1,1-diacetoxy-3-oxo-1,3-dihydro-1λ5,2-benziodaoxol-1-yl acetate (0.7 g, 1.1 eq., 1.65 mmol) and the reaction was stirred at 23 °C for 1 h. The reaction was quenched with sat. Na2S2O3 (5 mL) and stirred for 5 min. The mixture was diluted with dichloromethane (10 mL) and the phases were separated. The organic was washed with water (10 mL), brine (10 mL), dried over MgSO4, filtered and was concentrated under reduced pressure to afford the crude product as a colorless oil. The material was used without further purification assuming 100% conversion. LCMS observed m / z = 292.2 [M+Na]+. Step 2: Preparation of tert-butyl ((4-(4-(trifluoromethyl)-1H-imidazol-2-yl)-2- oxabicyclo[2.2.2]octan-1-yl)methyl)carbamate Intermediate BI.2To a solution of 3,3-dibromo-1,1,1-trifluoro-2-propanone (206 µL, 1.1 eq., 1.67 mmol) in water (869 µL, 48.2 mmol) was added sodium acetate (138 mg, 1.1 eq., 1.68 mmol) and the mixture was heated to 100 °C for 1 h. The mixture was cooled to 23 °C and a solution of (4-formyl-2-oxabicyclo[2.2.2]oct-1-yl)methyl 2-methyl-2-propanecarbamate (404 mg, 1.5 mmol) in MeOH (6.52 mL, 161 mmol) and ammonium hydroxide (1.5 mL) was added and the mixture was heated to 100 °C for 20 h. The reaction was cooled to 23 °C and the mixture was extracted with EtOAc (2 x 20 mL). The combined organics were washed with water (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford the crude imidazole as a brown resin. The material was used in the next step without purification (370 mg crude). LCMS observed m / z = 376.2 [M+H]+. Step 3: Preparation of tert-butyl ((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol- 2-yl)-2-oxabicyclo[2.2.2]octan-1-yl)methyl)carbamate Intermediate BI.3To a suspension of tert-butyl ({4-[4-(trifluoromethyl)-2-imidazolyl]-2- oxabicyclo[2.2.2]oct-1-yl}methyl)carbamate (563 mg, 1.5 mmol) and dicaesium carbonate (1.47 g, 3 eq., 4.5 mmol) in acetonitrile (6 mL, 115 mmol) stirring at 23 °C was added 2- iodopropane (0.6 mL, 4 eq., 6 mmol) and the mixture was heated to 70 °C for 18 h. LCMS indicated conversion to the desired product. The reaction was cooled to 23 °C and filtered, washing with EtOAc (10 mL). The filtrate was concentrated under reduced pressure and The crude product was purified by flash chromatography (silica gel, 0–75% EtOAc in hexanes, 12 g Column) to afford the product (205 mg) as a pale yellow oil that solidified on standing. LCMS observed m / z = 418.3 [M+H]+. Step 4: Preparation of ({4-[1-isopropyl-4-(trifluoromethyl)-2-imidazolyl]-2- oxabicyclo[2.2.2]oct-1-yl}methyl)amine—hydrogen chloride (1 / 1) Intermediate BITo a solution of tert-butyl ({4-[1-isopropyl-4-(trifluoromethyl)-2-imidazolyl]-2- oxabicyclo[2.2.2]oct-1-yl}methyl)carbamate (201 mg, 481 µmol) in 1,4-dioxane (481 µL, 5.64 mmol) stirring at 23 °C was added HCl in 1,4-dioxane (4M, 3.0 mmol, 3.0 mL and the reaction was stirred at 23 °C for 1 h. The reaction was concentrated under reduced pressure as an azeotropic mixture with heptanes (5 mL) to afford the product as a white solid. 1H NMR (CD3OD, 400 MHz): 8.04 (s, 1H), 5.00 (sept. J = 6.5 Hz, 1H), 4.26 (s, 2H), 2.38 – 2.30 (m, 2H), 2.20 – 2.12 (m, 2H), 2.09 – 1.99 (m, 2H), 1.89 – 1.80 (m, 2H), 1.49 (d, J = 6.5 Hz, 6H). 2H obscured by dioxane solvent impurity. LCMS observed m / z = 318.3 [M+H]+. Intermediate BJ Synthesis of (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol Intermediate BJStep 1: Preparation of methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1- yl)benzoate Intermediate BJ.1To a stirred solution of^5-methyl-3-(trifluoromethyl)-1H-pyrazole (4.5 g, 30.00 mmol) and (4-(methoxycarbonyl)phenyl)boronic acid (9.00 g, 44.97 mmol) in 1,2- dichloroethane (50 mL)was added copper(II) acetate (8.17 g, 44.97 mmol) followed by pyridine (4.83 mL, 59.96 mmol) at 25° C. The reaction mixture was stirred at 25 °C for 12 h. After completion of reaction, the reaction mixture was filtered through celite, diluted with cold^water (100 mL), and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (Davisil silica gel, 10–15% EtOAc in petroleum ether) to afford methyl 4- (5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) benzoate (6.5 g) as an off-white solid. LCMS observed m / z = 285.3 [M+H]+. Step 2: Preparation of (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)methanol Intermediate BJTo a stirred solution of methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1- yl)benzoate (6.5 g, 22.87 mmol) in tetrahydrofuran (60 mL) was added diisobutylaluminium hydride, 1M solution in hexane (91 mL, 91.47 mmol) at 0° C. The reaction mixture was stirred at 25 °C for 2 h and the progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was quenched with saturated ammonium chloride solution (200 mL), diluted with EtOAc (300 mL), stirred for 15 min and filtered through celite. The organic layer was partitioned and the aqueous layer was extracted withEtOAc (200 mL). The combined organic layer was washed with brine (100^mL),^dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (Davisil silica gel, 5–10% EtOAc in petroleum ether) to afford (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl) phenyl) MeOH (4.3 g) as yellow gum.1H NMR (400 MHz, DMSO-d6) δ 7.53-7.48 (m, 4H), 6.75 (br s, 1H), 5.35 (t, J = 5.8 Hz, 1H), 4.59 (d, J = 5.6 Hz, 2H), 2.33 (s, 3H). LCMS observed m / z = 257.0 [M+H]+. Intermediate BK Synthesis of (2-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)methanol Intermediate BKThe title compound was prepared using a similar procedure as Intermediate BJ, replacing (4-(methoxycarbonyl)phenyl)boronic acid with [3-Fluoro-4- (methoxycarbonyl)phenyl]boronic acid.1H NMR (400 MHz, DMSO-d6) δ 7.65 (t, J = 8.2 Hz, 1H), 7.51-7.43 (m, 2H), 6.78 (s, 1H), 5.43 (t, J = 5.6 Hz, 1H), 4.62 (d, J = 5.6 Hz, 2H), 2.37 (s, 3H). LCMS observed m / z = 275.1 [M+H]+. Intermediate BL Synthesis of (4-(5-(oxetan-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)methanol Intermediate BLTo a stirred solution of 5-(oxetan-3-yl)-3-(trifluoromethyl)-1H-pyrazole (Intermediate AZ.1) (2 g, 10.41 mmol) and (4-(hydroxymethyl) phenyl) boronic acid (1.18 g, 7.8 mmol) in 1,2-dichloroethane (100 mL), copper(II) acetate (1.42 g, 7.8 mmol) was added, followed by pyridine (0.84 mL, 10.41 mmol) at 25 °C. After completion, the reaction mixture was filtered through celite and diluted with cold water (100 mL), then extractedwith EtOAc (2 × 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (Davisil silica gel, 15–20% EtOAc in petroleum ether ) to afford (4-(5-(oxetan-3-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl) phenyl) MeOH (198 mg) as a colorless gum.1H NMR (400 MHz, DMSO-d6) δ 7.49 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.21 (s, 1H), 5.36 (t, J = 5.8 Hz, 1H), 4.77-4.73 (m, 2H), 4.67-4.64 (m, 2H), 4.59 (d, J = 5.8 Hz, 2H), 4.40-4.29 (m, 1H). LCMS observed m / z = 299.1 [M+H]+. Intermediate BM Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-iodobenzyl)-7H- purin-6-amine Intermediate BMThe title compound was prepared according to General Procedure E, using 2-(4- cyclopropyl-6-methoxypyrimidin-5-yl)-6-(methylsulfonyl)-7H-purine as the substituted pyrimidine and using (4-iodophenyl)methanamine as the amine. LCMS observed m / z = 500.2 [M+H]+. Intermediate BN Synthesis of (2-(trifluoromethyl)-6,7-dihydro-5H-benzo[b]imidazo[2,1- d][1,5]oxazocin-10-yl)methanamine Intermediate BNStep 1: Preparation of 2-(2-(trifluoromethyl)-6,7-dihydro-5H-benzo[b]imidazo[2,1- d][1,5]oxazocin-10-yl)acetonitrile Intermediate BN.1To a stirred solution of 3-fluoro-4-(4-(trifluoromethyl)-1H-imidazol-2- yl)benzonitrile (2.0 g, 7.84 mmol) in DMF (20.0^mL), were added Cs2CO3 (7.64 g, 23.51 mmol) followed by (3-bromopropoxy)(tert-butyl)dimethylsilane (2.38 g, 9.41 mmol) and reaction mixture was stirred at 60 °C for 16 h. On completion, the reaction mixture was diluted with ice cold water (80 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (Davisil silica gel, 30–35% EtOAc in petroleum ether) to afford 2-(trifluoromethyl)-6,7-dihydro-5H- benzo[b]imidazo[2,1-d][1,5]oxazocine-10-carbonitrile (2.0^g) as an off-white solid. LCMS observed m / z = 294.1 [M+H]+. Step 2: Preparation of tert-butyl ((2-(trifluoromethyl)-6,7-dihydro-5H- benzo[b]imidazo[2,1-d][1,5]oxazocin-10-yl)methyl)carbamate Intermediate BN.2To the stirred solution of 2-(trifluoromethyl)-6,7-dihydro-5H-benzo[b]imidazo[2,1- d][1,5]oxazocine-10-carbonitrile (1.8 g, 6.14^mmol) in EtOAc (30 mL) and MeOH (30 mL) was added palladium on carbon (50% wet basis) (1.8 g) and di-tert-butyl dicarbonate (8.03^g, 36.83^mmol) at 25 °C. The resulting reaction mixture was stirred at 25 °C for 16 h under H2 gas (80^psi). After completion, the reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (Davisil silica & EtOAc: petroleum ether = 3:7) to afford tert-butyl ((2-(trifluoromethyl)-6,7- dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocin-10-yl)methyl)carbamate (1.8^g) as an off-white solid. LCMS observed m / z = 398.7 [M+H]+. Step 3: Preparation of (2-(trifluoromethyl)-6,7-dihydro-5H-benzo[b]imidazo[2,1- d][1,5]oxazocin-10-yl)methanamine Intermediate BNTo a stirred solution of tert-butyl ((2-(trifluoromethyl)-6,7-dihydro-5H- benzo[b]imidazo[2,1-d][1,5]oxazocin-10-yl)methyl)carbamate (1.0 g, 2.156 mmol) in^dichloromethane (10 mL) was added^TFA (1.0 mL) at 0 °C and reaction mixture was allowed to stir at 25 °C for 4 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated under reduced pressure. The crude product was triturated with pentane (10 mL) and diethyl ether (10 mL) to afford^(2-(trifluoromethyl)-6,7-dihydro-5H-benzo[b]imidazo[2,1-d][1,5]oxazocin-10- yl)methanamine (1.0 g) as an off-white solid. LCMS observed m / z = 298.6 [M+H]+. Intermediate BO Synthesis of (2-(trifluoromethyl)-5,6,7,8-tetrahydrobenzo[b]imidazo[2,1- d][1,5]oxazonin-11-yl)methanamine. Intermediate BOThe title compound was prepared using a similar procedure as Intermediate BN, replacing (3-bromopropoxy)(tert-butyl)dimethylsilane with (4-bromobutoxy)(tert- butyl)dimethylsilane. LCMS observed m / z = 312.8 [M+H]+. Intermediate BP Synthesis of (2-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin- 9-yl)methanamine Intermediate BPThe title compound was prepared using a similar procedure as Intermediate BN, replacing (3-bromopropoxy)(tert-butyl)dimethylsilane with (4-bromoethoxy)(tert- butyl)dimethylsilane. LCMS observed m / z = 284.3 [M+H]+. Intermediate BQSynthesis of (2-(trifluoromethyl)-5,6,7,8-tetrahydrobenzo[c]imidazo[1,2-a]azocin- 10-yl)methanamine Intermediate BQStep 1: Preparation of 3-allyl-4-(1-allyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzonitrile. Intermediate BQ.1A stirred solution of 4-(1-allyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- bromobenzonitrile (1.5 g, 4.21 mmol, Intermediate BH.2) in 1,4-dioxane (15 mL) and water (1 mL) was prepared. Allylboronic acid (1.80 g, 21.05 mmol) and potassium phosphate (2.23 g, 10.52 mmol) were added, and the reaction was purged with nitrogen gas for 30 minutes. Next, XPhos Pd G3 (0.17 g, 0.21 mmol) and CataCXium A (0.075 g, 0.21 mmol) were added. The reaction mixture was stirred at 70 °C for 4 hours. Upon completion, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 15%–20% EtOAc in petroleum ether) to afford 3-allyl-4-(1-allyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzonitrile (0.8 g) as a pale brown liquid. LCMS observed m / z = 318.0 [M+H]+. Step 2: Preparation of (Z)-2-(trifluoromethyl)-5,8-dihydrobenzo[c]imidazo[1,2- a]azocine-10-carbonitrile Intermediate BQ.2A stirred solution of 3-allyl-4-(1-allyl-4-(trifluoromethyl)-1H-imidazol-2-yl) benzonitrile (0.8 g, 2.52 mmol) in DCE (25 mL) was prepared, and 1,3- dimesitylimidazolidin-2-ylidene)(2-isopropoxybenzylidene)ruthenium(VI) chloride (0.31g, 0.50 mmol) was added under a nitrogen atmosphere. The resulting reaction mixture was stirred at 25 °C for 16 hours. Upon completion, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to afford the crude product (0.2 g). The crude product was used directly in the next step without further purification. LCMS observed m / z = 289.9 [M+H]+. Step 3: Preparation of tert-butyl ((2-(trifluoromethyl)-5,6,7,8- tetrahydrobenzo[c]imidazo[1,2-a]azocin-10-yl)methyl)carbamate Intermediate BQ.3A stirred solution of 2-(trifluoromethyl)-5,6,7,8-tetrahydrobenzo[c]imidazo[1,2- a]azocine-10-carbonitrile (0.2 g, 0.68 mmol) in MeOH (3 mL) and THF (3 mL) was cooled to 0 °C, and nickel(II) chloride hexahydrate (0.016 g, 0.06 mmol) was added. NaBH4(0.10 g, 2.74 mmol) was then added portion-wise, and the reaction mixture was allowed to stir at room temperature for 1 hour. Upon completion, the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product (0.12 g). The crude product was used directly in the next step without further purification. LCMS observed m / z = 396.1 [M+H]+. Step 4: Preparation of (2-(trifluoromethyl)-5,6,7,8-tetrahydrobenzo[c]imidazo[1,2- a]azocin-10-yl)methanamine Intermediate BQA stirred solution of tert-butyl ((2-(trifluoromethyl)-5,6,7,8- tetrahydrobenzo[c]imidazo[1,2-a]azocin-10-yl)methyl)carbamate (0.12 g, 0.30 mmol) in dichloromethane (3 mL) was cooled to 0 °C, and TFA (1.5 mL) was added. The reaction mixture was allowed to stir at room temperature for 2 hours. Upon completion, the reaction mixture was concentrated under reduced pressure. The crude product was triturated with diethyl ether (50 mL) to afford (2-(trifluoromethyl)-5, 6, 7, 8-tetrahydrobenzo[c]imidazo [1, 2-a] azocin-10-yl) methanamine (0.075 g) as a pale brown gum. LCMS observed m / z = 296.2 [M+H]+.Intermediate BR Synthesis of (2-(trifluoromethyl)-5,6-dihydro-8H-benzo[f]imidazo[1,2- d][1,4]oxazocin-10-yl)methanamine Intermediate BRStep 1: Preparation of methyl 5-cyano-2-(4-(trifluoromethyl)-1H-imidazol-2- yl)benzoate Intermediate BR.1To the stirred solution of 3-bromo-4-(4-(trifluoromethyl)-1H-imidazol-2- yl)benzonitrile (3 g, 9.49 mmol) in MeOH (30 mL) was added N,N- diisopropylethylamine (4.93 mL, 28.47 mmol) purged with nitrogen gas for 20 min. [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II).dichloromethane (0.69 g, 0.95^mmol) was added and the reaction vessel (steel bomb) was filled with CO gas (120 psi) and stirred at 70 °C for 6 h. After completion, the reaction mixture^was filtered and^concentrated under reduced pressure. The crude product was purified by flash chromatography (Davisil silica & EtOAc: petroleum ether =3:7) to afford methyl 5-cyano- 2-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (1.2 g) as yellow gum. LCMS observed m / z = 296.1 [M+H]+. Step 2: Preparation of methyl 5-cyano-2-(1-(tetrahydro-2H-pyran-2-yl)-4- (trifluoromethyl)-1H-imidazol-2-yl)benzoate Intermediate BR.2To a solution of methyl 5-cyano-2-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (3 g, 10.16 mmol) in toluene (30 mL), p-toluenesulfonic acid monohydrate (0.38 g, 2.03 mmol) followed by 3,4-dihydropyran (1.79 mL, 20.32 mmol) were added at room temperature and the reaction mixture was stirred at 80 °C for 12 h. Upon completion, thereaction mixture was concentrated under reduced pressure, diluted with water (60^mL), and extracted with EtOAc (3 x 60 mL). The combined organic layer was washed with brine (80 mL),^dried over Anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (Davisil^silica gel & EtOAc: petroleum ether = 2:8) to afford methyl 5-cyano-2-(1-(tetrahydro-2H-pyran- 2-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (2 g) as a yellow gum. LCMS observed m / z = 380.4 [M+H]+. Step 3: Preparation of 3-(hydroxymethyl)-4-(1-(tetrahydro-2H-pyran-2-yl)-4- (trifluoromethyl)-1H-imidazol-2-yl)benzonitrile Intermediate BR.3To a stirred solution of methyl 5-cyano-2-(1-(tetrahydro-2H-pyran-2-yl)-4- (trifluoromethyl)-1H-imidazol-2-yl)benzoate (2.5 g, 6.59 mmol) in tetrahydrofuran (25 mL), MeOH (25 mL) was added NaBH4 (0.997 g, 26.36 mmol) at 0 °C. The reaction mixture was stirred at 50 °C for 6 h. On completion, the reaction mixture^was diluted with ice cold water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate^and concentrated under reduced pressure. The crude product was purified by flash chromatography (Davisil silica-gel) using 40% EtOAc in petroleum ether as an eluent to afford 3-(hydroxymethyl)-4-(1-(tetrahydro-2H-pyran-2- yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (2.3 g) as a pale yellow gum. LCMS observed m / z = 352.4 [M+H]+. Step 4: Preparation of 3-((2-((tert-butyldimethylsilyl)oxy)ethoxy)methyl)-4-(1- (tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile Intermediate BR.4To a stirred solution of 3-(hydroxymethyl)-4-(1-(tetrahydro-2H-pyran-2-yl)-4- (trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (450 mg, 1.28 mmol) inTHF (5 mL), was added sodium hydride (60%, dispersion in paraffin liquid) (0.12 g, 5.12 mmol)^at 0°C. After 10 min (2-bromoethoxy)(tert-butyl)dimethylsilane (0.36mL, 2.56 mmol) was added at 0 °C and the reaction mixture was stirred at 50 °C for 12 h. On completion, the reactionmixture was diluted with ice cold water (80 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (Davisil silica-gel) using 20% EtOAc in petroleum ether as an eluent to afford 3-((2-((tert- butyldimethylsilyl)oxy)ethoxy)methyl)-4-(1-(tetrahydro-2H-pyran-2-yl)-4- (trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (0.4 g, 13.79%) as a pale yellow gum. LCMS observed m / z = 510.6 [M+H]+. Step 5: Preparation of 3-((2-hydroxyethoxy)methyl)-4-(4-(trifluoromethyl)-1H- imidazol-2-yl)benzonitrile Intermediate BR.5To a stirred solution of 3-((2-((tert-butyldimethylsilyl)oxy)ethoxy)methyl)-4-(1- (tetrahydro-2H-pyran-2-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (2.0 g, 3.92 mmol) in dichloromethane^(10^mL) was added TFA (4.0 mL) at 0°C and allowed to stirred at 25 °C for 4 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated under reduced pressure. The crude product was triturated with pentane (20 mL) and diethyl ether (20 mL) to afford 3-((2- hydroxyethoxy)methyl)-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (1.0 g) as a yellow^gum. LCMS observed m / z = 312.1 [M+H]+. Step 6: Preparation of 2-(trifluoromethyl)-5,6-dihydro-8H-benzo[f]imidazo[1,2- d][1,4]oxazocine-10-carbonitrile Intermediate BR.6To a stirred solution of 3-((2-hydroxyethoxy)methyl)-4-(4-(trifluoromethyl)-1H- imidazol-2-yl)benzonitrile (1.3 g, 4.17 mmol) in toluene (20^mL) was added 2-(tributyl-l5- phosphaneylidene)acetonitrile (1.16 g, 4.82 mmol) at 25°C and allowed to stirred at 100 °C for 6 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated under reduced pressure, diluted with ice cold water (60 mL), and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate^and concentrated under reduced pressure. The crude productwas purified by flash chromatography (Davisil silica-gel) using 20% EtOAc in petroleum ether as an eluent to afford^2-(trifluoromethyl)-5,6-dihydro-8H-benzo[f]imidazo[1,2- d][1,4]oxazocine-10-carbonitrile (0.5 g) as a brown^gum. LCMS observed m / z = 294.3 [M+H]+. Step 7: Preparation of tert-butyl ((2-(trifluoromethyl)-5,6-dihydro-8H- benzo[f]imidazo[1,2-d][1,4]oxazocin-10-yl)methyl)carbamate Intermediate BR.7To the stirred solution of^2-(trifluoromethyl)-5,6-dihydro-8H-benzo[f]imidazo[1,2- d][1,4]oxazocine-10-carbonitrile (0.5 g, 1.71 mmol) in EtOAc (50 mL) and Methanol (50 mL) was added di-tert-butyl dicarbonate (0.78 mL, 3.41 mmol) followed by palladium 10% on carbon (wetted with ca.55% Water) (0.5 g) at 25 °C.^The resulting reaction mixture was stirred at 25 °C under H2gas (80^psi) for 16 h. After completion, the reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (Davisil silica & EtOAc: petroleum ether =3:7) to afford tert-butyl ((2-(trifluoromethyl)-5,6-dihydro-8H-benzo[f]imidazo[1,2-d][1,4]oxazocin-10- yl)methyl)carbamate (0.5 g) as a pale brown^solid. LCMS observed m / z = 398.5 [M+H]+. Step 8: Preparation of (2-(trifluoromethyl)-5,6-dihydro-8H-benzo[f]imidazo[1,2- d][1,4]oxazocin-10-yl)methanamine Intermediate BRTo a stirred solution of^tert-butyl ((2-(trifluoromethyl)-5,6-dihydro-8H- benzo[f]imidazo[1,2-d][1,4]oxazocin-10-yl)methyl)carbamate (0.230 g, 0.579 mmol) in^dichloromethane (5^mL) was added^TFA (0.5 mL) at 0 °C and allowed to stirred at 25 °C for 4 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated under reduced pressure. The crude product was triturated with pentane (10 mL) and diethyl ether (10 mL) to afford^(2-(trifluoromethyl)-5,6- dihydro-8H-benzo[f]imidazo[1,2-d][1,4]oxazocin-10-yl)methanamine (0.2^g) as a colorless liquid. LCMS observed m / z = 298.5 [M+H]+. Intermediate BSSynthesis of 9-(aminomethyl)-2-(trifluoromethyl)-5H-benzo[f]imidazo[1,2- d][1,4]diazepin-6(7H)-one. Intermediate BSStep 1: Preparation of 2-(2-(2-bromo-4-cyanophenyl)-4-(trifluoromethyl)-1H- imidazol-1-yl)acetamide Intermediate BS.1To a stirred solution of 3-bromo-4-(4-(trifluoromethyl)-1H-imidazol-2- yl)benzonitrile (2 g, 6.33 mmol) in DMF (20 mL), was added Cs2CO3(6.19 g, 18.98 mmol) at 0 °C. The reaction mixture was stirred for 30 minutes, after which 2-bromoacetamide (1.75 g, 12.6 mmol) was added. The mixture was then stirred at room temperature for 2 hours. Upon completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 35–40% EtOAc in petroleum ether) to afford 2-(2-(2-bromo-4- cyanophenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)acetamide (1.8 g) as a pale yellow solid. LCMS observed m / z = 373.2 [M+H]+. Step 2: Preparation of 6-oxo-2-(trifluoromethyl)-6,7-dihydro-5H- benzo[f]imidazo[1,2-d][1,4]diazepine-9-carbonitrile. Intermediate BS.2To a stirred solution of 2-(2-(2-bromo-4-cyanophenyl)-4-(trifluoromethyl)-1H- imidazol-1-yl)acetamide (1.8 g, 4.82 mmol) in N,N-Dimethylformamide (20 mL) was added copper iodide (2.756 g, 14.47 mmol), Cs2CO3(0.157 g, 0.48 mmol), and trans-N,N'- Dimethylcyclohexane-1,2-diamine (3.81 mL, 24.12 mmol). The reaction mixture washeated at 100 °C for 16 hours. Upon completion, the mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 40–45% EtOAc in petroleum ether) to afford 6-oxo-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[f]imidazo[1,2-d][1,4]diazepine-9- carbonitrile (0.3 g) as a brown gum. LCMS observed m / z = 293.2 [M+H]+. Step 3: Preparation of tert-butyl ((6-oxo-2-(trifluoromethyl)-6,7-dihydro-5H- benzo[f]imidazo[1,2-d][1,4]diazepin-9-yl)methyl)carbamate Intermediate BS.3To a stirred solution of 6-oxo-2-(trifluoromethyl)-6,7-dihydro-5H- benzo[f]imidazo[1,2-d][1,4]diazepine-9-carbonitrile (0.3 g, 1.03 mmol) in a mixture of EtOAc (25 mL) and MeOH (25 mL), palladium on carbon (10%, wetted with approximately 55% water) (0.33 g, 3.08 mmol) and di-tert-butyl dicarbonate (0.71 mL, 3.08 mmol) were added. The reaction mixture was stirred at room temperature in a parr shaker under a hydrogen atmosphere (80 psi) for 16 hours. Upon completion, the mixture was filtered through a celite pad and washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl ((6-oxo-2-(trifluoromethyl)-6,7-dihydro-5H- benzo[f]imidazo[1,2-d][1,4]diazepin-9-yl)methyl)carbamate (0.2 g) as a yellow gum. LCMS observed m / z = 397.3 [M+H]+. Step 4: Preparation of 9-(aminomethyl)-2-(trifluoromethyl)-5H- benzo[f]imidazo[1,2-d][1,4]diazepin-6(7H)-one Intermediate BSTo a stirred solution^of^tert-butyl ((6-oxo-2-(trifluoromethyl)-6,7-dihydro-5H- benzo[f]imidazo[1,2-d][1,4]diazepin-9-yl)methy (0.2 g, 0.51 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.155 mL, 2.02 mmol) at 0 °C and stirred at rt for 2 h. On completion, the reaction mixture was concentrated under reduced pressure. The crude product was triturated with diethyl ether and dried to afford 9-(aminomethyl)-2-(trifluoromethyl)-5H-benzo[f]imidazo[1,2-d][1,4]diazepin-6(7H)-one (0.14^g) as a pale brown solid. LCMS observed m / z = 297.1 [M+H]+. Intermediate BT Synthesis of 9-(aminomethyl)-2-(trifluoromethyl)-6,7-dihydro-5H- benzo[c]imidazo[1,2-a]azepin-7-ol Intermediate BTStep 1: Preparation of 7-oxo-2-(trifluoromethyl)-6,7-dihydro-5H- benzo[c]imidazo[1,2-a]azepine-9-carbonitrile Intermediate BT.1To a stirred solution of 2-(trifluoromethyl)-5H-benzo[c]imidazo[1,2-a]azepine-9- carbonitrile (Intermediate BH.4) (2.0 g, 7.27 mmol) in ethanol (100 mL) under an oxygen atmosphere, anhydrous iron(III) chloride (2.36 g, 14.53 mmol) was added, followed by phenylsilane (1.79 mL, 14.5 mmol) at 25°C. The reaction mixture was stirred at 25 °C for 16 hours. Upon completion, the reaction mixture was quenched with cold water (100 mL) and extracted with EtOAc (2 × 250 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (Davisil silica gel, 25–30% EtOAc in petroleum ether) to afford 7-oxo-2- (trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-carbonitrile (1.1 g) as a pale brown solid. LCMS observed m / z = 292.2 [M+H]+. Step 2: Preparation of tert-butyl ((7-hydroxy-2-(trifluoromethyl)-6,7-dihydro-5H- benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)carbamate Intermediate BT.2A solution of 7-oxo-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2- a]azepine-9-carbonitrile (1.3 g, 4.46 mmol) in a mixture of EtOAc (150 mL) and MeOH(150 mL) was stirred, and di-tert-butyl dicarbonate (2.05 mL, 8.93 mmol) was added, followed by 10% palladium on carbon (wet with approximately 55% water; 1.5 g). The reaction mixture was stirred under hydrogen gas pressure (80 psi) in a Paar shaker at room temperature for 16 hours. Upon completion, the reaction mixture was filtered through a celite bed, which was then washed with THF (100 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (Davisil silica gel, 75–80% EtOAc in petroleum ether) to afford tert-butyl ((7-hydroxy-2- (trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)carbamate (0.80 g) as an off-white solid. LCMS observed m / z = 398.3 [M+H]+. Step 3: Preparation of 9-(aminomethyl)-2-(trifluoromethyl)-6,7-dihydro-5H- benzo[c]imidazo[1,2-a]azepin-7-ol Intermediate BTTo a stirred solution of tert-butyl ((7-hydroxy-2-(trifluoromethyl)-6,7-dihydro-5H- benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)carbamate (500 mg, 1.26 mmol) in dichloromethane (15 mL), trifluoroacetic acid (2.0 mL) was added at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. Upon completion, the reaction mixture was concentrated under reduced pressure and triturated with pentane (2 × 5 mL). The resulting solid was dried under vacuum to afford 9-(aminomethyl)-2-(trifluoromethyl)-6,7-dihydro- 5H-benzo[c]imidazo[1,2-a]azepin-7-ol (350 mg) as a pale brown gummy substance. LCMS observed m / z = 298.2 [M+H]+. Intermediate BU Synthesis of (4-(5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)methanamine Intermediate BUThe title compound was prepared using a similar procedure as Intermediate BF, replacing 5-bromo-3-(trifluoromethyl)-1H-pyrazole with 5-cyclopropyl-3- (trifluoromethyl)-1H-pyrazole.1H NMR (400 MHz, DMSO-d6) δ 7.58-7.54 (m, 4H), 6.61(s, 1H), 3.81 (s, 2H), 2.03 (br s, 2H), 1.83-1.79 (m, 1H), 0.98-0.94 (m, 2H), 0.84-0.83 (m, 2H), LCMS observed m / z 282.2 [M+H]+. Intermediate BV Synthesis of 3-fluoro-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile Intermediate BVThe title compound was prepared using a similar procedure as Intermediate BH.1, replacing 3-bromo-4-formylbenzonitrile with 3-fluoro-4-formylbenzonitrile.1H NMR (400 MHz, DMSO-d6) δ 7.58-7.54 (m, 4H), 6.61 (s, 1H), 3.81 (s, 2H), 2.03 (br s, 2H), 1.83-1.79 (m, 1H), 0.98-0.94 (m, 2H), 0.84-0.83 (m, 2H), LCMS observed m / z 256.9 [M+H]+. Intermediate BW Synthesis of (2-(trifluoromethyl)-5,6,8,9-tetrahydrobenzo[i]imidazo[1,2- g][1,4,7]dioxazecin-12-yl)methanamine Intermediate BWStep 1: Preparation of 3-fluoro-4-(1-(2-(2-hydroxyethoxy)ethyl)-4- (trifluoromethyl)-1H-imidazol-2-yl)benzonitrile Intermediate BW.1To a stirred solution of 3-fluoro-4-(4-(trifluoromethyl)-1H-imidazol-2-yl) benzonitrile (Intermediate BV) (1 g, 3.91 mmol) in DMF (10 mL) was added Cs2CO3 (2.55 g, 7.83 mmol) followed by (2-(2-bromoethoxy) ethoxy) (tert-butyl) dimethylsilane (2.2 g, 7.8 mmol) at 25 °C. The reaction mixture was stirred at 100 °C for 16 hours. Upon completion, the reaction mixture was diluted with ice water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with water (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (30–50% EtOAc / petroleum ether eluent) toafford 3-fluoro-4-(1-(2-(2-hydroxyethoxy)ethyl)-4-(trifluoromethyl)-1H-imidazol-2- yl)benzonitrile (1.1 g) as a pale yellow gum. LCMS observed m / z = 344.0 [M+H]+. Step 2: Preparation of 2-(trifluoromethyl)-5,6,8,9-tetrahydrobenzo[i]imidazo[1,2- g][1,4,7]dioxazecine-12-carbonitrile Intermediate BW.2To a stirred solution of 3-fluoro-4-(1-(2-(2-hydroxyethoxy)ethyl)-4- (trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (0.9 g, 2.62 mmol)^in DMF (9^mL)^was added^ Cs2CO3 (1.7^g, 5.24^mmol)^and the reaction was heated at 100 °C for 6 h. Upon completion, the reaction mixture was diluted with water (100^mL)^and product was precipitated out. The mixture was filtered, washed with cold water (25 mL), and dried to afford 2-(trifluoromethyl)-5,6,8,9-tetrahydrobenzo[i]imidazo[1,2-g][1,4,7]dioxazecine-12- carbonitrile (0.57 g) as white solid. LCMS observed m / z = 324.1 [M+H]+. Step 3: Preparation of tert-butyl ((2-(trifluoromethyl)-5,6,8,9- tetrahydrobenzo[i]imidazo[1,2-g][1,4,7]dioxazecin-12-yl)methyl)carbamate Intermediate BW.3In a Parr shaker, a stirred solution of 2-(trifluoromethyl)-5,6,8,9- tetrahydrobenzo[i]imidazo[1,2-g][1,4,7]dioxazecine-12-carbonitrile (0.5 g, 1.54 mmol) in MeOH (10 mL) and EtOAc (10 mL) was combined with Boc-anhydride (2.02 g, 9.28 mmol), followed by 10% palladium on carbon (50% wet basis, 0.5 g). The reaction mixture was stirred at room temperature under H₂ gas (80 psi) for 16 hours. Upon completion, the reaction mixture was filtered through celite and concentrated under reduced pressure. The crude product was purified by flash chromatography (Davisil silica gel, 30–35% EtOAc in petroleum ether) to afford tert-butyl ((2-(trifluoromethyl)-5,6,7,8- tetrahydrobenzo[b]imidazo[2,1-d][1,5]oxazonin-11-yl)methyl)carbamate (0.5 g, 75.63%) as a white solid. LCMS observed m / z = 428.1 [M+H]+.Step 4: Preparation of (2-(trifluoromethyl)-5,6,8,9-tetrahydrobenzo[i]imidazo[1,2- g][1,4,7]dioxazecin-12-yl)methanamine Intermediate BWTo a stirred solution of tert-butyl ((2-(trifluoromethyl)-5,6,8,9- tetrahydrobenzo[i]imidazo[1,2-g][1,4,7]dioxazecin-12-yl)methyl)carbamate (0.5 g, 1.17 mmol) in dichloromethane (10 mL) at 0 °C under an argon atmosphere, TFA (3 mL) was added. The reaction mixture was stirred at 0 °C for 1 hour. Upon completion, the reaction mixture was concentrated under reduced pressure. The crude product was triturated with diethyl ether (2 × 20 mL) to afford (2-(trifluoromethyl)-5,6,8,9- tetrahydrobenzo[i]imidazo[1,2-g][1,4,7]dioxazecin-12-yl)methanamine (0.38 g) as a white solid. LCMS observed m / z = 328.2 [M+H]+. Intermediate BX Synthesis of (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1- yl)cyclohexyl)methanamine Intermediate BXStep 1: Preparation of 4-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl methanesulfonate Intermediate BX.1To a stirred solution of^tert-butyl ((4-hydroxycyclohexyl)methyl)carbamate (0.2 g, 0.87^mmol)^in dichloromethane (5 mL)^was added^Triethylamine (0.269 mL, 2.00^mmol) followed by Methane sulfonyl chloride (0.078 mL, 0.95^mmol) at 0 °C and^reaction mixture was allowed stir at room temperature for 1 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was cooled, diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 4-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl methane sulfonate) (0.2 g, 74.60 %) as a semi solid. LCMS observed m / z = 308.2 [M+H]+. Step 2: Preparation of tert-butyl ((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1- yl)cyclohexyl)methyl)carbamate Intermediate BX.2To a stirred solution of^5-methyl-3-(trifluoromethyl)-1H-pyrazole (1 g, 6.66 mmol) in DMF (10^mL)^were added Cs2CO3(6.512 g, 19.98 mmol) followed by 4-(((tert- butoxycarbonyl)amino)methyl)cyclohexyl methanesulfonate (3.072 g, 9.99^mmol) at 0 °C and^reaction was allowed to stir at^80 °C for 16 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was cooled, diluted with water (500 mL) and extracted with EtOAc (300 mL x 3). The combined organic layer was dried over^anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (Davisil silica-gel, 20 % EtOAc in petroleum ether) to afford tert-butyl ((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1- yl)cyclohexyl)methyl)carbamate (0.8 g, 33.23%) as a pale yellow liquid. LCMS observed m / z = 362.1 [M+H]+. Step 3: Preparation of (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1- yl)cyclohexyl)methanamine Intermediate BXTo a stirred solution of tert-butyl ((4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1- yl)cyclohexyl)methyl)carbamate (0.8 g, 2.21 mmol) in dichloromethane (10 mL) was added TFA (2 mL) at 0 °C and reaction mixture was stirred^the at room temperature for 2 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated under reduced pressure. The crude product was triturated with diethyl ether (20 mL) to afford^(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1- yl)cyclohexyl)methanamine (0.8 g) as a semi solid. LCMS observed m / z = 262.6 [M+H]+. Intermediate BYSynthesis of (1-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-4- yl)methanamine Intermediate BYStep 1: Preparation of tert-butyl ((1-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol- 2-yl)piperidin-4-yl)methyl)carbamate Intermediate BY.1A solution of tert-butyl (piperidin-4-ylmethyl)carbamate (2.0 g, 9.33 mmol) and 2- bromo-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (2.98 g, 14.0 mmol) in N,N- diisopropylethylamine (20.0 mL) was stirred at 140 °C for 4 days. Upon completion, the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography (Davisil silica gel, 25–30% EtOAc in petroleum ether) to afford tert-butyl ((1-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-4- yl)methyl)carbamate (0.3 g, 8% yield) as a pale brown gum. LCMS observed m / z = 391.7 [M+H]+. Step 2: Preparation of (1-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)piperidin-4-yl)methanamine Intermediate BYTo a stirred solution of tert-butyl ((1-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol- 2-yl)piperidin-4-yl)methyl)carbamate (0.3 g, 0.77 mmol) in dichloromethane (10 mL), trifluoroacetic acid (2.0 mL) was added at 0 °C. The reaction mixture was then stirred from 0 °C to 25 °C for 2 hours. Upon completion, the mixture was concentrated under reduced pressure and triturated with pentane (2 × 10 mL). The resulting product was concentrated again under reduced pressure to afford (1-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-4-yl)methanamine (0.22 g) as a pale brown gum. LCMS observed m / z = 291.7 [M+H]+. Intermediate BZ Synthesis of (1-(pyridin-3-yl)piperidin-4-yl)methanamine Intermediate BZThe title compound was prepared using a similar procedure as Intermediate BY, replacing 2-bromo-1-isopropyl-4-(trifluoromethyl)-1H-imidazole with 3-bromopyridine.1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 2.8 Hz, 1H), 8.17 (d, J = 5.2 Hz, 1H), 8.07 (dd, J = 9.2, 2.4 Hz, 1H), 7.85-7.78 (m, 3H), 3.98 (d, J = 13.2 Hz, 2H), 2.92 (t, J = 11.8 Hz, 2H), 2.77 (t, J = 6.0 Hz, 2H), 1.84-1.82 (m, 3H), 1.27-1.25 (m, 2H), LCMS observed m / z 192.1 [M+H]+. Intermediate CA Synthesis of (1-(6-methylpyridin-3-yl)piperidin-4-yl)methanamine Intermediate CAThe title compound was prepared using a similar procedure as Intermediate BY, replacing 2-bromo-1-isopropyl-4-(trifluoromethyl)-1H-imidazole with 5-bromo-2- methylpyridine. LCMS observed m / z 206.4 [M+H]+. Intermediate CB Synthesis of 2-(1-(4-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5- yl)propan-2-ol Intermediate CBStep 1: Preparation of ethyl 1-(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3- (trifluoromethyl)-1H-pyrazole-5-carboxylate Intermediate CB.1To a stirred solution of ethyl 3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (5.0 g, 24.0 mmol) in acetonitrile (80.0 mL), 4-(((tert-butoxycarbonyl)amino)methyl)phenyl boronic acid (6.03 g, 24.0 mmol) and pyridine (5.70 g, 72.0 mmol) were added, and the mixture was purged with oxygen gas. Copper(II) acetate (0.873 g, 4.80 mmol) was then added, and the reaction was stirred for 24 hours at 60 °C. Upon completion, the reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2 × 250 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (Davisil silica, 25–30% EtOAc in petroleum ether) to afford ethyl 1-(4-(((tert-butoxycarbonyl) amino) methyl) phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (7.00 g). LCMS observed m / z = 358.3 [M–C4H9+H]+. Step 2: Preparation of tert-butyl (4-(5-(2-hydroxypropan-2-yl)-3-(trifluoromethyl)- 1H-pyrazol-1-yl)benzyl)carbamate Intermediate CB.2To a stirred solution of ethyl 1-(4-(((tert-butoxycarbonyl) amino) methyl) phenyl)- 3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (6.0 g, 41.3 mmol) in tetrahydrofuran (80.0 mL), was added methylmagnesium bromide (1.4 M, 103 mL, 145 mmol) dropwise at -78 °C. The reaction mixture was stirred for 8 hours at -20 °C. Upon completion, the reaction was quenched with saturated ammonium chloride solution (150 mL) and extracted with EtOAc (2 × 150 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (Davisil silica gel, 20–25% EtOAc in petroleum ether) to afford ethyl 1- (4-(((tert-butoxycarbonyl) amino) methyl) phenyl)-3-(trifluoromethyl)-1H-pyrazole-5- carboxylate (3.00 g). LCMS observed m / z = 400.3 [M+H]+. Step 3: Preparation of 2-(1-(4-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H- pyrazol-5-yl)propan-2-ol Intermediate CBTo a stirred solution of tert-butyl (4-(5-(2-hydroxypropan-2-yl)-3-(trifluoromethyl)- 1H-pyrazol-1-yl) benzyl) carbamate (3.3 g, 8.26 mmol) in dichloromethane (20 mL), was added trifluoroacetic acid (5 mL) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 2 hours. Upon completion, the mixture was evaporated and diluted with cold water (50 mL), then extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), and dried over anhydrous sodium sulfate, then filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 8–10% MeOH in dichloromethane) to afford 2-(1-(4-(aminomethyl) phenyl)-3-(trifluoromethyl)-1H-pyrazol- 5-yl) propan-2-ol (1.5 g). LCMS observed m / z = 300.3 [M+H]+. Intermediate CC Synthesis of (4-(1-(2-methoxyethyl)-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine Intermediate CCThe title compound was prepared using a similar procedure as Intermediate A, replacing methyl iodide with 1-iodo-2-methylpropane and using general procedure C to reduce the nitrile. LCMS observed m / z = 300.2 [M+H]+. Intermediate CD Synthesis of (4-(1-(propan-2-yl-d7)-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine Intermediate CDThe title compound was prepared using a similar procedure as Intermediate A, replacing methyl iodide with 2-iodopropane-1,1,1,2,3,3,3-d7and using general procedure C to reduce the nitrile. LCMS observed m / z = 291.2 [M+H]+Intermediate CE Synthesis of (3,5-difluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine Intermediate CEThe title compound was prepared using a similar procedure as Intermediate A, replacing 4-formylbenzonitrile with 3,5-difluoro-4-formylbenzonitrile, methyl iodide with 2-iodopropane, and using general procedure C to reduce the nitrile. LCMS observed m / z = 320.1 [M+H]+. Intermediate CF Synthesis of (4-(1-(2-fluoroethyl)-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine Intermediate CFThe title compound was prepared using a similar procedure as Intermediate A, replacing methyl iodide with 1-fluoro-2-iodoethane and using general procedure C to reduce the nitrile. LCMS observed m / z = 288.2 [M+H]+. Intermediate CG Synthesis of (2,6-difluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine Intermediate CGThe title compound was prepared using a similar procedure as Intermediate A, replacing 4-formylbenzonitrile with 2,6-difluoro-4-formylbenzonitrile, methyl iodide with2-iodopropane, and using general procedure C to reduce the nitrile. LCMS observed m / z = 320.1 [M+H]+. Intermediate CH Synthesis of (4-(1-cyclobutyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine Intermediate CHThe title compound was prepared using a similar procedure as Intermediate A, replacing methyl iodide with bromocyclobutane and using general procedure C to reduce the nitrile. LCMS observed m / z = 296.2 [M+H]+. Intermediate CI Step 1: Preparation of tert-butyl (R)-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H- imidazol-2-yl)phenyl)ethyl)carbamate–HCl. Intermediate CI.1To a stirred solution of 2-bromo-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (1.5 g, 5.83 mmol, Intermediate P.2) in 1,4-dioxane (15 mL) and water (3 mL) was added (R)- (4-(1-((tert-butoxycarbonyl)amino)ethyl)phenyl)boronic acid (1.70 g, 6.41 mmol) followed by potassium phosphate (0.20 g, 0.97 mmol) and the mixture was purged with nitrogen gas for 30 min. XPhosPdG3 (0.033 g, 0.03 mmol) was added and reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was diluted with water (25 mL) and the product was extracted with ethyl acetate (2 x 50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (20-25% ethyl acetate / petroleum ether eluent) to afford tert-butyl (R)-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)ethyl)carbamate (1.5 g, 64 %) as an off-white solid. LCMS observed m / z = 398.4 [M+H]+.Step 2: Preparation of (R)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)ethan-1-amine–HCl. Intermediate CITo a stirred solution of tert-butyl (R)-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H- imidazol-2-yl)phenyl)ethyl)carbamate (1 g, 2.51 mmol) in DCM (10 mL) was added hydrogen chloride (3.14 mL, 4.0 M in 1,4-dioxane 12.58 mmol) at 0 °C and reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford crude product. The crude was triturated with diethyl ether (25.0 mL) and n-pentane (25.0 mL) to afford (R)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)ethan-1-amine (0.8g, 95%) as a pale brown solid.1H NMR (400 MHz, DMSO- d6) δ 8.47 (br s, 3H), 8.21 – 8.21 (m, 1H), 7.67 – 7.63 (m, 4H), 4.52 – 4.42 (m, 2H), 1.55 (d, J = 6.8 Hz, 3H), 1.42 (d, J = 6.8 Hz, 6H). LCMS observed m / z = 298.4 [M+H]+. Intermediate CJ Synthesis of (4-(1-(cyclopropylmethyl)-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine Intermediate CJThe title compound was prepared using a similar procedure as Intermediate A, replacing methyl iodide with (bromomethyl)cyclopropane and using general procedure C to reduce the nitrile. LCMS observed m / z = 296.1 [M+H]+. Intermediate CK Synthesis of (2,3-difluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine Intermediate CKThe title compound was prepared using a similar procedure as Intermediate A, replacing 4-formylbenzonitrile with 2,3-difluoro-4-formylbenzonitrile and using general procedure C to reduce the nitrile. LCMS observed m / z = 320.1 [M+H]+. Intermediate CL Synthesis of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methan- d2-amine Intermediate CLStep 1: Preparation of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzamide Intermediate CL.1To a stirred solution of methyl 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl) benzoate (10.0 g, 32.0 mmol) in MeOH (200 mL), was added saturated aqueous ammonia (200 mL) at 25 °C, and the reaction mixture was stirred for 16 hours at this temperature. Upon completion, the mixture was concentrated under reduced pressure and extracted with EtOAc (2 × 250 mL). The combined organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was triturated with diethyl ether (25 mL) to afford 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl) benzamide (6.5 g) as an off-white solid. The crude material was then forwarded to the next step without further purification. LCMS observed m / z = 298.2 [M+H]+. Step 2: Preparation of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methan-d2-amine Intermediate CLThe title compound was prepared using a similar procedure to Intermediate BA, replacing 4-(1-isopropyl-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl) benzonitrile with 4-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl) benzamide and using LiAlD4 to reduce the carboxamide. LCMS observed m / z = 286.4 [M+H]+. Intermediate CM Synthesis of (4-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)methanamine Intermediate CMThe title compound was prepared using a similar procedure as Intermediate X, replacing 4,4,4-trifluoro-3-oxobutanoate with 1,1,1-trifluoropentane-2,4-dione and using general procedure E to reduce the nitrile. LCMS observed m / z = 256.3 [M+H]+. Intermediate CN Synthesis of (6-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinolin- 8-yl)methanamine Intermediate CNStep 1: Preparation of (3-bromo-4-(4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine Intermediate CN.1A stirred solution of 3-bromo-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (Intermediate BH.1) (3 g, 9.4 mmol) in THF (25 mL) was cooled to 0 °C, and Borane-DMS (5 mL) was added. The reaction mixture was then allowed to stir at room temperature for 16 hours. Upon completion, the reaction was quenched with water (100 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with ice-cold water (100 mL) and saturated sodium bicarbonate solution (100 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resultant residue was washed with pentane and diethyl ether before being concentrated underreduced pressure to afford (3-bromo-4-(4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine (2.5 g) as a brown solid. LCMS observed m / z = 320.2 [M+H]+. Step 2: Preparation of tert-butyl (3-bromo-4-(4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)carbamate Intermediate CN.2A stirred solution of (3-bromo-4-(4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine (2 g, 6.2 mmol) in dichloromethane (20 mL) was cooled to 0 °C, and N,N-diisopropylethylamine (2.4 g, 18.7 mmol), 4-(dimethylamino)pyridine (0.076 g, 0.625 mmol), and di-tert-butyl dicarbonate (2.7 g, 12.4 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 16 hours. Upon completion, the reaction was diluted with water (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with ice-cold water (100 mL) and brine (100 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 30– 50% EtOAc in petroleum ether) to afford tert-butyl (3-bromo-4-(4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)carbamate (1.5 g) as a white solid. LCMS observed m / z = 420.4 [M+H]+. Step 3: Preparation of tert-butyl (3-(prop-1-en-2-yl)-4-(4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)carbamate Intermediate CN.3To a stirred solution of tert-butyl (3-bromo-4-(4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)carbamate (1.5 g, 3.5 mmol) and potassium trifluoro(prop-1-en-2-yl)borate (2.6 g, 17.8 mmol) in 1,4-dioxane (20 mL) and water (5 mL), was added K₃PO₄ (2.273 g, 10.708 mmol), and the reaction mixture was purged with argon gas for 15 minutes. XPhosPd(G2) (0.2 g, 0.35 mmol) was introduced, and the reaction mixture was stirred at 70 °C for 2 hours. Upon completion, the reaction was diluted with water (200 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flashchromatography (silica gel, 70% EtOAc in petroleum ether) to afford tert-butyl (3-(prop-1- en-2-yl)-4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)carbamate (1.5 g) as an off-white solid. LCMS observed m / z = 382.5 [M+H]+. Step 4: Preparation of tert-butyl (3-(1-hydroxypropan-2-yl)-4-(4-(trifluoromethyl)- 1H-imidazol-2-yl)benzyl)carbamate Intermediate CN.4A stirred solution of tert-butyl (3-(prop-1-en-2-yl)-4-(4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)carbamate (1 g, 2.6 mmol) in THF (10 mL) was cooled to 0 °C, and 1 M borane in THF (10 mL, 7.86 mmol) was added. The reaction mixture was stirred at 0 °C for 1 hour. After 1 hour, hydrogen peroxide (35% in water) (0.76 mL, 7.8 mmol) was added, followed by potassium carbonate (0.725 g, 5.24 mmol), and the mixture was stirred at room temperature for 1 hour. Upon completion, the reaction was quenched with water (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 70% EtOAc in petroleum ether) to afford tert- butyl (3-(1-hydroxypropan-2-yl)-4-(4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)carbamate (0.8 g) as an off-white solid. LCMS observed m / z = 400.4 [M+H]+. Step 5: Preparation of tert-butyl ((6-methyl-2-(trifluoromethyl)-5,6- dihydroimidazo[2,1-a]isoquinolin-8-yl)methyl)carbamate Intermediate CN.5A stirred solution of tert-butyl (3-(1-hydroxypropan-2-yl)-4-(4-(trifluoromethyl)- 1H-imidazol-2-yl)benzyl)carbamate (0.8 g, 2.0 mmol) in toluene (10 mL) was heated to 100 °C, and 2-(tributylphosphoranylidene)acetonitrile (1.2 g, 5.0 mmol) was added. The reaction mixture was stirred at 100 °C for 16 hours. Upon completion, the reaction was quenched with water (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 70% EtOAc in petroleum ether) to afford tert-butyl ((6-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinolin-8-yl)methyl)carbamate (0.6 g) as an off-white solid (two inseparable regio- isomers which were carried forward and separated at the final step). LCMS observed m / z = 382.2 [M+H]+. Step 5: Preparation of (6-methyl-2-(trifluoromethyl)-5,6-dihydroimidazo[2,1- a]isoquinolin-8-yl)methanamine Intermediate CNTo a stirred solution of tert-butyl ((6-methyl-2-(trifluoromethyl)-5,6- dihydroimidazo[2,1-a]isoquinolin-8-yl)methyl)carbamate (0.5 g, 1.311 mmol) in dichloromethane (10 mL) was added TFA (2 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 2 hours. Upon completion, the mixture was concentrated under reduced pressure. The residue was triturated with diethyl ether to afford (6-methyl-2- (trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinolin-8-yl)methanamine (0.3 g) as a white solid. LCMS observed m / z = 282.2 [M+H]+. Intermediate CO Synthesis of (6-methyl-3-(trifluoromethyl)-5,6-dihydroimidazo[2,1-a]isoquinolin- 8-yl)methanamine Intermediate COThe title compound is the regioisomer that formed during the synthesis of Intermediate CN. LCMS observed m / z = 282.2 [M+H]+. Intermediate CP Synthesis of 6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2,3- dihydrobenzofuran-3-amine Intermediate CPStep 1: Preparation of tert-butyl (6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol- 2-yl)-2,3-dihydrobenzofuran-3-yl)carbamate Intermediate CP.1To a stirred solution of tert-butyl (6-bromo-2,3-dihydrobenzofuran-3-yl)carbamate (0.5 g, 1.59 mmol) in 1,4-dioxane (15 mL), bis(pinacolato)diboron (0.61 g, 2.39 mmol), 2- bromo-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (0.41 g, 1.59 mmol), and potassium acetate (0.312 g, 3.18 mmol) were added, and the mixture was purged with nitrogen gas for 30 minutes. XPhos Pd G2 (0.13 g, 0.16 mmol) was then added, and the reaction was stirred at 100 °C for 16 hours. Upon completion, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 40 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 5–10% EtOAc in petroleum ether) to afford tert-butyl (6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2,3-dihydrobenzofuran-3- yl)carbamate (0.15 g) as a colorless liquid. LCMS observed m / z = 412.3 [M+H]+. Step 2: Preparation of 6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2,3- dihydrobenzofuran-3-amine Intermediate CPTo a stirred solution of tert-butyl (6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol- 2-yl)-2,3-dihydrobenzofuran-3-yl)carbamate (180 mg, 0.44 mmol) in dichloromethane (10 mL), TFA (0.5 mL) was added, and the reaction mixture was stirred at room temperature for 4 hours. Upon completion, the reaction mixture was concentrated under reduced pressure. The crude material was triturated with pentane (10 mL) and diethyl ether (10 mL) to afford 6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2,3-dihydrobenzofuran-3- amine (60 mg) as a colorless liquid. LCMS observed m / z = 312.3 [M+H]+. Intermediate CQSynthesis of 2-bromo-1-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H- imidazole Intermediate CQStep 1: Preparation of 1-(3,6-dihydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H- imidazole Intermediate CQ.1To a stirred solution of^4-(trifluoromethyl)-1H-imidazole (5 g, 36.7^mmol)^and^(3,6- dihydro-2H-pyran-4-yl) boronic acid (7.05^g, 55.1^mmol)^in 1,2-dichloroethane (50^mL)^was added copper(II) acetate (7.3^g, 40.4^mmol) followed by the addition of 2,2'- bipyridine (5.73^g, 36.7^mmol)^and sodium carbonate (7.78^g, 73.4^mmol) at 25° C. The reaction mixture was stirred at 70^°C^for 16 h. the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was filter through celite,^diluted with water (50^mL) and extracted with dichloromethane (3 × 30^mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 25% EtOAc in hexanes) to afford 1-(3,6-dihydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H-imidazole (2.2 g) as pale-yellow liquid. LCMS observed m / z = 219.1 [M+H]+. Step 2: Preparation of 1-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H- imidazole Intermediate CQ.2To a stirred solution of^1-(3,6-dihydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H- imidazole (2.2 g, 10^mmol)^in EtOAc (22^mL) was added palladium hydroxide, 20% on carbon (wet) (3.11^g, 22.1^mmol) at room temperature under nitrogen atmosphere and reaction mixture was allowed to shake in parr shaker under 50 psi of hydrogen pressure at rt^for 16 h. Progress of reaction was monitored by TLC and LCMS. The reaction mixturewas filtered through celite, washed with EtOAc (33 mL) and concentrated to afford crude 1-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H-imidazole (2 g) as a white solid, which was used in next step without further purification. LCMS observed m / z = 220.9 [M+H]+. Step 3: Preparation of 2-bromo-1-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)- 1H-imidazole Intermediate CQTo a stirred solution of 1-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H- imidazole (2 g, 9.08 mmol) in anhydrous tetrahydrofuran (10 mL) was added n-butyl lithium, 1.6 M in hexane (0.75 g, 11.8 mmol) dropwise at -78 °C and reaction mixture was allowed to stir 30 min as same temperature. N-bromosuccinimide (1.77 g, 9.99 mmol) in tetrahydrofuran (Dry) (10 mL) was added and reaction mixture was stirred at -78 °C for 2 h. Reaction progress was monitored by TLC, LCMS. Upon completion, the reaction mixture was quenched with saturated ammonium chloride solution (50 mL) and extracted with EtOAc (2 × 40 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to get afford crude. The crude was purified by flash chromatography (silica gel, 25% EtOAc in hexanes) to afford 2-bromo-1-(tetrahydro-2H-pyran-4-yl)-4- (trifluoromethyl)-1H-imidazole (0.85^g) as a pale brown solid. LCMS observed m / z = 299.2 [M+H]+. Intermediate CR Synthesis of (4-(1-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine Intermediate CRStep 1: Preparation of tert-butyl (4-(1-(tetrahydro-2H-pyran-4-yl)-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)carbamate Intermediate CR.1To a stirred solution of 2-bromo-1-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)- 1H-imidazole (0.1 g, 0.33 mmol) in 1,4-dioxane (0.8 mL) and water (0.2 mL) were added (4-(((tert-butoxycarbonyl) amino) methyl)phenyl) boronic acid (0.07 g, 0.43^mmol)^followed by potassium phosphate (0.21 g, 1.003 mmol) and degassed the reaction mixture with nitrogen for 10 minutes. XPhosPdG3 (0.02 g, 0.03 mmol) was added and the reaction mixture was heated at 70 °C for 16^h. The progress of the reaction was monitored by LCMS and TLC. Upon completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 20–25% EtOAc in hexanes) to afford tert-butyl (4-(1-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)carbamate (0.085 g) as a pale yellow gum. LCMS observed m / z = 426.5 [M+H]+. Step 2: Preparation of (4-(1-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H- imidazol-2-yl)phenyl)methanamine Intermediate CRTo a stirred solution of tert-butyl (4-(1-(tetrahydro-2H-pyran-4-yl)-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)carbamate (0.085 g, 0.20 mmol) in^dichloromethane (0.8 mL) was added trifluoroacetic acid (0.306 mL, 3.99 mmol) at 0° C. The reaction mixture was allowed to stir at room temperature for 2 h. The progress of the reaction was monitored by LCMS and TLC. Upon completion, the reaction mixture was concentrated under reduced pressure, diluted with saturated sodium bicarbonate (10 mL), and extracted with dichloromethane (3 × 15 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude (4- (1-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl) phenyl) methanamine as a pale-yellow solid (0.06 g) which was used in the next step without further purification. LCMS observed m / z = 326.2 [M+H]+.Intermediate CS Synthesis of (4-(1-(tetrahydrofuran-3-yl)-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine Intermediate CSThe title compound was prepared using a similar procedure as Intermediate A, replacing methyl iodide with 3-bromotetrahydrofuran and using general procedure C to reduce the nitrile. LCMS observed m / z = 312.0 [M+H]+. Intermediate CT Synthesis of (R)-1-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethan- 1-amine Intermediate CTThe title compound was prepared using a similar procedure as Intermediate CP, replacing 2-bromo-1-isopropyl-4-(trifluoromethyl)-1H-imidazole with 2-bromo-1-ethyl-4- (trifluoromethyl)-1H-imidazole and replacing tert-butyl (6-bromo-2,3-dihydrobenzofuran- 3-yl)carbamate with (R)-(4-(1-aminoethyl)phenyl)boronic acid. LCMS observed m / z = 384.7 [M+H]+. Intermediate CU Synthesis of (4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine Intermediate CUStep 1: Preparation of 4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzonitrile Intermediate CU.1To a stirred solution of methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (25 g, 105.403 mmol) and cyclopropylboronic acid (45.269 g, 527.015 mmol) in DCE (500 mL)under oxygen atmosphere was added Sodium carbonate (27.929 g, 263.507 mmol), 2,2'-Bipyridine (16.462 g, 105.403 mmol) followed by Cu(OAc)2(21.63 g, 119.10 mmol). The reaction mixture was stirred at 70 ° C for 24 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture^was diluted with water^(800 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer^was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 25% EtOAc in petroleum ether) to afford methyl 4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl) benzoate (6^g) as an off-white solid. LCMS observed m / z = 278.3 [M+H]+. Step 2: Preparation of tert-butyl (4-(1-cyclopropyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)carbamate Intermediate CU.2In a paar shaker, the stirred solution of 4-(1-cyclopropyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzonitrile (9 g, 32.462 mmol) in EtOAc (150 mL) and MeOH (150 mL) were added Di-tert-butyl Dicarbonate (ca. 30% in Tetrahydrofuran) (14.915 mL, 64.923 mmol) followed by Palladium 10% on carbon (wetted with ca.55% Water) (8.636 g, 81.154 mmol) and stirred the reaction mixture at rt for 16 h under hydrogen 80 psi. The progress of the reaction was monitored by LCMS and TLC. Upon completion, the reaction was filtered through celite and concentrated under reduced pressure. The crude product was purified by flash chromatography (Davisil silica gel, 30% EtOAc in petroleum ether)^to afford tert-butyl ((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9- yl)methyl)carbamate (9.0 g) as white solid. LCMS observed m / z = 382.2 [M+H]+. Step 3: Preparation of (4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine Intermediate CUTo a stirred solution of tert-butyl (4-(1-cyclopropyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)carbamate (8 g, 20.975 mmol) in dichloromethane (50 mL) was added Trifluoroacetic acid (6 mL, 209.754 mmol) at 0 °C and stirred the reaction mixture at rt^for 5^h.^The progress of the reaction was monitored by LCMS and TLC. The reaction mixture was concentrated under reduced pressure. The crude residue was triturated with diethyl ether and dried to afford^(4-(1-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl) phenyl) methanamine (5^g) as off-white^gum. LCMS observed m / z = 282.2 [M+H]+. Intermediate CV Synthesis of ((1R,5S,6r)-3-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- azabicyclo[3.1.0]hexan-6-yl)methanamine Intermediate CVThe title compound was prepared using a similar procedure as Intermediate BY, replacing tert-butyl (piperidin-4-ylmethyl)carbamate with tert-butyl (((1R,5S,6s)-3- azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate. LCMS observed m / z = 289.2 [M+H]+. Intermediate CW Synthesis of 1-(4-(chloromethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole Intermediate CWThe title compound was prepared using a similar procedure as Intermediate D, replacing (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (Intermediate C) with (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol (Intermediate BJ). LCMS observed m / z = 275.1 [M+H]+. Intermediate CXSynthesis of 2-(4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H- imidazole Intermediate CXThe title compound was prepared using a similar procedure as Intermediate D, replacing (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (Intermediate C) with (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (Intermediate AG). LCMS observed m / z = 275.1 [M+H]+. Intermediate CY Synthesis of 1-(4-(chloromethyl)-3-fluorophenyl)-5-methyl-3-(trifluoromethyl)- 1H-pyrazole Intermediate CYThe title compound was prepared using a similar procedure as Intermediate CW, replacing (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol (Intermediate BJ) with (2-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)methanol (Intermediate BK). LCMS observed m / z = 293.0 [M+H]+. Intermediate CZ Synthesis of (2-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)methanol Intermediate CZThe title compound was prepared using a similar procedure as Intermediate BJ, replacing (4-(methoxycarbonyl)phenyl)boronic acid with (3-fluoro-4- (methoxycarbonyl)phenyl)boronic acid. LCMS observed m / z = 275.1 [M+H]+. Intermediate DASynthesis of 2-(4-(1-chloroethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H- imidazole Intermediate DAThe title compound was prepared using a similar procedure as Intermediate D, replacing (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (Intermediate C) with 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)ethan-1-ol (Intermediate Q). LCMS observed m / z = 317.1 [M+H]+. Intermediate DB Synthesis of (4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanol Intermediate DBThe title compound was prepared using a similar procedure as Intermediate A, replacing 4-formylbenzonitrile with methyl 4-formylbenzoate, replacing methyl iodide with 3-iodooxetane and using General Procedure C (diisobutyl aluminum hydride) to reduce the ester.1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 1.2 Hz, 1H), 7.47 (q, J = 7.6 Hz, 4H), 5.56-5.49 (m, 1H), 5.32 (t, J = 5.6 Hz, 1H), 4.87 (t, J = 7.4 Hz, 2H), 4.79 (t, J = 6.6 Hz, 2H), 4.58 (d, J = 5.6 Hz, 2H). LCMS observed m / z = 299.3 [M+H]+. Intermediate DC Synthesis of 2-(4-(chloromethyl)phenyl)-1-(oxetan-3-yl)-4-(trifluoromethyl)-1H- imidazole Intermediate DCThe title compound was prepared using a similar procedure as Intermediate D, replacing (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (Intermediate C) with (4-(1-(oxetan-3-yl)-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanol (Intermediate DB). LCMS observed m / z = 317.0 [M+H]+. Intermediate DD Synthesis of 2-(4-(chloromethyl)cuban-1-yl)-1-isopropyl-4-(trifluoromethyl)-1H- imidazole Intermediate DDThe title compound was prepared using a similar procedure as Intermediate D, replacing (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (Intermediate C) with 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1- yl)methanol (Intermediate M). LCMS observed m / z = 329.1 [M+H]+. Intermediate DE Synthesis of (S)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)ethan-1-amine.The title compound was prepared using a similar procedure as Intermediate CI, replacing tert-butyl (R)-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)ethyl)carbamate with tert-butyl (S)-(1-(4-(1-isopropyl-4-(trifluoromethyl)-1H- imidazol-2-yl)phenyl)ethyl)-carbamate. LCMS observed m / z = 298.4 [M+H]+. Intermediate DF Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4- (methylsulfonyl)imidazo[2,1-f][1,2,4]triazine Intermediate DFThe title compound was prepared using a similar procedure as Intermediate Z, replacing 2,6-dichloro-7-methyl-7H-purine with 2,4-dichloroimidazo[2,1- f][1,2,4]triazine. LCMS observed m / z = 347.0 [M+H]+. Intermediate DG Synthesis of 2,4-dichloro-5-fluoro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine Intermediate DGTo a solution of 4,6-dichloro-3-fluoro-1H-1,5,7-triazaindene (400mg, 1.94mmol) in DMF (6.5mL) stirring at 0 °C was added NaH (85 mg, 2.14mmol, 60%w / w) and the reaction was stirred for 30 min. (2-chloromethoxyethyl)tris(methyl)silane (340mg, 2.04mmol) was added and the mixture was warmed to 23 °C and stirred for 3 h. The reaction was diluted with water (5 mL) and extracted with EtOAc in hexanes (1:1, 2 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 0–10% EtOAc in hexanes) to afford 2,4-dichloro-5-fluoro-7- ((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as a white solid. LCMS observed m / z = 336.3 [M+H]+.Synthesis of Exemplified Compounds: 1.1 EXAMPLE 1 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4- amine. Compound 1Step 1: Preparation of tert-butyl 2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate. Compound 1.1To a stirred solution of (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine (0.176 g, 0.69 mmol, Intermediate A) dissolved in N,N- dimethylformamide (5 mL) was added N,N-diisopropylethylamine (0.37 mL, 2.07 mmol) followed by tert-butyl 2,4-dichloro-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidine-7- carboxylate (0.2 g, 0.69 mmol, Intermediate AE) at 23 °C. The reaction mixture was stirred at 100 °C for 16 h. After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layer was washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and The crude product was purified by flash chromatography (silica gel, 25% EtOAc in petroleum ether) to afford tert-butyl 2-chloro-4- ((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-5,6-dihydro-7H- pyrrolo[2,3-d]pyrimidine-7-carboxylate (0.07 g). LCMS observed m / z = 509.63 [M+H]+.Step 2: Preparation of tert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4- (1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-5,6-dihydro-7H- pyrrolo[2,3-d]pyrimidine-7-carboxylate. Compound 1.2To a stirred solution of tert-butyl 2-chloro-4-((4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-5,6-dihydro-7H-pyrrolo[2,3- d]pyrimidine-7-carboxylate (70.0 mg, 0.14 mmol) and (4-cyclopropyl-6- methoxypyrimidin-5-yl)boronic acid (53.3 mg, 0.28 mmol) in 1,2-dimethoxyethane (3.00 mL), milli-Q water (0.50 mL) was added potassium carbonate (47.4 mg, 0.34 mmol) at room temperature. The reaction mixture was degassed with nitrogen gas for 10 minutes before adding tetrakis(triphenylphosphine)palladium(0) (15.9 mg, 0.014 mmol). The reaction mixture was further degassed with nitrogen gas for additional 5 minutes and stirred under microwave at 100 °C for 1.5 h. After completion, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and The crude product was purified by flash chromatography (silica gel, 60% EtOAc in petroleum ether) to afford tert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-5,6-dihydro-7H-pyrrolo[2,3- d]pyrimidine-7-carboxylate (25.0 mg, 29 % yield) as an off-white solid. LCMS observed m / z = 623.59 [M+H]+. Step 3: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-methyl- 4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4- amine. Compound 1To a stirred solution of tert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4- ((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-5,6-dihydro-7H- pyrrolo[2,3-d]pyrimidine-7-carboxylate (25.0 mg, 0.04 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.5 mL) at 0 ºC. The reaction mixture was stirred at room temperature for 4 h. After completion, the reaction mixture was concentrated under reduced pressure and the residue was triturated with pentane (5 mL x 2) and diethyl ether (5 mL x 2) to afford 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4- amine•TFA (7.5 mg) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.16 (brs, 1H), 7.93 (s, 2H), 7.66 (d, J = 7.6 Hz, 2H), 7.41 (d, J = 7.6 Hz, 2H), 4.66-4.65 (m, 2H), 3.88 (s, 3H), 3.76-3.71 (m, 5H), 2.96-2.95 (m, 2H), 1.83-1.82 (m, 1H), 0.99-0.98 (m, 2H), 0.83-0.82 (m, 2H). LCMS observed m / z = 523.44 [M+H]+. 2.1 EXAMPLE 2 Synthesis of 2-(2-(4-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)-4-((4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)acetonitrile. Compound 2Step 1: Preparation of tert-butyl 2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate.Compound 2.1To a mixture of (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine (600 mg, 2.35 mmol, Intermediate A) and triethylamine (1.94 mL, 11.75 mmol) in chloroform (6.00 mL) was added tert-butyl 2,4-dichloro-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidine-6-carboxylate (200 mg, 0.690 mmol) and stirred at 23 °C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3 X 30 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (600 mg) of tert-butyl 2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate. LCMS observed m / z = 509.5 [M+H]+. Step 2: Preparation of tert-butyl 2-(4-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)-4-((4- (1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidine-6-carboxylate. Compound 2.2To a mixture of tert-butyl 2-chloro-4-((4-(1-methyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)amino)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate (300 mg, 0.590 mmol) in DME (4.00 mL) was added water (2.00 mL), (4-cyclopropyl-1- ethyl-1H-pyrazol-5-yl)boronic acid (130 mg, 0.710 mmol), and potassium carbonate (200 mg, 1.47 mmol) and purged with N2 for 15 minutes. To the mixture was added tetrakis(triphenylphosphine)-palladium(0) (70.0 mg, 0.0600 mmol) and the resulting mixture was stirred at 100 °C for 16 hours. The mixture was diluted with cold water (5 mL) and extracted with EtOAc (30 mL). The combined organic layer was washed with brine (5mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 0–25% EtOAc in hexanes) to afford (150 mg) of tert-butyl 2-(4-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)-4- ((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidine-6-carboxylate. LCMS observed m / z = 610.0 [M+H]+. Step 3: Preparation of 2-(4-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)-N-(4-(1-methyl- 4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4- amine. Compound 2.3To a mixture of tert-butyl 2-(4-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)-4-((4- (1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidine-6-carboxylate (150 mg, 0.290 mmol) in dichloromethane (1.50 mL) was added dropwise trifluoroacetic acid (0.200 mL) at 0 °C under N2. The resulting mixture was stirred at 23 °C for 6 hours. The mixture was concentrated under reduced pressure and the residue was triturated in diethyl ether (5 mL) to afford (120 mg) of tert-butyl 2-(4-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)-4-((4-(1- methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidine-6-carboxylate. LCMS observed m / z = 610.0 [M+H]+. Step 4: Preparation of 2-(2-(4-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)-4-((4-(1- methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)acetonitrile. Compound 2To a mixture of 2-(4-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)-N-(4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4- amine (180 mg, 0.250 mmol) in acetonitrile (1.80 mL) was added triethylamine (0.140 mL, 1.06 mmol) and the mixture was stirred at 0 °C for 15 minutes. To the mixture was added 2-bromoacetonitrile (50.0 mg, 0.430 mmol). The resulting mixture was stirred at 23 °C for 16 hours. The mixture was concentrated under reduced pressure, diluted with cold water (5 mL) and extracted with EtOAc (3 X 20 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 0–70% EtOAc in hexanes) to afford 2-(2-(4-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)-4-((4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)acetonitrile.1H NMR (400 MHz, DMSO-d6) δ 8.03 (t, J = 6.0 Hz 1H), 7.93 – 7.91 (m, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.04 (s, 1H), 4.73 (d, J = 6.0 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 4.06 (s, 2H), 4.02 (s, 2H), 3.95 (s, 2H), 3.75 (s, 3H), 2.22 – 2.15 (m, 1H), 1.09 (t, J= 7.0 Hz, 3H), 0.63 – 0.60 (m, 2H), 0.43 – 0.39 (m, 2H). LCMS observed m / z = 548.5 [M+H]+. 3.1 EXAMPLE 3 Synthesis of 2-(2-(4-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)-4-((4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)acetonitrile. Compound 3The title compound was prepared using a similar route as Compound 2, replacing (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine with (4-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine (Intermediate B).1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 0.8 Hz, 1H), 8.03 (t, J = 6.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.05 (s, 1H), 4.73 (d, J = 2.8 Hz, 2H), 4.47 – 4.40 (m, 1H), 4.31 (q, J = 7.1 Hz, 2H), 4.06 (s, 2H), 4.02 (s, 2H), 3.95 (s, 2H), 2.21 – 2.14 (m,1H), 1.40 – 1.38 (m, 6H), 1.09 (t, J = 7.2 Hz, 3H), 0.61 – 0.56 (m, 2H), 0.44 – 0.39 (m, 2H). LCMS observed m / z = 576.4 [M+H]+. 4.1 EXAMPLE 4 Synthesis of 2-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine. Compound 4The title compound was prepared using a similar procedure as Compound 2, replacing (4-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)boronic acid with (2- isopropylphenyl)boronic acid. 1H NMR (400 MHz , DMSO-d6) ^ 9.39 (s, 2H), 8.20 (t, J = 6.0 Hz, 1H), 7.93 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.45 – 7.38 (m, 5H), 7.23 – 7.19 (m, 1H), 4.76 (d, J = 5.6 Hz, 2H), 4.47 – 4.43 (m, 4H), 3.76 (s, 3H), 3.49 – 3.48 (m, 1H), 1.04 – 1.02 (m, 6H). LCMS observed m / z = 493.56 [M+H]+. 5.1 EXAMPLE 5 Preparation of 2-(2-(2-isopropylphenyl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)acetonitrile. Compound 5To a stirred solution of 2-(2-isopropylphenyl)-N-(4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4- amine (110 mg, 0.22 mmol, Compound 4) in acetonitrile (3.0 mL) was added triethylamine (0.15 mL, 1.12 mmol) at 0 °C and was stirred for 15 min before adding 2-bromoacetonitrile (40.2 mg, 0.33 mmol) at 0 °C. The reaction mixture was stirred at room temperature for20 h. Upon completion, the reaction was diluted with water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was triturated with a mixture of n-pentane in diethyl ether (1:1) and the resulting compound was further purified by preparative HPLC (mobile phase:10–98% acetonitrile in water w / 0.1% NH4CO3) to afford 2-(2-(2-isopropylphenyl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidin-6-yl)acetonitrile (50 mg) as an off-white solid..1H NMR (400 MHz, DMSO-d6) δ 7.91 – 7.87 (m, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.43 – 7.41 (m, 3H), 7.35 – 7.31 (m, 2H), 7.20 – 7.16 (m, 1H), 4.72 (d, J = 5.6 Hz, 2H), 4.06 (s, 2H), 4.00 (s, 2H), 3.93 (s, 2H), 3.75 (s, 3H), 3.49 – 3.42 (m, 1H), 1.02 – 1.0 (m, 6H). LCMS observed m / z = 532.45 [M+H]+. 6.1 EXAMPLE 6 Compound 6The title compound was prepared using a similar procedure as Compound 5, replacing 2-bromoacetonitrile with 2-(bromomethyl)oxirane.1H NMR (400 MHz, DMSO- d6) δ 7.91 (d, J = 0.8 Hz, 1H), 7.81 (t, J = 6.0 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.42 – 7.40 (m, 3H), 7.35 – 7.31 (m, 2H), 7.20 – 7.16 (m, 1H), 4.70 (d, J = 6.0 Hz, 2H), 4.00 – 3.90 (m, 4H), 3.75 (s, 3H), 3.50 – 3.43 (m, 1H), 3.14 – 3.10 (m, 1H), 3.08 – 3.03 (m, 1H), 2.78 – 2.76 (m, 1H), 2.71 – 2.67 (m, 1H), 2.59 – 2.58 (m, 1H), 1.01 – 1.00 (m, 6H). LCMS observed m / z = 549.44 [M+H]+. 7.1 EXAMPLE 7 Preparation of 2-(2-isopropylphenyl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carbonitrile. Compound 7To a stirred solution of 2-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)- 1H-imidazol-2-yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine (200 mg, 0.41 mmol, Compound 4) in THF (2 mL) was added sodium carbonate (129 mg, 1.22 mmol) at -20 °C and stirred at -20 °C for 15 min before adding cyanogen bromide (51.6 mg, 0.49 mmol) at -20 °C. The reaction mixture was stirred at 0 °C for 1 h. Upon completion, the reaction was diluted with water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was triturated with a mixture of n-pentane in diethyl ether (1:1) and the resulting compound was further purified by PREP-HPLC purification to afford 2-(2- isopropylphenyl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)- 5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carbonitrile (29 mg) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.05 (t, J = 6.0 Hz, 1H), 7.92 (d, J = 1.2 Hz, 1H), 7.67 – 7.65 (m, 2H), 7.43 – 7.41 (m, 3H), 7.37 – 7.32 (m, 2H), 7.21 – 7.17 (m, 1H), 4.74 – 4.68 (m, 6H), 3.75 (s, 3H), 3.51 – 3.40 (m, 1H), 1.02 – 1.0 (m, 6H). LCMS observed m / z = 518.55 [M+H]+. 8.1 EXAMPLE 8 Synthesis of 2-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)acetonitrile. Compound 8The title compound was prepared using a similar procedure as Compound 2, replacing (4-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)boronic acid with (4-cyclopropyl-6- methoxypyrimidin-5-yl)boronic acid.1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.99 (t, J = 6.0 Hz, 1H), 7.92 (d, J = 1.2 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 4.65 (d, J = 6.0 Hz, 2H), 4.05 (s, 2H), 3.98 (s, 2H), 3.93 (s, 2H), 3.81 (s, 3H), 3.75 (s, 3H), 1.70 – 1.64 (m, 1H), 0.97 – 0.94 (m, 2H), 0.80 – 0.79 (m, 2H). LCMS observed m / z = 562.55 [M+H]+. 9.1 EXAMPLE 9 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(oxiran-2-ylmethyl)-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidin-4-amine. Compound 9The title compound was prepared using a similar procedure as Compound 8, replacing 2-bromoacetonitrile with 2-(bromomethyl)oxirane.1H NMR (400 MHz, DMSO- d6) δ 8.59 (s, 1H), 7.92 – 7.89 (m, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 4.63 (d, J = 6.0 Hz, 2H), 3.98 – 3.89 (m, 4H), 3.81 (s, 3H), 3.75 (s, 3H), 3.12 – 3.08 (m, 1H), 3.07 – 3.03 (m, 1H), 2.76 (t, J = 4.6 Hz, 1H), 2.70 – 2.67 (m, 1H), 2.58 – 2.50 (m, 1H), 1.68 – 1.64 (m, 1H), 0.95 – 0.94 (m, 2H), 0.78 – 0.75 (m, 2H). LCMS observed m / z = 579.43 [M+H]+. 10.1 EXAMPLE 10 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidine-6-carbonitrile. Compound 10The title compound was prepared using a similar procedure as Compound 7, replacing 2-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine with 2-(4-cyclopropyl-6- methoxypyrimidin-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)- 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine (Compound 8.3).1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.15 (t, J = 6.0 Hz, 1H), 7.92 (s, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 4.70 – 4.66 (m, 6H), 3.81 (s, 3H), 3.75 (s, 3H), 1.68-1.64 (m, 1H), 0.97 – 0.96 (m, 2H), 0.79 – 0.76 (m, 2H). LCMS observed m / z = 548.38 [M+H]+. 11.1 EXAMPLE 11 Synthesis of 2-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4- (trifluoro-methyl)-1H-imidazol-2-yl)benzyl)amino)-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)acetonitrile. Compound 11The title compound was prepared using a similar procedure as Compound 8, replacing (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine with (4- (1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine (Intermediate B).1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.16 (d, J = 1.2 Hz, 1H), 8.00 (t, J = 6.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 4.66 (d, J = 6.0 Hz, 2H), 4.47 – 4.40 (m, 1H), 4.06 (s, 2H), 3.98 (s, 2H), 3.93 (s, 2H), 3.81 (s, 3H), 1.70 – 1.63 (m, 1H), 1.40 – 1.38 (m, 6H), 0.94 – 0.93 (m, 2H), 0.80 – 0.70 (m, 2H). LCMS observed m / z = 590.5 [M+H]+.12.1 EXAMPLE 12 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine. Compound 12Step 1: Preparation of 2-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol- 2-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine. Compound 12.1To a mixture of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine (224 mg, 0.790 mmol) and N,N-diisopropylethylamine (1.10 mL, 6.34 mmol) in N,N-dimethylformamide (3.00 mL) was added 2,4-dichloroimidazo[2,1- f][1,2,4]triazine (150 mg, 0.790 mmol) and stirred at 23 °C for 16 hours. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 25– 30% EtOAc in hexanes) to afford (100 mg) of methyl 2-chloro-N-(4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine. LCMS observed m / z = 436.6 [M+H]+. Step 2: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4- amine.Compound 12To a mixture of 2-chloro-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (120 mg, 0.275 mmol) in 1,4-dioxane (4.00 mL) was added water (1.00 mL), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (267 mg, 1.37 mmol), and potassium carbonate (114 mg, 0.826 mmol) and purged with N2 for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (31.8 mg, 0.0280 mmol) and the resulting mixture was subjected to microwave heating under N2at 110 °C for 1 hour. The mixture was diluted with cold water (5 mL) and extracted with EtOAc (3 X 20 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by achiral SFC (mobile phase: 23% MeOH) to afford (17.0 mg) of 2-(4-cyclopropyl-6- methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)imidazo[2,1-f][1,2,4]triazin-4-amine as a white solid.1H NMR (400 MHz, DMSO-d6) 9.59 (t, J = 6.4 Hz, 1H), 8.66 (s, 1H), 8.16 (s, 2H), 7.68 (s, 1H), 7.50 (s, 4H), 4.77 (d, J = 6.4 Hz, 2H), 4.46-4.40 (m, 1H), 3.85 (s, 3H), 1.89-1.83 (m, 1H), 1.38 (d, J = 6.4 Hz, 6H), 1.10-0.98 (m, 2H), 0.83-0.80 (m, 2H). LCMS observed m / z = 550.4 [M+H]+. 13.1 EXAMPLE 13 Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2-methyl-N-(4-(5- methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)thiazolo[5,4-d]pyrimidin-7-amine. Compound 13The title compound was prepared using a similar procedure as Compound 12, replacing (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine and 2,4-dichloroimidazo[2,1-f][1,2,4]triazine with (4-(5-methyl-3-(trifluoromethyl)-1H- pyrazol-1-yl)phenyl)methanamine•HCl (Intermediate Y) and 5,7-dichloro-2- methylthiazolo[5,4-d]pyrimidine.1H NMR (400 MHz, CD3OD) δ 8.55 (s, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 6.56 (s, 1H), 4.87 (s, 2H), 3.90 (s, 3H), 2.83 (s, 3H), 2.32 (s, 3H), 1.73 (tt, J = 8.6, 4.7 Hz, 1H), 1.12 – 1.03 (m, 2H), 0.90 – 0.74 (m, 2H). LCMS observed m / z = 553.6 [M+H]+. 14.1 EXAMPLE 14 Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(5-methyl-3- (trifluoromethyl)-1H-pyrazol-1-yl)benzyl)thiazolo[5,4-d]pyrimidin-7-amine. Compound 14The title compound was prepared using a similar procedure as Compound 12, replacing (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine and 2,4-dichloro-imidazo[2,1-f][1,2,4]triazine with (4-(5-methyl-3-(trifluoromethyl)-1H- pyrazol-1-yl)phenyl)-methanamine•HCl (Intermediate Y) and 5,7-dichlorothiazolo[5,4- d]pyrimidine.1H NMR (400 MHz, CD3OD) δ 9.12 (s, 1H), 8.57 (s, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 8.1 Hz, 2H), 6.57 (s, 1H), 4.91 (s, 2H), 3.91 (s, 3H), 2.32 (s, 3H), 1.74 (tt, J = 8.5, 4.7 Hz, 1H), 1.12 – 1.05 (m, 2H), 0.88 – 0.80 (m, 2H). LCMS observed m / z = 539.6 [M+H]+. 15.1 EXAMPLE 15 Synthesis of 5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)thiazolo[5,4-d]pyrimidin-7-amine. Compound 15The title compound was prepared using a similar procedure as Compound 12, replacing 2,4-dichloro-imidazo[2,1-f][1,2,4]triazine with 5,7-dichlorothiazolo[5,4- d]pyrimidine.1H NMR (400 MHz, CD3OD) δ 9.12 (s, 1H), 8.57 (s, 1H), 7.94 – 7.88 (m, 1H), 7.61 – 7.54 (m, 2H), 7.54 – 7.46 (m, 2H), 4.92 (s, 2H), 4.53 (hept, J = 6.7 Hz, 1H), 3.92 (s, 3H), 1.83 – 1.69 (m, 1H), 1.44 (d, J = 6.8 Hz, 6H), 1.14 – 1.04 (m, 2H), 0.90 – 0.76 (m, 2H). LCMS observed m / z = 567.2 [M+H]+. 16.1 EXAMPLE 16 Synthesis of 5-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)thiazolo[5,4-d]pyrimidin-7-amine. Compound 16The title compound was prepared using a similar procedure as Compound 12, replacing 2,4-dichloro-imidazo[2,1-f][1,2,4]triazine and (4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine with 5,7-dichlorothiazolo[5,4- d]pyrimidine and (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine in the SNAr reaction (General Procedure F) and using (2-isopropylphenyl)boronic acid in the Suzuki coupling step (General Procedure F).1H NMR (400 MHz, CD3OD) δ 9.08 (s, 1H), 7.67 (s, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 7.7 Hz, 1H), 7.43 – 7.35 (m, 2H), 7.26 – 7.20 (m, 1H), 4.95 (s, 2H), 3.75 (s, 3H), 3.42 (hept, J = 6.8 Hz, 1H), 1.10 (d, J = 6.8 Hz, 6H). LCMS observed m / z = 509.2 [M+H]+. 17.1 EXAMPLE 17 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine.Compound 17The title compound was prepared using a similar procedure as Compound 12, replacing 2,4-dichloro-imidazo[2,1-f][1,2,4]triazine with 2,4-dichloropyrrolo[2,1- f][1,2,4]triazine.1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.90 (s, 1H), 7.57 – 7.49 (m, 5H), 6.94 – 6.91 (m, 1H), 6.73 – 6.70 (m, 1H), 4.88 (s, 2H), 4.58 – 4.48 (m, 1H), 3.94 (s, 3H), 1.94 – 1.86 (m, 1H), 1.44 (d, J = 6.7 Hz, 6H), 1.12 – 1.08 (m, 2H), 0.90 – 0.85 (m, 2H). LCMS observed m / z = 549.6 [M+H]+. 18.1 EXAMPLE 18 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)pyrido[3,2-d]pyrimidine. Compound 18The title compound was prepared using a similar procedure as Compound 12, replacing 2,4-dichloro-imidazo[2,1-f][1,2,4]triazine and (4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine with 2,4-dichloropyrido[3,4- d]pyrimidine and (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (Intermediate C).1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 3.2 Hz, 1H), 8.72 (s, 1H), 8.44 (dd, J = 8.6, 1.2 Hz, 1H), 8.20 (s, 1H), 8.03 (dd, J = 8.6, 4.2 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 5.74 (s, 2H), 4.53-4.46 (m, 1H), 3.87 (s, 3H), 1.86-1.81 (m, 1H), 1.41 (d, J = 6.8 Hz, 6H), 1.31-1.24 (m, 2H), 0.93-0.84 (m, 2H). LCMS observed m / z = 562.3 [M+H]+.19.1 EXAMPLE 19 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)quinazolin-6-ol. Compound 19The title compound was prepared using a similar procedure as Compound 12, replacing 2,4-dichloro-imidazo[2,1-f][1,2,4]triazine with 2,4-dichloroquinazolin-6-ol.1H NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 7.90 (s, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.48 (dd, J = 5.6, 2.7 Hz, 3H), 7.39 (dd, J = 8.9, 2.6 Hz, 1H), 4.93 (s, 2H), 4.52 (h, J = 6.7 Hz, 1H), 3.90 (s, 3H), 1.75 (tt, J = 8.6, 4.7 Hz, 1H), 1.44 (d, J = 6.6 Hz, 6H), 1.07 (m, 2H), 0.79 (m, 2H). LCMS observed m / z = 576.6 [M+H]+. 20.1 EXAMPLE 20 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrido[3,4-d]pyrimidin-4-amine. Compound 20The title compound was prepared using a similar procedure as Compound 12, replacing 2,4-dichloro-imidazo[2,1-f][1,2,4]triazine with 2,4-dichloropyrido[3,4- d]pyrimidine.1H NMR (400 MHz, DMSO-d6) δ 9.42 (t, J = 5.8 Hz, 1H), 9.16 (s, 1H), 8.70 (d, J = 5.6 Hz, 1H), 8.64 (s, 1H), 8.24 (d, J = 5.6 Hz, 1H), 8.16 (s, 1H), 7.50 (s, 4H), 4.86 (d, J = 6.0 Hz, 2H), 4.45 – 4.41 (m, 1H), 3.82 (s, 3H), 1.78 – 1.72 (m, 1H), 1.38 (d, J = 6.8 Hz, 6H), 0.99 – 0.97 (m, 2H), 0.78 – 0.75 (m, 2H). LCMS observed m / z = 561.4 [M+H]+. 21.1 EXAMPLE 21Synthesis of N-cyclopropyl-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7H-purin-6-amine. Compound 21Step 1: Preparation of N-cyclopropyl-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)- 7-(tetrahydro-2H-pyran-2-yl)-7H-purin-6-amine. Compound 21.1To a mixture of cyclopropanamine (100 mg, 1.74 mmol) in 1,4-dioxane (5.00 mL) was added N,N-diisopropylethylamine (1.00 mL, 5.81 mmol) and the mixture was stirred at 0 °C for 15 minutes. To the resulting mixture was added 2-(4-cyclopropyl-6- methoxypyrimidin-5-yl)-6-(methylsulfonyl)-7-(tetrahydro-2H-pyran-2-yl)-7H-purine (500 mg, 1.29 mmol, Intermediate AB). The resulting mixture was stirred at 90 °C for 16 hours. The mixture was concentrated under reduced pressure and the residue was diluted with water (20 mL) and extracted with EtOAc (2 X 50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 0– 55% EtOAc in hexanes) to afford (250 mg) of N-cyclopropyl-2-(4-cyclopropyl-6- methoxypyrimidin-5-yl)-7-(tetrahydro-2H-pyran-2-yl)-7H-purin-6-amine as a white solid. LCMS observed m / z = 408.8 [M+H]+. Step 2: Preparation of N-cyclopropyl-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)- N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7-(tetrahydro-2H-pyran- 2-yl)-7H-purin-6-amine.Compound 21.2To a mixture of N-cyclopropyl-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7- (tetrahydro-2H-pyran-2-yl)-7H-purin-6-amine (250 mg, 0.610 mmol) in N,N- dimethylformamide (3.00 mL) was added molecular sieves powder (200 mg), 2-(4- (chloromethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (223 mg, 0.730 mmol, Intermediate D), and Cs2CO3 (600 mg, 1.84 mmol). The resulting mixture was stirred at 70 °C for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (5 mL) and extracted with EtOAc (2 X 5 mL). The combined organic layer was washed with brine (2 X 5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, 0–55% EtOAc in hexanes) to afford (15.0 mg) of N- cyclopropyl-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7-(tetrahydro-2H-pyran-2-yl)-7H-purin-6- amine as a yellow solid. LCMS observed m / z = 674.3 [M+H]+. Step 3: Preparation of N-cyclopropyl-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)- N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7H-purin-6-amine. Compound 21To N-cyclopropyl-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl- 4-(trifluoro-methyl)-1H-imidazol-2-yl)benzyl)-7-(tetrahydro-2H-pyran-2-yl)-7H-purin-6- amine (150 mg, 0.220 mmol) in dichloromethane (3.00 mL) was added dropwise trifluoroacetic acid (0.0510 mL, 0.660 mmol) at 0 °C under N2. The resulting mixture wasstirred at 23 °C for 4 hours. The reaction mixture was diluted with a saturated sodium bicarbonate solution (5 mL) and extracted with dichloromethane (2 X 5 mL). The combined organic layer was washed with brine (2 X 5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparatory HPLC (mobile phase: 25-100% acetonitrile in water) to afford (35.0 mg) of N- cyclopropyl-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7H-purin-6-amine as a white solid.1H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.59 (s, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 5.35 (br s, 2H), 4.48 – 4.41 (m, 1H), 3.80 (s, 3H), 3.15 (br s, 1H), 1.83 (br s, 1H), 1.39 (d, J = 6.4 Hz, 6H), 0.98 – 0.80 (m, 8H). LCMS observed m / z = 590.5 [M+H]+. 22.1 EXAMPLE 22 Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(5-methyl-3- (trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-7H-purin-6-amine. Compound 22To 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-6-(methylsulfonyl)-7H-purine (100 mg, 0.289 mmol, Intermediate AC) was added a mixture of (4-(5-methyl-3- (trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine (77.4 mg, 0.303 mmol) and N,N- diisopropylethylamine (0.126 mL, 0.722 mmol) in dimethyl sulfoxide (0.867 mL). The mixture was stirred at 50 °C for 1 hour. The mixture was concentrated under reduced pressure and The crude product was purified by preparatory HPLC (mobile phase: 10–90% acetonitrile in water w / 0.1% formic acid) to afford (6.00 mg, 3.99% yield) of 2-(4- cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1- yl)benzyl)-7H-purin-6-amine as a white solid.1H NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 8.14 (s, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 8.1 Hz, 2H), 6.57 (s, 1H), 4.87 (s, 2H), 3.90 (d, J = 1.0 Hz, 3H), 2.33 (s, 3H), 1.72 (tt, J = 8.5, 4.8 Hz, 1H), 1.08 (m, 2H), 0.84 (m, 2H). LCMS observed m / z = 522.5 [M+H]+. 23.1 EXAMPLE 23Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-((-4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)methyl)-N-methyl-7H-purin-6-amine. Compound 23The title compound was prepared using a similar procedure as Compound 22, replacing (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine with 1-4- (1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)-N- methylmethanamine•HCl (Intermediate N).1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.05 (s, 1H), 7.72 (s, 1H), 4.87 (s, 2H), 4.28 (t, J = 5.0 Hz, 3H), 4.23 – 4.13 (m, 1H), 4.02 (t, J = 5.0 Hz, 3H), 3.92 (s, 3H), 3.73 – 3.54 (m, 3H), 1.80 – 1.72 (m, 1H), 1.45 (d, J = 6.6 Hz, 6H), 1.16 – 1.10 (m, 2H), 0.95 – 0.88 (m, 2H). LCMS observed m / z = 590.6 [M+H]+. 24.1 EXAMPLE 24 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-((2-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)pyrimidin-5-yl)methyl)-7H-purin-6-amine. Compound 24The title compound was prepared using a similar procedure as Compound 22, replacing (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine with (2- (1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrimidin-5-yl)methanamine•TFA (Intermediate U).1H NMR (400 MHz, CD3OD) δ 8.96 (s, 2H), 8.56 (s, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 5.72 (hept, J = 6.8 Hz, 1H), 4.90 (s, 2H), 3.89 (s, 3H), 1.74 – 1.62 (m, 1H), 1.51 (d, J = 6.7 Hz, 6H), 1.12 – 1.03 (m, 2H), 0.91 – 0.81 (m, 2H). LCMS observed m / z = 552.2 [M+H]+. 25.1 EXAMPLE 25Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(2-fluoro-4-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7H-purin-6-amine. Compound 25The title compound was prepared using a similar procedure as Compound 22, replacing (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine with (2- fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-methanamine (Intermediate J).1H NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 8.15 (s, 1H), 7.92 (s, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.32 (t, J = 10.7 Hz, 2H), 4.96 (s, 2H), 4.55 (hept, J = 6.6 Hz, 1H), 3.90 (s, 3H), 1.77 – 1.69 (m, 1H), 1.45 (d, J = 6.6 Hz, 6H), 1.13 – 1.05 (m, 2H), 0.90 – 0.74 (m, 2H). LCMS observed m / z = 568.3 [M+H]+. 26.1 EXAMPLE 26 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-isopropyl-4- (trifluoro-methyl)-1H-imidazol-2-yl)-3-methylbenzyl)-N-methyl-7H-purin-6-amine. Compound 26The title compound was prepared using a similar procedure as Compound 22, replacing (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine with 1- (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3-methylphenyl)-N-methylmethanamine•TFA (Intermediate H). 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H),8.09 (s, 1H), 7.90 (s, 1H), 7.35 (s, 1H), 7.33 – 7.25 (m, 2H), 5.35 (s, 2H), 4.12 (hept, J = 6.7 Hz, 1H), 3.92 (s, 3H), 3.53 (s, 3H), 2.13 (s, 3H), 1.89 – 1.78 (m, 1H), 1.39 (d, J = 6.7 Hz, 6H), 1.16 – 1.08 (m, 2H), 0.93 – 0.81 (m, 2H). LCMS observed m / z = 578.3 [M+H]+.27.1 EXAMPLE 27 Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-((5-(1-isopropyl-4- (trifluoro-methyl)-1H-imidazol-2-yl)pyrazin-2-yl)methyl)-7H-purin-6-amine. Compound 27The title compound was prepared using a similar procedure as Compound 22, replacing (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine with (5- (1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyrazin-2-yl)methanamine•HCl (Intermediate V).1H NMR (400 MHz, CD3OD) δ 9.16 (s, 1H), 8.74 (s, 1H), 8.55 (s, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 5.62 (hept, J = 6.6 Hz, 1H), 5.01 (s, 2H), 4.58 (s, 1H), 3.87 (s, 3H), 1.72 – 1.62 (m, 1H), 1.50 (d, J = 6.7 Hz, 6H), 1.16 – 0.99 (m, 2H), 0.87 – 0.75 (m, 2H). LCMS observed m / z = 552.2 [M+H]+. 28.1 EXAMPLE 28 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-((-4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)methyl)-7-methyl-7H-purin-6-amine. Compound 28The title compound was prepared using a similar procedure as Compound 22, replacing (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine and 2-(4- cyclopropyl-6-methoxypyrimidin-5-yl)-6-(methylsulfonyl)-7H-purine with (4-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)methanamine (Intermediate L) and 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7-methyl-6-(methylsulfonyl)-7H-purine (Intermediate Z).1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.15 (s, 1H), 7.72 (s, 1H), 4.26 – 4.20 (m, 3H), 4.20 – 4.13 (m, 4H), 4.06 – 3.99 (m, 3H), 3.93 (s, 2H), 3.90 (s, 3H),1.78 – 1.69 (m, 1H), 1.46 (d, J = 6.7 Hz, 6H), 1.17 – 1.10 (m, 2H), 0.95 – 0.86 (m, 2H). LCMS observed m / z = 590.3 [M+H]+. 29.1 EXAMPLE 29Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-((6-(1-isopropyl-4- (trifluoro-methyl)-1H-imidazol-2-yl)pyridin-3-yl)methyl)-7H-purin-6-amine. Compound 29The title compound was prepared using a similar procedure as Compound 22, replacing (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine with (6- (1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)methanamine•HCl (Intermediate R).1H NMR (400 MHz, CD3OD) δ 8.72 (s, 1H), 8.56 (s, 1H), 8.14 (s, 1H), 8.00 – 7.88 (m, 3H), 5.66 (hept, J = 6.8 Hz, 1H), 4.91 (s, 2H), 3.90 (s, 3H), 1.75 – 1.66 (m, 1H), 1.48 (d, J = 6.7 Hz, 6H), 1.15 – 1.03 (m, 2H), 0.89 – 0.79 (m, 2H). LCMS observed m / z...

Claims

CLAIMS 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:wherein: R1is selected from C3-C8 cycloalkyl ring, C6-C10aryl, or 4-, 5-, 6-, or 7- membered heterocyclyl ring, and C6-C10aryl fused with 3-8 membered heterocyclic group; wherein R1is optionally substituted with one or more groups selected from -OH, - COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, - OCD3, C1-6haloalkoxy, C1-6hydroxyalkyl, C6-10aryl, 5-8 membered heteroaryl, C3- 8 cycloalkyl, 3-8 membered heterocyclyl, -O-C1-6alkyl, -O-C1-6alkylene, -O-C1-6haloalkyl, -NH-C1-6alkyl, and -NH-C3-8cycloalkyl, wherein the C6-10aryl, 5-8 membered heteroaryl, C3-8 cycloalkyl, and 3-8 membered heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of -OH, - COOH, -NH2, -CN, halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6hydroxyalkyl; R2is selected from:, , , and ; R3is selected from H, D, -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6hydroxyalkyl; Z, U, V, W, P, Q, S, and T are independently selected from C, O, N, and S; wherein Z, U, V, W, P, Q, S, and T are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C1-6alkyl, C2- 6 alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring;wherein when R2is , the phenyl ring is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2- 6 alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8cycloalkyl ring;wherein when R2is , the 5- or 6-membered ring is saturated or unsaturated;wherein when R2is , the 5-membered ring is saturated or unsaturated;wherein when R2is , is saturated or unsaturated; X1is selected from C and N; X2is selected from C and N; wherein when X2is C, the said C is optionally substituted with hydrogen, halogen, -CN, -OR4, -SR4, -N(R5)2, C1-C6alkyl, C1-C6haloalkyl, wherein R4and R5are independently selected from C1-C6alkyl; andRing A is a C6-C8 cycloalkyl ring, C6-C10 aryl, or 4-, 5-, 6-, or 7- membered heterocyclylring; wherein the said ring A is optionally substituted with one or more groups selected from -OH, -COOH, -C(O)-, -NH2, -(NH)-, =O, =NH, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and -C1-6alkyl-epoxide; wherein the said -C(O)- is optionally substituted with H, -OH, NH2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl;wherein the said –(NH)- is optionally substituted with one or more groups selected from H, C1-6alkyl, C1-6nitrile, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, and C1-6alkyl-epoxide; wherein the said C1-6alkyl-epoxide is optionally substituted with one or more C1-6alkyl; wherein when ring A contains ring carbon atoms and one or more heteroatoms, the heteroatoms are selected from N and S; wherein when ring A is a 5-membered heterocyclyl ring and contains oneheteroatom selected from N, ring A is selected from , , and;wherein when ring A is and R2is , V and W are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring;wherein when ring A is and Z is O, ring A is optionally substituted with one or more groups selected from -OH, -COOH, - C(O)-, -NH2, -(NH)-, =O, =NH, halogen, C2-6alkyl, C2-6alkynyl, C1- 6 haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and -C1-6alkyl-epoxide; wherein the said -C(O)- is optionally substituted with H, -OH, NH2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl; wherein the said –(NH)- is optionally substituted with one or more groups selected from H, C1-6alkyl, C1-6nitrile, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, and C1-6alkyl-epoxide;wherein the said C1-6alkyl-epoxide is optionally substituted with one or more C1-6alkyl; wherein when ring A is a 5-membered heterocyclyl ring and at least oneheteroatom is S, ring A is selected from , , or , where Z is N;wherein when ring A is selected from or , Z is N,and R2is where S and P are N, wherein: (i) when S or P are substituted with C1 alkyl then R1is C6-C10aryl; (ii) S or P are substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl; or (iii) V or W are substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1- 6 haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring;wherein when ring A is and Z is N, R1is selected from C3-C8 cycloalkyl ring, 4-, 5-, 6-, or 7- membered heterocyclyl ring, and C6-C10aryl fused with 3-8 membered heterocyclic group;wherein when ring A is a 5-membered heterocyclyl ring and contains two heteroatoms selected from N, ring A is selected from, ,, and ; wherein when ring A is, Z is O, and R2iswhere S and P are N, S and P are optionally substituted with one or more groups selected from -OH, -COOH, - NH2, -CN, -CD(CD3)2, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring;wherein when ring A is or, Z is O, and R2iswhere Q and P are N, S is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, - CD(CD3)2, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring; wherein when ring A isand Z is O, S and P are optionally substituted with one or more groups selected from -OH, -COOH, - NH2, -CN, -CD(CD3)2, halogen, C3-6alkyl, C2-6alkynyl, C1-6haloalkyl, C2-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C4-C8 cycloalkyl ring;wherein when ring A is a 6-membered heterocyclyl ring and contains one or two heteroatoms selected from N, ring A is selected from,,, , , , , and ;wherein when ring A is, or , Z is O; wherein when ring A is, , or , Z is O and R2is, P and S are substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C3-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C4-C8cycloalkyl ring; wherein when ring A is, Z is N and ring A is optionally substituted with one or more groups selected from -COOH, -NH2, - (NH)-, =O, =NH, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6 haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and -C1-6alkyl-epoxide.

2. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R1is selected from C3-C8 cycloalkyl ring, C6-C10aryl, or 4-, 5-, 6-, or 7- membered heterocyclyl ring, and C6-C10aryl fused with 3-8 membered heterocyclic group; wherein R1is optionally substituted with one or more groups selected from -OH, -COOH, - NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, -OCD3, C1-6haloalkoxy, C1-6hydroxyalkyl, C6-10aryl, 5-8 membered heteroaryl, C3-8cycloalkyl, 3-8 membered heterocyclyl, -O-C1-6alkyl, -O-C1-6alkylene, -O-C1-6haloalkyl, -NH-C1-6alkyl,and -NH-C3-8cycloalkyl, wherein the C6-10aryl, 5-8 membered heteroaryl, C3-8cycloalkyl, and 3-8 membered heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6hydroxyalkyl.

3. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein R1is selected from C6aryl, 5- or 6-memered heterocyclic ring and C6aryl fused with 5-membered heterocyclic group; wherein R1is optionally substituted with one or more groups selected from -OH, - COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, - OCD3, C1-6haloalkoxy, C1-6hydroxyalkyl, C6-10aryl, 5-8 membered heteroaryl, C3- 8 cycloalkyl, 3-8 membered heterocyclyl, -O-C1-6alkyl, -O-C1-6alkylene, -O-C1-6haloalkyl, -NH-C1-6alkyl, and -NH-C3-8 cycloalkyl, wherein the C6-10aryl, 5-8 membered heteroaryl, C3-8cycloalkyl, and 3-8 membered heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C1-6haloalkyl, C1- 6 alkoxy, C1-6haloalkoxy, and C1-6hydroxyalkyl.

4. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, wherein R1is selected from:

5. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 4, wherein R2is selected from:, , , and ; R3is selected from H, D, -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6hydroxyalkyl; Z, U, V, W, P, Q, S, and T are independently selected from C, O, N, and S, wherein Z, U, V, W, P, Q, S, and T are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C1-6alkyl, C2-6 alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring;wherein when R2is , the phenyl ring is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2- 6 alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8cycloalkyl ring; wherein when R2is, the 5- or 6-membered ring is saturated or unsaturated;wherein when R2is , the 5-membered ring is saturated or unsaturated;wherein when R2is , wherein is saturated or unsaturated; 6. The compound of formula (I), or a pharmaceutically acceptable salt thereof,according to any of claims 1 to 5, wherein R2is , Z is selected from C, O, N, and S; and R3 is selected from H, D, -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6hydroxyalkyl; wherein the phenyl ring is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1- 6 alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8cycloalkyl ring.

7. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 6, wherein R2is selected from:, , and .

8. The compound of formula (I), or a pharmaceutically acceptable salt thereof,according to any one of claims 1 to 5, wherein R2is and the 5 or 6 membered ring is saturated or unsaturated; R3is selected from H, D, -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6hydroxyalkyl; and Z, U, V, W, P, Q, S, and T are independently selected from C, O, N, and S,wherein Z, U, V, W, P, Q, S and T are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring.

9. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 8 wherein R2is selected from:

10. The compound of formula (I), or a pharmaceutically acceptable salt thereof,according to any of claims 1 to 5, wherein R2is , and the 5-membered ring is saturated or unsaturated; R3 is selected from H, D, -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6hydroxyalkyl; and Z, P, Q, and S are independently selected from C, O, N, and S, wherein Z, P, Q, and S are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1- 6 alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8cycloalkyl ring.

11. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 10, wherein R2is selected from:, , , and .

12. The compound of formula (I), or a pharmaceutically acceptable salt thereof,according to any one of claims 1 to 5, wherein R2is ,is saturated or unsaturated; Z, P, Q, and S are independently selected from C, O, N, and S, wherein Z, P, Q, and S are optionally substituted with one or more groups selected from - OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8cycloalkyl ring.

13. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 12, wherein R2is selected from:, , and .

14. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 13, wherein X1 is selected from C and N.

15. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 14, wherein X2is selected from C and N; wherein when X2is C, the said C is optionally substituted with hydrogen, halogen, -CN, -OR4, -SR4, -N(R5)2, C1-C6alkyl, C1-C6haloalkyl, wherein R4and R5are independently selected from C1-C6alkyl.

16. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 15, wherein ring A is a C6-C8cycloalkyl ring, C6-C10aryl, or 4-, 5-, 6-, or 7- membered heterocyclyl ring wherein the said ring A is optionally substituted with one or more groups selected from -OH, -COOH, -C(O)-, -NH2, -(NH)-, =O, =NH, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and C1-6alkyl-epoxide; wherein the said -C(O)- is optionally substituted with H, -OH, NH2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl; wherein the said –(NH)- is optionally substituted with one or more groups selected from H, C1-6alkyl, C1-6nitrile, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, and C1- 6 alkyl-epoxide; wherein the said C1-6alkyl-epoxide is optionally substituted with one or more C1-6alkyl;wherein when ring A contains ring carbon atoms and one or more heteroatoms, the heteroatoms are selected from N and S wherein when ring A is a 5-membered heterocyclyl ring and contains one heteroatom selected from N, ring A is selected from, , and ; wherein when ring Ais and R2is , V and W are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring;wherein when ring A is and Z is O, ring A is optionally substituted with one or more groups selected from -OH, -COOH, - C(O)-, -NH2, -(NH)-, =O, =NH, halogen, C2-6alkyl, C2-6alkynyl, C1- 6 haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and -C1-6alkyl-epoxide; wherein the said -C(O)- is optionally substituted with H, -OH, NH2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl; wherein the said –(NH)- is optionally substituted with one or more groups selected from H, C1-6alkyl, C1-6nitrile, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, and C1-6alkyl-epoxide; wherein the said C1-6alkyl-epoxide is optionally substituted with one or more C1-6alkyl; wherein when ring A is a 5-membered heterocyclyl ring and at least one heteroatom is S, ring A is selected from where Z is N;wherein when ring A is selected from or , Z is N, and R2is where S and P are N, wherein: (i) when S or P are substituted with C1 alkyl then R1is C6-C10aryl; (ii) S or P are substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl; or (iii) V or W are substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1- 6 haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring;wherein when ring A is and Z is N, R1is selected from C3- C8 cycloalkyl ring or 4-, 5-, 6-, or 7- membered heterocyclyl ring, and C6-C10aryl fused with 3-8 membered heterocyclic group; wherein when ring A is a 5-membered heterocyclyl ring and contains twoheteroatoms selected from N, ring A is selected from , ,, and ;wherein when ring A is , Z is O, and R2iswhere S and P are N, S and P are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring; wherein when ring A is, Z is O, and R2iswhere Q and P are N, S is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, - CD(CD3)2, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring;wherein when ring A is and Z is O, S and P are optionally substituted with one or more groups selected from -OH, -COOH, - NH2, -CN, -CD(CD3)2, halogen, C3-6alkyl, C2-6alkynyl, C1-6haloalkyl, C2-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C4-C8cycloalkyl ring; wherein when ring A is a 6-membered heterocyclyl ring and contains one or two heteroatoms selected from N, ring A is selected from,wherein when ring A isor , Z is O; N wherein when ring A is, or , Z is O and R2is, P and S are substituted with one or more groups selected from -OH, -COOH, -NH2, -CN,-CD(CD3)2, halogen, C3-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C4-C8 cycloalkyl ring;wherein when ring A is , Z is N and ring A is optionally substituted with one or more groups selected from -COOH, -NH2, - (NH)-, =O, =NH, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6 haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and -C1-6alkyl-epoxide.

17. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 16, wherein ring A is a 5-membered heterocyclyl ring; wherein the said ring A is optionally substituted with one or more groups selected from -OH, -COOH, -C(O)-, -NH2, -(NH)-, =O, =NH, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and -C1-6alkyl-epoxide; wherein the said -C(O)- is optionally substituted with H, -OH, NH2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl; wherein the said –(NH)- is optionally substituted with one or more groups selected from H, C1-6alkyl, C1-6nitrile, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, and C1- 6 alkyl-epoxide; wherein the said C1-6alkyl-epoxide is optionally substituted with one or more C1-6alkyl; wherein when ring A contains ring carbon atoms and one or more heteroatoms, the heteroatoms are selected from N and S wherein when ring A is a 5-membered heterocyclyl ring and contains oneheteroatom selected from N, ring A is selected from , , and;wherein when ring Ais and R2 is , Vand W are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring; wherein when ringAis and Z is O, ring A is optionallysubstituted with one or more groups selected from -OH, -COOH, - C(O)-, -NH2, -(NH)-, =O, =NH, halogen, C2-6alkyl, C2-6alkynyl, C1-6 haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and -C1-6alkyl-epoxide; wherein the said -C(O)- is optionally substituted with H, -OH, NH2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl; wherein the said –(NH)- is optionally substituted with one or more groups selected from H, C1-6alkyl, C1-6nitrile, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, and C1-6alkyl-epoxide; wherein the said C1-6alkyl-epoxide is optionally substituted with one or more C1-6alkyl; wherein when ring A is a 5-membered h l l i l neheteroatom is S, ring A is selected from , , or , where Z is N;wherein when ring A is selected from or , Z is N,and R2is where S and P are N, wherein: (i) when S or P are substituted with C1 alkyl then R1 isC6-C10aryl;(ii) S or P are substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl; or (iii) V or W are substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1- 6 haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring;wherein when ring A is and Z is N, R1is selected from C3- C8 cycloalkyl ring or 4-, 5-, 6-, or 7- membered heterocyclyl ring, and C6-C10aryl fused with 3-8 membered heterocyclic group; wherein when ring A is a 5-membered heterocyclyl ring and contains twoheteroatoms selected from N, ring A is selected from , ,, and ;wherein when ring A is , Z is O, and R2iswhere S and P are N, S and P are optionally substituted with one or more groups selected from -OH, -COOH, - NH2, -CN, -CD(CD3)2, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring;wherein when ring A is , Z is O, and R2iswhere Q and P are N, S is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, - CD(CD3)2, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6haloalkoxy, C1-6hydroxyalkyl, and C3-C8 cycloalkyl ring;wherein when ring A is and Z is O, S and P are optionally substituted with one or more groups selected from -OH, -COOH, - NH2, -CN, -CD(CD3)2, halogen, C3-6alkyl, C2-6alkynyl, C1-6haloalkyl, C2-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C4-C8 cycloalkyl ring.

18. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 17 wherein ring A is selected from:, 19. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 16, wherein ring A is a 6-membered heterocyclyl ring,wherein the said ring A is optionally substituted with one or more groups selected from -OH, -COOH, -C(O)-, -NH2, -(NH)-, =O, =NH, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and -C1-6alkyl-epoxide; wherein the said -C(O)- is optionally substituted with H, -OH, NH2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl; wherein the said –(NH)- is optionally substituted with one or more groups selected from H, C1-6alkyl, C1-6nitrile, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, and C1-6alkyl-epoxide; wherein the said C1-6alkyl-epoxide is optionally substituted with one or more C1-6alkyl wherein when ring A contains ring carbon atoms and one or more heteroatoms, the heteroatoms are selected from N and S wherein when ring A is a 6-membered heterocyclyl ring and contains one or two heteroatomsO and R2is , P and S are substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, -CD(CD3)2, halogen, C3-6 alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, and C4-C8 cycloalkyl ring;wherein when ring A is , Z is N and ring A is optionally substituted with one or more groups selected from -COOH, -NH2, - (NH)-, =O, =NH, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1- 6 haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and -C1-6alkyl-epoxide.

20. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 19 wherein ring A is selected from:

21. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 16, wherein ring A is a C6-C10aryl wherein the said ring A is optionally substituted with one or more groups selected from -OH, -COOH, -C(O)-, -NH2, -(NH)-, =O, =NH, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C1-6nitrile, and C1-6alkyl-epoxide; wherein the said -C(O)- is optionally substituted with H, -OH, NH2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl; wherein the said –(NH)- is optionally substituted with one or more groups selected from H, C1-6alkyl, C1-6nitrile, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, and C1-6alkyl-epoxide; wherein the said C1-6alkyl-epoxide is optionally substituted with one or more C1-6alkyl.

22. The compound of formula (I), or a pharmaceutically acceptable salt thereof,according to claim 21, wherein ring A is .

23. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-22, wherein the compound is selected from:

24. A compound of formula (II), or a pharmaceutically acceptable salt thereof:(II) wherein: X’ and X” are independently selected from N or C;R1is wherein Z is selected from O or N optionally substituted with R1a or -CH2R1a, wherein R1a is C3-C6cycloalkyl or 4-, 5-, or 6- membered heterocyclyl; wherein R2is selected from H or deuterium; R3 is selected from , , and , wherein W is selected from C or N, and wherein R3a, R3b, and R3c are independently selected from -H or halogen, R3a and R2optionally form a bond to form a 5- or 6-membered heterocyclyl, or R3a and R3b optionally combine to form a bridge;, , , , and , wherein U and Y are independently selected from C or N, and wherein when U is N, Y is C, and when U is C, Y is N or C; wherein R5, R6, and R7 are independently selected from -H, -OH, - COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl,C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl ring is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, C3-C8spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein when R7 is a 4-, 5-, or 6- membered heterocyclyl ring, R4isor ;andwherein R3c optionally forms a bond with R5 or R7 to form a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl or C5-C12cycloalkyl, wherein the 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl or C5-C12cycloalkyl is optionally substituted with one or more groups selected from C1-6alkyl, -OH, =O, C1-6alkoxy, and halogen; Ring A is a 5- or 6- membered heterocyclyl ring comprising one to three heteroatoms selected from N, O, or S; wherein when ring A is a 5-membered heterocyclyl ring and contains one heteroatom, ring A is selected fromwhere X’ and X” are C andwhere X’ and X” are C; wherein when ring A iswhere X’ and X” are C, R4is, and Z is O, R7is selected from -H, -OH, -COOH, - NH2, -CN, halogen, C3-6 alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C4-C8cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, C3- C8spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein when ring A iswhere X’ and X” are C and R4is, R7 is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl or C3-C8cycloalkyl ring are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, C3-C8spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein when ring A is a 5-membered heterocyclyl ring and contains two heteroatoms, ring A is selected fromwhere X’ and X” are C,where X’ and X” are C, where X’ is N and X” is C,where X’ is C and X” is N, and where X’ is C and X” is N;wherein when where X’ and X” are C or where X’ and X” are C, R4isor , and Z is O, R7 is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C2-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl or C3-C8 cycloalkyl ring are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, C3-C8 spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein when ring A is a 5-membered heterocyclyl ring and contains three heteroatoms, ring A iswhere X’ is C and X” is N; wherein when ring A is 6-membered heterocyclyl ring, ring A iswhere X’ and X” are C and Z is N; wherein when ring A is where X’ and X” are C, Z is N, and R4is, R7 is selected from -H, -OH, -COOH, -NH2, - CN, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring;wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, C3- C8 spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said ring A is optionally substituted with one or more groups selected from =O, C1-6alkyl, C2-C6alkenyl, and C2-6alkynyl; wherein when ring A iswhere X’ and X” are C, the compound of formula (II) or a pharmaceutically acceptable salt thereof comprises one or more of: Z is substituted with R1aor -CH2R1a, R3aand R3bare halogen, R5, R6, or R7 is a 4-, 5-, or 6- membered heterocyclyl ring,R4 is , , or where U and Y are C,where U is C and Y is N, or R3iswhere U is N and Y is C, or a combination thereof; wherein when ring A iswhere X’ and X” are C , the compound of formula (II) or a pharmaceutically acceptable salt thereof comprises a ring A substituted with a C2-C6alkenyl;wherein when ring A iswhere X’ is N and X” is C, the compound offormula (II) or a pharmaceutically acceptable salt thereof comprises one or more of: R3a and R2form a bond to form a 5- or 6-membered heterocyclyl,R3aand R3bcombine to form a bridge,R3 is ,R4is , , or , R5, R6, or R7 a 4-, 5-, or 6- membered heterocyclyl ring, R3c forms a bond with R5 to form a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- memberedheterocyclyl or C5-C12cycloalkyl, or a combination thereof.

25. The compound of formula (II) or a pharmaceutically acceptable salt thereof,according to claim 24, wherein R1 is;wherein Z is selected from O or N optionally substituted with R1aor -CH2R1a, wherein R1a is C3-C6cycloalkyl or 4-, 5-, or 6- membered heterocyclyl wherein R2is selected from H or deuterium; R3 is selected from, , and , wherein W isselected from C or N, and wherein R3a, R3b, and R3c are independently selected from -H or halogen, R3aand R2optionally form a bond to form a 5- or 6-membered heterocyclyl, or R3aand R3boptionally combine to form a bridge;wherein U and Y are independently selected from C or N, and wherein when U is N, Y is C, and when U is C, Y is N or C; wherein R5, R6, and R7 are independently selected from -H, -OH, - COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl or C3-C8cycloalkyl ring are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, C3-C8spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein R3c optionally forms a bond with R5 or R7 to form a 5-, 6-, 7-, 8-, 9- , 10-, 11-, or 12- membered heterocyclyl or C5-C12 cycloalkyl, wherein the 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl or C5-C12 cycloalkyl is optionally substituted with one or more groups selected from C1-6alkyl, -OH, =O, C1-6alkoxy, and halogen; wherein when R7 is a 4-, 5-, or 6- membered heterocyclyl ring, R4isor .

26. The compound of formula (II), or a pharmaceutically acceptable salt thereof, according to claim 24-25, wherein R3 is selected from , , and27. The compound of formula (II), or a pharmaceutically acceptable salt thereof, according to claims 24-26 wherein R3 is selected from28. The compound of formula (II), or a pharmaceutically acceptable salt thereof, according to claim 24-25, wherein when R3a and R2form a bond to form a 5- or 6-memberedheterocyclyl, R3 is .

29. The compound of formula (II), or a pharmaceutically acceptable salt thereof, according to claim 24-25, wherein when R3a and R3b combine to form a bridge, R3 is.

30. The compound of formula (II), or a pharmaceutically acceptable salt thereof,according to claims 24-29, wherein R4is selected from , ,wherein U and Y are independently selected from C or N, and wherein when U is N, Y is C, and when U is C, Y is N or C; wherein R5, R6, and R7 are independently selected from -H, -OH, -COOH, -NH2, - CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring;wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3- C8cycloalkyl ring, C3-C8spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring;wherein when R7is a 4-, 5-, or 6- membered heterocyclyl ring, R4isor .

31. The compound of formula (II), or a pharmaceutically acceptable salt thereof according to claim 30, wherein R4is selected from:, ,, and .

32. The compound of formula (II), or a pharmaceutically acceptable salt thereof, according to any of claims 25-31, wherein when R3 is, R1is selected from:.

33. The compound of formula (II), or a pharmaceutically acceptable salt thereof,according to any of claims 24-27 and 31, wherein when R3 is , R1is34. The compound of formula (II), or a pharmaceutically acceptable salt thereof,according to any of claims 24-27 and 31, wherein when R3 is , R1is.

35. The compound of formula (II), or a pharmaceutically acceptable salt thereof,according to any of claims 24-27 and 31, wherein when R3 is , R1is, 36. The compound of formula (II), or a pharmaceutically acceptable salt thereof,according to any of claims 24-37 and 31, wherein when R3is , R1is selectedfrom and .

37. The compound of formula (II), or a pharmaceutically acceptable salt thereof, according to claims 28 and 31, wherein when R3a and R2form a bond to form a 5- or 6-membered heterocyclyl, R1is .

38. The compound of formula (II), or a pharmaceutically acceptable salt thereof, di t l i 29 d 31 herein when R3a and R3b combine to form a bridge, R1is39. The compound of formula (II), or a pharmaceutically acceptable salt thereof, according to claims 24-30, wherein when R3c forms a bond with R5 or R7 to form a 5-, 6-, 7- , 8-, 9-, 10-, 11-, or 12- membered heterocyclyl or C5-C12 cycloalkyl, wherein the 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12- membered heterocyclyl or C5-C12 cycloalkyl is optionally substituted with one or more groups selected from C1-6alkyl, -OH, =O, C1-6alkoxy, and halogen, R1is selected from:

40. The compound of formula (II), or a pharmaceutically acceptable salt thereof, according to any one of claim 24, wherein ring A is a 5- or 6- membered heterocyclyl ring comprising one to three heteroatoms selected from N, O, or S; wherein when ring A is a 5-membered heterocyclyl ring and contains oneheteroatom, ring A is selected from where X’ and X” are C and where X’ and X” are C;wherein when ring A is where X’ and X” are C, R4is , and Z is O, R7 is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C3- 6 alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C4-C8cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl or C4-C8 cycloalkyl ring are optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, C3-C8 spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring;wherein when ring A is where X’ and X” are C and R4is, R7 is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, C3-C8spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein when ring A is a 5-membered heterocyclyl ring and contains two heteroatoms, ring A is selected fromwhere X’ and X” are C, where X’ and X” are C where X’ is N and X” is C where X’ is Cand X” is N, and where X’ is C and X” is N; wherein whenwhere X’ and X” are C orwhere X’ and X” are C, R4isor , and Z is O, R7 is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C2-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C2-6alkyl, C1-6haloalkyl or C3-C8 cycloalkyl ring are optionally substituted with one or more groups selected from -OH, - COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, C3-C8spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein when ring A is a 5-membered heterocyclyl ring and contains three heteroatoms, ring A iswhere X’ is C and X” is N; wherein when R ring A is 6-membered heterocyclyl ring, ring A iswhere X’ and X” are C and Z is N;wherein when ring A iswhere X’ and X” are C and R4is, R7 is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C2-6alkyl, C1-6haloalkyl or C3-C8 cycloalkyl ring are optionally substituted with one or more groups selected from -OH, - COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, C3-C8spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said ring A is optionally substituted with one or more groups selected from =O, C1-6alkyl, C2-C6alkenyl, and C2-6alkynyl.

41. The compound of formula (II), or a pharmaceutically acceptable salt thereof, according to claim 40, wherein Ring A is a 5- membered heterocyclyl ring comprising one to three heteroatoms selected from N, O, or S; wherein when ring A is a 5-membered heterocyclyl ring and contains one heteroatom, ring A is selected fromwhere X’ and X” are C andwhere X’ and X” are C; wherein when ring A iswhere X’ and X” are C, R4is, and Z is O, R7 is selected from -H, -OH, -COOH, - NH2, -CN, halogen, C3-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C4-C8cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, C3- C8spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein when ring A iswhere X’ and X” are C and R4is, R7 is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, C3- C8spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein when ring A is a 5-membered heterocyclyl ring and contains twoheteroatoms, ring A is selected from where X’ and X” are C,where X’ and X” are C, where X’ is N and X” is C,where X’ is C and X” is N, andwhere X’ is C and X” is N;wherein when where X’ and X” are C or where X’ and X” areC, R4is or , and Z is O, R7 is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C2-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, C3- C8 spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein when ring A is a 5-membered heterocyclyl ring and contains three Nheteroatoms, ring A is where X’ is C and X” is N; wherein the said ring A is optionally substituted with one or more groups selected from =O, C1-6alkyl, C2-C6alkenyl, and C2-6alkynyl.

42. The compound of formula (II), or a pharmaceutically acceptable salt thereof, according to claim 41, wherein ring A is selected from: , , ,, , , , 43. The compound of formula (II), or a pharmaceutically acceptable salt thereof, according to claim 40, wherein Ring A is a 6- membered heterocyclyl ring comprising one to three heteroatoms selected from N, O, or S;wherein when R ring A is 6-membered heterocyclyl ring, ring A is where X’ and X” are C and Z is N;wherein when ring A is where X’ and X” are C and R4is, R7 is selected from -H, -OH, -COOH, -NH2, -CN, halogen, C2-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8 cycloalkyl ring, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said C1-6haloalkyl is optionally substituted with one or more groups selected from -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C1-6hydroxyalkyl, C3-C8cycloalkyl ring, C3-C8spiro-cycloalkyl, and 4-, 5-, or 6- membered heterocyclyl ring; wherein the said ring A is optionally substituted with one or more groups selected from =O, C1-6alkyl, C2-C6alkenyl, and C2-6alkynyl.

44. The compound of formula (II), or a pharmaceutically acceptable salt thereof,according to claim 42, wherein ring A is .

45. The compound of formula (II), or a pharmaceutically acceptable salt thereof, according to any one of claims 24-44 wherein the compound is selected from:and .

46. A method of modulating USP1 activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-45.

47. A method of inhibiting USP1 activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-45.

48. A method of treating a disorder or disease with a USP1 inhibitor in a subject, comprising administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-45.

49. A method of treating cancer with a USP1 inhibitor in a subject, comprising administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-45.

50. A method of treating cancer with a USP1 inhibitor in a subject, comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-45, wherein the cancer is characterized by over expression of USP1.

51. The method according to claim 50, wherein the cancer characterized by overexpression of USP1 is selected from prostate, breast, ovarian, non-small cell lungcancer, mesothelioma, Merkel cell carcinoma, synovial sarcoma, renal cell carcinoma, and osteosarcoma.

52. The use of a compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-45, in the manufacture of a medicament for the treatment of cancer.

53. The use according to claim 52, of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1-45, wherein the cancer is characterized by overexpression of USP1.

54. A process to manufacture a compound according to any one of claims 1-45, or a pharmaceutically acceptable salt thereof.