Pyridopyrimidine and quinazoline derivatives as USP1 inhibitors, compositions comprising them and methods of using the same

Abstract

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

Description

[0001] PYRIDOPYRIMIDINE AND QUINAZOLINE DERIVATIVES AS USP1 INHIBITORS, COMPOSITIONS COMPRISING THEM AND METHODS OF USING THE SAME

[0002] CROSS-REFERENCE TO RELATED APPLICATION

[0003] This application claims priority to U.S. Provisional Application No. 63 / 610,849 filed December 15, 2023, the contents of which are incorporated herein by reference in their entirety.

[0004] TECHNICAL FIELD

[0005] The subject matter described herein relates to compositions comprising Ubiquitin- Specific Protease 1 (USP1) inhibitors and methods of using the same.

[0006] BACKGROUND

[0007] 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.

[0008] SUMMARY OF THE INVENTION

[0009] 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.

[0010] In certain embodiments, the compositions and methods described herein relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein X1and Y are independently selected from C, N, O and S; 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; 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; wherein R1is 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, 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; R2is selected from: R3is selected from H, -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, 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; and 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 one or more groups selected from H, -OH, -NH2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and 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 X1is C, Y is N, and R2is where S and P are N, ring A is 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 when X1is N, Y is C, and R2is where S and P are N, ring A is 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 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-C6alkyl, C1-C6haloalkyl, wherein R4and R5are 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 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; wherein R1is 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, 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. 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-membered 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, 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. 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: R3is selected from H, -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, 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. 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, -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 selectedfrom -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: 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; R3is selected from H, -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, N, O, 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, 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: ,

[0011] . 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; R3is selected from H, -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, N, O, 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: . In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein X and Y are independently selected from C, N, O, or S; wherein 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 -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 C1-6alkyl, C1-6nitrile, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, or C1-6alkyl-epoxide; wherein the C1-6alkyl-epoxide can be optionally substituted with 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 selected from: . 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:

[0012]

[0013] 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.

[0014] 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.

[0015] 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.

[0016] 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.

[0017] 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.

[0018] 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.

[0019] 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 USP 1.

[0020] In certain embodiments, the present disclosure is directed to a process to manufacture a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0021] DETAILED DESCRIPTION

[0022] 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:

[0023] 1. Definitions

[0024] 2. Compositions of Matter

[0025] 3. Methods of Use

[0026] 4. Examples

[0027] 1. Definitions

[0028] 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 acid salts 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.

[0029] 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 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-C6alkyl, C1-C6haloalkyl, wherein R4and R5are 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 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, 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. 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: R3is selected from H, -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, 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. 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, -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 selectedfrom -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: 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; R3is selected from H, -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, N, O, 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, 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:

[0030] . 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; R3is selected from H, -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, N, O, 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: . In certain embodiments, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein X and Y are independently selected from C, N, O, or S; wherein 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 -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 C1-6alkyl, C1-6nitrile, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, or C1-6alkyl-epoxide; wherein the C1-6alkyl-epoxide can be optionally substituted with 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 selected from: ,

[0031] In certain embodiments, when X1is C, Y is N, and R2is where S and P are N, ring A is 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 In certain embodiments, when X1is N, Y is C, and R2is where S and P are N, ring A is 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 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:

[0032] , ,

[0033]

[0034] 3. Methods of Use In certain embodiments, the present disclosure is directed to a method of modulating

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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 USP 1.

[0043] In certain embodiments, the present disclosure is directed to a process to manufacture a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0044] 4. Examples

[0045] 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.

[0046] Table 1: Exemplary compounds. Table 2: Abbreviations Used.

[0047] Synthetic Examples

[0048] General Procedures

[0049] General Procedure A

[0050] Imidazole Formation

[0051] To 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 methanol 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 h. The reaction was cooled to 23 °C and the methanol was removed under reduced pressure. The aqueous phase was extracted with ethyl acetate and the organics were washed with sat. sodium bicarbonate, brine, dried over magnesium or sodium sulfate, filtered and concentrated. General Procedure B Imidazole Alkylation To a stirred solution of imidazole in acetonitrile or N,N-dimethylformamide (0.4 M) was added cesium carbonate (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 ethyl acetate. The organics were washed with sat. sodium bicarbonate, brine, dried over magnesium or sodium sulfate, filtered and concentrated. General Procedure C Reduction of Nitriles or Esters To a stirred solution of the benzonitrile (1.0 equiv.) in THF (0.3 M) was added lithium aluminum hydride (1.2 equiv, 2.0 M in THF) or diisobutyl aluminum 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 wasquenched with saturated ammonium chloride solutionand extracted with ethyl acetate.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 Nitriles To solution of the benzonitrile (1.0 equiv.) in ethyl acetate 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 8 - 16 h. The mixture was filtered through celite and the bed was thoroughly washed with ethanol followed by ethyl acetate. The filtrate was evaporated under reduced pressure. General Procedure E SNAr Substitution To 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 DMF was added NaH (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 16 h. The reactions were concentrated under reduced pressure or extracted with ethyl acetate then washed with water, brine, dried over anhydrous sodium or magnesium sulfate, filtered, and concentrated under reduced pressure. General Procedure F Suzuki Coupling To 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 cesium carbonate (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 ethyl acetate 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 A Step 1: Preparation of 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile. Intermediate A1 To 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 methanol (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 methanol was removed under reduced pressure. The resulting solution was diluted with water (1000 mL) and extracted with ethyl acetate (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 evaporated under reduced pressure and the residue was purified via flash chromatography (mobile phase: 30% ethyl acetate in petroleum ether) to obtain 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (51.0 g, 46 % yield) as a pale yellow solid. LCMS (ESI) m / z = 238.07 [M+H]+. Step 2: Preparation of 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzonitrile. Intermediate A2 To 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 ethyl acetate (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 evaporated under reduced pressure and the residue was purified by flash column chromatography (mobile phase: 30% ethyl acetate in petroleum ether) to obtain 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (15.5 g, 73%) as a pale yellow solid. LCMS (ESI) m / z = 252.15 [M+H]+. Step 3: Preparation of (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)- methanamine. Intermediate A To a solution of 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzonitrile (15.5 g, 61.70 mmol) in ethyl acetate (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. The mixture was filtered through celite and the bed was thoroughly washed with ethanol followed by ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was purified by flash column chromatography (mobile phase: 10% methanol in dichloromethane) to obtain (4-(1-methyl- 4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-methanamine (9.60 g, 61% yield) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6) 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 (ESI) m / z = 256.06 [M+H]+. Intermediate B Synthesis of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine. Intermediate B The 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). MS (ESI) m / z = 284.32 [M+H]+. Intermediate C Synthesis of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanol. Intermediate C The 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). MS (ESI) m / z = 285.18 [M+H]+. Intermediate D Synthesis of 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)-N- methyl-methanamine•HCl. Intermediate D Step 1: Preparation of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzaldehyde. Intermediate D.1 To 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 evaporated under reduced pressure to obtain a residue. The residue was triturated with pentane to afford 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzaldehyde (1.70 g, 95% yield) as an off-white solid. LCMS (ESI): 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 D To 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 methanol (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 methanol was evaporated under reduced pressure. The material was extracted with ethyl acetate (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 evaporated under reduced pressure to afford a residue. 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 evaporated under reduced pressure to get residue. The residue was triturated with diethyl ether (5 mL) to obtain 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)-N-methylmethanamine•HCl (1.20 g, 67 % yield) 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 (ESI): m / z = 298.22 [M+H]+. Intermediate E Synthesis of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- methylphenyl)-methanamine•HCl. Intermediate E Step 1: Preparation of 1-isopropyl-4-(trifluoromethyl)-1H-imidazole. Intermediate E.1 To 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 cesium carbonate (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 ethyl acetate (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 (mobile phase: 12-15% ethyl acetate in petroleum ether) to afford 1-isopropyl-4-(trifluoromethyl)-1H-imidazole (11.3 g, 69% yield) as a yellow liquid. LCMS (ESI): m / z = 178.74[ M+H]+. Step 2: Preparation of 2-bromo-1-isopropyl-4-(trifluoromethyl)-1H-imidazole. Intermediate E.2 To 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. The reaction mixture was quenched with a saturated ammonium chloride solution (25 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product. The material was purified by flash chromatography (mobile phase: 8-10% ethyl acetate in petroleum ether) to afford 2-bromo- 1-isopropyl-4-(trifluoromethyl)-1H-imidazole (2.10 g, 24% yield) as a yellow liquid. LCMS (ESI): m / z = 257.01 & 259.03 [M+H]+. Step 3: Preparation of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzonitrile. Intermediate E.3 To a stirred solution of 4-bromo-3-methylbenzonitrile (5.00 g, 25.5 mmol) in N,N- dimethylformamide (50.0 mL) was added octamethyl-2,2′-bi-1,3,2-dioxaborolane (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 dichloro[1,1'-bis(diphenylphosphino)-ferrocene]palladium(II) dichloromethane adduct (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 (20.0 mL) and extracted with ethyl acetate (3 x 20.0 mL). The combined organic layers were washed with water (50.0 mL), brine (50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified using flash chromatography (mobile phase: 10% ethyl acetate in petroleum ether) to afford 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzonitrile (3.50 g, 56% yield) 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 4: Preparation of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- methyl-benzonitrile. Intermediate E.4 To 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) in1,4-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, Intermediate E.2), followed bythe 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 dichloro[1,1'-bis(diphenylphosphino)-ferrocene]palladium(II) dichloromethane adduct (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 (20mL) and extracted with ethyl acetate(3x 20mL).The combined organic layer was washed with water (50mL), brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography (mobile phase: 10- 20% ethyl acetate in petroleum ether) to afford4-(1-isopropyl-4-(trifluoromethyl)-1H- imidazol-2-yl)-3-methylbenzonitrile (1.10 g,91% yield) as a brown solid. LCMS (ESI) m / z = 294.26 [M+H]+. Step 5: Preparation of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- methylphenyl)-methanamine•HCl. Intermediate E To a stirred solution of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- methylbenzonitrile (1.10 g, 3.75 mmol) intetrahydrofuran (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. The reaction mixture wasquenched with saturated ammonium chloride solution(10mL) and extracted with ethyl acetate(2x 50mL).The combined organic layer was washed with water (20mL), brine (20mL), dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the residue was dissolved in 4M hydrochloric acid solution in dioxane (10 mL). The mixture was stirred at 25 °Cfor 1 h andthen 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, 52% yield)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 (ESI) m / z = 298.18 [M+H]+. Intermediate F Synthesis of (2-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)-methanamine. Intermediate F The 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 (lithium aluminum hydride).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 (ESI) m / z = 302.2 [M+H]+. Intermediate G Synthesis of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanethiol. Intermediate G Step 1: Preparation of 2-(4-(chloromethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)- 1H-imidazole. Intermediate G.1 To 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 evaporated under reduced pressure and the residue was purified by flash chromatography (mobile phase: 10% ethyl acetate in petroleum ether) to obtain 2-(4-(chloromethyl)phenyl)-1-isopropyl-4- (trifluoromethyl)-1H-imidazole (7.2 g, 96% yield) 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). MS (ESI) m / z = 303.32 [M+H]+. Step 2: Preparation of S-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl) ethanethioate. Intermediate G.2 To 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 ethyl acetate (2 x 20 mL). The combined organic phases were washed with water (10 mL), brine (5 mL), dried over 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, 62% yield) as a tan solid. The material was used in the subsequent reaction. LCMS (ESI) m / z = 343.43 [M+H]+. Step 3: Preparation of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanethiol. Intermediate G To a solution of S-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl) ethane-thioate (60.0 mg, 0.175 mmol) in methanol (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 ethyl acetate (30 mL) and washed with water (10 mL), brine (5 mL), dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified via flash chromatography (mobile phase: 20-25% ethyl acetate in petroleum ether) to afford (4-(1-isopropyl-4-(trifluoromethyl)-1H- imidazol-2-yl)phenyl)methanethiol (30.0 mg, 57% yield) as a white solid. LCMS (ESI) m / z = 300.26 [M+H]+. Intermediate H Synthesis of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1- yl)methanamine. Intermediate H Step 1: Preparation of 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-1- carboxamide. Intermediate H.1 To 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 methanol (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, 32% yield) as an off white solid. The compound was used in the next step without further purification. MS (ESI) m / z = 280.19 [M-H]-. Step 2: Preparation of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cubane- 1-carboxamide. Intermediate H.2 To 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 cesium carbonate (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 obtain 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-1-carboxamide (2.80 g, 54% yield) as white solid. The material was used without further purification. LCMS (ESI) m / z = 324.41 [M+H]+. Step 3: Synthesis of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1- yl)methanamine. Intermediate H To 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 aluminum 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 reaction mixture was quenched with saturated aqueous sodium sulfate solution (25 mL) and diluted with dichloromethane (100 mL). The resulting mixture was filtered through celite washing thoroughly with dichloromethane (2 x 50 mL).The filtrate was concentrated under reduced pressure and theresidue 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,34% yield of the 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 (ESI) m / z = 310.321 [M+H]+. Intermediate I Synthesis of 1-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)-N- methylmethanamine•HCl. Intermediate I Step 1: Preparation of methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)cubane-1- carboxylate. Intermediate I.1 A 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 methanol (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 methanol. The material was then extracted with ethyl acetate (3 x 250 mL), and the combined organic layers were washed with brine (50 mL), dried over 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, 55% yield) as an off- white solid. LCMS (ESI): m / z = 296.97 [M+H]+. Step 2: Preparation of methyl 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)cubane-1-carboxylate. Intermediate I.2 To 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 cesium carbonate (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 ethyl acetate (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 evaporated under reduced pressure to obtain a residue. The residue was purified by flash chromatography (mobile phase: 10- 20% ethyl acetate in petroleum ether) to afford methyl 4-(1-isopropyl-4-(trifluoromethyl)- 1H-imidazol-2-yl)cubane-1-carboxylate (5.50 g, 40% yield) as a pale brown solid. LCMS (ESI): m / z = 339.62 [M+H]+. Step 3: Preparation of 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban- 1-yl)methanol. Intermediate I.3 A 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 methanol (2.0 mL) was prepared at 0 °C. Sodium borohydride (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 methanol. The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine (25 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (mobile phase: 35-50% ethyl acetate in petroleum ether) to afford (4-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl) methanol (1.10 g, 60% yield) 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 (ESI): m / z = 311.22 [M+H]+. Step 4-5: Synthesis of 1-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)cuban-1-yl)-N-methylmethanamine•HCl. Intermediate I The title compound was prepared using a similar procedure as Intermediate E, replacing (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol with (4- (1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl) methanol (Intermediate I.3).1H-NMR (400 MHz, DMSO-d6) δ 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 (ESI): m / z = 324.38 [M+H]+. Intermediate J Synthesis of 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethan- 1-amine. Intermediate J Step 1: Preparation of 1-isopropyl-4-(trifluoromethyl)-1H-imidazole. Intermediate J.1 To 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 cesium carbonate (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 ethyl acetate (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 (mobile phase: 12- 15% ethyl acetate in petroleum ether) to afford 1-isopropyl-4-(trifluoromethyl)-1H- imidazole (11.3 g, 69% yield) as a yellow liquid. LCMS (ESI): m / z = 178.74[ M+H]+. Step 2: Preparation of 2-bromo-1-isopropyl-4-(trifluoromethyl)-1H-imidazole. Intermediate J.2 To 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 ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product. The material was purified by flash chromatography (mobile phase: 8-10% ethyl acetate in petroleum ether) to afford 2-bromo-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (2.10 g, 24% yield) as a yellow liquid. LCMS (ESI): m / z = 257.01 & 259.03 [M+H]+. Step 3: Preparation of 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)ethan-1-one. Intermediate J.3 A 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 cesium carbonate (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 min in a microwave reactor. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (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 to yield the product. The product was purified by flash chromatography (mobile phase: 10-20% ethyl acetate in petroleum ether) to afford 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)ethan-1-one (690 mg, 86% yield) as a yellow solid. LCMS (ESI): 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 J To 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 methanol (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 ethyl acetate (2 x 25 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the product. The material was purified by flash chromatography (mobile phase: 5-10% methanol in dichloromethane) to afford 1-(4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethan-1-amine (0.600 g, 42% yield) as a white solid.1H-NMR (400 MHz, DMSO-d6) δ 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 (ESI): m / z = 298.37 [M+H]+. Intermediate K Synthesis of (6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3- yl)methanamine•HCl. Intermediate K Preparation of 5-bromo-2-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)pyridine. Intermediate K.1 The 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 (ESI): 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 K.2 To a stirredsolution of 5-bromo-2-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)pyridine (2.90 g, 8.68 mmol) in1,4-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 cesium carbonate(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(10mL)and extracted with ethyl acetate (3 x 20mL). The combined organic phases were washed with water (20mL), brine (20mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified via flash chromatography (mobile phase: 60% ethyl acetate in petroleum ether) to afford^tert- butyl((6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3- yl)methyl)carbamate (1.57 g, 47% yield) as a yellow solid. LCMS (ESI): 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 K To 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 to afford product. The residue was triturated with pentane (5 mL) to obtain the desired product (6-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)methanamine•HCl (1.10 g, 95 %) 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 (ESI): m / z = 285.23 [M+H]+. Intermediate L Synthesis of 1-(6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)- N-methyl-methanamine•HCl. Intermediate L Step 1: Preparation of tert-butyl ((6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol- 2-yl)pyridin-3-yl)methyl)(methyl)carbamate. Intermediate L.1 A solution of tert-butyl ((6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)pyridin-3-yl)methyl)carbamate (0.900 g, 2.34 mmol, Intermediate K.2) in tetrahydrofuran (10.0 mL) was prepared and cooled to 0 °C. Sodium hydride (0.280 g, 7.03 mmol) was carefully added to the solution, and the mixture was stirred for 20 minutes at 0 °C. Iodomethane (0.400 g, 2.34 mmol) was added and the reaction mixture was warmed to 23 °C and stirred for 16 h. After completion of the reaction, the mixture was quenched with a saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic phases were washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure, and the resulting residue was purified by flash chromatography (mobile phase: 10- 20% ethyl acetate in petroleum ether) to afford tert-butyl ((6-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)methyl)(methyl)carbamate (0.900 g, 96% yield) as a brown solid. LCMS (ESI) m / z = 399.46 [M+H]+. Step 2: Preparation of 1-(6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)pyridin-3-yl)-N-methyl-methanamine•HCl. Intermediate L A stirred solution of tert-butyl ((6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)pyridin-3-yl)methyl)(methyl)carbamate (0.900 g, 2.26 mmol) in dichloromethane (18.0 mL) was prepared and cooled to 0 °C. Hydrogen chloride (0.2 mL, 4.0 M solution in dioxane, 8.00 mmol) was slowly added to the solution, and the mixture was stirred at 23 °C for 2 h. The mixture was concentrated, and the residue was triturated with diethyl ether (10 mL). The resulting solid was filtered, washed with pentane (2 x 10 mL), and dried to yield the desired product1-(6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)- N-methylmethanamine•HCl (0.92 g, 99% yield) as an off-white solid. 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 (ESI) m / z = 299.17 [M+H]+. Intermediate M Synthesis of (6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3- yl)methanol. Intermediate M Step 1: Preparation of 6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)nicotinaldehyde. Intermediate M.1 To a stirred solution of 5-bromo-2-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)pyridine (2.10 g, 6.28 mmol, Intermediate K.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 ethyl acetate (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 evaporated under reduced pressure and the residue was purified by flash chromatography (mobile phase: 10-20% ethyl acetate in petroleum ether) to obtain 6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)nicotinaldehyde (1.40 g, 78% yield) as an off white solid. LCMS (ES+): m / z = 283.98 [M+H]+. Step 2: Preparation of (6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)pyridin-3-yl)methanol. Intermediate M To a stirred solution of 6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)nicotinaldehyde (1.40 g, 4.94 mmol) in methanol (14.0 mL) was added sodium borohydride (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 ethyl acetate (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 residue was purified by flash chromatography (mobile phase: 10-20% ethyl acetate in petroleum ether) to obtain (6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)pyridin-3-yl)methanol (1.05 g, 50% yield) 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 (ESI): m / z = 286.09 [M+H]+. Intermediate N Synthesis of (4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)methanamine. Intermediate N Step 1: Preparation of 4-(5-hydroxy-3-(trifluoromethyl)-1H-pyrazol-1- yl)benzonitrile. Intermediate N.1 A 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 reaction mixture was cooled to room temperature and filtered through celite, the filtrate was evaporated 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 obtain 4- (5-hydroxy-3-(trifluoromethyl)-1H-pyrazol-1-yl) benzonitrile (4.0 g, 74 %) as an off white solid. LCMS (ESI) m / z = 254.05 [M+H]+. Step 2: Preparation of 4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1- yl)benzonitrile. Intermediate N.2 To 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, 60% 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 ethyl acetate (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 evaporated under reduced pressure and the residue was purified by flash column chromatography (mobile phase: 30% ethyl acetate in petroleum ether) to obtain 4-(5- methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (1.5 g, 48%) as an off white solid. LCMS (ESI) m / z = 268.30 [M+H]+. Step 3: Preparation of (4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)-methanamine. Intermediate N To 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 lithium aluminum hydride (15 mL, 2.0 M in THF, 24 mmol) at 0 ºC. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (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 evaporated under reduced pressure to obtain residue. The residue was triturated with diethyl ether (300 mL x 3) and dried over vacuum to obtained (4-(5-methoxy- 3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-methanamine (2.3 g, 43%).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 (ESI) m / z = 272.10 [M+H]+. Intermediate O Synthesis of (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)methanamine•HCl. Intermediate O The title compound was prepared using a similar procedure as Intermediate N, 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 (ESI) m / z = 256.06 [M+H]+. Intermediate P Synthesis of tert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4- (methylsulfonyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate. Intermediate P Step 1: Preparation of tert-butyl 2-chloro-4-(methylthio)-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carboxylate. Intermediate P.1 To a solutionoftert-butyl 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)- carboxylate (10.0 g, 32.9 mmol) intetrahydrofuran (100.0 mL) stirring at 0 °C was addedsodium thiomethoxide (15.3 g, 15% solution in water, 32.9 mmol) and the reaction mixture was warmed to 23 °C and stirred for 6 h. Upon completion, the reaction mixture wasquenched with water (150mL) andextracted withethyl acetate (3x 200mL). The combined organic phases were washed with brine (50 mL),dried over sodium sulfate and filtered. The filtratewas concentrated under reduced pressure and the residue was purified via flash chromatography (mobile phase: 10% ethyl acetate in petroleum ether) to afford tert-butyl 2-chloro-4-(methylthio)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (8.20 g, 78% yield) as a white solid. LCMS (ESI) m / z = 316.29 [M+H]+. Step 2: Preparation of tert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4- (methylthio)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate. Intermediate P.2 To a stirred solution oftert-butyl 2-chloro-4-(methylthio)-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carboxylate (6.00 g, 19.0 mmol)and(4-cyclopropyl-6- methoxypyrimidin-5-yl)boronic acid (4.05 g, 20.9 mmol)in1,2-dimethoxyethane (40.0 mL) andwater (10.0mL)was addedpotassium carbonate(7.88 g, 57.0 mmol)at 23 °C. The reaction mixture was degassed with nitrogen gas for 10 min before adding tetrakis(triphenylphosphine)palladium(0) (2.19 g, 1.90 mmol) andthe reaction mixturewas heated at 100°Cfor 16 h. Upon completion, the reaction mixture wasquenched with cold- water (100mL) and extracted with ethyl acetate(2x 300mL).The combined organic phases were washed with water (50mL), brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (mobile phase: 25% ethyl acetate in petroleum ether) to afford tert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(methylthio)-7,8-dihydropyrido- [4,3-d]pyrimidine-6(5H)-carboxylate (5.00 g, 61% yield) as white solid. LCMS (ESI) m / z = 430.53 [M+H]+. Step 3: Preparation of tert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4- (methylsulfonyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate. Intermediate P To a solutionoftert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4- (methylthio)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (5.00 g, 11.6 mmol)indichloromethane (50.0 mL) stirring at 0 °C was addedmeta-chloroperbenzoic acid (4.42 g, 25.6 mmol) andthe reaction mixture was warmed to 23 °C and stirred for 4 h. Upon completion, the reaction mixture wasquenched with saturated sodium bicarbonate^solution (50mL) andextracted with dichloromethane(3x 50mL). The combined organic phases were washed with brine (30 mL), dried over sodium sulfate, and filtered. The filtratewas concentrated under reduced pressure and the residue was purified via flash chromatography (mobile phase: 50% ethyl acetate in petroleum ether) to afford tert-butyl 2-(4-cyclopropyl- 6-methoxypyrimidin-5-yl)-4-(methylsulfonyl)-7,8-dihydro-pyrido[4,3-d]pyrimidine- 6(5H)-carboxylate (2.05 g, 38% yield) as an off white solid.1H-NMR (DMSO-d6,400 MHz) δ 8.71 (s, 1H), 5.03 (s, 2H), 3.87 (s, 3H), 3.77 (t, J = 5.8 Hz, 2H), 3.43 (s, 3H), 3.10-3.08 (m, 2H), 1.86-1.82 (m, 1H), 1.44 (s, 9H), 1.10-1.06 (m, 2H), 0.95-0.91 (m, 2H). LCMS (ESI) m / z = 462.31 [M+H]+. Intermediate Q Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(methylsulfonyl)-7,8- dihydropyrido-[4,3-d]pyrimidine-6(5H)-carbonitrile. Intermediate Q Step 1: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(methylthio)- 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. Intermediate Q.1 To a stirred solution of tert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4- (methylthio)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (2.00 g, 4.65 mmol, Intermediate P.2) in dichloromethane (20 mL) at 0 °C was added trifluoroacetic acid (3.60 mL, 46.6 mmol) and the reaction mixture was warmed to 23 °C and stirred for 4 h. Upon completion, the reaction mixture was concentrated under reduced pressure and the residue was washed with pentane (70 mL) and the solvent was decanted. The residue was dried under reduced pressure to afford 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4- (methylthio)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (1.50 g, 97% yield) as a light-red liquid. LCMS (ESI) m / z = 330.06 [M+H]+. Step 2: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(methylthio)- 7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carbonitrile. Intermediate Q.2 To a solution of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(methylthio)- 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (1.70 g, 5.16 mmol) in tetrahydrofuran (25.0 mL) stirring at 0 °C was added sodium bicarbonate (1.30 g, 15.5 mmol) and the mixture was stirred for 15 min. cyanogen bromide (1.09 g, 10.3 mmol) was added and the resulting reaction mixture was stirred at 23 °C for 16 h. After completion, the mixture was quenched with cold water (100 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic phases were washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified via flash chromatography (mobile phase: 30-40% ethyl acetate in petroleum ether) to afford 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(methylthio)- 7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carbonitrile (1.60 g, 87% yield) as a pale brown solid. LCMS (ESI) m / z = 355.33 [M+H]+. Step 3: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4- (methylsulfonyl)-7,8-dihydropyrido-[4,3-d]pyrimidine-6(5H)-carbonitrile. Intermediate Q To astirred solutionof2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(methylthio)- 7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carbonitrile (1.60 g, 4.51mmol)indichloromethane (16.0 mL) was addedmeta-chloroperoxybenzoic acid (2.33g, 13.5mmol)at 0 °Cand the reaction mixture was warmed to 23 °Cand stirred for 4 h. Upon completion, the reaction mixture wasquenched with saturated sodium bicarbonatesolution (50mL) andextracted with dichloromethane(3x 40mL). The combined organic phases were washed with brine (50 mL),dried over sodium sulfate, and filtered. The filtratewas concentrated under reduced pressure and the residue was purified via flash chromatography (mobile phase: 70% ethyl acetate in petroleum ether) to affordtert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(methylsulfonyl)-7,8- dihydro-pyrido[4,3-d]pyrimidine-6(5H)-carbonitrile (1.15g, 66% yield) as an off whitesolid.1H-NMR (DMSO-d6, 400 MHz) δ 8.72 (s, 1H), 4.88 (s, 2H), 3.88 (s, 3H), 3.71 (t, J = 6.0 Hz, 2H), 3.44 (s, 3H), 3.21 (t, J = 5.8 Hz, 2H), 1.86-1.80 (m, 1H), 1.11-1.07 (m, 2H), 0.95-0.94 (m, 2H). LCMS (ESI) m / z = 387.20 [M+H]+. Intermediate R Synthesis of 2,4-dichloro-7,8-dihydro-5H-spiro[quinazoline-6,2'-[1,3]dioxolane]. Intermediate R Step 1: Preparation of methyl 8-oxo-1,4-dioxaspiro[4.5]decane-7-carboxylate. Intermediate R.1 To a stirred solution of dimethyl carbonate (100 mL) was added sodium hydride (15.4 g, 60% dispersion in mineral oil, 640 mmol) portion-wise at 23 °C and the mixture was stirred for 10 min. A solution of 1,4-dioxaspiro[4.5]decan-8-one (50.0 g, 320 mmol) in dimethyl carbonate (200 mL) was added to the reaction mixture and the reaction was heated at 80°C for 4 h. Upon completion, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (40 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic phases were washed with brine (100 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (mobile phase: 10% ethyl acetate in petroleum ether) to afford methyl 8-oxo-1,4-dioxaspiro[4.5]decane-7-carboxylate (50.0 g, 73% yield) as a yellow oil. LCMS (ESI) m / z = 213.28 [M-H]-. Step 2: Preparation of 7,8-dihydro-5H-spiro[quinazoline-6,2'-[1,3]dioxolane]-2,4- diol. Intermediate R.2 To a stirred solution of methyl 8-oxo-1,4-dioxaspiro[4.5]decane-7-carboxylate (50.0 g, 233 mmol) inethanol (500mL) at 23 °C was added urea (70.1 g, 1.17 mol) followed by sodium methoxide (63.0 g, 117 mol) and the reaction mixture was heated at 80 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure andthe residue was diluted with water (200mL) and then acidified with acetic acid (25 mL, the pH was adjusted to ~7). The precipitated solid was filtered off and dried to obtain7,8-dihydro- 5H-spiro[quinazoline-6,2'-[1,3]dioxolane]-2,4-diol (25.0g, 47% yield) asan off white solid. LCMS (ESI) m / z = 225.00 [M+H]+. Step 3: Preparation of 2,4-dichloro-7,8-dihydroquinazolin-6(5H)-one. Intermediate R.3 A solution of 7,8-dihydro-5H-spiro[quinazoline-6,2'-[1,3]dioxolane]-2,4-diol (10.0 g, 44.6 mmol) in phosphorus oxychloride (100mL) was heated at 120 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (200 mL) and then neutralized to pH ~7 with saturated sodium bicarbonate solution at 0 °C. The organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography (mobile phase: 25% ethyl acetate in petroleum ether) to afford 2,4-dichloro-7,8-dihydroquinazolin-6(5H)-one (3.00 g, 31% yield) as a brown solid. LCMS (ESI) m / z = 217.1 & 219.12 [M+H]+. Step 4: Preparation of 2,4-dichloro-7,8-dihydro-5H-spiro[quinazoline-6,2'- [1,3]dioxolane]. Intermediate R To a stirred solution of 2,4-dichloro-7,8-dihydroquinazolin-6(5H)-one (3.1 g, 14.3 mmol) in toluene (30.0 mL) at 23 °C was added ethane-1,2-diol (3.54 g, 57.1 mmol) followed by p-toluenesulfonic acid monohydrate (0.271 g, 1.43 mmol) and the reaction mixture was heated at 100 °C for 4 h. Upon completion, the reaction mixture was concentrated and the residue was diluted with saturated sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with water (15 mL), brine (15 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (mobile phase: 25% ethyl acetate in petroleum ether) to afford 2,4- dichloro-7,8-dihydro-5H-spiro[quinazoline-6,2'-[1,3]dioxolane] (2.90 g, 78% yield) as a brown solid. LCMS (ESI) m / z = 261.3 [(M+H]+. Synthesis of Exemplified Compounds: 1.1 EXAMPLE 1 Synthesis of 4-(cyclopropyl(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)amino)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carbonitrile. Compound 1 Step 1: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4- (methylsulfonyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carbonitrile. Compound 1.1 To a mixture of cyclopropanamine (111 mg, 1.94 mmol) in 1,4-dioxane (5.00 mL) was added N,N-diisopropylethylamine (1.13 mL, 6.47 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)-4-(methylsulfonyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)- carbonitrile (500 mg, 1.29 mmol, Intermediate Q). 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 ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine (25 mL), dried over sodium sulfate, and concentrated under reduced pressure The residue was purified by flash chromatography (mobile phase: 0-55% ethyl acetate in hexanes) to afford (200 mg, 42% yield) of 2-(4-cyclopropyl-6- methoxypyrimidin-5-yl)-4-(methylsulfonyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)- carbonitrile as a brown solid. LCMS (ESI) m / z = 364.7 [M+H]+. Step 2: Preparation of 4-(cyclopropyl(4-(1-isopropyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)amino)-2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-7,8- dihydropyrido[4,3-d]pyrimidine-6(5H)-carbonitrile. Compound 1 To a mixture of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(methylsulfonyl)- 7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carbonitrile (200 mg, 0.550 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 (180 mg, 0.600 mmol, Intermediate G.1), and cesium carbonate (530 mg, 1.65 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 (3 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layer was washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparatory HPLC (mobile phase: 35-100% acetonitrile in water w / 0.1% formic acid) to afford (33.0 mg, 10% yield) of 4-(cyclopropyl(4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-2-(4-cyclopropyl-6-methoxypyrimidin- 5-yl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carbonitrile as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.17 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 4.81 (s, 2H), 4.76 (s, 2H), 4.49 – 4.42 (m, 1H), 3.80 (s, 3H), 3.63 (t, J = 6.0 Hz, 2H), 3.11 – 3.09 (m, 1H), 2.96 (t, J = 6.0 Hz, 2H), 1.64 – 1.60 (m, 1H), 1.40 (d, J = 6.8 Hz, 6H), 0.95 – 0.90 (m, 2H), 0.85 – 0.73 (m, 4H), 0.71 – 0.65 (m, 2H). LCMS (ESI) m / z = 630.5 [M+H]+. 2.1 EXAMPLE 2 Synthesis of 2-(2-(cyclopropylamino)pyridin-3-yl)-4-((4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carbonitrile. Compound 2 Step 1: Preparation of tert-butyl 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)- 1H-imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate. Compound 2.1 To a solution of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine (2.05 g, 7.23 mmol, Intermediate B) in N,N-dimethylformamide (25.0 mL) was added N,N-diisopropylethylamine (5.73 mL, 32.9 mmol) and the mixture was stirred at 0 °C for 15 min. To the mixture was added tert-butyl 2,4-dichloro-7,8- dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (2.00 g, 6.56 mmol) and the resulting mixture was stirred at 70 °C for 16 h. The reaction mixture was concentrated under reduced pressure, diluted with water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (mobile phase: 0-80% ethyl acetate in hexanes) to afford (1.90 g, 52% yield) of tert-butyl 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate as a white solid. LCMS (ESI) m / z = 551.3 [M+H]+. Step 2: Preparation of tert-butyl 2-(2-fluoropyridin-3-yl)-4-((4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carboxylate. Compound 2.2 To a mixture of tert-butyl 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (400 mg, 0.720 mmol) in 1,2-dimethoxyethane (10.0 mL) was added water (2.00 mL), (2- fluoropyridin-3-yl)boronic acid (205 mg, 1.45 mmol), and cesium carbonate (710 mg, 2.17 mmol) and purged with nitrogen for 15 min. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (83.9 mg, 0.0700 mmol) and the resulting mixture was heating under microwave irradiation at 110 °C for 30 min. The mixture was diluted with cold water (10 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: 0-20% ethyl acetate in hexanes) to afford (320 mg, 72% yield) of tert-butyl 2-(2-fluoropyridin-3-yl)-4-((4-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carboxylate as a pale yellow oil. LCMS (ESI) m / z = 612.3 [M+H]+. Step 3: Preparation of tert-butyl 2-(2-(cyclopropylamino)pyridin-3-yl)-4-((4-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carboxylate. Compound 2.3 To a mixture of tert-butyl 2-(2-fluoropyridin-3-yl)-4-((4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carboxylate (100 mg, 0.160 mmol) and cesium carbonate (160 mg, 0.49 mmol) in N,N-dimethylformamide (5.00 mL) was added cyclopropanamine (10.0 mg, 0.320 mmol) and the reaction mixture was stirred at 60 °C for 8 hours. The mixture was diluted with cold water (5 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: 0-20% ethyl acetate in hexanes) to afford (70.0 mg, 66% yield) of tert-butyl 2-(2-fluoropyridin-3-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate as a pale brown gum. LCMS (ESI) m / z = 649.5 [M+H]+. Step 4: Preparation of 2-(2-(cyclopropylamino)pyridin-3-yl)-N-(4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- amine. Compound 2.4 To tert-butyl 2-(2-(cyclopropylamino)pyridin-3-yl)-4-((4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carboxylate (70.0 mg, 0.100 mmol) in dichloromethane (3.00 mL) was added dropwise trifluoroacetic acid (0.500 mL, 0.320 mmol) at 0 °C under N2. The resulting mixture was stirred at 23 °C for 1 hour. The mixture was concentrated under reduced pressure and the residue was triturated in pentane (5 mL) to afford (50.0 mg, 84% yield) of 2-(2-(cyclopropylamino)pyridin-3-yl)-N-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol- 2-yl)benzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine as a pale brown gum. LCMS (ESI) m / z = 549.9 [M+H]+. Step 5: Synthesis of 2-(2-(cyclopropylamino)pyridin-3-yl)-4-((4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carbonitrile. Compound 2 To a mixture of 2-(2-(cyclopropylamino)pyridin-3-yl)-N-(4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- amine (50.0 mg, 0.0900 mmol) in acetonitrile (2.50 mL) was added sodium bicarbonate (38.2 mg, 0.450 mmol) and the mixture was stirred at 0 °C for 15 min. To the mixture was added cyanogen bromide (38.2 mg, 0.360 mmol) and the reaction was stirred at 0 °C for 2 h. The mixture was diluted with cold water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was concentrated under reduced pressure and the residue was purified by preparatory HPLC (mobile phase: 10-85% acetonitrile in water w / 0.1% formic acid) to afford (11.0 mg, 20% yield) of 2-(2- (cyclopropylamino)pyridin-3-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carbonitrile as a tan oil. 1H NMR (400 MHz, DMSO-d6) δ 9.59 (d, J = 3.6 Hz, 1H), 8.48 (dd, J = 8.0, 2.0 Hz, 1H), 8.16 – 8.15 (m, 2H), 7.71 (t, J = 5.8 Hz, 1H), 7.52 (s, 4H), 6.63 (dd, J = 7.8, 4.6 Hz, 1H), 4.76 (d, J = 5.6 Hz, 2H), 4.46 – 4.39 (m, 1H), 4.28 (s, 2H), 3.58 (t, J = 5.8 Hz, 2H), 2.88 – 2.80 (m, 3H), 1.37 (d, J = 6.8 Hz, 6H), 0.71 – 0.66 (m, 2H), 0.34. – 0.33 (m, 2H). LCMS (ESI) m / z = 574.3 [M+H]+. 3.1 EXAMPLE 3 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4- ((((1s,2R,3s,4r,5S,6r,7R,8S)-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban- 1-yl)methyl)(methyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carbonitrile. Compound 3 To 2-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(methylsulfonyl)-7,8-dihydro- pyrido[4,3-d]pyrimidin-6(5H)-yl)acetonitrile (50.0 mg, 0.129 mmol, Intermediate Q) was added a mixture of 1-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)-N- methylmethanamine (46.0 mg, 0.142 mmol) and N,N-diisopropylethylamine (0.0563 mL, 0.323 mmol) in dimethyl sulfoxide (0.389 mL), and the mixture was stirred at 50 °C for 1 h. The mixture 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 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(((-4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)methyl)(methyl)-amino)-7,8- dihydropyrido[4,3-d]pyrimidine-6(5H)-carbonitrile (8.00 mg, 8.8% yield) as a tan solid.1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.73 (s, 1H), 4.55 (s, 2H), 4.26 (t, J = 5.0 Hz, 3H), 4.20 – 4.12 (m, 1H), 3.96 (t, J = 5.0 Hz, 3H), 3.91 (s, 3H), 3.89 (s, 2H), 3.65 (t, J = 6.2 Hz, 2H), 3.23 (s, 3H), 3.01 (t, J = 6.2 Hz, 2H), 1.78 – 1.69 (m, 1H), 1.46 (d, J = 6.6 Hz, 6H), 1.18 – 1.11 (m, 2H), 0.97 – 0.90 (m, 2H). LCMS (ESI) m / z = 630.7 [M+H]+. 4.1 EXAMPLE 4 Synthesis of 2-(2-(difluoromethoxy)pyridin-3-yl)-4-((4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carbonitrile. Compound 4 The title compound was prepared using a similar procedure as Compound 2, replacing (2-fluoropyridin-3-yl)boronic acid with (2-(difluoromethoxy)pyridin-3- yl)boronic acid.1H NMR (400 MHz, DMSO-d6) δ 8.31 (dd, J = 4.8, 1.6 Hz, 1H), 8.15 – 8.13 (m, 2H), 7.75 (t, J = 72.8 Hz, 1H), 7.65 (t, J = 5.8 Hz, 1H), 7.49 (s, 4H), 7.35 (dd, J = 7.4, 5.0 Hz, 1H), 4.75 (d, J = 5.6 Hz, 2H), 4.44 (m, 1H), 4.28 (s, 2H), 3.58 (t, J = 5.6 Hz, 2H), 2.84 (t, J = 5.4 Hz, 2H), 1.38 (d, J = 6.8 Hz, 6H). LCMS (ESI) m / z = 585.4 [M+H]+. 5.1 EXAMPLE 5 Synthesis of 4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)amino)-2-(1-methyl-1H-indazol-7-yl)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carbonitrile. Compound 5 The title compound was prepared using a similar procedure as Compound 2, replacing (2-fluoropyridin-3-yl)boronic acid with (1-methyl-1H-indazol-7-yl)boronic acid.1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 1.2 Hz, 1H), 8.11 (s, 1H), 7.81 (dd, J = 8.0, 0.8 Hz, 1H), 7.70 (t, J = 5.8 Hz, 1H), 7.53 – 7.47 (m, 5H), 7.15 (t, J = 7.6 Hz, 1H), 4.74 (d, J = 5.6 Hz, 2H), 4.48 – 4.45 (m, 1H), 4.35 (s, 2H), 3.71 (s, 3H), 3.62 (t, J = 5.8 Hz, 2H), 2.88 (t, J = 5.6 Hz, 2H), 1.40 (d, J = 6.8 Hz, 6H). LCMS (ESI) m / z = 572.4 [M+H]+. 6.1 EXAMPLE 6 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)phenethyl)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carbonitrile. Compound 6 Step 1: Preparation of 2-(4-ethynylphenyl)-1-isopropyl-4-(trifluoromethyl)-1H- imidazole. Compound 6.1 To a stirred solution of 2-bromo-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (1.00 g, 3.89 mmol, Intermediate E.2) and (4-ethynylphenyl)boronic acid (0.680 g, 4.66 mmol) in 1,4-dioxane (8.0 mL) and water (2.0 mL) at 23 °C was added cesium carbonate (3.16 g, 9.72 mmol). The reaction mixture was purged with nitrogen gas for 20 min, then tetrakis(triphenylphosphine)palladium(0) (450 mg, 0.380 mmol) was added and the reaction mixture was heated in a microwave reactor at 100 °C for 1 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic phases were washed with water (10 mL), brine (10 mL), and dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (mobile phase: 20-30% ethyl acetate in petroleum ether) to afford 2-(4-ethynylphenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (400 mg, 36% yield) as a pale yellow liquid. LCMS (ESI): m / z = 279.0 [M+H]+. Step 2: Preparation of tert-butyl 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)- 1H-imidazol-2-yl)phenyl)ethynyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)- carboxylate. Compound 6.2 To a solution of 2-(4-ethynylphenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (250 mg, 0.90 mmol) and tert-butyl 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carboxylate (327.91 mg, 1.08 mmol) in tetrahydrofuran (5.0 mL) stirring at 23 °C was added triethylamine (0.51 mL, 3.59 mmol) and the mixture was purged with nitrogen gas for 30 min. Tetrakis(triphenylphosphine)palladium(0) (83.1 mg, 0.070 mmol) was added, and the reaction mixture was heated in a sealed tube at 80 °C for 8 h. The reaction mixture was diluted with water (5 mL) and the product was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with water (5 mL), brine (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (mobile phase: 25-30% ethyl acetate in petroleum ether) to afford tert-butyl 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)ethynyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (220 mg, 44% yield) as a pale yellow solid. LCMS (ESI): m / z = 546.19 [M+H]+. Step 3: Preparation of tert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4- (1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethynyl)-7,8- dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate. Compound 6.3 To a solution of tert-butyl 2-chloro-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H- imidazol-2-yl)phenyl)ethynyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.700 g, 1.28 mmol) and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (0.620 g, 3.20 mmol) in 1,4-dioxane (8.0 mL) and water (2.0 mL) stirring at 23 °C was added potassium carbonate (0.530 g, 3.84 mmol). The reaction mixture was purged with nitrogen gas for 20 minutes then tetrakis(triphenylphosphine)palladium(0) (0.290 g, 0.25 mmol) was added. The reaction mixture was heated in a microwave reactor at 120 °C for 2 h. Upon completion, the reaction mixture was diluted with cold water (10 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic phases were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (mobile phase: 10- 20% ethyl acetate in petroleum ether) to afford tert-butyl 2-(4-cyclopropyl-6- methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)ethynyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (500 mg, 59% yield) as a pale yellow liquid. LCMS (ESI): m / z = 660.22 [M+H]+. Step 4: Preparation of tert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4- (1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenethyl)-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carboxylate. Compound 6.4 A solution of tert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)ethynyl)-7,8-dihydropyrido[4,3- d]-pyr-imidine-6(5H)-carboxylate (250 mg, 0.38 mmol) in ethyl acetate (50.0 mL) stirring at 23 °C was purged with nitrogen gas for 10 min. (250 mg, 10%wt on activated carbon- 50% wet basis, 0.047 mmol) was added and the reaction mixture was placed under a hydrogen atmosphere (80 Psi) for 4 h. Upon completion, the mixture was filtered through celite, washing with ethanol (25 mL) and ethyl acetate (25 mL), and the filtrate was concentrated under reduced pressure. The residue was triturated with pentane (5 mL) to afford tert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)phenethyl)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carboxylate (140 mg, 56% yield) as a pale brown gum. LCMS (ESI): m / z = 664.3[M+H]+. Step 5-6: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenethyl)-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carbonitrile. Compound 6 The title compound was prepared using a similar procedure as Compound 2, replacing tert-butyl 2-(2-(cyclopropylamino)pyridin-3-yl)-4-((4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carboxylate with tert-butyl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(4-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenethyl)-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carboxylate (Compound 6.4)1H-NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.16 (s, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 4.58 (s, 2H), 4.49 – 4.42 (m, 1H), 3.85 (s, 3H), 3.60 (t, J = 5.8 Hz, 2H), 3.08 (s, 4H), 3.02 (t, J = 5.6 Hz, 2H), 1.62 – 1.57 (m, 1H), 1.40 (d, J = 6.4 Hz, 6H), 1.06 – 1.05 (m, 2H), 0.90 – 0.87 (m, 2H). LCMS (ESI): m / z = 589.43 [M+H]+. 7.1 EXAMPLE 7 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((2-fluoro-4-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carbonitrile. Compound 7 The title compound was prepared using a similar procedure as Compound 3, replacing 1-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)-N- methylmethanamine with (2-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine (Intermediate F).1H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H), 7.93 (s, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.32 – 7.26 (m, 2H), 4.83 (s, 2H), 4.55 (s, 1H), 4.32 (s, 2H), 3.88 (s, 3H), 3.64 (t, J = 5.9 Hz, 2H), 2.93 (t, J = 5.8 Hz, 2H), 1.72 – 1.64 (m, 1H), 1.45 (d, J = 6.7 Hz, 6H), 1.10 – 1.03 (m, 2H), 0.82 – 0.75 (m, 2H). LCMS (ESI) m / z = 304.6, M / 2+H+. 8.1 EXAMPLE 8 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(((6-(1-isopropyl-4- (trifluoro-methyl)-1H-imidazol-2-yl)pyridin-3-yl)methyl)(methyl)amino)-7,8- dihydropyrido[4,3-d]pyrimi-dine-6(5H)-carbonitrile. Compound 8 The title compound was prepared using a similar procedure as Compound 3, replacing 1-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)-N- methylmethanamine with 1-(6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin- 3-yl)-N-methylmethanamine (Intermediate L).1H NMR (400 MHz, CD3OD) δ 8.64 (d, J = 2.2 Hz, 1H), 8.55 (s, 1H), 7.97 – 7.87 (m, 3H), 5.69 (p, J = 6.7 Hz, 1H), 4.89 (s, 2H), 4.64 (s, 2H), 3.90 (s, 3H), 3.66 (t, J = 6.3 Hz, 2H), 3.22 (s, 3H), 3.04 (t, J = 6.2 Hz, 2H), 1.71 (tt, J = 8.4, 4.5 Hz, 1H), 1.49 (d, J = 6.7 Hz, 6H), 1.11 – 1.07 (m, 2H), 0.91 – 0.86 (m, 2H). LCMS (ESI) m / z = 303.3, M / 2+H+. 9.1 EXAMPLE 9 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((6-(1-isopropyl-4- (trifluoro-methyl)-1H-imidazol-2-yl)pyridin-3-yl)methoxy)-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carbonitrile. Compound 9 The title compound was prepared using a similar procedure as Compound 3, replacing 1-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)-N- methylmethanamine with (6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3- yl)methanol (Intermediate M).1H NMR (400 MHz, CD3OD) δ 8.78 (s, 1H), 8.60 (s, 1H), 8.04 (s, 2H), 7.96 (s, 1H), 5.72 (p, J = 6.7 Hz, 1H), 5.64 (s, 2H), 4.48 (s, 2H), 3.90 (s, 3H), 3.67 (t, J = 5.8 Hz, 2H), 3.05 (t, J = 5.8 Hz, 2H), 1.68 (tt, J = 8.2, 4.6 Hz, 1H), 1.50 (d, J = 6.7 Hz, 6H), 1.16 – 1.11 (m, 2H), 0.93 – 0.87 (m, 2H). LCMS (ESI) m / z = 396.7, M / 2+H+. 10.1 EXAMPLE 10 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((1-(4-(1-isopropyl-4- (trifluoro-methyl)-1H-imidazol-2-yl)phenyl)ethyl)amino)-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carbonitrile. Compound 10 The title compound was prepared using a similar procedure as Compound 3, replacing 1-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)-N- methylmethanamine with 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)ethan-1-amine.1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.16 (d, J = 1.2 Hz, 1H), 7.51 – 7.47 (m, 4H), 7.30 (br s, 1H), 5.45 – 5.41 (m, 1H), 4.47 – 4.31 (m, 3H), 3.77 (s, 3H), 3.58 (t, J = 5.8 Hz, 2H), 2.81 (br s, 2H), 1.57 – 1.53 (m, 4H), 1.41 – 1.39 (m, 6H), 0.92 (br s, 2H), 0.80 – 0.75 (m, 1H), 0.62 – 0.60 (m, 1H). LCMS (ESI) m / z = 604.4 [M+H]+. 11.1 EXAMPLE 11 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4- (trifluoro-methyl)-1H-imidazol-2-yl)-3-methylbenzyl)amino)-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carbonitrile. Compound 11 The title compound was prepared using a similar procedure as Compound 3, replacing 1-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)-N- methylmethanamine with (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-3- methylphenyl)methanamine•HCl (Intermediate E).1H NMR (400 MHz, CD3OD) δ 8.55 (s, 1H), 7.90 (s, 1H), 7.35 – 7.22 (m, 3H), 4.76 (s, 2H), 4.30 (s, 2H), 4.09 (hept, J = 6.8 Hz, 1H), 3.90 (s, 3H), 3.64 (t, J = 5.9 Hz, 2H), 2.93 (t, J = 5.9 Hz, 2H), 2.12 (s, 3H), 1.74 (tt, J = 8.3, 4.7 Hz, 1H), 1.38 (d, J = 6.7 Hz, 6H), 1.12 – 1.05 (m, 2H), 0.86 – 0.79 (m, 2H). LCMS (ESI) m / z = 604.7 [M+H]+. 12.1 EXAMPLE 12 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4- (trifluoro-methyl)-1H-imidazol-2-yl)benzyl)thio)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carbonitrile. Compound 12 The title compound was prepared using a similar procedure as Compound 3, replacing 1-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)-N- methylmethanamine with (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanethiol (Intermediate G). 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.17 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 4.61 (s, 2H), 4.47 – 4.40 (m, 1H), 4.34 (s, 2H), 3.87 (s, 3H), 3.62 (t, J = 5.6 Hz, 2H), 2.99 (t, J = 5.4 Hz, 2H), 1.73 – 1.67 (m, 1H), 1.39 (d, J = 6.8 Hz, 6H), 1.07 – 1.06 (m, 2H), 0.91 –0.90 (m, 2H). LCMS (ESI) m / z = 607.4 [M+H]+. 13.1 EXAMPLE 13 Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4- (trifluoro-methyl)-1H-imidazol-2-yl)benzyl)(methyl)amino)-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carbonitrile. Compound 13 The title compound was prepared using a similar procedure as Compound 3, replacing 1-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)-N- methylmethanamine with 1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)- N-methyl-methanamine•HCl (Intermediate D).1H NMR (400 MHz, CD3OD) δ 8.55 (s, 1H), 7.91 (d, J = 1.4 Hz, 1H), 7.51 (q, J = 8.3 Hz, 4H), 4.88 (s, 2H), 4.59 (s, 2H), 4.53 (q, J = 6.7 Hz, 1H), 3.92 (s, 3H), 3.65 (t, J = 6.3 Hz, 2H), 3.18 (s, 3H), 3.03 (t, J = 6.2 Hz, 2H), 1.76 (tt, J = 8.4, 4.7 Hz, 1H), 1.46 (d, J = 6.7 Hz, 6H), 1.13 – 1.07 (m, 2H), 0.91 – 0.85 (m, 2H). LCMS (ESI) m / z = 604.7 [M+H]+. 14.1 EXAMPLE 14 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(((6-(1-isopropyl-4- (trifluoro-methyl)-1H-imidazol-2-yl)pyridin-3-yl)methyl)amino)-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carbonitrile. Compound 14 The title compound was prepared using a similar procedure as Compound 3, replacing 1-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)-N- methylmethanamine with (6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3- yl)methanamine•HCl (Intermediate K).1H NMR (400 MHz, CD3OD) δ 8.65 (d, J = 2.1 Hz, 1H), 8.55 (s, 1H), 7.96 – 7.89 (m, 2H), 7.88 (dd, J = 8.2, 2.2 Hz, 1H), 5.74 – 5.59 (m, 1H), 4.77 (s, 2H), 4.30 (s, 2H), 3.88 (s, 3H), 3.63 (t, J = 5.8 Hz, 2H), 2.93 (t, J = 5.9 Hz, 2H), 1.69 – 1.62 (m, 1H), 1.48 (d, J = 6.8 Hz, 6H), 1.09 – 1.04 (m, 2H), 0.85 – 0.79 (m, 2H). LCMS (ESI) m / z = 296.7, M / 2+H+. 15.1 EXAMPLE 15 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(((-4-(1-isopropyl-4- (trifluoro-methyl)-1H-imidazol-2-yl)cuban-1-yl)methyl)amino)-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carbonitrile. Compound 15 The title compound was prepared using a similar procedure as Compound 3, replacing 1-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)-N- methylmethanamine with 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1- yl)methanamine (Intermediate H). 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.72 (s, 1H), 4.26 – 4.20 (m, 5H), 4.20 – 4.13 (m, 1H), 3.98 (t, J = 5.0 Hz, 3H), 3.91 (s, 3H), 3.82 (s, 2H), 3.62 (t, J = 5.8 Hz, 2H), 2.90 (t, J = 5.9 Hz, 2H), 1.76 – 1.69 (m, 1H), 1.46 (d, J = 6.6 Hz, 6H), 1.18 – 1.11 (m, 2H), 0.97 – 0.90 (m, 2H). LCMS (ESI) m / z = 308.8, M / 2+H+. 16.1 EXAMPLE 16 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(5-methyl-3- (trifluoromethyl)-1H-pyrazol-1-yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carbonitrile. Compound 16 The title compound was prepared using a similar procedure as Compound 3, replacing 1-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)-N- methylmethanamine with (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)methanamine•HCl (Intermediate O). 1H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 6.57 (s, 1H), 4.78 (s, 2H), 4.31 (s, 2H), 3.88 (s, 3H), 3.64 (t, J = 5.8 Hz, 2H), 2.93 (t, J = 5.8 Hz, 2H), 2.32 (s, 3H), 1.71 – 1.63 (m, 1H), 1.09 – 1.02 (m, 2H), 0.84 – 0.78 (m, 2H). LCMS (ESI) m / z = 562.6 [M+H]+. 17.1 EXAMPLE 17 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(5-methoxy-3- (trifluoro-methyl)-1H-pyrazol-1-yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carbonitrile. Compound 17 The title compound was prepared using a similar procedure as Compound 3, replacing 1-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)-N- methylmethanamine with (4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1- yl)phenyl)methanamine.1H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H), 7.59 – 7.54 (m, 2H), 7.43 (d, J = 8.5 Hz, 2H), 6.21 (s, 1H), 4.74 (s, 2H), 4.31 (s, 2H), 4.01 (s, 3H), 3.87 (s, 3H), 3.64 (t, J = 5.9 Hz, 2H), 2.92 (t, J = 5.9 Hz, 2H), 1.66 – 1.58 (m, 1H), 1.06 – 1.01 (m, 2H), 0.81 – 0.75 (m, 2H). LCMS (ESI) m / z = 578.6 [M+H]+. 18.1 Example 18 Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carbonitrile. Compound 18 The title compound was prepared using a similar procedure as Compound 3, replacing 1-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)-N- methylmethanamine with (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine.1H NMR (CD3OD, 400 MHz) δ 8.53 (s, 1H), 7.67 (s, 1H), 7.58 - 7.54 (m, 2H), 7.49 - 7.45 (m, 2H), 4.77 (s, 2H), 2.11 (s, 2H), 3.87 (s, 3H), 3.75 (s, 3H), 3.64 - 3.61 (m, 2H), 2.93-2.90 (m, 2H), 1.70 - 1.64 (m, 1H), 1.06 - 1.02 (m, 2H), 0.81 - 0.77 (m, 2H). LCMS (ESI) m / z = 562.2 [M+H]+. 19.1 EXAMPLE 19 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4- (trifluoro-methyl)-1H-imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carbonitrile. Compound 19 The title compound was prepared using a similar procedure as Compound 3, replacing 1-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)-N- methylmethanamine with (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine.1H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H), 7.92 – 7.89 (m, 1H), 7.52 – 7.46 (m, 4H), 4.79 (s, 2H), 4.58 – 4.47 (m, 1H), 4.31 (s, 2H), 3.89 (s, 3H), 3.64 (t, J = 5.8 Hz, 2H), 2.93 (t, J = 5.8 Hz, 2H), 1.73 – 1.65 (m, 1H), 1.45 (d, J = 6.7 Hz, 6H), 1.08 – 1.03 (m, 2H), 0.83 – 0.76 (m, 2H). LCMS (ESI) m / z = 281.7, M / 2+H+. 20.1 EXAMPLE 20 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)oxy)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-carbonitrile. Compound 20 The title compound was prepared using a similar procedure as Compound 3, replacing 1-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)-N- methylmethanamine with (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanol (Intermediate C).1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.19 (d, J = 1.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 5.54 (s, 2H), 4.51 - 4.44 (m, 3H), 3.85 (s, 3H), 3.63 (t, J = 5.8 Hz, 2H), 2.98 (t, J = 5.4 Hz, 2H), 1.70 - 1.65 (m, 1H), 1.41 (d, J = 6.8 Hz, 6H), 1.05 - 1.02 (m, 2H), 0.89 - 0.88 (m, 2H). LCMS (ESI) m / z = 591.5 [M+H]+. 21.1 EXAMPLE 21 Synthesis of 2-(2-isopropylphenyl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carbonitrile. Compound 21 Step 1: Preparation of 2-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)- 1H-imidazol-2-yl)benzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine. Compound 21.1 The title compound was prepared using a similar procedure as Compound 2, replacing (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine and (2-fluoropyridin-3-yl)boronic acid with (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine (Intermediate A) and (2-isopropylphenyl)boronic acid. LCMS (ESI) m / z = 507.3 [M+H]+. Step 2: Preparation of 2-(2-isopropylphenyl)-4-((4-(1-methyl-4-(trifluoromethyl)- 1H-imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carbonitrile. Compound 21 To a solution of 2-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (25.3 mg, 0.050 mmol) in dichloromethane (0.758 mL, 0.2 M) stirring at 23 °C was added N,N- diisopropylethylamine (0.0792 mL, 0.455 mmol) followed by cyanogen bromide (24.1 mg, 0.227 mmol) and the mixture was stirred at 23 °C for 2 h. The reaction was diluted with dichloromethane (5 mL) and washed with saturated sodium bicarbonate solution (3 mL), water (3 mL), and brine (3 mL). The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified via reverse phase chromatography (mobile phase: 20-100% acetonitrile in water w / 0.1% formic acid) to afford 2-(2-isopropylphenyl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carbonitrile (6.8 mg, 26% yield) as a white solid.1H NMR (CD3OD, 400 MHz): 7.66 (s, 1H), 7.59-7.54 (m, 2H), 7.47 – 7.43 (m, 2H), 7.36 – 7.30 (m, 3H), 7.22 – 7.16 (m, 1H), 4.81 (s, 2H), 4.31 (s, 2H), 3.74 (s, 3H), 3.64 – 3.60 (m, 2H), 3.26 (sept, J = 6.9 Hz, 1H), 2.94 – 2.87 (m, 2H), 1.04 (d, J = 6.9 Hz, 6H). LCMS (ESI) m / z = 532.3 [M+H]+. 22.1 EXAMPLE 22 Preparation of 2-(2-(2-isopropylphenyl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)acetonitrile. Compound 22 To a mixture of 2-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (25.0 mg, 0.0494 mmol, Compound 21.1) in N,N-dimethylformamide (0.150 mL) was added sodium hydride (4.93 mg, 60% dispersion in mineral oil, 0.0123 mmol) and the mixture was stirred at 23 °C for 30 min. To the mixture was added bromoacetonitrile (0.00516 mL, 0.0740 mmol) and the reaction was stirred at 23 °C for 1 h. The mixture 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 2-(2-(2-isopropylphenyl)-4-((4- (1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3- d]pyrimidin-6(5H)-yl)acetonitrile (12.0 mg, 45% yield) as a white solid.1H NMR (400 MHz, CD3OD) δ 7.68 (s, 1H), 7.63 – 7.56 (m, 2H), 7.46 (d, J = 7.8 Hz, 2H), 7.41 – 7.33 (m, 3H), 7.26 – 7.19 (m, 1H), 4.85 (s, 2H), 3.96 (s, 2H), 3.76 (s, 3H), 3.64 (s, 2H), 3.24 (sept, J = 6.8 Hz, 1H), 2.95 (dt, J = 30.8, 5.9 Hz, 4H), 1.06 (d, J = 6.8 Hz, 6H). LCMS (ESI) m / z = 546.6 [M+H]+. 23.1 EXAMPLE 23 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- amine. Compound 23 The title compound was prepared using a similar procedure as Compound 2, replacing (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine and (2-fluoropyridin-3-yl)boronic acid with (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid.1H NMR (400 MHz, CD3OD) δ 8.53 (s, 1H), 8.44 (br. s, 1H), 7.67 (s, 1H), 7.60 - 7.53 (m, 2H), 7.50 - 7.43 (m, 2H), 4.77 (s, 2H), 3.99 (s, 2H), 3.86 (s, 3H), 3.75 (s, 3H), 3.43 - 3.34 (m, 2H), 2.93 - 2.84 (m, 2H), 1.66 (m, 1H), 1.08 - 1.00 (m, 2H), 0.81 - 0.73 (m, 2H). LCMS (ESI) m / z = 537.3 [M+H]+. 24.1 EXAMPLE 24 Preparation of 1-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl-4- (trifluoro-methyl)-1H-imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin- 6(5H)-yl)prop-2-en-1-one. Compound 24 To a mixture of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- amine (36.4 mg, 0.0559 mmol, Compound 23) and N,N-diisopropylethylamine (0.0341 mL, 0.196 mmol) in dichloromethane (0.280 mL) was added acryloyl chloride (0.00678 mL, 0.0839 mmol) and the mixture was stirred at 23 °C for 16 h. The reaction 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 1-(2-(4- cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol- 2-yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)prop-2-en-1-one (8.62 mg, 26% yield) as a white solid.1H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H), 8.17 (s, 1H), 7.68 (s, 1H), 7.58 (d, J = 7.9 Hz, 2H), 7.50 (d, J = 7.9 Hz, 2H), 6.99 – 6.81 (m, 1H), 6.30 (d, J = 16.7 Hz, 1H), 5.83 (d, J = 10.6 Hz, 1H), 4.81 (s, 2H), 4.64 (s, 2H), 3.99 (t, J = 4.3 Hz, 2H), 3.88 (s, 3H), 3.76 (s, 3H), 2.94 – 2.78 (m, 2H), 1.75 – 1.62 (m, 1H), 1.10 – 1.01 (m, 2H), 0.87 – 0.74 (m, 2H). LCMS (ESI) m / z = 591.3 [M+H]+. 25.1 EXAMPLE 25 Synthesis of 2-chloro-1-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1- methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3- d]pyrimidin-6(5H)-yl)ethan-1-one. Compound 25 The title compound was prepared using a similar procedure as Compound 24, replacing acryloyl chloride with chloroacetyl chloride.1H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H), 8.24 (s, 1H), 7.68 (s, 1H), 7.62 – 7.55 (m, 2H), 7.50 (t, J = 7.6 Hz, 2H), 4.81 (d, J = 12.2 Hz, 2H), 4.58 (d, J = 5.8 Hz, 2H), 4.42 (s, 2H), 3.99 – 3.89 (m, 2H), 3.88 (s, 3H), 3.76 (s, 3H), 2.99 – 2.77 (m, 2H), 1.73 – 1.62 (m, 1H), 1.09 – 1.01 (m, 2H), 0.84 – 0.74 (m, 2H). LCMS (ESI) m / z = 614.2 [M+H]+. 26.1 Example 26 Synthesis of 1-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin- 6(5H)-yl)ethan-1-one. Compound 26 The title compound was prepared using a similar procedure as Compound 24, replacing acryloyl chloride with acetic anhydride.1H NMR (400 MHz, CD3OD): 8.52 (s, 1H), 7.66 (s, 1H), 7.60 - 7.53 (m, 2H), 7.52 - 7.43 (m, 2H), 4.81 - 4.74 (m, 2H), 4.57 - 4.48 (m, 2H), 3.92 - 3.85 (m, 2H), 3.86 (s, 3H), 3.74 (s, 3H), 2.90 - 2.83 (m, 1H), 2.80-2.73 (m, 1H), 2.25 - 2.19 (m, 3H), 1.70 - 1.61 (m, 1H), 1.05 - 0.99 (m, 2H), 0.81 - 0.73 (m, 2H). LCMS (ESI) m / z = 579.3 [M+H]+. 27.1 Example 27 Synthesis of 1,1,1,3,3,3-hexafluoropropan-2-yl 2-(4-cyclopropyl-6- methoxypyrimidin-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate. Compound 27 To a solution of triphosgene (11.6 mg, 0.0391 mmol) in dichloromethane (1.12 mL, 0.050 M) stirring at 0 °C was added 1,1,1,3,3,3-hexafluoro-2-propanol (0.0117 mL, 0.112 mmol) and the mixture was warmed to 23 °C and stirred for 2 h. A solution of 2-(4- cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol- 2-yl)benzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (30.0 mg, 0.0559 mmol, Compound 23) in dichloromethane (0.5 mL) was added and the reaction was stirred for 16 h. The reaction was quenched with saturated sodium bicarbonate solution (2 mL) and the mixture was extracted with dichloromethane (2 x 2 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated. The residue was purified via preparatory HPLC (mobile phase: 10-100% acetonitrile in water w / 0.1% formic acid) to afford 1,1,1,3,3,3-hexafluoropropan-2-yl 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1- methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carboxylate (13.8 mg, 34% yield) as a white powder.1H NMR (CD3OD, 400 MHz): 8.53 (s, 1H), 7.67 (s, 1H), 7.60 - 7.54 (m, 2H), 7.51 - 7.43 (m, 2H), 6.31 - 6.19 (m, 1H), 4.78 (s, 2H), 4.60 - 4.52 (m, 2H), 3.94 - 3.85 (m, 2H), 3.87 (s, 3H), 3.75 (s, 3H), 2.88 - 2.80 (m, 2H), 1.70 - 1.62 (m, 1H), 1.06 - 1.00 (m, 2H), 0.81 - 0.75 (m, 2H). LCMS (ESI) m / z = 731.3 [M+H]+. 28.1 Example 28 Synthesis of 2-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin- 6(5H)-yl)acetonitrile. Compound 28 To a solution of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- amine (28.8 mg, 0.044.3 mmol, Compound 23) in acetonitrile (0.295 mL, 0.15M) stirring at 23 °C was added potassium carbonate (18.4 mg, 0.133 mmol) followed by bromoacetonitrile (3.28 µL, 0.0487 mmol) and the reaction was stirred at 23 °C for 16 h. The solvent was removed under reduced pressure and the residue was purified via preparatory HPLC (mobile phase: 10-100% acetonitrile in water w / 0.1% formic acid) to afford 2-(2-(4-cyclopropyl-6- methoxypyrimidin-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)acetonitrile (4.3 mg, 16% yield) as a white powder.1H NMR (CD3OD, 400 MHz): 8.52 (s, 1H), 7.66 (s, 1H), 7.59 - 7.54 (m, 2H), 7.49 - 7.44 (m, 2H), 4.77 (s, 2H), 3.94 (s, 2H), 3.87 (s, 3H), 3.75 (s, 3H), 3.59 (s, 2H), 2.97 - 2.94 (m, 2H), 2.88 - 2.85 (m, 2H), 1.69 - 1.62 (m, 1H), 1.05 - 1.01 (m, 2H), 0.81 - 0.76 (m, 2H). LCMS (ESI) m / z = 576.3 [M+H]+. 29.1 Example 29 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)-6-(oxiran-2-ylmethyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-4-amine. Compound 29 The title compound was prepared using a similar procedure as Compound 28, replacing 2-bromoacetonitrile with 2-(bromomethyl)oxirane.1H NMR (400 MHz, CD3OD) δ 8.52 (s, 1H), 7.66 (s, 1H), 7.57 - 7.52 (m, 2H), 7.49 - 7.43 (m, 2H), 4.70 (s, 2H), 3.87 (s, 3H), 3.75 (s, 3H), 3.58 (s, 2H), 3.23 - 3.19 (m, 1H), 3.09 - 2.99 (m, 2H), 2.96 - 2.89 (m, 1H), 2.88 - 2.81 (m, 3H), 2.61 - 2.60 (m, 1H), 2.59 - 2.51 (m, 1H), 1.70 - 1.62 (m, 1H), 1.06 - 1.00 (m, 2H). LCMS (ESI) m / z = 593.3 [M+H]+. 30.1 EXAMPLE 30 Synthesis of 2-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(((4-(1-isopropyl-4- (trifluoro-methyl)-1H-imidazol-2-yl)cuban-1-yl)methyl)amino)-7,8-dihydropyrido[4,3- d]pyrimidin-6(5H)-yl)acetonitrile. Compound 30 Step 1: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-((-4-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)methyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-4-amine. Compound 30.1 The title compound was prepared using a similar procedure as Compound 2, replacing (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine and (2- fluoropyridin-3-yl)boronic acid with 4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)cuban-1-yl)methanamine (Intermediate H) and (4-cyclopropyl-6-methoxypyrimidin-5- yl)boronic acid. LCMS (ESI) m / z = 296.4 [M / 2+H]+. Step 2: Preparation of 2-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(((4-(1- isopropyl-4-(trifluoro-methyl)-1H-imidazol-2-yl)uban-1-yl)methyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)acetonitrile. Compound 30 The title compound was prepared using a similar procedure as Compound 28, replacing 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-methyl-4-(trifluoromethyl)- 1H-imidazol-2-yl)benzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine with 2-(4- cyclopropyl-6-methoxypyrimidin-5-yl)-N-((-4-(1-isopropyl-4-(trifluoromethyl)-1H- imidazol-2-yl)cuban-1-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (Compound 30.1). 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.73 (s, 1H), 4.23 (dd, J = 5.7, 4.3 Hz, 3H), 4.17 (q, J = 6.6 Hz, 1H), 3.98 (t, J = 5.0 Hz, 3H), 3.95 (s, 2H), 3.92 (s, 3H), 3.81 (s, 2H), 3.54 (s, 2H), 2.96 (t, J = 5.7 Hz, 2H), 2.86 (t, J = 5.5 Hz, 2H), 1.72 (tt, J = 8.4, 4.6 Hz, 1H), 1.46 (d, J = 6.7 Hz, 6H), 1.17 – 1.12 (m, 2H), 0.97 – 0.91 (m, 2H). LCMS (ESI) m / z = 630.7 [M+H]+. 31.1 EXAMPLE 31 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-(((4-(1-isopropyl-4- (trifluoro-methyl)-1H-imidazol-2-yl)cuban-1-yl)methyl)amino)-7,8-dihydropyrido[4,3- d]pyrimidine-6(5H)-carboxamide. Compound 31 To a mixture of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-((4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)cuban-1-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimi-din-4-amine (81.0 mg, 0.129 mmol, Compound 30.1) in dimethyl sulfoxide (0.391 mL) was added sodium hydride (60 w / w%, 18.1 mg, 0.452 mmol). The mixture was stirred at 23 °C for 30 minutes. To the mixture was added cyanogen bromide (20.5 mg, 0.194 mmol). The resulting mixture was stirred at 23 °C for 1 hour. The mixture was concentrated under reduced pressure and the residue was purified by preparatory HPLC (mobile phase: 10-100% acetonitrile in water w / 0.1% formic acid) to afford 2-(4-cyclopropyl-6- methoxypyrimidin-5-yl)-4-(((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)cuban- 1-yl)methyl)amino)-7,8-di-hydropyrido[4,3-d]pyrimidine-6(5H)-carboxamide (2.00 mg, 2.4% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.73 (s, 1H), 4.36 (s, 2H), 4.23 (t, J = 5.0 Hz, 3H), 4.20 – 4.13 (m, 1H), 3.99 (t, J = 5.0 Hz, 3H), 3.92 (s, 3H), 3.83 (s, 2H), 3.73 (t, J = 5.8 Hz, 2H), 2.80 (t, J = 5.7 Hz, 2H), 1.76 – 1.68 (m, 1H), 1.46 (d, J = 6.7 Hz, 6H), 1.17 – 1.11 (m, 2H), 0.97 – 0.89 (m, 2H). LCMS (ESI) m / z = 317.8, M / 2+H+. 32.1 EXAMPLE 32 Synthesis of 2-(2-(2-isopropylphenyl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)acetonitrile. Compound 32 The title compound can be prepared using a similar procedure as Compound 28, replacing tert-butyl 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate with tert-butyl 2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate.1H NMR (400 MHz, CD3OD) δ 7.67 (s, 1H), 7.58 (d, J = 7.8 Hz, 2H), 7.47 (d, J = 7.9 Hz, 2H), 7.39 – 7.28 (m, 3H), 7.23 – 7.16 (m, 1H), 4.83 (s, 2H), 3.91 (s, 2H), 3.76 (s, 3H), 3.65 (s, 2H), 3.29 – 3.21 (m, 1H), 2.99 (t, J = 5.9 Hz, 2H), 2.70 (t, J = 5.9 Hz, 2H), 1.05 (d, J = 6.8 Hz, 6H). LCMS (ESI) m / z = 546.6 [M+H]+. 33.1 EXAMPLE 33 Synthesis of 2-(2-isopropylphenyl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)amino)-6-(oxiran-2-ylmethyl)-7,8-dihydropyrido[4,3-d]pyrimidin- 5(6H)-one. Compound 33 Step 1: Preparation of 2-(2-isopropylphenyl)-4-((4-(1-methyl-4-(trifluoromethyl)- 1H-imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one. Compound 33.1 The title compound can be prepared using a similar procedure as Compound 2.2, replacing (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine, tert- butyl 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate and (2- fluoropyridin-3-yl)boronic acid with (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine, 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one, and (2-isopropylphenyl)boronic acid. LCMS (ESI) m / z = 521.6 [M+H]+. Step 2: Preparation of 2-(2-isopropylphenyl)-4-((4-(1-methyl-4-(trifluoromethyl)- 1H-imidazol-2-yl)benzyl)amino)-6-(oxiran-2-ylmethyl)-7,8-dihydropyrido[4,3- d]pyrimidin-5(6H)-one Compound 33 To a mixture of 2-(2-isopropylphenyl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (30.0 mg, 0.0576 mmol) in N,N-dimethylformamide (0.384 mL) was added sodium hydride (3.00 mg, 60% dispersion in mineral oil, 0.0749 mmol) and the mixture was stirred at 23 °C for 30 min. 2-(bromomethyl)oxirane (0.00587 mL, 0.0749 mmol) was added and the resulting mixture was stirred at 23 °C for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by preparatory HPLC (mobile phase: 10-100% acetonitrile in water w / 0.1% formic acid) to afford 2-(2-isopropylphenyl)-4-((4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-6-(oxiran-2-ylmethyl)-7,8- dihydropyrido[4,3-d]pyrimidin-5(6H)-one (3.40 mg, 10% yield) as a white solid.1H NMR (400 MHz, CD3OD) δ 7.69 – 7.66 (m, 1H), 7.61 – 7.57 (m, 2H), 7.51 – 7.44 (m, 3H), 7.36 – 7.33 (m, 2H), 7.21 – 7.16 (m, 1H), 4.86 (s, 2H), 4.13 – 4.06 (m, 1H), 3.88 – 3.81 (m, 1H), 3.78 – 3.71 (m, 1H), 3.75 (s, 3H) 3.51 – 3.44 (m, 1H), 3.44 – 3.35 (m, 1H), 3.27 – 3.21 (m, 1H), 2.92 (t, J = 6.8 Hz, 2H), 2.81 (t, J = 4.4 Hz, 1H), 2.63 (dd, J = 4.8, 2.6 Hz, 1H), 1.06 (d, J = 6.9 Hz, 6H. LCMS (ESI) m / z = 577.2 [M+H]+. 34.1 EXAMPLE 34 Synthesis of 2-(2-(2-isopropylphenyl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)amino)-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)- yl)acetonitrile. Compound 34 The title compound can be prepared using a similar procedure as Compound 33, replacing 2-(bromomethyl)oxirane with bromoacetonitrile.1H NMR (400 MHz, DMSO-d6) δ 8.05 (t, J = 6.0 Hz, 1H), 7.92 (d, J = 1.4 Hz, 1H), 7.68 – 7.62 (m, 2H), 7.45 – 7.39 (m, 3H), 7.38 – 7.33 (m, 2H), 7.24 – 7.17 (m, 1H), 4.76 (d, J = 5.9 Hz, 2H), 4.60 (s, 2H), 3.79 (t, J = 6.7 Hz, 2H), 3.75 (s, 3H), 3.42 (p, J = 6.8 Hz, 1H), 2.95 (d, J = 6.7 Hz, 2H), 1.00 (d, J = 6.8 Hz, 6H). LCMS (ESI) m / z = 560.6 [M+H]+. 35.1 EXAMPLE 35 Synthesis of 4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)amino)-2-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-6,7-dihydropyrido[3,4- d]pyrimidin-8(5H)-one. Compound 35 The title compound can be prepared using a similar procedure as Compound 2.2, replacing tert-butyl 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate and (2-fluoropyridin-3-yl)boronic acid with 2,4-dichloro-6,7-dihydropyrido[3,4- d]pyrimidin-8(5H)-one and 1-isopropyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole. 1H NMR (400 MHz, CD3OD) δ 7.95 – 7.85 (m, 1H), 7.51 (s, 4H), 7.31 (s, 1H), 5.26 (hept, J = 6.6 Hz, 1H), 4.52 (hept, J = 6.7 Hz, 1H), 3.62 (t, J = 6.9 Hz, 2H), 2.91 (t, J = 6.9 Hz, 2H), 2.12 (s, 3H), 1.44 (d, J = 6.7 Hz, 6H), 1.35 – 1.21 (m, 8H), 1.10 (s, 1H). LCMS (ESI) m / z = 553.3 [M+H]+. 36.1 EXAMPLE 36 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4- (trifluoro-methyl)-1H-imidazol-2-yl)benzyl)amino)-6,7-dihydropyrido[3,4-d]pyrimidin- 8(5H)-one. Compound 36 The title compound can be prepared using a similar procedure as Compound 2.2, replacing tert-butyl 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate and (2-fluoropyridin-3-yl)boronic acid with 2,4-dichloro-6,7-dihydropyrido[3,4- d]pyrimidin-8(5H)-one, and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid.1H NMR (400 MHz, CD3OD) δ 8.53 (s, 1H), 7.95 – 7.87 (m, 1H), 7.56 – 7.44 (m, 4H), 4.81 (s, 2H), 4.53 (hept, J = 6.7 Hz, 1H), 3.88 (s, 3H), 3.61 (t, J = 6.8 Hz, 2H), 2.88 (t, J = 6.8 Hz, 2H), 1.76 – 1.67 (m, 1H), 1.44 (d, J = 6.7 Hz, 6H), 1.10 – 1.02 (m, 2H), 0.83 – 0.74 (m, 2H). LCMS (ESI) m / z = 579.3 [M+H]+. 37.1 EXAMPLE 37 Synthesis of 2-(2-isopropylphenyl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)amino)-6,7-dihydropyrido[3,4-d]pyrimidin-8(5H)-one. Compound 37 The title compound can be prepared using a similar procedure as Compound 2.2, replacing (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine, tert- butyl 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate and (2- fluoropyridin-3-yl)boronic acid with (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)phenyl)methanamine Intermediate A), 2,4-dichloro-6,7-dihydropyrido[3,4-d]pyrimidin- 8(5H)-one, and (2-isopropylphenyl)boronic acid.1H NMR (400 MHz, CD3OD) δ 8.26 (s, 1H), 7.67 (s, 1H), 7.59 (d, J = 7.8 Hz, 2H), 7.52 – 7.42 (m, 3H), 7.39 – 7.33 (m, 2H), 7.24 – 7.14 (m, 1H), 4.86 (s, 3H), 3.75 (s, 3H), 3.61 (t, J = 6.8 Hz, 2H), 3.39 (hept, J = 6.8 Hz, 1H), 2.89 (t, J = 6.8 Hz, 2H), 1.06 (d, J = 6.8 Hz, 6H). LCMS (ESI) m / z = 521.3 [M+H]+. 38.1 EXAMPLE 38 Synthesis of 2-(2-(2-isopropylphenyl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)amino)-8-oxo-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)- yl)acetonitrile. Compound 38 To a mixture of 2-(2-isopropylphenyl)-4-((4-(1-methyl-4-(trifluoromethyl)-1H- imidazol-2-yl)benzyl)amino)-6,7-dihydropyrido[3,4-d]pyrimidin-8(5H)-one (12.0 mg, 0.0231 mmol, Compound 37) in N,N-dimethylformamide (0.0922 mL) was added sodium hydride (1.38 mg, 60% dispersion in mineral oil, 0.0346 mmol) and the mixture was stirred at 23 °C for 30 min. 2-bromoacetonitrile (0.00241 mL, 0.0346 mmol) was added and the resulting mixture was stirred at 23 °C for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by preparatory HPLC (mobile phase: 15-100% acetonitrile in water w / 0.1% formic acid) to afford 2-(2-(2-isopropylphenyl)-4-((4-(1- methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-8-oxo-5,8- dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)acetonitrile (5.0 mg, 39% yield) as a white solid.1H NMR (400 MHz, CD3OD) δ 8.47 (s, 1H), 7.67 (s, 1H), 7.59 (d, J = 7.8 Hz, 2H), 7.49 (d, J = 7.9 Hz, 2H), 7.44 (d, J = 7.7 Hz, 1H), 7.40 – 7.30 (m, 2H), 7.24 – 7.14 (m, 1H), 4.86 (s, 2H), 4.63 (s, 2H), 3.86 (t, J = 6.8 Hz, 2H), 3.75 (s, 3H), 3.38 (hept, J = 6.8 Hz, 1H), 3.00 (t, J = 6.8 Hz, 2H), 1.06 (d, J = 6.7 Hz, 6H). LCMS (ESI) m / z = 560.3 [M+H]+. 39.1 EXAMPLE 39 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-isopropyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-5,8-dihydropyrido[4,3-d]pyrimidin- 7(6H)-one. Compound 39 Step 1: Preparation of 4-cyclopropyl-6-methoxypyrimidine-5-carbonitrile. Compound 39.1 To a stirred solution of 5-bromo-4-cyclopropyl-6-methoxypyrimidine (25.0 g, 109 mmol) in dimethyl sulfoxide (100 mL) was added copper(I) cyanide (39.0 g, 437 mmol) at 23 °C. The reaction mixture was purged with nitrogen gas for 20 minutes, then tetrakis(triphenylphosphine)palladium(0) (6.30 g, 5.45 mmol) was added to the reaction mixture and the reaction was heated at 140 °C for 16 h. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with brine (50 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a brown residue. The residue was purified by flash chromatography (mobile phase: 10% ethyl acetate in petroleum ether) to afford 4-cyclopropyl-6-methoxypyrimidine-5-carbonitrile (6.00 g, 32% yield) as an off- white solid. LCMS (ESI): m / z = 175.9 [M+H]+. Step 2: Preparation of 4-cyclopropyl-6-methoxypyrimidine-5-carboximidamide. Compound 39.2 A stirred solution of ammonium chloride (5.95 g, 111 mmol) in toluene (200 mL) was prepared and cooled to 0 °C under a nitrogen atmosphere. Trimethylaluminum (60 mL, 2.0 M in toluene, 120 mmol) was added dropwise over a period of 15 min. This was followed by the addition of 4-cyclopropyl-6-methoxypyrimidine-5-carbonitrile (6.50 g, 37.1 mmol) in toluene (30 mL) and the reaction mixture was heated at 120 °C for 16 h. Upon completion, the reaction mixture was cooled to 23 °C and slowly poured onto a suspension of silica gel (25 g) in methanol / dichloromethane (1:9, 150 mL). The mixture was stirred for 20 min, and the silica plug was washed with methanol / dichloromethane (1:9, 2 x 100 mL). The filtrate was concentrated under reduced pressure to obtain the product. The solid was washed with diethyl ether (2 x 50 mL) and dried under reduced pressure to yield 4-cyclopropyl-6- methoxypyrimidine-5-carboximidamide (6.50 g, 91% yield) as an off-white solid.1H-NMR (400 MHz, DMSO-d6) δ 9.57 (br s, 3H), 8.77 (s, 1H), 3.98 (s, 3H), 1.96-1.93 (m, 1H), 1.13- 1.12 (m, 4H). Step 3: Preparation of methyl 2-(4'-cyclopropyl-6'-methoxy-6-oxo-1,6-dihydro- [2,5'-bipyrimidin]-4-yl) acetate. Compound 39.3 To a stirred solution of 4-cyclopropyl-6-methoxypyrimidine-5-carboximidamide (2.00 g, 10.4 mmol) and dimethyl 3-oxopentanedioate (3.60 g, 20.8 mmol) in methanol (25.0 mL) was added sodium methoxide (1.40 g, 26.0 mmol) at 0 °C under a nitrogen atmosphere. The reaction mixture was heated at 80 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash chromatography (mobile phase: 70-90% ethyl acetate in petroleum ether) to afford methyl 2-(4'-cyclopropyl-6'-methoxy-6-oxo-1,6-dihydro-[2,5'-bipyrimidin]-4-yl) acetate (1.70 g, 51% yield) as an off-white solid. LCMS (ESI): m / z = 317.02 [M+H]+. Step 4: Preparation of methyl 2-(5-bromo-4'-cyclopropyl-6'-methoxy-6-oxo-1,6- dihydro-[2,5'-bipyrimidin]-4-yl) acetate. Compound 39.4 A solution of methyl 2-(4'-cyclopropyl-6'-methoxy-6-oxo-1,6-dihydro-[2,5'- bipyrimidin]-4-yl) acetate (1.70 g, 5.37 mmol) in acetonitrile (10.0 mL) was prepared and cooled to 0 °C under a nitrogen atmosphere. A solution of N-Bromosuccinimide (1.00 g, 5.64 mmol) dissolved in acetonitrile (10 mL) was then added dropwise to the reaction mixture. The resulting mixture was stirred at 0 °C for 0.5 h. The reaction was then diluted with water (20 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to obtain a residue. The residue was further purified by flash chromatography (mobile phase: 40-50% ethyl acetate in petroleum ether) to afford methyl 2-(5-bromo-4'-cyclopropyl-6'-methoxy-6-oxo-1,6- dihydro-[2,5'-bipyrimidin]-4-yl) acetate (700 mg, 33% yield) as an off-white solid. LCMS (ESI): m / z = 396.98 [M+H]+. Step 5: Preparation of methyl 2-(5-(((tert-butoxycarbonyl)amino)methyl)-4'- cyclopropyl-6-hydroxy-6'-methoxy-[2,5'-bipyrimidin]-4-yl)acetate. Compound 39.5 A stirred solution of methyl 2-(5-bromo-4'-cyclopropyl-6'-methoxy-6-oxo-1,6- dihydro-[2,5'-bipyrimidin]-4-yl) acetate (0.700 g, 1.77 mmol) and potassium (((tert- butoxycarbonyl)amino)methyl)trifluoroborate (1.05 g, 4.43 mmol) in 1,4-dioxane (16.0 mL) and water (4.00 mL) was prepared. Cesium carbonate (1.00 g, 3.10 mmol) was added to the reaction and the mixture was purged with nitrogen gas for 20 min. Palladium(II) acetate (79.6 mg, 0.354 mmol) and cataCXium-A (139 mg, 0.389 mmol) were added to the mixture. The reaction was heated in a sealed tube at 100 °C for 1.5 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 25 mL). The organic phases were combined, dried over sodium sulfate, and concentrated under reduced pressure to yield a residue which was purified flash chromatography (mobile phase: 40-50% ethyl acetate in hexane) to afford methyl 2-(5-(((tert-butoxycarbonyl)amino)methyl)-4'- cyclopropyl-6-hydroxy-6'-methoxy-[2,5'-bipyrimidin]-4-yl)acetate (350 mg, 38% yield) as a brown solid. LCMS (ESI): m / z = 446.38 [M+H]+. Step 6: Preparation of 2-(5-(((tert-butoxycarbonyl) amino) methyl)-4'-cyclopropyl- 6'-methoxy-6-(((trifluoromethyl)sulfonyl) oxy)-[2,5'-bipyrimidin]-4-yl) acetate. Compound 39.6 To a stirred solution of methyl 2-(5-(((tert-butoxycarbonyl) amino) methyl)-4'- cyclopropyl-6'-methoxy-6-oxo-1,6-dihydro-[2,5'-bipyrimidin]-4-yl) acetate (350 mg, 0.786 mmol) in dichloromethane (15.0 mL) at 0 °C was added trifluoromethanesulfonic anhydride (244 mg, 0.864 mmol) followed by N,N-diisopropylethylamine (305 mg, 2.35 mmol) and the reaction mixture was stirred at 0°C for 2 h. Upon completion, the reaction mixture was diluted with water (15 mL) and extracted with dichloromethane (2 x 50 mL). The organic phase was separated, dried over sodium sulfate, and concentrated under reduced pressure to give 2-(5-(((tert-butoxycarbonyl) amino) methyl)-4'-cyclopropyl-6'-methoxy-6- (((trifluoromethyl)sulfonyl) oxy)-[2,5'-bipyrimidin]-4-yl) acetate (300 mg, 66% yield) as a brown semisolid. The material was forwarded to next step without any further purification. LCMS (ESI): m / z = 578.33 [M+H]+. Step 7: Preparation of 2-(5-(((tert-butoxycarbonyl) amino) methyl)-4'-cyclopropyl- 6-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl) benzyl) amino)-6'-methoxy-[2,5'- bipyrimidin]-4-yl) acetate. Compound 39.7 To a stirred solution of methyl 2-(5-(((tert-butoxycarbonyl) amino) methyl)-4'- cyclopropyl-6'-methoxy-6-(((trifluoromethyl)sulfonyl) oxy)-[2,5'-bipyrimidin]-4-yl) acetate (180 mg, 0.312 mmol) in dichloromethane (10.0 mL) at 0 °C was added (4-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine (106 mg, 0.374 mmol) followed by N,N-diisopropylethylamine (81.0 mg, 0.623 mmol) and the reaction mixture was warmed to 23 °C and stirred for 16 h. Upon completion, the reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (2 x 50 mL). The organic phase was separated, dried over sodium sulfate, and concentrated under reduced pressure to yield methyl 2-(5-(((tert-butoxycarbonyl) amino) methyl)-4'-cyclopropyl-6-((4- (1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl) benzyl) amino)-6'-methoxy-[2,5'- bipyrimidin]-4-yl) acetate (180 mg, 81% yield over 2 steps) as an off-white solid. LCMS (ESI): m / z = 711.76 [M+H]+. Step 8: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1- isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-5,8-dihydropyrido[4,3- d]pyrimidin-7(6H)-one. Compound 39 To a stirred solution of methyl 2-(5-(((tert-butoxycarbonyl) amino) methyl)-4'- cyclopropyl-6-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl) benzyl) amino)-6'- methoxy-[2,5'-bipyrimidin]-4-yl) acetate (180 mg, 0.253 mmol) in dichloromethane (5.00 mL) was added trifluoroacetic acid (0.200 mL)slowly at 0 °C.The reaction mixture was stirred at 23 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced and the residue was purified via preparatory HPLC (mobile phase: 10-100% acetonitrile in water w / 0.1% formic acid) to afford 2-(4-cyclopropyl-6-methoxypyrimidin- 5-yl)-4-((4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl) benzyl) amino)-5,8- dihydropyrido[4,3-d] pyrimidin-7(6H)-one (0.024 g, 16% yield) as a white solid.1H-NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.34 (brs, 2H), 8.17 (s, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 4.74 (d, J = 5.6 Hz, 2H), 4.45-4.39 (m, 1H), 4.30 (s, 2H), 3.75 (s, 3H), 3.48 (s, 2H), 1.74-1.72 (m, 1H), 1.39 (d, J = 6.4 Hz, 6H), 1.18-0.92 (m, 2H), 0.77-0.75 (m, 2H). LCMS (ESI): m / z = 579.51 (M+H)+. 40.1 EXAMPLE 40 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N4-(4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5,6,7,8-tetrahydroquinazoline-4,6-diamine. Compound 40 Step 1: Synthesis of 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)-7,8-dihydro-5H-spiro[quinazoline-6,2'-[1,3]dioxolan]-4-amine. Compound 40.1 To a stirred solution of 2,4-dichloro-7,8-dihydro-5H-spiro[quinazoline-6,2'- [1,3]dioxolane] (2.60 g, 9.99 mmol, Intermediate R) in acetonitrile (30.0 mL) at 23 °C was added N,N-diisopropylethylamine (5.15 mL, 29.9 mmol) followed by(4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine (2.54 g, 9.99 mmol, Intermediate A) and the reaction mixture was heatedat 80 °Cfor 16 h. Upon completion, the reaction mixture wasdiluted with water (50mL) andextracted withethyl acetate (3x 50mL). The combined organic phases were washed with water (15 mL) and brine solution (15 mL), dried over sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure and the residue was purified via flash chromatography (mobile phase: 20% ethyl acetate in petroleum ether) to afford 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)-7,8-dihydro-5H-spiro[quinazoline-6,2'-[1,3]dioxolan]-4-amine (3.30 g, 69% yield) as a brown solid. LCMS (ESI) m / z = 480.49 [(M+H]+. Step 2: Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1-methyl-4- (trifluoro-methyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydro-5H-spiro[quinazoline-6,2'- [1,3]dioxolan]-4-amine. Compound 40.2 To a solution of 2-chloro-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)-7,8-dihydro-5H-spiro[quinazoline-6,2'-[1,3]dioxolan]-4-amine (2.50 g, 5.21 mmol) in 1,2-dimethoxyethane (30.0mL) and water (3.0 mL) stirring at 23 °C was added (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (1.51 g, 7.81 mmol) and potassium carbonate (1.79 g, 13.0 mmol).The reaction mixture was degassed with nitrogen for 15 min before adding tetrakis(triphenylphosphine)palladium(0) (0.60 g, 0.52 mmol) and the reaction was heated at 100 °C^under microwave irradiation for 4 h. Upon completion, the reaction mixture wasdiluted with water (20mL) and extracted withethyl acetate (3x 100mL). The combined organic phases were washed with water (30 mL) and brine solution (30 mL), dried over sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure and the residue was purified via flash chromatography (mobile phase: 10% ethyl acetate in petroleum ether) to afford 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1- methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydro-5H-spiro[quinazoline- 6,2'-[1,3]dioxolan]-4-amine (2.80 g, 91% yield) as a brown solid. LCMS (ESI) m / z = 594.7 [(M+H]+. Step 3: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl- 4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-7,8-dihydroquinazolin-6(5H)-one. Compound 40.3 To a stirred solution of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N-(4-(1- methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-7,8-dihydro-5H-spiro[quinazoline- 6,2'-[1,3]dioxolan]-4-amine (2.80 g, 4.72 mmol) in dichloromethane (15.0 mL)at 0 °C was addedtrifluoroacetic acid(10.8 mL, 142 mmol) and the reaction was warmed to 23 °C and stirred for 16 h. Upon completion, the reaction mixture was concentrated and the residue was neutralized with saturated sodium bicarbonate solution^(50mL) andextracted withethyl acetate (3x 50mL). The combined organic phases were washed with water (5 mL), brine, (5 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified via flash chromatography (mobile phase: 10% ethyl acetate in petroleum ether) to afford 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1- methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-7,8-dihydroquinazolin- 6(5H)-one (2.20 g, 85% yield) as a brown solid. LCMS (ESI) m / z = 550.7 [(M+H]+. Step 4: Preparation of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N4-(4-(1- methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5,6,7,8-tetrahydroquinazoline-4,6- diamine. Compound 40 To a stirred solution 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl- 4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-7,8-dihydroquinazolin-6(5H)-one (300 mg, 0.550 mmol) inmethanol (2.0 mL) at 23 °C was added ammonium acetate (210 mg, 2.73 mmol) the reaction mixture was heated at 60 °C for 2 h. The reaction was cooled to 0 °C and sodium cyanoborohydride (600 mg, 1.64 mmol) was added. The reaction mixture was heated at 60 °C for 2 h at which time it was complete by LCMS. The reaction was filtered through celite, washing with dichloromethane (3 x 10 mL). The filtrate was washed with water (20mL), brine (20mL), dried overanhydrous sodium sulfateand filtered. The filtrate was concentrated under reduced pressure and the residue was purified via achiral SFC purification to afford 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N4-(4- (1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5,6,7,8-tetrahydroquinazoline- 4,6-diamine. (70.0 mg, 23% yield)as an off white solid.1H-NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.92 (d, J = 1.2 Hz, 1H), 7.63 - 7.60 (m, 3H), 7.40 (d, J = 8.4 Hz, 2H), 4.65 (d, J = 6.0 Hz, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 3.49 - 3.47 (m, 1H), 2.83 - 2.73 (m, 3H), 2.41 - 2.37 (m, 1H), 2.10 - 2.05 (m, 1H), 1.79 - 1.77 (m, 1H), 1.68 - 1.64 (m, 1H), 0.96 - 0.92 (m, 2H), 0.76 - 0.72 (m, 2H). LCMS (ESI) m / z = 549.29 [M-H]-. 41.1 EXAMPLE 41 Synthesis of N-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl-4- (trifluoro-methyl)-1H-imidazol-2-yl)benzyl)amino)-5,6,7,8-tetrahydroquinazolin-6- yl)acetamide. Compound 41 To a solution of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N4-(4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5,6,7,8-tetrahydroquinazoline-4,6-diamine (100 mg, 0.180 mmol, Compound 40) indichloromethane (2.0 mL) at 0 °C was added triethylamine (0.080 mL, 0.550 mmol) andacetic anhydride (0.030 mL, 0.270 mmol) and the reaction mixture was warmed to 23 °C and stirred for 2 h. Upon completion, the reaction mixture was diluted with water (3mL) and extracted with dichloromethane (3 x 10mL). The combined organic phases were washed with brine (10 mL)dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparatory HPLC (mobile phase: 20-100% acetonitrile in water w / 0.1% formic acid) to afford N-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-5,6,7,8-tetrahydro-quinazolin-6- yl)acetamide (21.0mg, 20% yield)as an off white solid. 1H-NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.06 (d, J = 7.2 Hz, 1H), 7.91 (d, J = 0.8 Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.51 (t, J = 6.0 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 4.63 - 4.61 (m, 2H), 4.07 - 4.08 (m, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 2.83 - 2.72 (m, 3H), 2.30 - 2.26 (m, 1H), 1.92 - 1.79 (m, 5H), 1.69 - 1.65 (m, 1H), 0.94 - 0.93 (m, 2H), 0.76 - 0.73 (m, 2H). LCMS (ESI) m / z = 593.41 [M+H]+. 42.1 EXAMPLE 42 Synthesis of 2-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl-4- (trifluoro-methyl)-1H-imidazol-2-yl)benzyl)amino)-5,6,7,8-tetrahydroquinazolin-6- yl)amino)acetonitrile. Compound 42 To a solution of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N4-(4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5,6,7,8-tetrahydroquinazoline-4,6-diamine (100 mg, 0.180 mmol, Compound 40) in acetonitrile stirring at 23 °C was added triethylamine (0.070 mL, 0.54 mmol) and 2-bromoacetonitrile (0.030 g, 0.27 mmol) and the reaction mixture wasstirred at 50 °Cfor 2 h. Upon completion, the reaction mixture wasdiluted with cold water (10mL) and extracted with ethyl acetate(2x 20mL).The combined organic phases were washed with water (10mL), brine (10 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparatory HPLC (mobile phase: 20-100% acetonitrile in water w / 0.1% formic acid) to afford 2-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1- methyl-4-(trifluoro-methyl)-1H-imidazol-2-yl)benzyl)amino)-5,6,7,8- tetrahydroquinazolin-6-yl)amino)acetonitrile (0.0040 g, 4% yield) as an off white solid. 1H-NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.74 (s, 1H), 7.94 (d, J = 1.2 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 4.80 (d, J = 4.8 Hz, 2H), 3.90 (s, 6H), 3.75 (s, 3H), 3.33 - 3.31 (m, 1H), 2.86 - 2.79 (m, 3H), 2.41 - 2.35 (m, 1H), 2.09 - 2.04 (m, 1H), 1.83 - 1.80 (m, 2H), 1.05 - 1.03 (m, 2H), 0.82 - 0.80 (m, 2H). LCMS (ESI) m / z = 590.41 [M+H]+. 43.1 EXAMPLE 43 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N6-methyl-N4-(4-(1- methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5,6,7,8-tetrahydroquinazoline-4,6- diamine. Compound 43 To a stirred solution 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl- 4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-7,8-dihydroquinazolin-6(5H)-one (100 mg, 0.180 mmol, Compound 40) inmethanol (5.0 mL) and 1,2-dichloroethane (5.0 mL) at 23 °C was added methylamine (0.27 mL, 2.0 M in methanol, 0.55 mmol) followed bysodium acetate (0.050 g, 0.55 mmol) andacetic acid (1.0mL) and the reaction mixture was heated at 60 °C for 2 h. The reaction was cooled to 0 °C and sodium cyanoborohydride (0.100 mg, 0.273 mmol) was added and the reaction mixture was warmed to 23 °C and stirred for 2 h at which time it was complete by LCMS. The reaction mixture was concentrated and diluted with water (50 mL) and extracted withethyl acetate (3x 30mL). The combined organic phases were washed with water (5 mL) and brine solution (5 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified via preparatory HPLC (mobile phase: 20-100% acetonitrile in water w / 0.1% formic acid) to afford 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N6- methyl-N4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5,6,7,8- tetrahydroquinazoline-4,6-diamine (0.015 g, 15% yield) as a brown solid.1H-NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.91 (s, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.47 (t, J = 6.0 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 4.64 (d, J = 5.6 Hz, 2H), 3.79 (s, 3H), 3.74 (s, 3H), 2.84 - 2.82 (m, 1H), 2.75 - 2.70 (m, 1H), 2.63 - 2.61 (m, 2H), 2.37 (s, 3H), 2.20 - 2.15 (m, 1H), 1.97 - 1.94 (m, 1H), 1.68 - 1.59 (m, 2H), 1.24 (s, 1H), 0.95 - 0.93 (m, 2H), 0.74 - 0.71 (m, 2H). LCMS (ESI) m / z = 565.29 [(M+H]+. 44.1 EXAMPLE 44 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N6-methyl-N4-(4-(1- methyl-4-(trifluoro-methyl)-1H-imidazol-2-yl)benzyl)-N6-(oxiran-2-ylmethyl)-5,6,7,8- tetrahydro-quinazoline-4,6-diamine. Compound 44 To a stirred solution of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N6-methyl-N4- (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5,6,7,8-tetrahydroquinazoline- 4,6-diamine (0.10 g, 0.18 mmol, Compound 43) inacetonitrile (4.0mL) at 0 °C was addedtriethylamine (0.070mL, 0.530mmol) followed by 2-(bromomethyl)oxirane (0.040 g, 0.260 mmol) and the reaction mixture was heated at 60 °C for 16 h. Upon completion, the reaction mixture wasdiluted with cold-water (10mL) and extracted with ethyl acetate(2x 10mL).The combined organic phases were washed with water (10mL), brine (50 mL), dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified via preparatory HPLC (mobile phase: 15-100% acetonitrile in water w / 0.1% formic acid) to afford 2-(4-cyclopropyl-6-methoxypyrimidin- 5-yl)-N6-methyl-N4-(4-(1-methyl-4-(trifluoro-methyl)-1H-imidazol-2-yl)benzyl)-N6- (oxiran-2-ylmethyl)-5,6,7,8-tetrahydroquinazoline-4,6-diamine (0.011 g, 10% yield) as an off white solid.1H-NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.91 (s, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.54 (t, J = 5.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 4.64 - 4.64 (m, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 3.04 - 3.03 (m, 1H), 2.95 - 2.95 (m, 1H), 2.87 - 2.79 (m, 1H), 2.78 - 2.71 (m, 3H), 2.64 - 2.55 (m, 2H), 2.42 - 2.33 (m, 5H), 2.02 - 1.97 (m, 1H), 1.67 - 1.61 (m, 2H), 0.93 - 0.92 (m, 2H), 0.76 - 0.73 (m, 2H). LCMS (ESI) m / z = 621.52 [M+H]+. 45.1 EXAMPLE 45 Synthesis of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N6-methyl-N4-(4-(1- methyl-4-(trifluoro-methyl)-1H-imidazol-2-yl)benzyl)-N6-((2-methyloxiran-2-yl)methyl)- 5,6,7,8-tetrahydroquinazoline-4,6-diamine. Compound 45 The title compound can be prepared using a similar procedure as Compound 44, replacing 2-(bromomethyl)oxirane with 2-(bromomethyl)-2-methyloxirane.1H-NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.91 (s, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.54 - 7.51 (m, 1H), 7.41 (d, J = 8.0 Hz, 2H), 4.65 - 4.61 (m, 2H), 3.80 (s, 3H), 3.74 (s, 3H), 2.96 - 2.91 (m, 1H), 2.73 - 2.69 (m, 2H), 2.67 - 2.54 (m, 5H), 2.41 - 2.38 (m, 1H), 2.36 - 2.32 (m, 3H), 1.96 - 1.94 (m, 1H), 1.67 - 1.60 (m, 2H), 1.30 (s, 3H), 0.93 - 0.92 (m, 2H), 0.76 - 0.73 (m, 2H). LCMS (ESI) m / z = 635.6 [M+H]+. 46.1 EXAMPLE 46 Synthesis of 2-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl-4- (trifluoro-methyl)-1H-imidazol-2-yl)benzyl)amino)-5,6,7,8-tetrahydroquinazolin-6- yl)(methyl)amino)acetonitrile. Compound 46 The title compound can be prepared using a similar procedure as Compound 42, replacing 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N4-(4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5,6,7,8-tetrahydroquinazoline-4,6-diamine with 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-N6-methyl-N4-(4-(1-methyl-4- (trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5,6,7,8-tetrahydroquinazoline-4,6-diamine (Compound 43).1H-NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.92 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.55 (t, J = 6.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 4.66 (d, J = 6.0 Hz, 2H), 3.89 (s, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 2.73 - 2.67 (m, 4H), 2.51 - 2.36 (m, 4H), 2.16 - 2.12 (m, 1H), 1.69 - 1.62 (m, 2H), 0.93 - 0.92 (m, 2H), 0.76 - 0.73 (m, 2H). LCMS (ESI) m / z = 604.5 [M+H]+. 47.1 EXAMPLE 47 Synthesis of N-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl-4- (trifluoro-methyl)-1H-imidazol-2-yl)benzyl)amino)-5,6,7,8-tetrahydroquinazolin-6-yl)-N- methylcyanamide. Compound 47 The title compound can be prepared using a similar procedure as Compound 21, replacing 2-(2-isopropylphenyl)-N-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine with 2-(4-cyclopropyl-6- methoxypyrimidin-5-yl)-N6-methyl-N4-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2- yl)benzyl)-5,6,7,8-tetrahydro-quinazoline-4,6-diamine (Compound 43).1H-NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.92 - 7.91 (m, 1H), 7.67 - 7.61 (m, 3H), 7.41 (d, J = 8.0 Hz, 2H), 4.65 (d, J = 6.0 Hz, 2H), 3.79 (s, 3H), 3.74 (s, 3H), 3.44 - 3.43 (m, 1H), 2.95 - 2.90 (m, 4H), 2.80 - 2.77 (m, 2H), 2.46 - 2.41 (m, 1H), 2.16 - 2.14 (m, 1H), 1.82 - 1.78 (m, 1H), 1.66 - 1.62 (m, 1H), 0.94 - 0.92 (m, 2H), 0.76 - 0.75 (m, 2H). LCMS (ESI) m / z = 590.5 [M+H]+. 48.1 EXAMPLE 48 Preparation of N-(2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-4-((4-(1-methyl-4- (trifluoro-methyl)-1H-imidazol-2-yl)benzyl)amino)-5,6,7,8-tetrahydroquinazolin-6-yl)-N- methylacetamide. Compound 48 To a stirred solution of 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-N6-methyl-N4- (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-5,6,7,8-tetrahydroquinazoline- 4,6-diamine (0.100 g, 0.170 mmol, Compound 43) inacetonitrile (5.0 mL) at 0 °C was added triethylamine (0.050 g, 0.530 mmol) followed byacetic anhydride (0.050 mL,0.53 mmol) and the reaction mixture was warmed to 23 °C and stirred for 2 h. The reaction mixture wasquenched with cold-water (10mL) and extracted with ethyl acetate(2x 10mL).The combined organic phases were washed with water (10mL), brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by achiral SFC purification to afford N-(2-(4-cyclopropyl-6- methoxypyrimidin-5-yl)-4-((4-(1-methyl-4-(trifluoro-methyl)-1H-imidazol-2- yl)benzyl)amino)-5,6,7,8-tetrahydroquinazolin-6-yl)-N-methylacetamide (0.035 g, 32% yield) as an off white solid.1H-NMR (400 MHz, DMSO-d6) δ 8.58 - 8.58 (m, 1H), 7.91 (s, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.53 - 7.52 (m, 1H), 7.41 (t, J = 8.6 Hz, 2H), 4.69 - 4.61 (m, 3H), 3.80 (s, 3H), 3.74 (s, 3H), 2.95 - 2.71 (m, 5H), 2.67 - 2.61 (m, 2H), 2.12 - 2.00 (m, 4H), 1.68 - 1.65 (m, 1H), 0.94 - 0.93 (m, 2H), 0.77 ^ 0.74 (m, 2H). LCMS (ESI) m / z = 607.5 [M+H]+. 49.1 EXAMPLE 33 Synthesis of 2-(2-isopropylphenyl)-4-((4-methylbenzyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidine-6(5H)-carbonitrile. Compound 49 The title compound was prepared using a similar procedure as Compound 2, replacing (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine and (2-fluoropyridin-3-yl)boronic acid with (4-methylphenyl)methanamine and (2- isopropylphenyl)boronic acid.1H NMR (400 MHz, CD3OD) δ 7.40 – 7.30 (m, 3H), 7.25 – 7.18 (m, 1H), 7.16 (d, J = 7.8 Hz, 2H), 7.09 (d, J = 7.7 Hz, 2H), 4.69 (s, 2H), 4.26 (s, 2H), 3.60 (t, J = 5.9 Hz, 2H), 3.24 (hept, J = 6.8 Hz, 1H), 2.90 (t, J = 6.0 Hz, 2H), 2.29 (s, 3H), 1.03 (d, J = 1.8 Hz, 6H) LCMS (ESI) m / z = 398.3 [M+H]+. 50.1 EXAMPLE 50 Synthesis of N-(4-fluorobenzyl)-2-(2-isopropylphenyl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-4-amine. Compound 50 The title compound was prepared using a similar procedure as Compound 2, replacing (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine and (2-fluoropyridin-3-yl)boronic acid with (4-fluorphenyl)methanamine and (2- isopropylphenyl)boronic acid. 1H NMR (400 MHz, CD3OD) δ 7.67 – 7.48 (m, 3H), 7.45 – 7.31 (m, 3H), 7.07 (t, 2H), 4.88 (s, 2H), 4.32 (s, 2H), 3.69 (t, J = 6.4 Hz, 2H), 3.24 (t, J = 6.2 Hz, 2H), 3.15 (hept, J = 6.8 Hz, 1H), 1.13 (d, J = 6.3 Hz, 6H). LCMS (ESI) m / z = 377.2 [M+H]+. 51.1 EXAMPLE 51 Synthesis of 4-((4-fluorobenzyl)amino)-2-(2-isopropylphenyl)-7,8- dihydropyrido[4,3-d]pyrimidine-6(5H)-carbonitrile. Compound 51 The title compound was prepared using a similar procedure as Compound 2, replacing (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine and (2-fluoropyridin-3-yl)boronic acid with (4-fluorphenyl)methanamine and (2- isopropylphenyl)boronic acid. 1H NMR (400 MHz, CD3OD) δ 7.42 – 7.25 (m, 5H), 7.25 – 7.17 (m, 1H), 7.04 – 6.93 (m, 2H), 4.71 (s, 2H), 4.28 (s, 2H), 3.60 (t, J = 5.9 Hz, 2H), 3.20 (hept, J = 6.9 Hz, 1H), 2.91 (t, J = 5.9 Hz, 2H), 1.04 (d, J = 1.7 Hz, 6H). LCMS (ESI) m / z = 402.3 [M+H]+. 52.1 EXAMPLE 52 Synthesis of 2-(4-(benzylamino)-2-(2-isopropylphenyl)-7,8-dihydropyrido[4,3- d]pyrimidin-6(5H)-yl)acetonitrile. Compound 52 The title compound was prepared using a similar procedure as Compound 22, replacing (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanamine with benzylamine. 1H NMR (400 MHz, CD3OD) δ 8.25 (s, 1H), 7.50 – 7.34 (m, 3H), 7.33 – 7.16 (m, 6H), 4.79 (s, 2H), 3.96 (s, 2H), 3.62 (s, 2H), 3.16 (hept, J = 6.8 Hz, 1H), 3.05 – 2.88 (m, 4H), 1.03 (d, J = 6.8 Hz, 6H). LCMS (ESI) m / z = 398.2 [M+H]+. Test EXAMPLES The compounds’ activities that target USP-1 protein complex and the compounds’ physiochemical and pharmacological properties can be assessed by the following in vitro and in vivo methods. USP1 and USP30 Ubiquitin-Rhodamine Activity Assay To measure USP1 activity, purified recombinant USP1-UAF1 heterodimer (R&D Systems, Cat# E-568) was diluted into assay buffer containing 50mM HEPES pH 8.0, 100nM NaCl, 1 mM EDTA, 1 mM TCEP, 0.01% Tween-20, and 0.5 mg / mL Bovine Serum Albumin. Compounds were dispensed into black, round bottom, low binding, 384-well assay plates (Corning, Cat# 4514) in a 10-pt 3.16 step serial dilution and backfilled with dimethyl sulfoxide to a final concentration of 1% using an Echo acoustic liquid dispenser (Labcyte / Beckman Coulter). 1 µM KSQ-4279 (Cpos) and dimethyl sulfoxide (Cneg) were used as reference compounds for USP1. Enzymes were dispensed into compound- containing plates using a MultidropTMCombi liquid dispenser (ThermoFisher). Enzymes were incubated with compounds for 45 minutes at room temperature before adding Ubiquitin-Rhodamine110 substrate (R&D systems, Cat# U-555) for a final concentration of 0.1 nM USP1-UAF1. Reaction proceeded for 45 minutes at room temperature before adding an acetic acid stop solution to a final concentration of 100 mM acetic acid. Assay was read on an Envision 2105 multimode plate reader (Perkin Elmer) with filters and mirrors for 485 nm excitation and 535 nm emission wavelengths. Percent inhibition was calculated using the following equation: % Inhibition = (FI – Cpos) / (Cpos-Cneg) * 100, where FI is the fluorescence intensity of wells treated with test compound. The compound concentration of compound leading to 50% inhibition of enzyme activity (IC50) was carried out by fitting a 4-parameter non-linear regression using GraphPad Prism. IC50s were measured in at least 3 independent experiments for each compound. Ubiquityl-PCNA Immunofluorescence Assay All cell lines used were obtained from ATCC. To measure ubiquityl-PCNA (Ub- PCNA) levels, the human colorectal cancer cell lines HCT-116 (CVCL_1724) were used. Cells were cultured in McCoy 5A media (ThermoFisher Cat# 16600082) supplemented with 10% fetal bovine serum (Cytiva Cat# SH30071.03IH25), 1x penicillin / streptomycin (ThermoFisher Cat# 15140122), 1x non-essential ammino acids (ThermoFisher Cat# 11140050), 2 mM GlutaMAX (ThermoFisher Cat# 35050079). Cells were cultured at 37 ºC in a humidified 5% CO2incubator. To seed cells for the assay, cells were trypsinized and resuspended in complete culture media to the desired concentration (60,000 cells / mL). Cell suspensions were seeded in 50 μL of complete culture media and onto 384-well black clear-bottom optical plastic plates (Greiner Bio-One Cat# 781097) using a MultidropTMCombi liquid dispenser in the slowest setting in triplicate. After 24 h, cells were treated with compounds in a 10-pt, 3.16 step serial dilution using an Echo acoustic liquid dispenser and incubated at 37 °C in a humidified 5% CO2incubator. 10 μM KSQ- 4279 (Cpos) and dimethyl sulfoxide (Cneg) were used as reference compounds. 6 h after compound treatments, cells were fixed in ice cold 100% methanol for 10 min, washed three times with PBS, with extreme care taken to prevent sample dehydration. Samples were blocked and further permeabilized in 1x PBS containing 10% goat serum and 0.1% triton X-100 for at least 30 min. After blocking and permeabilization, plates were evacuated to decant all media. Recombinant rabbit primary antibody against Ub-PCNA (Lys 164) (Cell Signaling Technology, Cat# #13439, clone D5C7P) in blocking / permeabilization solution was added to plates and incubated for 16 h at 4 °C. After 1° antibody incubation, plates were evacuated and decanted to remove all media. Blocking / permeabilization solution containing the DNA counterstain Hoechst, and a secondary antibody against rabbit (raised in goats) conjugated to a AlexaFluor 647 fluorophore (ThermoFisher Cat# A32728), were added to empty plates, and incubated for 30 min at 25 °C, in the dark. After 2° antibody incubation, plates were washed 5 times in PBS, and sealed with thermal foil seals. Sealed plates were imaged using an ImageXpress Micro slit confocal microscope (Molecular Devices) using a 40x water immersion objective, and 6 fields of views per well. Exposure parameters were optimized to prevent pixel saturation for each channel. Images were analyzed using MetaXpress Custom Module Editor, by using a Hoechst mask to identify nuclei, then measuring the average AlexaFluor 648 intensity across all nuclei in the FOV, background corrected, then averaged. Percent Ub-PCNA signal was calculated by using the following equation: %S = (T - Cpos) / (Cpos– Cneg) * 100, where %S is percent Ub-PCNA signal and T is the measured Ub- PCNA fluorescence of the wells treated with test compound, Cposand Cnegare reference compounds defined above. The effective compound concentration leading to a 50% induction of Ub-PCNA signal (EC50), and the resulting cell Ub-PCNA signal measured at the highest tested compound tested (cmax) was carried out by fitting a 4-parameter non-linear regression using GraphPad Prism. At least three biological replicates were done per compound tested. MDA-MB-436 Cell Viability Assay: The human breast cancer cell line MDA-MB-436 (ATCC cat. no. HTB-130) was used to assess the effect of compound treatment on cellular viability. The complete media for the cells was prepared by supplementing RPMI 1640 + GlutaMAX (Gibco cat. no. 61870-036) with 10% fetal bovine serum (Corning cat. no. 35-015-CV), and 1x penicillin / streptomycin (Gibco cat. no. 15140-122). The cells were maintained at 37°C / 5% CO2(similar incubation conditions were used throughout the experiment). For the Viability Assay, cells were resuspended in complete media at 6,250 cells / mL and seeded into 384-well, white, clear-bottom plates (ThermoFisher cat. no.142762) at 40 mL / well (250 cells / well). Following overnight incubation, cells were compound treated (10-pt 3.16 step serial dilution) and backfilled with dimethyl sulfoxide to a final concentration of 1% using an Echo acoustic liquid dispenser (Labcyte / Beckman Coulter). 10 mM KSQ-4279 (Cpos) and dimethyl sulfoxide (Cneg) were used as reference compounds. Eleven days post compound addition, viability was assessed by measuring cellular ATP concentrations. Briefly, an equivalent volume (40 mL / well) of CellTiter-Glo 2.0 reagent (Promega cat. no. G9241) was added and plates were mixed on a plate shaker (700rpm) for 2 minutes. Plates were then allowed to equilibrate for 10 minutes at room temperature before taking luminescence readings using an EnVision Multimode Plate Reader (Perkin Elmer). Percent inhibition of cell growth (%INH) was calculated by the following equation: %INH = 100 - ((RLUTC- RLUCpos) / ( RLUCpos– RLUCneg) * 100), where RLUTCis the measured luminescence of the wells treated with test compound, and RLUCposand RLUCnegthe measured luminescence of the positive and negative controls, respectively. The effective compound concentration leading to a 50% inhibition of cell growth (IC50) was determined by fitting %INH and compound concentration values to a 4-parameter non- linear regression equation (using GraphPad Prism or CDD). At least three biological replicates were done per compound tested. Table 3: Exemplary Compounds and Biological Data.

Claims

CLAIMS 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:wherein: X1and Y are independently selected from C, N, O and S; 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; 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; wherein R1is 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, 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; R2is selected from:R3is selected from H, -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, 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; and ring Ais 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 one or more groups selected from H, -OH, -NH2, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and 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 X1is C, Y is N, and R2iswhere S and P are N, ring A is 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 when X1is N, Y is C, and R2iswhere S and P are N, ring A is 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, C1-6 hydroxyalkyl, C1-6nitrile, and C1-6alkyl-epoxide.

2. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1, wherein X1and Y are independently selected from C, N, O and S.

3. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, 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.

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

5. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-4, 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, 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 moresubstituents selected from the group consisting of -OH, -COOH, -NH2, -CN, halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and C1-6hydroxyalkyl.

6. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 5, wherein R1is selected from:

7. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6, wherein R2is selected from:R3is selected from H, -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, 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, C2-6 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.

8. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, wherein R2is, Z is selected from C, O, N, and S; and R3is selected from H, -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.

9. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 8, wherein R2is selected from:

10. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, wherein R2is, the 5 and 6 membered ring are saturated or unsaturated; R3is selected from H, -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, N, O, 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, halogen, C1-6alkyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, 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:.

12. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, wherein R2is,the 5-membered ring is saturated or unsaturated; R3is selected from H, -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, N, O, 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:.

14. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-13, wherein X and Y are independently selected from C, N, O, or S; wherein ring Ais 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 -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 C1-6alkyl, C1-6nitrile, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, or C1-6hydroxyalkyl, and C1-6alkyl-epoxide; wherein the C1-6alkyl-epoxide can be optionally substituted with one or more C1-6alkyl.

15. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 14, wherein ring A is selected from:

16. The compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-15, wherein the compound is selected from:

17. 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 1-16.

18. 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 1-16.

19. 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 1-16.

20. 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 1-16.

21. 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 1-16, wherein the cancer is characterized by over expression ofUSPl.

22. The method according to claim 21, 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.

23. The use of a compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-16, in the manufacture of a medicament for the treatment of cancer.

24. The use according to claim 23, of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1-16, wherein the cancer is characterized by overexpression of USP1.

25. A process to manufacture a compound according to any one of claims 1-16, or a pharmaceutically acceptable salt thereof.

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