Condensed azines as inhibitors of cyclic ADP ribose hydrolase

Abstract

The disclosure provides compounds, in part, compounds of Formula (I) or Formula (II) and their use in treating medical diseases or disorders, such as neurodegenerative diseases, e.g., Parkinson's disease. Pharmaceutical compositions and methods of making compounds of the disclosure are provided. The compounds are contemplated to be modulators, e.g., inhibitors, of cyclic ADP ribose hydrolase (CD38).

Description

CONDENSED AZINES AS INHIBITORS OF CYCLIC ADP RIBOSE HYDROLASECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, U.S.S.N. 63 / 506,642, filed on June 7, 2023; and U.S.S.N. 63 / 561,950, filed on March 6, 2024; the content of each of which is incorporated herein by reference in its entirety.BACKGROUND

[0002] The glycoprotein CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase, is a multifunctional enzyme that, for example, catalyzes the degradation of nicotinamide adenine dinucleotide (NAD+) to adenosine diphosphate ribose (ADP ribose or ADPR). CD38 can also serve as a cyclase converting NAD+ to cyclic ADP- ribose (cADPR). Its NADase activity is more predominant than its function as an ADP- rybosyl-cyclase, being 100-fold less efficient in cyclizing NAD+ to cADPR than in hydrolzing NAD+ to ADP ribose. CD38 can also hydrolyze nicotinamide adenine dinucleotide phosphate (NADP) to nicotinic acid adenine dinucleotide phosphate (NAADP), both of which are derived from NAD+. Thus, CD38 is thought to be a significant consumer of NAD+ and a regulator of NAD+ levels.

[0003] Dysregulation of NAD+ levels is associated with a variety of disease states. For example, disease states associated with NAD+ depletion and disregulation in NAD+ related metabolites include, but are not limited to, e.g., obesity, diabetes, cancer, heart disease, asthma, and inflammation. Therefore, returning NAD+ to its normal level in disease states that consume significant amounts of NAD+ may result in therapeutic benefits.

[0004] For example, reduced NAD+ levels are associated with aging, and this age- related dysfunction may contribute to increased neurogeneration and the onset of neurodegenerative disorders. It is contemplated that expression of CD38, the enzyme responsible for NAD+ degradation, increases as a consequence of aging, thus providing a plausible rational for descreased NAD+ levels as a consequence of aging. As such, one approach to modulating cellular NAD+ levels may be inhibiting enzymes that consume NAD+, for example, CD38.

[0005] Inhibition of CD38 enzyme activity, which in turn modulates NAD+ tissue levels, presents a useful approach for the treatment of diseases associted with increased CD38 expression and / or decreased cellular NAD+ levels. Therefore, there is an ongoing need for small molecule inhibitors of CD38 in treating diseases or conditions responsive to modulation, e.g., inhibition, of cellular levels of NAD+. SUMMARY

[0006] The disclosure is directed, at least in part, to compounds that modulate, e.g., inhibit, the expression and / or activity of CD38. Also disclosed herein are pharmaceutical compositions comprising at least one disclosed compound and a pharmaceutically acceptable excipient.

[0007] For example, disclosed herein is a compound represented by Formula I:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: X1and X2are each independently selected from N and CH; Y is -C(O)-NRa- or -S(O)2-NRa-; R1is 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl; wherein R1may optionally be substituted by one or more substituents each independently selected from R11; R11is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, -CN, -CF3-NRaRb, - C(O)-NRaRb, -NRa-C(O)-Rb, and deuterium; wherein -C1-6alkyl and -C1-6alkoxy may optionally be substituted by one or more substituents each independently selected from hydroxyl, halogen, deuterium, and -C1-3alkoxy;Ring A is a 5-6 membered ring selected from the group consisting of phenyl, 5-6 membered carbocycle, and 5-6 membered heterocyclyl; and wherein ring A may optionally be substituted by one, two or three substituents each independently selected from RA; Ring B is selected from the group consisting of a 4-12 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic carbocycle, and a 5-7 membered heterocyclyl; wherein ring B may optionally be substituted by one, two or three substituents each independently selected from RB; RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, deuterium, -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, 5-6 membered heterocyclyl, -CN, -CF3-OC(O)-C1-6alkyl, -NRaRb, -C(O)-NRaRb, and -NRa-C(O)-Rb; wherein -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, and 5-6 membered heterocyclyl may optionally be substituted by one or more substituents each independently selected from hydroxyl, halogen, deuterium, and -C1-3alkoxy; RBis independently selected for each occurrence from the group consisting of halogen, hydroxyl, deuterium, -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, 5-6 membered heterocyclyl, -CN, -CF3, oxo, -OC(O)-C1-6alkyl, -NRaRb, -C(O)-NRaRb, and -NRa-C(O)-Rb; wherein -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, and 5-6 membered heterocyclyl may optionally be substituted by one or more substituents each independently selected from hydroxyl, halogen, oxo, deuterium, and -C1-3alkoxy; Raand Rbare each independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl, wherein C1-C6alkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1-C6alkoxy; or Raand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; p is 0, 1, or 2; and q is 01, or 2.

[0008] Also disclosed herein is a compound represented by Formula II:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: A is phenyl, cyclohexyl, cyclopentyl, or dihydrofuranyl; X1is N and X2is CH; or X1is N and X2is N; R1is 5-6 membered heteroaryl containing at least one ring nitrogen; wherein R1may optionally be substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, deuterium, -NH2, -C1-3alkyl, -C1-3alkyl-OH, and - C1-3alkoxy; R2is selected from the group consisting of halogen, hydroxyl, deuterium, -C1-6alkyl, - C1-6alkoxy, -C3-6cycloalkyl, phenyl, 5-6 membered heterocyclyl, -CN, -CF3, oxo, -OC(O)-C1-6alkyl, -NRaRb, -C(O)-NRaRb, and -NRa-C(O)-Rb; wherein -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, and 5-6 membered heterocyclyl may optionally be substituted by one or more substituents each independently selected from hydroxyl, halogen, oxo, deuterium, and - C1-3alkoxy; R3is selected from the group consisting of hydrogen, -CH3, and -CH2CH3; RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, deuterium, -C1-6alkyl, -C1-6alkoxy, -CN, and 5-6 membered heterocyclyl, wherein -C1-6alkyl and -C1-6alkoxy may optionally be substituted by one or more substituents each independently selected from hydroxyl, deuterium, and halogen; and p is 0, 1, 2, or 3.

[0009] Also disclosed herein is a method of treating a disease (e.g., a neurodegenerative disease) that benefits from inhibition of CD38 and / or an increase in NAD+ in a patient inneed thereof, comprising administering to the patient an effective amount of a disclosed CD38 inhibitor. In some embodiments, the neurodegenerative disease is, for example, Parkinson’s disease, Alzheimer’s disease, or Huntington’s disease. DETAILED DESCRIPTION

[0010] The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. Definitions

[0011] The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C1-6alkyl, C1-4alkyl, and C1-3alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1- butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

[0012] The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as C1-C5alkenyl, C2-C6alkenyl, and C3-C4alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

[0013] The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6, or 3-6 carbon atoms, referred to herein as C2-6alkynyl, and C3-6alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.

[0014] The term “alkoxy” as used herein refers to a straight or branched alkyl group attached to oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as C1-C5alkoxy, C1-C6alkoxy, and C2-C6alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.

[0015] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6–14aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Examples of representative substituted aryls include the followingwherein one of R56and R57may be hydrogen and at least one of R56and R57is each independently selected from C1-C8alkyl, C1-C8haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C1-C8alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR58COR59, NR58SOR59NR58SO2R59, COOalkyl, COOaryl, CONR58R59, CONR58OR59, NR58R59, SO2NR58R59, S-alkyl, SOalkyl, SO2alkyl, Saryl, SOaryl, SO2aryl; or R56and R57may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionallycontaining one or more heteroatoms selected from the group N, O, or S. R60and R61are each independently hydrogen, C1-C8alkyl, C1-C4haloalkyl, C3-C10cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, substituted C6-C10aryl, 5-10 membered heteroaryl, or substituted 5- 10 membered heteroaryl.

[0016] The term “carbonyl” as used herein refers to the radical -C(O)-.

[0017] The term “cyano” as used herein refers to the radical -CN.

[0018] The terms “cycloalkyl,” “carbocyle,” or a “carbocyclic group” as used herein refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3-6, or 4-6 carbons, referred to herein as C3-C10cycloalkyl, C3-6cycloalkyl or C4-6cycloalkyl, respectively. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl or cyclopropyl. The term may also be used to refer to 4-10 membered saturated or partially unsaturated ring structures that are bridged, fused or spirocyclic ring structures.

[0019] The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.

[0020] The terms “haloalkyl” as used herein refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl (i.e. CF3), difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like. Exemplary haloalkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms substituted with a halogen (i.e. Cl, F, Br and I), referred to herein as C1-6haloalkyl, C1-4haloalkyl, and C1-3haloalkyl, respectively.

[0021] The term “hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g,. heteroaryl, cycloalkenyl, e.g,. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0022] The terms “heteroaryl” or “heteroaromatic group” as used herein refers to an aromatic 5-10 membered ring system containing one or more heteroatoms, for example oneto three heteroatoms, such as nitrogen, oxygen, and sulfur. The term may also be used to refer to a 5-7 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl. Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, pyrrolopyridine, indole, thiazole, oxazole, isothiazole, isoxazole, imidazole, benzoimidazole, imidazopyridine, pyrazole, triazole, pyridine or pyrimidine, etc.

[0023] The terms “heterocyclyl,” “heterocycle,” or “heterocyclic group” are art- recognized and refer to saturated or partially unsaturated 4-10 membered ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen. The term may also be used to refer to 4-10 membered saturated or partially unsaturated ring structures that are bridged, fused or spirocyclic ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, dihydrofuran, dihydropyran, tetrahydropyran, etc. In some embodiments, the heterocycle is a spiro heterocycle (e.g., 2,8- diazaspiro[4.5]decane). In some embodiments, the heterocycle is a bridged heterocycle (e.g., octahydro-1H-4,7-methanoisoindole). "Spiro heterocyclyl," or “spiro heterocycle” refers to a polycyclic heterocyclyl with rings connected through one common atom (called a spiro atom), wherein the rings have one or more heteroatoms selected from the group consisting of N, O, and S(O)m(wherein m is an integer of 0 to 2) as ring atoms.

[0024] The terms “hydroxy” and “hydroxyl” as used herein refers to the radical -OH.

[0025] The term “oxo” as used herein refers to the radical =O.

[0026] “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.

[0027] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceuticaladministration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0028] The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0029] The term "pharmaceutically acceptable salt(s)" as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.

[0030] The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “ “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The present disclosure encompasses various stereoisomers of these compoundsand mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.

[0031] The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symbol denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.

[0032] Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers. Substituents around a carbocyclic or heterocyclic rings may also be referred to as “cis” or “trans”, where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis / trans.”

[0033] Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomerson chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations, and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0034] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.

[0035] The disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.

[0036] Certain isotopically-labeled disclosed compounds (e.g., those labeled with3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon-14 (i.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the disclosure can generally beprepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0037] The term “prodrug” refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al, Nature Reviews Drug Discovery 2008, 7, 255). For example, if a compound of the disclosure or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C1-8)alkyl, (C2-12)alkylcarbonyloxymethyl, 1- (alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkylcarbonyloxy)- ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C1-2)alkylamino(C2-3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C1-2)alkyl, N,N-di(C1-2)alkylcarbamoyl-(C1-2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-3)alkyl.

[0038] Similarly, if a compound of the disclosure contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C1-6)alkylcarbonyloxymethyl, 1-((C1-6)alkylcarbonyloxy)ethyl, 1-methyl-1-((C1-6)alkylcarbonyloxy)ethyl (C1-6)alkoxycarbonyloxymethyl, N-(C1-6)alkoxycarbonylaminomethyl, succinoyl, (C1-6)alkylcarbonyl, α-amino(C1-4)alkylcarbonyl, arylalkylcarbonyl and α-aminoalkylcarbonyl, or α-aminoalkylcarbonyl-α- aminoalkylcarbonyl, where each α-aminoalkylcarbonyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C1-6)alkyl)2or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

[0039] If a compound of the disclosure incorporates an amine functional group, a prodrug can be formed, for example, by creation of an amide or carbamate, an N-alkylcarbonyloxyalkyl derivative, an (oxodioxolenyl)methyl derivative, an N-Mannich base, imine or enamine. In addition, a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can metabolically cleaved to generate a bioactive primary or secondary amine. For examples, see Simplício, et al., Molecules 2008, 13, 519 and references therein.

[0040] The term “treatment” or “treating,” refers to the medical management of a patient with the intent to improve, ameliorate, stabilize (i.e., not worsen), prevent or cure a disease, pathological condition, or disorder. “Treatment” includes active treatment (treatment directed to improve the disease, pathological condition, or disorder), causal treatment (treatment directed to the cause of the associated disease, pathological condition, or disorder), palliative treatment (treatment designed for the relief of symptoms), preventative treatment (treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder); and supportive treatment (treatment employed to supplement another therapy). Treatment also includes diminishing the extent of the disease or condition; preventing spread of the disease or condition; delaying or slowing the progress of the disease or condition; ameliorating or palliating the disease or condition; and remission (whether partial or total), whether detectable or undetectable. “Ameliorating” or “palliating” a disease or condition means that the extent and / or undesirable clinical manifestations of the disease, disorder, or condition are lessened and / or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment. “Treatment” also includes prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.

[0041] The term “effective amount,” “therapeutically effective amount,” or “sufficient amount” refers to a quantity sufficient to, when administered to a patient (e.g., a mammal such as a human patient), effect treatment (e.g., produce beneficial or desired results), including effects at cellular, tissue or clinical levels, etc. As such, the term depends upon the context in which it is being applied. For example, in the context of treating a disclosed neurodegenerative disease, it is an amount of a disclosed CD38 inhibitor sufficient to achieve a response as compared to the response obtained without administration of the CD38 inhibitor. The amount of a given composition described herein that will correspond to such anamount will vary depending upon various factors, such as the given CD38 inhibitor, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the patient (e.g., age, sex, weight) or host being treated, and the like, but can nevertheless be routinely determined by one skilled in the art. In some embodiments, a “therapeutically effective amount” of a composition of the present disclosure is an amount that results in a beneficial or desired result in a patient (e.g., as compared to a control). A therapeutically effective amount of a composition of the present disclosure may be readily determined by one of ordinary skill by routine methods known in the art. Dosage regimen may be adjusted to provide the optimum therapeutic response.

[0042] “Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).

[0043] In some embodiments, the patient is a human. In some embodiments, the patient is an adult human patient. In some embodiments, the patient is 30 years of age or older, e.g., at least: 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or 90 years old. I. Compounds

[0044] The disclosure is directed to, in part, to compounds that are contemplated to be modulators, e.g., inhibitors, of CD38.

[0045] For example, disclosed herein is a compound represented by Formula I:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X1and X2are each independently selected from N and CH; Y is -C(O)-NRa- or -S(O)2-NRa-; R1is 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl; wherein R1may optionally be substituted by one or more substituents each independently selected from R11; R11is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, -CN, -CF3-NRaRb, - C(O)-NRaRb, -NRa-C(O)-Rb, and deuterium; wherein -C1-6alkyl and -C1-6alkoxy may optionally be substituted by one or more substituents each independently selected from hydroxyl, halogen, deuterium, and -C1-3alkoxy; Ring A is a 5-6 membered ring selected from the group consisting of phenyl, 5-6 membered carbocycle, and 5-6 membered heterocyclyl; and wherein ring A may optionally be substituted by one, two or three substituents each independently selected from RA; Ring B is selected from the group consisting of a 4-12 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic carbocycle, and a 5-7 membered heterocyclyl; wherein ring B may optionally be substituted by one, two or three substituents each independently selected from RB; RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, deuterium, -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, 5-6 membered heterocyclyl, -CN, -CF3-OC(O)-C1-6alkyl, -NRaRb, -C(O)-NRaRb, and -NRa-C(O)-Rb; wherein -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, and 5-6 membered heterocyclyl may optionally be substituted by one or more substituents each independently selected from hydroxyl, halogen, deuterium, and -C1-3alkoxy; RBis independently selected for each occurrence from the group consisting of halogen, hydroxyl, deuterium, -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, 5-6 membered heterocyclyl, -CN, -CF3, oxo, -OC(O)-C1-6alkyl, -NRaRb, -C(O)-NRaRb, and -NRa-C(O)-Rb; wherein -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, and 5-6 membered heterocyclyl may optionally be substituted by one or more substituents each independently selected from hydroxyl, halogen, oxo, deuterium, and -C1-3alkoxy;Raand Rbare each independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl, wherein C1-C6alkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1-C6alkoxy; or Raand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; p is 0, 1, or 2; and q is 01, or 2.

[0046] In some embodiments, a compound disclosed herein is represented by Formula 1A:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: X1and X2are each independently selected from N and CH; Y is -C(O)-NRa- or -S(O)2-NRa-; R1is 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl; wherein R1may optionally be substituted by one or more substituents each independently selected from R11; R11is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, -CN, -CF3-NRaRb, - C(O)-NRaRb, -NRa-C(O)-Rb, and deuterium; wherein -C1-6alkyl and -C1-6alkoxy may optionally be substituted by one or more substituents each independently selected from hydroxyl, halogen, deuterium, and -C1-3alkoxy;Ring A is a 5-6 membered ring selected from the group consisting of phenyl, 5-6 membered carbocycle, and 5-6 membered heterocyclyl; and wherein ring A may optionally be substituted by one, two or three substituents each independently selected from RA; RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, deuterium, -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, 5-6 membered heterocyclyl, -CN, -CF3-OC(O)-C1-6alkyl, -NRaRb, -C(O)-NRaRb, and -NRa-C(O)-Rb; wherein -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, and 5-6 membered heterocyclyl may optionally be substituted by one or more substituents each independently selected from hydroxyl, halogen, deuterium, and -C1-3alkoxy; R2is selected from the group consisting of halogen, hydroxyl, deuterium, -C1-6alkyl, - C1-6alkoxy, -C3-6cycloalkyl, phenyl, 5-6 membered heterocyclyl, -CN, -CF3, oxo, -OC(O)-C1-6alkyl, -NRaRb, -C(O)-NRaRb, and -NRa-C(O)-Rb; wherein -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, and 5-6 membered heterocyclyl may optionally be substituted by one or more substituents each independently selected from hydroxyl, halogen, oxo, deuterium, and - C1-3alkoxy; R3is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, - C1-6alkyl, -C1-6alkoxy, -CN, -NRaRb, -C(O)-NRaRb, and -NRa-C(O)-Rb; R4and R5are each independently selected from the group consisting of hydrogen and -C1-3alkyl optionally substituted by one or more halogens; Raand Rbare each independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl, wherein C1-C6alkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1-C6alkoxy; or Raand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; m is 1 or 2; n is 1, 2, or 3; andp is 0, 1, 2, or 3.

[0047] In some embodiments, m and n are each 2, or m and n are each 1. In other embodiments, a compound of the present disclosure is represented by, for example:

[0048] In some embodiments, Y is -C(O)-NH-. In other embodiments, a compound of the present disclosure is represented by, for example:

[0049] In some embodiments, X1is N and X2is CH. In other embodiments, X1is CH and X2is N. In still other embodiments, X1is N and X2is N. In further embodiments, X1is CH and X2is CH.

[0050] In some embodiments, R1is a 5-6 membered heteroaryl containing at least one ring nitrogen, wherein R1may optionally be substituted by one or two substituents each independently selected from R11. In other embodiments, R1is selected from the group consisting of, for example, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, and pyridyl, wherein R1may optionally be substituted by one or two substituents each independently selected from the group consisting of -CH2OH, -OH and -NH2. For example, in certain embodiments R1is selected from the group consisting of.

[0053] In some embodiments, p is 1 and RAis selected from the group consisting of - CN, -CH2OH, -OC(O)CH3, morpholino, fluoro, chloro, and bromo. In other embodiments, wherein p is 0. In further embodiments, R3and R5are, for each occurrence, hydrogen. In certain embodiments, R4is selected from the group consisting of hydrogen, -CH3, and - CH2CH3.

[0054] Also disclosed herein is a compound represented by Formula II:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: A is phenyl, cyclohexyl, cyclopentyl, or dihydrofuranyl; X1is N and X2is CH; or X1is N and X2is N; R1is 5-6 membered heteroaryl containing at least one ring nitrogen; wherein R1may optionally be substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, deuterium, -NH2, -C1-3alkyl, -C1-3alkyl-OH, and - C1-3alkoxy; R2is selected from the group consisting of halogen, hydroxyl, deuterium, -C1-6alkyl, - C1-6alkoxy, -C3-6cycloalkyl, phenyl, 5-6 membered heterocyclyl, -CN, -CF3, oxo, -OC(O)-C1-6alkyl, -NRaRb, -C(O)-NRaRb, and -NRa-C(O)-Rb; wherein -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, and 5-6 membered heterocyclyl may optionally be substituted by one or more substituents each independently selected from hydroxyl, halogen, oxo, deuterium, and - C1-3alkoxy; R3is selected from the group consisting of hydrogen, -CH3, and -CH2CH3; RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, deuterium, -C1-6alkyl, -C1-6alkoxy, -CN, and 5-6 membered heterocyclyl, wherein -C1-6alkyl and -C1-6alkoxy may optionally be substituted by one or more substituents each independently selected from hydroxyl, deuterium, and halogen; and p is 0, 1, 2, or 3.

[0055] For example, in some embodiments a compound of the present disclosure is represented by:.

[0058] In further embodiments, p is 1 and RAis selected from the group consisting of - CN, -CH2OH, morpholino, fluoro, chloro, and bromo. In certain embodiments, p is 0.

[0059] In some embodiments, the compound is a compound identified in Table 1 below, or a pharmaceutically acceptable salt thereof. Table 1. Exemplary compounds.

[0060] Procedures for making compounds described herein are provided in the examples below. In the reactions described below, it may be necessary to protect reactive functional groups (such as hydroxyl, amino, thio or carboxyl groups) to avoid their unwanted participation in the reactions. The incorporation of such groups, and the methods required to introduce and remove them are known to those skilled in the art (for example, see Greene, Wuts, Protective Groups in Organic Synthesis.2nd Ed. (1999)). The deprotection step may be the final step in the synthesis such that the removal of protecting groups affords compounds as disclosed herein. Starting materials used in the following scheme can be purchased or prepared by methods described in the chemical literature, or by adaptations thereof, using methods known by those skilled in the art. The order in which the steps are performed can vary depending on the groups introduced and the reagents used, but would be apparent to those skilled in the art.

[0061] Compounds disclosed herein, or any of the intermediates described in the schemes above, can be further derivatised by using one or more standard synthetic methods known to those skilled in the art. Such methods can involve substitution, oxidation or reduction reactions. These methods can also be used to obtain or modify dislosed compounds or any preceding intermediates by modifying, introducing or removing appropriate functional groups.

[0062] Where it is desired to obtain a particular enantiomer of a dislosed compound, this may be produced from a corresponding mixture of enantiomers by employing any suitable conventional procedure for resolving enantiomers known to those skilled in the art. For example, diastereomeric derivatives (such as salts) can be produced by reaction of a mixture of enantiomers of a dislosed compound (such a racemate) and an appropriate chiral compound (such as a chiral base). The diastereomers can then be separated by any conventional means such as crystallization or chromatography, and the desired enantiomer recovered (such as by treatment with an acid in the instance where the diastereomer is a salt).Alternatively, a racemic mixture of esters can be resolved by kinetic hydrolysis using a variety of biocatalysts (for example, see Patel Stereoselective Biocatalysts, Marcel Decker; New York 2000).

[0063] In another resolution process a racemate of dislosed compounds can be separated using chiral High Performance Liquid Chromatography. Alternatively, a particular enantiomer can be obtained by using an appropriate chiral intermediate in one of the processes described above. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the disclosure.

[0064] In an alternative embodiment, dislosed compounds may also comprise one or more isotopic substitutions. For example, hydrogen may be2H (D or deuterium) or3H (T or tritium); carbon may be, for example,13C or14C; oxygen may be, for example,18O; nitrogen may be, for example,15N, and the like. In other embodiments, a particular isotope (e.g.,3H,13C,14C,18O, or15N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound. II. Methods

[0065] Compounds of the present disclosure are contemplated to inhibit the activity of CD38. For example, provided herein is a method inhibiting the activity or a function of CD38 in a cell or in a patient in need of inhibition of CD38, comprising administering to the cell or patient an effective amount of a compound disclosed herein, e.g., a compound of Formula I or Formula II. Also disclosed herein, for example, is a method of treating a disease that benefits from inhibition of CD38 in a patient in need thereof, comprising administering to the patient an effective amount of a CD38 inhibitor described herein, thereby treating the disease in the patient.

[0066] Compounds of the present disclosure are contemplated to increase levels of NAD+. For example, provided herein is a method of increasing the level of NAD+ in a sample or in a patient in need thereof, comprising contacting the sample or administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of FormulaI or Formula II, wherein the increased level of NAD+ is relative to the level of NAD+ prior to the contacting or administering. Further disclosed herein is a method of treating a disease that benefits from an increase in NAD+ in a patient in need thereof, comprising administering to the patient an effective amount of a CD38 inhibtior described herein, e.g., a compound of Formula I or Formula II, thereby treating the disease in the patient.

[0067] Compounds of the present disclosure may be useful in the treatment of diseases associated with abnormal expression or activity of CD38. For example, the present disclosure provides a method of treating a cancer in a patient in need thereof, comprising administering to the patient an effective amount of a CD38 inhibitor described herein, e.g., a compound of Formula I or Formula II, thereby treating the cancer in the patient. In some embodiments, the cancer is characterized as having abnormal expression or activity of CD38, for example, elevated expression or activity, compared with normal cells. In other embodiments, the cancer may be selected from the group consisting of, for example, cancer of the breast, central nervous system, endometrium, kidney, large intestine, lung, esophagus, ovary, pancreas, prostate, stomach, head and neck, urinary tract, and colon. In some embodiments, the cancer is lung cancer. In other embodiments, the cancer is melanoma, In certain embodiments, the cancer is colon cancer. In still other embodiments, the cancer may be leukemia or lymphoma. Examples of lymphomas contemplated herein include, but are not limited to, Hodgkin’s or non-Hodgkin’s lymphoma, multiple myeloma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), chronic lymphocytic lymphoma (CLL), T- cell lymphoma, hairy cell lymphoma, and Burkett's lymphoma. Examples of leukemias contemplated herein include, but are not limited to, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML). In further embodiments, the cancer may be selected from the group consisting of, for example, checkpoint-therapy treated cancers, checkpoint therapy- treated resistant cancers, adenosine-dependent tumors, Treg-infiltrated tumors, and MDSC- infiltrated tumors.

[0068] For example, contemplated cancers of the present disclosure treatable by administration of the compounds described herein may be selected from the group consisting of bladder cancer, bone cancer, glioma, breast cancer, cervical cancer, colon cancer, endometrial cancer, epithelial cancer, esophageal cancer, Ewing's sarcoma, pancreatic cancer, gallbladder cancer, gastric cancer, gastrointestinal tumors, glioma, head and neck cancer(upper aerodigestive cancer), intestinal cancers, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, adenocarcinoma), melanoma, prostate cancer, rectal cancer, renal clear cell carcinoma, skin cancer, stomach cancer, testicular cancer, thyroid cancer, and uterine cancer. In some embodiments, contemplated cancers of the present disclosure treatable by administration of the compounds described herein may be selected from the group consisting of multiple myeloma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, bladder cancer, esophageal cancer, head and neck cancer (upper aerodigestive cancer), kidney cancer, prostate cancer, rectal cancer, stomach cancer, thyroid cancer, uterine cancer, and breast cancer.

[0069] Also provided herein are methods of treating a condition or disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula I or Formula II. In some embodiments, the disease or condition is selected from the group consisting of HIV / AIDS, acute lung injury, acute respiratory distress syndrome (ARDS), hyperphosphatemia, alcohol intolerance, lupus, rheumatoid arthritis ataxia-telangiectasia, sleep disorders, epilepsy, exercise intolerance, hypertension, hypoxic pulmonary vasoconstriction, hansen's disease, tuberculosis, leishmaniasis, cardiac hypertrophy, congestive heart failure (CHF), muscular dystrophy, stroke, organ reperfusion injury, idiopathic pulmonary fibrosis, pancreatitis, cystic fibrosis, asthma, chronic obstructive pulmonary disease (COPD), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), colitis, gout, obesity, sarcopenic obesity, end stage renal disease, dyslipidemia, hearing loss, liver disease, steatosis, nonalcoholic steatohepatitis (NASH / NAFLD), Alzheimer's disease, multiple sclerosis, neurocognitive disorders, optic neuropathy, postmenopausal osteoporosis, bipolar disorder, schizophrenia, Huntington's disease, diabetes, Hartnup disease, skin hyperpigmentation, diabetic neuropathy, radiation exposure, UV skin damage, psoriasis, periodontal disease, chronic lymphocytic leukemia, amyelotrophic lateral sclerosis, Parkinson's disease, Huntington’s disease, Leber's hereditary amaurosisinsulin resistance, type I diabetes, and type II diabetes.

[0070] The compounds describe herein are contempated to have have therapeutic utility in CD38-related disorders in disease areas such as, for example, cardiology, virology, neurodegeneration, inflammation, and pain, wherein the diseases are characterized by overexpression or increased activity of CD38.

[0071] Another aspect of the disclosure provides methods of treating patients suffering from a neurodegenerative disease or disorder, e.g., Parkinson’s disease. As used herein, the term “neurodegenerative disease” or “neurodegenerative disorder” encompasses a disease, disorder or condition in which cells of the central nervous system stop working or die. Neurodegenerative diseases usually get worse over time and have no cure. Such diseases may be genetic or be caused by a tumor or stroke. Neurodegenerative diseases also occur in people who consume large amounts of alcohol or are exposed to certain viruses or toxins. Non- limiting examples of neurodegenerative disorders include Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), multiple sclerosis (MS), multiple system atrophy (MSA), a prion disease, spinocerebellar ataxias (SCAs), vascular dementia, frontotemporal dementia (FTD), mixed dementia, and dementia with Lewy bodies (LBD). In some embodiments, the neurodegenerative disease is a late onset disease. In other embodiments, the disclosure provides methods of treating patients suffering from neuroinflammation.

[0072] In some embodiments, the neurodegenerative disease affects basal ganglia, thalamus, red nucleus, locus coeruleus, parahippocampal gyrus, or a combination thereof. In some embodiments, the neurodegenerative disease affects basal ganglia and / or thalamus.

[0073] In some embodiments, the neurodegenerative disease is ALS, HD, PD or SCAs. In particular embodiments, the neurodegenerative disease is PD. In certain embodiments, the PD is familial Parkinson's disease.

[0074] A patient to be treated according to the methods described herein may be one who has been diagnosed with a neurodegenerative disease (e.g., PD), or one at risk of developing such a disease. Diagnosis of a neurodegenerative disease or risk of developing a neurodegenerative disease may be performed by a skilled medical professional using any suitable method or technique known in the art. One skilled in the art will understand that a patient to be treated according to the present disclosure may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with the disease or condition.

[0075] In some embodiments, the patient has a neurodegenerative disease (e.g., PD). In some embodiments, the patient has been diagnosed with a neurodegenerative disease (e.g.,PD). In other embodiments, the patient is at risk of developing a neurodegenerative disease (e.g., PD). In some embodiments, the patient has or is at risk of developing PD.

[0076] For example, the disclosure provides a method of treating a neurodegenerative disease in a patient in need thereof, comprising administering to the patient an effective amount of a CD38 inhibitor described herein, e.g., a compound of Formula I or Formula II, thereby treating the neurodegenerative disease in the patient. In some embodiments, the neurodegenerative disease is, for example, Parkinson’s disease, Alzheimer’s disease, or Huntington’s disease.

[0077] Also disclosed herein is a method of slowing the progression of Parkinson’s disease in a patient in need thereof, comprising administering to the patient an effective amount of any of the compounds described herein, e.g., a compound of Formula I or Formula II, or a pharmaceutical composition comprising any of the compounds described herein, and a pharmaceutically acceptable carrier of excipient.

[0078] Also contemplated is a neurodegenerative disease that is an ocular disease or disorder comprising administering an effective amount of a disclosed CD38 inhibitor, e.g., a compound of Formula I or Formula II. For example, provided herein is a method of treating an ocular disorder such as one or more of: macular degeneration (e.g., age-related macular degeneration (AMD) or dry macular degeneration), diabetic macular edema (DME), diabetic retinopathy, glaucoma, cataracts, retinitis pigmentosa (RP), Stargardt disease, myopic macular degeneration (MMD), sub-macula hemorrhage, diabetic macular edema (DME), or uveitis.

[0079] Another aspect of the disclosure provides methods of treating patients suffering from a fatty liver disease or disorder, e.g., NAFLD or NASH. As used herein, the term “fatty liver disease” encompasses a disease, disorder or condition caused by the storage of extra fat in the liver. Alcoholic fatty liver is the accumulation of fat in the liver as a result of heavy consumption of alcohol. Nonalcoholic fatty liver disease (NAFLD) occurs in people who are not heavy alcohol consumers.

[0080] In some embodiments, the fatty liver disease is NAFLD. NAFLD is the spectrum of liver disease in which hepatic steatosis, the macrovesicular accumulation of triglyceride in hepatocytes, develops in the absence of secondary causes (e.g., medications, excessive alcohol consumption, or certain heritable conditions). In some embodiments, theNAFLD is simple hepatic steatosis (NAFL). In particular embodiments, the NAFLD is nonalcoholic steatohepatitis (NASH). NASH is the inflammatory subtype of NAFLD, with steatosis as well as evidence of hepatocyte injury (ballooning) and inflammation, with or without fibrosis.

[0081] A patient to be treated according to the methods described herein may be one who has been diagnosed with a fatty liver disease (e.g., NAFLD), or one at risk of developing such a disease. Diagnosis of a fatty liver disease or risk of developing a fatty liver disease may be performed by a skilled medical professional using any suitable method or technique known in the art. One skilled in the art will understand that a subject to be treated according to the present disclosure may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with the disease or condition.

[0082] In some embodiments, the patient has a fatty liver disease (e.g., NAFLD such as NASH). In some embodiments, the patient has been diagnosed with a fatty liver disease (e.g., NAFLD such as NASH). In other embodiments, the patient is at risk of developing a fatty liver disease (e.g., NAFLD such as NASH). In some embodiments, the patient has or is at risk of developing NAFLD. In some embodiments, the patient has or is at risk of developing NASH.

[0083] In some embodiments, the patient has NAFLD (e.g., NASH). In some embodiments, the patient also has hypertriglyceridemia, obesity, dyslipidemia, metabolic syndrome, hypertension, or type 2 diabetes, or a combination thereof.

[0084] For example, the disclosure provides a method of treating a metabolic disease in a patient in need thereof, comprising administering to the patient an effective amount of a CD38 inhibitor described herein, e.g., a compound of Formula I or Formula II, thereby treating the metabolic disease in the patient. In some embodiments, the metabolic disease is selected from the groups consisting of, for example, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and diabetes (type I or type II).

[0085] In another embodiment, the disclosure provides a method of inhibiting or slowing progression of a fatty liver disease, such as NAFLD (e.g., NASH), in a patient in need thereof, comprising administering to the patient an effective amount of a compounddisclosed herein, e.g., a compound of Formula I or Formula II, thereby inhibiting or slowing progression of the fatty liver disease in the patient.

[0086] In certain embodiments, the disclosure provides a method of treating the below medical indications comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein.

[0087] For example, disclosed herein is a method of treating neurodegenerative disease in patient in need thereof, comprising administering to the patient an effective amount of any of the compounds described herein, e.g., a compound of Formula I or Formula II, or a pharmaceutical composition comprising any of the compounds described herein, and a pharmaceutically acceptable carrier of excipient. In some embodiments, the neurodegenerative disease is Parkinson’s disease.

[0088] Also disclosed herein is a method of treating neuroinflammation in a patient in need thereof, comprising administering to the patient an effective amount of any of the compounds described herein, e.g., a compound of Formula I or Formula II, or a pharmaceutical composition comprising any of the compounds described herein, and a pharmaceutically acceptable carrier of excipient.

[0089] Further disclosed herein is a method of treating a fatty liver disease in a patient in need thereof, comprising administering to the patient an effective amount of any of the compounds described herein, e.g., a compound of Formula I or Formula II, or a pharmaceutical composition comprising any of the compounds described herein, and a pharmaceutically acceptable carrier of excipient. In some embodiments, the fatty liver disease is nonalcoholic fatty liver disease (NAFLD). In other embodiments, the fatty liver disease is nonalcoholic steatohepatitis (NASH). In further embodiments, the the fatty liver disease is simple hepatic steatosis. In certain embodiments, treating the fatty liver disease includes slowing progression of the fatty liver disease.

[0090] In addition, disclosed herein is a method of treating fibrosis in a patient in need thereof, comprising administering to the patient an effective amount of any of the compounds described herein, e.g., a compound of Formula I or Formula II, or a pharmaceutical composition comprising any of the compounds described herein, and a pharmaceutically acceptable carrier of excipient. In some embodiments, the fibrosis is multiple organ fibrosis. In other embodiments, the fibrosis is associated with sytemic sclerosis. For example, thepatient suffering from fibrosis also suffers from systemic sclerosis. In still other embodiments, the fibrosis is selected from the group consisting of skin fibrosis, lung fibrosis, and peritoneal fibrosis.

[0091] In certain embodiments, a method described herein further comprises administering to the patient an additional therapeutic agent that treats a disclosed disease or disorder, or that treats a disclosed disease or disorder that is affected by, associated with, or would benefit from selective modulation, e.g., inhibition, of CD38.

[0092] Compounds described herein can be administered in combination with one or more additional therapeutic agents to treat a disorder described herein. For clarity, contemplated herein are both a fixed composition comprising a disclosed compound and another therapeutic agent such as disclosed herein, and methods of administering, separately a disclosed compound and a disclosed therapeutic. For example, provided in the present disclosure is a pharmaceutical composition comprising a compound described herein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient. In some embodiments, a dislosed compound and one additional therapeutic agent is administered. In some embodiments, a disclosed compound as defined herein and two additional therapeutic agents are administered. In some embodiments, a disclosed compound as defined herein and three additional therapeutic agents are administered.

[0093] For example, in some embodiments the additional agent is NAD+ or a NAD+ precursor. Examples of contemplated NAD+ precursors may include, but are not limited to, e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, vitamin B3, and NAAD. In some embodiments, a NAD+ precursor is vitamin B3. In some embodiments, a NAD+ precursor is a form of vitamin B3. In some embodiments, a NAD+ precursor is nicotinamide riboside (NR), also known as 1-(β-D-ribofuranosyl)nicotinamide or N-ribosylnicotinamide. In some embodiments, a NAD+ precursor is nicotinic acid (NA), also known as niacin. In some embodiments, a NAD+ precursor is nicotinic acid riboside (NaR). In some embodiments a NAD+ precursor is nicotinamide (NAM), also known as 3-pyridinecarboxamide, niacinamide, nicotinic acid amide, or nicotinic amide . In some embodiments, a NAD+ precursor is nicotinamide mononucleotide (NMN), also known as, nicotinamide ribonucleoside 5'-phosphate, nicotinamide D-ribonucleotide, β -nicotinamide ribose monophosphate, or nicotinamide nucleotide. In some embodiments, a NAD+ precursor is nicotinic acid mononucleotide (NaMN). In some embodiments, a NAD+ precursor istryptophan (TRP), also known as (2S)-2-amino-3-(1H-indol-3-yl)propanoic acid or 2-amino- 3-(lH-indol-3-yl)propanoic acid. In some embodiments, a NAD+ precursor is deamido- NAD+, also known as dearnido-NAD, deamino-NAD+, or nicotinic acid adenine dinucleotide (NAAD). In some embodiments, a NAD+ precursor is nicotinic acid riboside, O-ethylnicotinate riboside, or O-methylnicotinate riboside. In some embodiments, a NAD+ precursor is β-nicotinamide riboside. In some embodiments, a NAD+ precursor is a nicotinate ester nucleoside derivative. In some embodiments, a NAD+ precursor is a triacetyl-O-ethylnicotinate riboside.

[0094] For example, provided herein is a pharmaceutical composition comprising a compound disclosed herein, e.g., a compound of Formula I or Formula II, NAD+ or a disclosed NAD+ precursor, and a pharmaceutally acceptable excipient. Provided herein, for example, is a method of treating a disease or disorder contemplated herein in a patient in need thereof, comprising administering to the patient a compound disclosed herein, e.g., a compound of Formula I or Formula II, and an NAD+ precursor. Also provided herein is a method of treating a disease or disorder contemplated herein in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound disclosed herein, e.g., a compound of Formula I or Formula II, NAD+ or a disclosed NAD+ precursor, and a pharmaceutally acceptable excipient.

[0095] Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately. For example, a dislosed compound and an additional therapeutic agent can be formulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, for example a pharmaceutical composition comprising a dislosed compound as one therapeutic agent and one or more additional therapeutic agents. For example, a dislosed compound and an additional therapeutic agent can be administered in a single formulation. Other combinations are also encompassed by combination therapy. While the two or more agents in the combination therapy can be administered simultaneously, they need not be. For example, administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, orweeks of each other. In some cases even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present in within the patient's body at the same time, this need not be so.

[0096] Combination therapy can also include two or more administrations of one or more of the agents used in the combination using different sequencing of the component agents. For example, if agent X and agent Y are used in a combination, one could administer them sequentially in any combination one or more times, e.g., in the order X-Y-X, X-X-Y, Y- X-Y, Y-Y-X, X-X-Y-Y, etc.

[0097] In particular, in certain embodiments, the disclosure provides a method of treating the above medical indications comprising administering a patient in need thereof a therapeutically effective amount of a compound described herein, e.g., a compound of Formula I or Formula II. III. Pharmaceutical Compositions and Kits

[0098] Another aspect of the disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with a pharmaceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, intranasal, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions may be formulated as a unit dose, and / or may be formulated for oral or subcutaneous administration.

[0099] Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compound of the disclosure, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non- toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active objectcompound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease. [000100] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the disclosure, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. [000101] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. [000102] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitablemachine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. [000103] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof. [000104] Suspensions, in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. [000105] Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent. [000106] Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required. [000107] The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch,tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. [000108] Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. [000109] Compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions. [000110] Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. [000111] Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity may be maintained, for example, by the use of coatingmaterials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. [000112] In another aspect, the disclosure provides enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5. Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate- chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e. g. , Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or is readily determinable in vitro. The foregoing is a list of possible materials, but one of skill in the art with the benefit of the disclosure would recognize that it is not comprehensive and that there are other enteric materials that would meet the objectives of the present disclosure. [000113] Advantageously, the disclosure also provides kits for use by a e.g. a consumer in need of treatment of a disease or disorder described herein. Such kits include a suitabledosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent inflammation. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art. Such kits could advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.[000114] It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . “ etc. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.EXAMPLES[000115] The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard forthat reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials. At least some of the compounds used as intermediates are contemplated as compounds of the disclosure.General MethodsReverse phase flash chromatography: Method i : Cl 8 silica; gel column; mobile phase, MeCN in water (0.1% formic acid); detector, UV 254 nm. Method 2 C18 silica gel column; mobile phase, MeCN in Water (lOmmol / L NH4HCO3), detector, UV 254 nm.Prep-HPLC: Method 3: XBridge Prep C18 OBD Column, 19*150 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: MeOH— HPLC; Flow rate: 25 mL / min; Wave Length: 254 / 220 nm. Method 4: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: MeOH— HPLC; Flow rate: 60 mL / min; Wave Length: 254 / 220 nm. Method 5: YMC-Actus Triart C18 ExRS, 30*150 mm, 5pm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Wave Length: 254 / 220 nm. Method 6: Sunfire Prep C18 OBD Column, 30*100 mm, 5pm; Mobile Phase A: Water(0.1% formic acid), Mobile Phase B: ACN; Flow rate: 60 mL / min; Wave Length: 254 / 220 nm. Method 7: XSelect CSH Prep C18 OBD Column, 30*150 mm, 5 pm; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 60 mL / min; Wave Length: 254 nm / 220 nm. Method 8: XBridge Shield RP18 OBD Column 30*150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Wave Length: 254 nm / 220 nm. Method 9: XBridge Prep Phenyl OBD Column 19*250 mm, 5 pm; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 60 mL / min; Wave Length: 254 nm / 220 nm. Method 10: XBridge Prep Phenyl OBD Column 19*250 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min.Example 1: Synthesis of 2-(imidazol-l-yl)-A-[(trans)-4-methoxycyclohexyl]quinoline-4- carboxamide (Compound 121)[000116] To a mixture of 2-chloroquinoline-4-carboxylic acid (500 mg, 2.408 mmol, 1 equiv) and trans-4-methoxycyclohexan-1-amine (934 mg, 7.224 mmol, 3 equiv) in DMF (50 mL) were added DIEA (1.56 g, 12.040 mmol, 5 equiv) and HATU (1.83 g, 4.816 mmol, 2 equiv) in portions at 0 °C under air atmosphere. The mixture was stirred for 1 h at room temperature and then diluted with water (500 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL), the organic phase was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (method 1) to afford desired product 2-chloro-N-[(trans)-4- methoxycyclohexyl]quinoline-4-carboxamide (520 mg, 67.73%) as a white solid . [000117] A mixture of 2-chloro-N-[(trans)-4-methoxycyclohexyl]quinoline-4- carboxamide (250 m g, 0.784 mmol, 1.00 equiv), imidazole (267 mg, 3.920 mmol, 5 equiv), CuI (299 mg, 1.568 mmol, 2 equiv) and K2CO3(325 mg, 2.352 mmol, 3 equiv) in DMF (5 mL) was stirred for 2 days at 120 °C under nitrogen atmosphere. The mixture was washed with 3x10 mL of MeOH and the resulting solution was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (method 1) to afford 2- (imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (46.1 mg, 16.78%) as a white solid. LCMS (ESI) [M+H]+: 351.15.1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J = 10.5 Hz, 2H), 8.19 (d, J = 1.5 Hz, 1H), 8.12 – 7.99 (m, 3H), 7.89 – 7.82 (m, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.20 (s, 1H), 3.99 – 3.72 (m, 1H), 3.25 (s, 3H), 3.20 – 3.05 (m, 1H), 2.21 – 1.98 (m, 4H), 1.42 – 1.22 (m, 4H). Example 2: Synthesis of N-[(trans)-4-methoxycyclohexyl]-2-(1,3-thiazol-5-yl)quinoline- 4-carboxamide (Compound 120)[000118] To a mixture of 2-chloroquinoline-4-carboxylic acid (500 mg, 2.408 mmol, 1 equiv) and trans-4-methoxycyclohexan-1-amine (934 mg, 7.224 mmol, 3 equiv) in DMF (10 mL) were added DIEA (1.56 g, 12.040 mmol, 5 equiv) and HATU (1.83 g, 4.816 mmol, 2 equiv) in portions at 0 °C under air atmosphere. The mixture was stirred for 1 h at room temperature and then diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL), and the organic phase dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (method 1) to afford 2-chloro-N-[(trans)-4- methoxycyclohexyl]quinoline-4-carboxamide (520 mg, 67.73%) as a white solid. [000119] A mixture of 2-chloro-N-[(trans)-4-methoxycyclohexyl]quinoline-4- carboxamide (250 mg, 0.784 mmol, 1 equiv), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1,3-thiazole (166 mg, 0.784 mmol, 1 equiv), Pd(dppf)Cl2(57 mg, 0.078 mmol, 0.1 equiv) and K2CO3(325 mg, 2.352 mmol, 3 equiv) in dioxane (5 mL) and H2O (1.25 mL) was stirred for 1 h at 90 °C under nitrogen atmosphere. The resulting mixture was filtered; the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase flash chromatography (method 1) to afford N- [(trans)-4-methoxycyclohexyl]-2-(1,3-thiazol-5-yl)quinoline-4-carboxamide (40.3 mg, 13.98%) as a white solid. LCMS (ESI) [M+H]+: 368.15.1H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.88 (s, 1H), 8.75 (d, J = 7.7 Hz, 1H), 8.17 (s, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.91 – 7.78 (m, 1H), 7.78 – 7.45 (m, 1H), 3.95 – 3.82 (m, 1H), 3.25 (s, 3H), 3.20 – 3.04 (m, 1H), 2.13 – 1.97 (m, 4H), 1.45 – 1.22 (m, 4H). Example 3: Synthesis of N-[(1r,4r)-4-(2-methoxyethoxy)cyclohexyl]-2-(1,3-thiazol-5-yl) quinoline-4-carboxamide (Compound 116)[000120] To a stirred solution of methyl 2-bromoquinoline-4-carboxylate (200 mg, 0.752 mmol, 1 equiv) in the mixture of 1,4-dioxane (10 mL) and H2O (2 mL) were added 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (190 mg, 0.902 mmol, 1.2 equiv), Pd(dppf)Cl2(55 mg, 0.075 mmol, 0.1 equiv) and K2CO3(311 mg, 2.256 mmol, 3 equiv) in portions at room temperature. The mixture was stirred for 2 h at80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 2-(1,3-thiazol-5-yl)quinoline-4-carboxylate (120 mg, 59.06%) as a brown solid. [000121] A mixture of LiOH (44 mg, 1.850 mmol, 5 equiv) and methyl 2-(1,3-thiazol-5- yl)quinoline-4-carboxylate (100 mg, 0.370 mmol, 1 equiv) in THF (2 mL) and H2O (2 mL) was stirred for 2 h at room temperature. The mixture was acidified to pH 5 with HCl (1 M). The resulting mixture was concentrated under reduced pressure to afford 2-(1,3-thiazol- 5-yl)quinoline-4-carboxylic acid (70 mg, 73.83%) as a white solid. [000122] To a stirred mixture of 2-(1,3-thiazol-5-yl)quinoline-4-carboxylic acid (60 mg, 0.234 mmol, 1 equiv) in ACN (3.00 mL) was added (1r,4r)-4-(2-methoxyethoxy)cyclohexan- 1-amine (49 mg, 0.281 mmol, 1.2 equiv), TCFH (98 mg, 0.351 mmol, 1.5 equiv) and NMI (58 mg, 0.702 mmol, 3 equiv) at RT. Then the mixture was stirred for 4 h at room temperature and then concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (method 2) to afford N-[(1r,4r)-4-(2- methoxyethoxy)cyclohexyl]-2-(1,3-thiazol-5-yl)quinoline-4-carboxamide (23.4 mg, 24.04%) as a white solid. LCMS (ESI) [M+H]+: 412.10.1H NMR (400 MHz, Methanol-d4) δ 9.12 (s, 1H), 8.69 (s, 1H), 8.13 – 8.03 (m, 3H), 7.91 – 7.72 (m, 1H), 7.70 – 7.50 (m, 1H), 4.12 – 3.88 (m, 1H), 3.68 – 3.63 (m, 2H), 3.58 – 3.50 (m, 2H), 3.37 (s, 4H), 2.22 – 2.08 (m, 4H), 1.56 – 1.37 (m, 4H). Example 4: Synthesis of 2-(imidazol-1-yl)-N-[(trans)-4-(2-methoxyethoxy)cyclohexyl]qu inoline-4-carboxamide (Compound 113)[000123] To a mixture of methyl 2-bromoquinoline-4-carboxylate (200 mg, 0.752 mmol, 1 equiv) and trans-4-(2-methoxyethoxy)cyclohexan-1-amine (156 mg, 0.902 mmol, 1.2 equiv) in Toluene (5 mL) was added trimethylaluminium (0.75 mL, 1.504 mmol, 2 equiv) in portions at 100 °C under nitrogen atmosphere. The resulting mixture was stirred for additional 1 h at 100 °C. The resulting mixture was extracted with EtOAc (3 x 30 mL), and the organic phase was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (method 1) to afford 2-bromo-N-[(trans)-4-(2- methoxyethoxy)cyclohexyl]quinoline-4-carboxamide (200 mg, 65.33%) as a yellow oil. [000124] To a mixture of 2-bromo-N-[(trans)-4-(2-methoxyethoxy)cyclohexyl]quinoline- 4-carboxamide (100 mg, 0.246 mmol, 1 equiv) and imidazole (84 mg, 1.230 mmol, 5 equiv) in DMF (5 mL) were added K2CO3(102 mg, 0.738 mmol, 3 equiv) and CuI (94 mg, 0.492 mmol, 2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 120 °C. The resulting mixture was filtered; the filter cake was washed with MeOH (3x30 mL). The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase flash chromatography (method 1) to afford 2- (imidazol-1-yl)-N-[(trans)-4-(2-methoxyethoxy)cyclohexyl]quinoline-4-carboxamide (30 mg, 30.98%) as a white solid. LCMS (ESI) [M+H]+: 395.05.1H NMR (400 MHz, DMSO-d6) δ 8.84 – 8.68 (m, 2H), 8.19 (s, 1H), 8.09 – 7.97 (m, 3H), 7.83 – 7.76 (m, 1H), 7.76 – 7.52 (m, 1H), 7.20 (s, 1H), 3.98 – 3.77 (m, 1H), 3.54 (dd, J = 5.9, 3.8 Hz, 2H), 3.43 (dd, J = 5.9, 3.8 Hz, 2H), 3.26 (d, J = 13.4 Hz, 4H), 2.13 – 1.95 (m, 4H), 1.43 – 1.22 (m, 4H). Example 5: Synthesis of (8-bromo-2-(1H-imidazol-1-yl)-N-((trans)-4-methoxycyclohexy l)quinoline-4-carboxamide (Compound 110)..[000125] To a stirred mixture of 1-(8-bromo-2-chloroquinolin-4-yl)ethanone (100 mg, 0.35 mmol, 1 equiv) and trans-4-methoxycyclohexan-1-amine (90 mg, 0.70 mmol, 2 equiv) in DMF (3 mL) was added HATU (260 mg, 0.70 mmol, 2 equiv) and DIEA (130 mg, 1.005 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The mixture was purified by reversed-phase flash chromatography (method 1) toafford 8-bromo-2-chloro-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (70 mg, 50.08% yield) as a yellow solid. [000126] A mixture of 8-bromo-2-chloro-N-[(trans)-4-methoxycyclohexyl]quinoline-4- carboxamide (80 mg, 0.201 mmol, 1 equiv), imidazole (16 mg, 0.241 mmol, 1.2 equiv), t- BuBrettPhos (19 mg, 0.040 mmol, 0.2 equiv), t-BuBrettPhos Pd G3(17 mg, 0.020 mmol, 0.1 equiv) and Cs2CO3(196 mg, 0.603 mmol, 3 equiv) in dioxane (8 mL) was stirred for 1 h at 100 °C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by reversed-phase flash chromatography (method 2) to afford 8- bromo-2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (30 mg, 34.74% yield) as a white solid. LCMS (ESI) [M+H]+:429.05.1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 8.9 Hz, 2H), 8.34 – 8.12 (m, 3H), 8.11 – 8.01 (m, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.23 (s, 1H), 3.88 (d, J = 11.2 Hz, 1H), 3.25 (s, 3H), 3.19 – 3.08(m, 1H), 2.01 – 2.09 (m, 3H), 1.45 – 1.15 (m, 5H). Example 6: Synthesis of 6-bromo-2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]qui nolone -4-carboxamide (Compound 109) .[000127] To a stirred mixture of 6-bromo-2-chloroquinoline-4-carboxylic acid (200 mg, 0.69 mmol, 1 equiv), NMI (286 mg, 3.49 mmol, 5 equiv) and trans-4-methoxycyclohexan-1- amine (108 mg, 0.83 mmol, 1.2 equiv) in DMF (4 mL) was added TCFH (391 mg, 1.39 mmol, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water and the mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 6-bromo-2-chloro-N-[(trans)-4- methoxy cyclohexyl] quinoline-4-carboxamide (263 mg, 94.73% yield) as a white solid.[000128] To a stirred mixture of 6-bromo-2-chloro-N-[(trans)-4-methoxycyclohexyl] quinoline-4-carboxamide (100 mg, 0.25 mmol, 1 equiv), Cs2CO3(246 mg, 0.75 mmol, 3 equiv) and imidazole (17 mg, 0.25 mmol, 1 equiv) in DMF (2 mL) at room atmosphere. The resulting mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the crude product (100 mg) was purified by Prep-HPLC (method 3) to afford 6-bromo-2-(imidazol-1-yl)-N-[(trans)-4- methoxycyclohexyl] quinoline-4-carboxamide (22.4 mg, 20.75% yield) as a white solid. LCMS (ESI) [M+H]+: 429.00.1H NMR (400 MHz, DMSO-d6) δ 8.86 – 8.72 (m, 2H), 8.27 (s, 1H), 8.18 (s, 1H), 8.11 (s, 1H), 8.02 – 7.90 (m, 2H), 7.21 (s, 1H), 3.96 – 3.76 (m, 1H), 3.26 (s, 3H), 3.20 – 3.10 (m, 1H), 2.12 – 1.94 (m, 4H), 1.48 – 1.19 (m, 4H). Example 7: Synthesis of 8-(hydroxymethyl)-2-(imidazol-1-yl)-N-[(trans)-4-methoxycycl ohexyl]quinoline-4-carboxamide (Compound 106) ..[000129] A mixture of 8-bromo-2-(imidazol-1-yl)-N-[(trans)-4- methoxycyclohexyl]quinoline-4-carboxamide (20 mg, 0.047 mmol, 1 equiv), (tributylstannyl)methanol (30 mg, 0.094 mmol, 2 equiv) and Pd(PPh3)2Cl2(3 mg, 0.005 mmol, 0.1 equiv) in DMF (6 mL) was stirred for 1 h at 80 °C under nitrogen atmosphere. The reaction was quenched with KF (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL) and the combined organic phase was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (method 9) to afford 8-(hydroxymethyl)-2-(imidazol-1-yl)-N- [(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (9 mg, 50.78% yield) as a white solid. LCMS (ESI) [M+H]+: 381.20.1H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.73 (d, J = 7.6 Hz, 1H), 8.20 (s, 1H), 8.02 (s, 1H), 7.85 – 7.94 (m, 2H), 7.71 – 7.55 (m, 1H), 7.19 (s, 1H), 5.43 – 5.29 (m, 1H), 5.17 (d, J = 5.4 Hz, 2H), 3.97 – 3.84 (m, 1H), 3.25 (s, 3H), 3.13 (d, J = 9.8 Hz, 1H), 2.10 – 1.95 (m, 4H), 1.46 – 1.16 (m, 4H). Example 8: Synthesis of 2-(imidazol-1-yl)-8-(morpholin-4-yl)-N-[(trans)-4-methoxycyclo hexyl]quinoline-4-carboxamide (Compound 105)..[000130] A mixture of 8-bromo-2-(imidazol-1-yl)-N-[(trans)-4- methoxycyclohexyl]quinoline-4-carboxamide (90 mg, 0.210 mmol, 1 equiv), morpholine (27 mg, 0.315 mmol, 1.5 equiv), Pd2(dba)3(19 mg, 0.021 mmol, 0.1 equiv), BINAP (26 mg, 0.042 mmol, 0.2 equiv) and Cs2CO3(205 mg, 0.630 mmol, 3 equiv) in dioxane (6 mL) was stirred for 1 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (45 mg) was purified by Prep-HPLC (method 4) to afford 2-(imidazol-1-yl)-8-(morpholin-4-yl)-N-[(trans)-4-methoxycyclohexyl]quinoline-4- carboxamide (25 mg, 27.38% yield) as a yellow solid. LCMS (ESI) [M+H]+: 436.20.1H NMR (400 MHz, DMSO-d6) δ 8.80 – 8.68 (m, 2H), 8.22 – 7.97 (m, 2H), 7.63 – 7.45 (m, 2H), 7.29 – 7.14 (m, 2H), 3.97 – 3.78 (m, 5H), 3.25 (s, 3H), 3.16 – 3.09 (m, 1H), 2.50 (d, J = 1.9 Hz, 4H), 2.10 – 1.94 (m, 4H), 1.45 – 1.18 (m, 4H). Example 9: Synthesis of N-((trans)-4-(methylcarbamoyl)cyclohexyl)-2-(thiazol-5-yl)quin oline-4-carboxamide (Compound 103) .[000131] To a mixture of 2-(1,3-thiazol-5-yl)quinoline-4-carboxylic acid (100 mg, 0.390 mmol, 1 equiv) and (trans)-4-amino-N-methylcyclohexane-1-carboxamide (91 mg, 0.585 mmol, 1.5 equiv) in DMF (2 mL) was added DIEA (151 mg, 1.170 mmol, 3 equiv) and HATU (223 mg, 0.585 mmol, 1.5 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0 °C. The resulting mixture was concentrated under reduced pressure and the crude product (80 mg) was purified by Prep-HPLC (method 5) to afford N-((trans)-4-(methylcarbamoyl)cyclohexyl)-2-(thiazol-5-yl)quinoline-4-carboxamide (25 mg, 16.24% yield) as a white solid. LCMS (ESI) [M+H]+: 395.15.1H NMR (400 MHz,DMSO-d6) δ 9.25 (s, 1H), 8.87 (s, 1H), 8.73 (d, J = 7.7 Hz, 1H), 8.17 (s, 1H), 8.04 – 8.10 (m, 2H), 7.83 – 7.80 (m, 1H), 7.74 – 7.51 (m, 2H), 3.90 – 3.77 (m, 1H), 2.57 (d, J = 4.5 Hz, 3H), 2.14 – 1.97 (m, 3H), 1.81 (d, J = 13.0 Hz, 2H), 1.59 – 1.43 (m, 2H), 1.37 – 1.25 (m, 2H). Example 10: Synthesis of 2-[5-(hydroxymethyl)imidazol-1-yl]-N-[(trans)-4-methoxycycl ohexyl]quinoline-4-carboxamide (Compound 102) .[000132] To a stirred solution of methyl 2-bromoquinoline-4-carboxylate (500 mg, 1.879 mmol, 1 equiv) in THF (4 mL) was added NaOH (752 mg, 18.790 mmol, 10 equiv) in H2O (1 mL) dropwise at 0 °C. The mixture was stirred for 1 h at room temperature and then acidified to pH 6 with 1 M HCl (aq.). The resulting mixture was concentrated under reduced pressure and the crude product (400 mg) was used in the next step directly without further purification. [000133] To a stirred mixture of 2-bromoquinoline-4-carboxylic acid (400 mg, 1.587 mmol, 1 equiv) and (trans)-4-methoxycyclohexan-1-amine (410 mg, 3.174 mmol, 2 equiv) in DMF (10 mL) was added DIEA (615 mg, 4.761 mmol, 3 equiv) and HATU (905 mg, 2.381 mmol, 1.5 equiv) in portions at 0 °C under nitrogen atmosphere. The mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was diluted with water (100 mL) and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford 2-bromo-N-[(trans)-4- methoxycyclohexyl]quinoline-4-carboxamide (250 mg, 43.37% yield) as a light yellow solid. [000134] A mixture of 2-bromo-N-[(trans)-4-methoxycyclohexyl]quinoline-4- carboxamide (150 mg, 0.413 mmol, 1 equiv), 3H-imidazol-4-ylmethanol (81 mg, 0.826mmol, 2 equiv), CuI (157 mg, 0.826 mmol, 2 equiv) and K2CO3(171 mg, 1.239 mmol, 3 equiv) in DMF (5 mL) was stirred for 2 h at 100 °C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 20 mL) and the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 6) to afford 2-[5-(hydroxymethyl)imidazol-1-yl]-N-[(trans)-4-methoxycyclohexyl]quinoline- 4-carboxamide (24.3 mg, 15.47% yield) as a white solid. LCMS (ESI) [M+H]+: 381.20.1H NMR (400 MHz, DMSO-d6) δ 8.83 – 8.64 (m, 2H), 8.13 – 7.91 (m, 4H), 7.87 – 7.80 (m, 1H), 7.66 – 7.62 (m, 1H), 5.09 (s, 1H), 4.46 (s, 2H), 3.94 – 3.78 (m, 1H), 3.25 (s, 3H), 3.17 – 3.08 (m, 1H), 2.10 – 1.98 (m, 4H), 1.44 – 1.26 (m, 4H). Example 11: Synthesis of 2-[4-(hydroxymethyl)imidazol-1-yl]-N-[(trans)-4-methoxycycl ohexyl]quinoline-4-carboxamide (Compound 101) . .[000135] A mixture of 2-bromo-N-[(trans)-4-methoxycyclohexyl]quinoline-4- carboxamide (150 mg, 0.413 mmol, 1 equiv), 3H-imidazol-4-ylmethanol (81 mg, 0.826 mmol, 2.00 equiv), CuI (157 mg, 0.826 mmol, 2 equiv) and K2CO3(171 mg, 1.239 mmol, 3 equiv) in DMF (5 mL) was stirred for 2 h at 100 °C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 20 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (method 6) to afford 2-[4-(hydroxymethyl)imidazol-1-yl]-N-[(trans)-4-methoxycyclohexyl]quinoline-4- carboxamide (1.5 mg, 0.95% yield) as a white solid. LCMS (ESI) [M+H]+: 381.15.1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 119.3 Hz, 2H), 8.25 – 7.46 (m, 5H), 7.09 (s, 1H), 5.34 (s, 1H), 4.80 (s, 2H), 3.87 (s, 1H), 3.09 (s, 4H), 2.02 (s, 4H), 1.33 (d, J = 36.0 Hz, 4H). Example 12: Synthesis of 8-cyano-2-(imidazol-1-yl)-N-[(trans)-4- methoxycyclohexyl]quinoline-4-carboxamide (Compound 128)[000136] A mixture of 7-bromo-1H-indole-2,3-dione (5 g, 22.121 mmol, 1 equiv) and malonic acid (4.60 g, 44.242 mmol, 2 equiv) in AcOH (100 mL) was stirred for 20 h at 90 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the residue was purified by reversed-phase flash chromatography (method 1) to afford 8- bromo-2-hydroxyquinoline-4-carboxylic acid (1.5 g, 25.30% yield) as a brown oil. [000137] A solution of 8-bromo-2-hydroxyquinoline-4-carboxylic acid (1.4 g, 5.223 mmol, 1 equiv) in POCl3(100 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the residue quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 x 200 mL), and the combined organic phase dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase (method 1) to afford 8-bromo-2-chloroquinoline-4-carboxylic acid (800 mg, 53.46% yield) as a brown solid. [000138] A mixture of 8-bromo-2-chloroquinoline-4-carboxylic acid (790 mg, 2.757 mmol, 1 equiv), (trans)-4-methoxycyclohexan-1-amine (534 mg, 4.136 mmol, 1.5 equiv), TCFH (1.54 g, 5.514 mmol, 2 equiv) and NMI (452 mg, 5.514 mmol, 2 equiv) in ACN (10 mL) was stirred for 2 h at room temperature. The mixture was concentrated under reduced pressure and the residue was purified by reversed-phase flash chromatography (method 1) to afford 8-bromo-2-chloro-N-[(trans)-4-methoxycyclohexyl] quinoline-4-carboxamide (610 mg, 55.63% yield) as a white solid. [000139] A mixture of 8-bromo-2-chloro-N-[(trans)-4-methoxycyclohexyl]quinoline-4- carboxamide (600 mg, 1.509 mmol, 1 equiv), imidazole (205 mg, 3.018 mmol, 2 equiv) and K2CO3(625 mg, 4.527 mmol, 3 equiv) in DMF (8 mL) was stirred for 2 h at 100 °C undernitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DMF (3 x 2 mL). The filtrate was concentrated under reduced pressure and the residue was purified by reversed-phase flash chromatography (method 1) to afford 8-bromo-2-(imidazol- 1-yl)-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (430 mg, 66.39% yield) as a yellow solid. [000140] A mixture of 8-bromo-2-(imidazol-1-yl)-N-[(trans)-4- methoxycyclohexyl]quinoline-4-carboxamide (150 mg, 0.349 mmol, 1 equiv) and CuCN (63 mg, 0.699 mmol, 2.00 equiv) in DMSO (4 mL) was stirred for 16 h at 150 °C under nitrogen atmosphere. The mixture was purified by Prep-HPLC (method 7) to afford 8-cyano-2- (imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (34.4 mg, 26.04% yield) as a white solid. LCMS (ESI) [M+H]+: 376.05.1H NMR (400 MHz, DMSO-d6) δ 8.91 – 8.79 (m, 2H), 8.49 – 8.41 (m, 1H), 8.40 – 8.32 (m, 1H), 8.26 (s, 1H), 8.20 (d, J = 1.5 Hz, 1H), 7.83 – 7.75 (m, 1H), 7.25 (s, 1H), 3.96 – 3.79 (m, 1H), 3.25 (s, 3H), 3.20 – 3.07 (m, 1H), 2.11 – 1.96 (m, 4H), 1.46 – 1.25 (m, 4H). Example 13: Synthesis of 8-bromo-2-(3-methylimidazol-4-yl)-N-[(trans)-4- methoxycyclohexyl] quinoline-4-carboxamide (Compound 146) .[000141] A solution of 8-bromo-2-chloroquinoline-4-carboxylic acid (290 mg, 1.012 mmol, 1 equiv), (trans)-4-methoxycyclohexan-1-amine (156 mg, 1.214 mmol, 1.2 equiv), TCFH (851 mg, 3.036 mmol, 3 equiv) and NMI (498 mg, 6.072 mmol, 6 equiv) in ACN (10 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure and the residue was purified by reversed-phase flash chromatography (method 1) to afford 8-bromo-2-chloro-N-[(trans)-4-methoxycyclohexyl] quinoline-4- carboxamide (200 mg, 49.68% yield) as a white solid.[000142] A solution of 8-bromo-2-chloro-N-[(trans)-4-methoxycyclohexyl]quinoline-4- carboxamide (78 mg, 0.196 mmol, 1 equiv), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)imidazole (48 mg, 0.235 mmol, 1.2 equiv), Pd(dppf)Cl2(28 mg, 0.039 mmol, 0.2 equiv) and K2CO3(81mg, 0.588 mmol, 3 equiv) in dioxane (5 mL) and H2O (1 mL) was stirred for 2 h at 90 °C under nitrogen atmosphere. The mixture was concentrated under reduced pressure and the residue was purified by reversed-phase flash chromatography (method 1) to afford 8-bromo-2-(3-methylimidazol-4-yl)-N-[(trans)-4- methoxycyclohexyl]quinoline-4-carboxamide (80 mg, 92.3% yield) as a light yellow solid. [000143] A mixture of 8-bromo-2-(3-methylimidazol-4-yl)-N-[(trans)-4- methoxycyclohexyl] quinoline-4-carboxamide (80 mg, 0.180 mmol, 1 equiv) and CuCN (32 mg, 0.360 mmol, 2 equiv) in DMSO (3 mL) was stirred for 16 h at 150 °C under nitrogen atmosphere. The residue was purified by Prep-HPLC (method 4) to afford 8-cyano-2-(3- methylimidazol-4-yl)-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (20.3 mg, 28.89% yield) as a yellow green solid. LCMS (ESI) [M+H]+: 390.15.1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 7.6 Hz, 1H), 8.40 – 8.35 (m, 1H), 8.33 – 8.29 (m, 1H), 8.09 (s, 1H), 8.06 (s, 1H), 7.94 (s, 1H), 7.75 – 7.70 (m, 1H), 4.23 (s, 3H), 3.92 – 3.80 (m, 1H), 3.25 (s, 3H), 3.20 – 3.09 (m, 1H), 2.20 – 1.85 (m, 4H), 1.60 – 1.32 (m, 2H), 1.32 – 1.20 (m, 2H). Example 14: Synthesis of 8-cyano-2-(imidazol-1-yl)-N-[(trans)-4- methoxycyclohexyl]quinazoline-4-carboxamide (Compound 134) .[000144] To a stirred solution of methyl 8-bromo-2-chloroquinazoline-4-carboxylate (250 mg, 0.829 mmol, 1 equiv) in THF (10 mL) was added LiOH (198 mg, 8.290 mmol, 10 equiv) in water (2 mL) dropwise at 0 °C. The mixture was stirred for 2 h at room temperature andthen acidified to pH 5 with 1 M HCl (aq.). The resulting mixture was concentrated under reduced pressure and the residue was purified by reversed-phase flash chromatography (method 1) to afford 8-bromo-2-chloroquinazoline-4-carboxylic acid (200 mg, 83.90% yield) as a yellow solid. [000145] To a stirred mixture of 8-bromo-2-chloroquinazoline-4-carboxylic acid (190 mg, 0.661 mmol, 1 equiv) and (trans)-4-methoxycyclohexan-1-amine (171 mg, 1.322 mmol, 2 equiv) in DMF (5 mL) was added DIEA (256 mg, 1.983 mmol, 3 equiv) and HATU (502 mg, 1.322 mmol, 2 equiv) in portions at 0 °C. The mixture was stirred for 1 h at room temperature and was diluted with water. The resulting mixture was extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford 8-bromo-2-chloro-N-[(trans)-4- methoxycyclohexyl]quinazoline-4-carboxamide (120 mg, 45.54% yield) as a light yellow solid. [000146] A mixture of 8-bromo-2-chloro-N-[(trans)-4-methoxycyclohexyl]quinazoline-4- carboxam ide (120 mg, 0.301 mmol, 1 equiv), imidazole (41 mg, 0.602 mmol, 2 equiv) and K2CO3(125 mg, 0.903 mmol, 3 equiv) in DMF (5 mL) was stirred for 2 h at 100 °C under nitrogen atmosphere. The reaction was diluted with water and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford 8-bromo-2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]quinazoline-4- carboxamide (75 mg, 57.91% yield) as a light brown solid. [000147] A mixture of 8-bromo-2-(imidazol-1-yl)-N-[(trans)-4- methoxycyclohexyl]quinazoline-4-carboxamide (70 mg, 0.163 mmol, 1 equiv), CuCN (29 mg, 0.326 mmol, 2 equiv) and Pd(PPh3)2Cl2(11 mg, 0.016 mmol, 0.1 equiv) in DMSO (5 mL) was stirred for 4 h at 140 °C under nitrogen atmosphere. The mixture was diluted with water and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (70 mg) was purified by Prep-HPLC (method 7) to afford 8-cyano-2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]quinazoline-4- carboxamide (21.2 mg, 34.62% yield) as a white solid. LCMS (ESI) [M+H]+: 377.25.1HNMR (400 MHz, DMSO-d6) δ 9.15 – 9.05 (m, 2H), 8.95 (s, 1H), 8.71 – 8.64 (m, 1H), 8.15 (d, J = 1.6 Hz, 1H), 7.92 – 7.84 (m, 1H), 7.26 (s, 1H), 3.94 – 3.87 (m, 1H), 3.27 (d, J = 1.0 Hz, 3H), 3.21 – 3.12 (m, 1H), 2.13 – 2.02 (m, 2H), 2.02 – 1.89 (m, 2H), 1.57 – 1.50 (m, 2H), 1.40 – 1.18 (m, 2H). Example 15: Synthesis of N-[(trans)-4-methoxycyclohexyl]-2-(1,3-thiazol-5- yl)quinazoline-4-carboxamide (Compound 140)..[000148] A mixture of ethyl 2-chloroquinazoline-4-carboxylate (200 mg, 0.845 mmol, 1.00 equiv), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (267 mg, 1.268 mmol, 1.5 equiv), Pd(dppf)Cl2(69 mg, 0.085 mmol, 0.10 equiv) and K2CO3 (350 mg, 2.535 mmol, 3equiv) in dioxane (4 mL) and H2O (1 mL) was stirred for 1 h at 100 °C under nitrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford 2-(1,3-thiazol-5-yl)quinazoline-4-carboxylic acid (120 mg, 55.19% yield) as a brown solid. [000149] To a stirred mixture of 2-(1,3-thiazol-5-yl)quinazoline-4-carboxylic acid (50 mg, 0.194 mmol, 1 equiv) and (trans)-4-methoxycyclohexan-1-amine (37 mg, 0.291 mmol, 1.5 equiv) in acetonitrile (4 mL) was added TCFH (109 mg, 0.388 mmol, 2 equiv) and NMI (48 mg, 0.582 mmol, 3 equiv) in portions at 0 °C under nitrogen atmosphere. The mixture was stirred for 1 h at room temperature under nitrogen atmosphere and then concentrated under reduced pressure. The crude product (50 mg) was purified by Prep-HPLC (method 5) to afford N-[(trans)-4-methoxycyclohexyl]-2-(1,3-thiazol-5-yl)quinazoline-4-carboxamide (23.9 mg, 32.71% yield) as a white solid. LCMS (ESI) [M+H]+: 369.00.1H NMR (400 MHz, DMSO-d6) δ 9.31 (d, J = 0.8 Hz, 1H), 8.98 – 8.84 (m, 2H), 8.53 (dt, J = 8.4, 1.1 Hz, 1H), 8.12 – 7.99 (m, 2H), 7.91 – 7.65 (m, 1H), 4.08 – 3.76 (m, 1H), 3.26 (s, 3H), 3.16 (td, J = 10.5, 5.3 Hz, 1H), 2.07 – 1.95 (m, 4H), 1.65 – 1.39 (m, 2H), 1.33 – 1.22 (m, 2H). Example 16: Synthesis of 2-(1H-imidazol-1-yl)-N-((trans)-4-methoxycyclohexyl)quinazoline-4-carboxamide (Compound 141) . .[000150] To a mixture of ethyl 2-chloroquinazoline-4-carboxylate (300 mg, 1.268 mmol, 1 equiv) and imidazole (172 mg, 2.536 mmol, 2 equiv) in DMF (10 mL) was added K2CO3(525 mg, 3.804 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The mixture was stirred for 1 h at 100 °C under nitrogen atmosphere and then concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford 2-(imidazol-1-yl)quinazoline-4-carboxylic acid (140 mg, 45.97% yield) as a white solid. [000151] To a stirred mixture of 2-(imidazol-1-yl)quinazoline-4-carboxylic acid (70 mg, 0.291 mmol, 1 equiv) and (trans)-4-methoxycyclohexan-1-amine (56 mg, 0.436 mmol, 1.5 equiv) in ACN (8 mL) were added TCFH (163 mg, 0.582 mmol, 2 equiv) and NMI (119 mg, 1.455 mmol, 5 equiv) in portions at 0 °C under nitrogen atmosphere. The mixture was stirred for 1 h at room temperature and concentrated under reduced pressure. The crude product (40 mg) was purified by Prep-HPLC (method 6) to afford 2-(imidazol-1-yl)-N-[(trans)-4- methoxycyclohexyl]quinazoline-4-carboxamide (27.9 mg, 27.25% yield) as a light yellow solid. LCMS (ESI) [M+H]+: 352.20.1H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 8.1 Hz, 1H), 8.95 (s, 1H), 8.76 – 8.68 (m, 1H), 8.23 – 8.16 (m, 1H), 8.17 – 7.99 (m, 2H), 7.83 – 7.73 (m, 1H), 7.31 – 7.21 (m, 1H), 4.01 – 3.84 (m, 1H), 3.26 (s, 3H), 3.23 – 3.11 (m, 1H), 2.13 – 2.02 (m, 2H), 2.01 – 1.92 (m, 2H), 1.59 – 1.51 (m, 2H), 1.37 – 1.20 (m, 2H). Example 17: Synthesis of 8-cyano-2-(3-methylimidazol-4-yl)-N-[(trans)-4- methoxycyclohexyl] quinazoline-4-carboxamide (Compound 145).[000152] A mixture of 8-bromo-2-chloroquinazoline-4-carboxylic acid (290 mg, 1.009 mmol, 1 equiv), (trans)-4-methoxycyclohexan-1-amine (156 mg, 1.211 mmol, 1.2 equiv), TCFH (849 mg, 3.027 mmol, 3 equiv) and NMI (496 mg, 6.054 mmol, 6 equiv) in DMF (10 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the residue was purified by reversed- phase flash chromatography (method 1) to afford 8-bromo-2-chloro-N-[(trans)-4- methoxycyclohexyl]quinazoline-4-carboxamide (210 mg, 52.22% yield) as a white solid. [000153] A mixture of 8-bromo-2-chloro-N-[(trans)-4-methoxycyclohexyl]quinazoline-4- carboxamide (200 mg, 0.502 mmol, 1 equiv), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)imidazole (125 mg, 0.602 mmol, 1.2 equiv), Pd(dppf)Cl2(73 mg, 0.100 mmol, 0.2 equiv) and K2CO3(208 mg, 1.506 mmol, 3 equiv) in dioxane (10 mL) and H2O (2 mL) was stirred for 2 h at 90 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the residue was purified by reversed-phase flash chromatography (method 1) to afford 8-bromo-2-(3-methylimidazol-4-yl)-N-[(trans)-4- methoxycyclohexyl]quinazoline-4-carboxamide (130 mg, 58.32% yield) as a white solid. [000154] A solution of 8-bromo-2-(3-methylimidazol-4-yl)-N-[(trans)-4- methoxycyclohexyl] quinazoline-4-carboxamide (120 mg, 0.270 mmol, 1 equiv), Pd(PPh3)2Cl2(38 mg, 0.054 mmol, 0.2 equiv) and CuCN (48 mg, 0.540 mmol, 2 equiv) in DMSO (15 mL) was stirred for 16 h at 150 °C under nitrogen atmosphere. The mixture was diluted with water. The resulting mixture was extracted with EtOAc (3 x 50 mL), the combined organic phase was dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reversed-phase flash chromatography (method 4) to afford 8-cyano-2-(3-methylimidazol-4-yl)-N-[(trans)-4- methoxycyclohexyl]quinazoline-4-carboxamide (27.0 mg, 25.61% yield) as a yellow solid.LCMS (ESI) [M+H]+: 391.20.1H NMR (400 MHz, DMSO-d6) δ 8.94 (d, J = 8.2 Hz, 1H), 8.88 (d, J = 8.5, 1.4 Hz, 1H), 8.60 (d, J = 7.4, 1.4 Hz, 1H), 8.18 (s, 1H), 8.00 (s, 1H), 7.82 (d, J = 8.5, 7.3 Hz, 1H), 4.22 (s, 3H), 4.02 – 3.79 (m, 1H), 3.26 (s, 3H), 3.21 – 3.09 (m, 1H), 2.19 – 1.82 (m, 4H), 1.60 – 1.40 (m, 2H), 1.32 – 1.25 (m, 2H). Example 18: Synthesis of 2-(imidazol-1-yl)-N-[(trans)-4-(2-hydroxypropan-2- yl)cyclohexyl]quinazoline-4-carboxamide (Compound 143)[000155] A mixture of methyl 2-chloroquinazoline-4-carboxylate (250 mg, 1.123 mmol, 1 equiv), K2CO3(465 mg, 3.369 mmol, 3 equiv) and imidazole (153 mg, 2.246 mmol, 2 equiv) in DMF (5 mL) was stirred for 6 h at 90 °C under nitrogen atmosphere. The mixture was diluted with water. The resulting mixture was extracted with EtOAc (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford 2- (imidazol-1-yl)quinazoline-4-carboxylic acid (150 mg, 55.65% yield) as a yellow solid. [000156] To a stirred mixture of 2-(imidazol-1-yl)quinazoline-4-carboxylic acid (150 mg, 0.624 mmol, 1 equiv) and 2-[(trans)-4-aminocyclohexyl]propan-2-ol (147 mg, 0.936 mmol, 1.5 equiv) in ACN (2 mL) were added TCFH (263 mg, 0.936 mmol, 1.5 equiv) and NMI (102 mg, 1.248 mmol, 2 equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 8) to afford 2-(imidazol-1-yl)-N- [(trans)-4-(2-hydroxypropan-2-yl)cyclohexyl]quinazoline-4-carboxamide (40.1 mg, 16.70% yield) as a light yellow solid. LCMS (ESI) [M+H]+: 380.10.1H NMR (400 MHz, DMSO-d6) δ 8.99 (d, J = 8.2 Hz, 1H), 8.90 (s, 1H), 8.79 – 8.61 (m, 1H), 8.19 (s, 1H), 8.12 – 7.96 (m, 2H), 7.80 – 7.73 (m, 1H), 7.21 (s, 1H), 4.08 (s, 1H), 3.91 – 3.79 (m, 1H), 2.04 – 1.92 (m, 2H), 1.92 – 1.78 (m, 2H), 1.51 – 1.30 (m, 2H), 1.26 – 1.11 (m, 3H), 1.07 (s, 6H). Example 19: Synthesis of 3-(imidazol-1-yl)-N-[(trans)-4- methoxycyclohexyl]naphthalene-1-carboxamide (Compound 114)[000157] To a mixture of methyl 3-bromonaphthalene-1-carboxylate (100 mg, 0.38 mmol, 1.0 equiv) in MeOH (2 mL) was added NaOH (151 mg, 3.78 mmol, 10.0 equiv) and H2O (0.5 mL). The resulting mixture was stirred for 1 h at 50 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and neutralized to pH 6 with HCl (aq.). The resulting mixture was concentrated under reduced pressure and the residue was purified by reverse phase flash chromatography (method 1) to afford 3-bromonaphthalene-1- carboxylic acid (90 mg, 95.03%) as a yellow solid. [000158] To a mixture of 3-bromonaphthalene-1-carboxylic acid (100 mg, 0.40 mmol, 1.0 equiv) in DMF (10 mL) was added trans-4-methoxycyclohexan-1-amine (77 mg, 0.60 mmol, 1.5 equiv), DIEA (154 mg, 1.20 mmol, 3.0 equiv) and HATU (454 mg, 1.20 mmol, 3.0 equiv) at room temperature under nitrogen atmosphere. The mixture was stirred at for 1 hour and diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL) and the combined organic phase was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (method 1) to afford 3-bromo-N-[(trans)-4-methoxycyc lohexyl]naphthalene-1-carboxamide (90 mg, 62.38%) as a yellow solid. [000159] To a mixture of 3-bromo-N-[(trans)-4-methoxycyclohexyl]naphthalene-1- carboxamide (90 mg, 0.250 mmol, 1.0 equiv) in DMF (5 mL) was added imidazole (34 mg, 0.50 mmol, 2.0 equiv), CuI (142 mg, 0.74 mmol, 3.0 equiv) and K2CO3(103 mg, 0.74 mmol, 3.0 equiv). The mixture was stirred overnight at 120 °C under nitrogen atmosphere and then allowed to cool down to room temperature. The reaction was quenched with sat. NH4Cl (aq.) at room temperature and the resulting mixture was extracted with EtOAc (10 x3 mL). The combined organic phase was washed with brine (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (90 mg) was purified by Prep-HPLC (method 5) to afford 3-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl] naphthalene-1-carboxamide (25 mg, 28.65%) as a white solid. LCMS (ESI) [M+H]+:350.10.1H NMR (400 MHz, DMSO-d6) δ 8.57 – 8.41 (m, 2H), 8.29 (d, J = 2.2 Hz, 1H), 8.19 – 8.14 (m, 1H), 8.03 – 7.92 (m, 2H), 7.85 (d, J = 2.3 Hz, 1H), 7.75 – 7.48 (m, 2H), 7.19 (s, 1H), 3.95 – 3.70 (m, 1H), 3.25 (s, 3H), 3.20 – 3.08 (m, 1H), 2.10 – 1.96 (m, 4H), 1.44 – 1.20 (m, 4H). Example 20: Synthesis of N-[(trans)-4-methoxycyclohexyl]-3-(1,3-thiazol-5- yl)naphthalene-1-carboxamide (Compound 117)[000160] To a mixture of methyl 3-bromonaphthalene-1-carboxylate (100 mg, 0.38 mmol, 1.0 equiv) in dioxane (10 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3-thiazole (120 mg, 0.57 mmol, 1.5 equiv), K2CO3(156 mg, 1.13 mmol, 3.0 equiv), Pd(dppf)Cl2(28 mg, 0.04 mmol, 0.1 equiv) and H2O (2 mL). The resulting mixture was stirred overnight at 90 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (method 1) to afford methyl 3-(1,3- thiazol-5-yl)naphthalene-1-carboxylate (77 mg, 75.80%) as a yellow solid. [000161] To a mixture of methyl 3-(1,3-thiazol-5-yl)naphthalene-1-carboxylate (67 mg, 0.25 mmol, 1.0 equiv) in MeOH (5 mL) was added NaOH (100 mg, 2.49 mmol, 10.0 equiv) and H2O (1 mL). The resulting mixture was stirred for 1 h at 50 °C under nitrogen atmosphere and allowed to cool down to room temperature. The mixture was neutralized to pH 6 with HCl (aq.) and the resulting mixture was concentrated under reduced pressure to afford 3-(1,3-thiazol-5-yl)naphthalene-1-carboxylic acid (60 mg,94.47%) as a yellow solid. The crude product was used in the next step directly without further purification. [000162] To a mixture of 3-(1,3-thiazol-5-yl)naphthalene-1-carboxylic acid (60 mg, 0.24 mmol, 1.0 equiv) in DMF (2 mL) was added trans-4-methoxycyclohexan-1-amine (61 mg, 0.47 mmol, 2.0 equiv), DIEA (91 mg, 0.70 mmol, 3.0 equiv) and HATU (179 mg, 0.47 mmol, 2.0 equiv). The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The crude product (50 mg) was purified by Prep- HPLC (method 7) to afford N-[(trans)-4-methoxycyclohexyl]-3-(1,3-thiazol-5- yl)naphthalene-1-carboxamide (10.6 mg, 12.31%) as a white solid. LCMS (ESI) [M+H]+:367.15.1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.55 (d, J = 7.8 Hz, 1H), 8.51 (s, 1H), 8.31 (d, J = 1.9 Hz, 1H), 8.16 – 8.09 (m, 1H), 8.08 – 8.02 (m, 1H), 7.85 (d, J = 1.9 Hz, 1H), 7.67 – 7.53 (m, 2H), 3.93 – 3.81 (m, 1H), 3.26 (s, 3H), 3.19 – 3.11 (m, 1H), 2.14 – 1.95 (m, 4H), 1.47 – 1.35 (m, 2H), 1.32 – 1.20 (m, 2H). Example 21: Synthesis of N-[(trans)-4-(2-methoxyethoxy)cyclohexyl]-2-(1,3-thiazol-5- yl)-5,6,7,8-tetrahydroquinazoline-4-carboxamide (Compound 119)[000163] A solution of 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (1 g, 4.92 mmol, 1 equiv), oxalic acid (4.4 g, 49.24 mmol, 10 equiv), Ac2O (1.507 g, 14.76 mmol, 3 equiv), Pd(OAc)2(440 mg, 1.97 mmol, 0.4 equiv), Xantphos (570 mg, 0.99 mmol, 0.2 equiv) and DIEA (3.2 g, 24.62 mmol, 5 equiv) in DMF (20 mL) was stirred for 3 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (method 1) to afford 2-chloro- 5,6,7,8-tetrahydroquinazoline-4-carboxylic acid (340 mg, 32.47%) as a white solid.[000164] A solution of 2-chloro-5,6,7,8-tetrahydroquinazoline-4-carboxylic acid (100 mg, 0.47 mmol, 1.0 equiv), trans-4-(2-methoxyethoxy) cyclohexan-1-amine (81 mg, 0.470 mmol, 1 equiv), TCFH (198 mg, 0.71 mmol, 1.5 equiv) and NMI (116 mg, 1.41 mmol, 3 equiv) in ACN (3 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure and the residue was purified by reverse phase flash chromatography (method 1) to afford 2-chloro-N-[(trans)-4-(2-methoxyethoxy)cyclohexyl]-5,6,7,8- tetrahydroquinazoline-4-carboxamide (105 mg, 60.69%) as a white solid. [000165] A solution of 2-chloro-N-[(trans)-4-(2-methoxyethoxy)cyclohexyl]-5,6,7,8- tetrahydroquinazoline-4-carboxamide (100 mg, 0.27 mmol, 1 equiv), 5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3-thiazole (86 mg, 0.41 mmol, 1.5 equiv), K2CO3(113 mg, 0.82 mmol, 3 equiv) and Pd(dppf)Cl2(20 mg, 0.03 mmol, 0.1 equiv) in dioxane (2 mL) and H2O (0.2 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 x 8 mL). The resulting solution was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (method 1) to afford N-[(trans)-4-(2-methoxyethoxy) cyclohexyl]-2-(1,3-thiazol-5-yl)-5,6,7,8- tetrahydroquinazoline-4-carboxamide (15.4 mg, 13.39%) as a light yellow solid. LCMS (ESI) [M+H]+: 417.15.1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.68 (s, 1H), 8.56 (d, J = 8.0 Hz, 1H), 3.81 – 3.70 (m, 1H), 3.55 – 3.50 (m, 2H), 3.44 – 3.40 (m, 2H), 3.31 – 3.21 (m, 4H), 2.95 – 2.79 (m, 4H), 2.15 – 1.65 (m, 8H), 1.51 – 1.12 (m, 4H). Example 22: Synthesis of N-[(trans)-4-methoxycyclohexyl]-2-(1,3-thiazol-5-yl)-5,6,7,8- tetrahydroquinazoline-4-carboxamide (Compound 118)[000166] A solution of 2-chloro-5,6,7,8-tetrahydroquinazoline-4-carboxylic acid (100 mg, 0.47 mmol, 1 equiv), trans-4-methoxycyclohexan-1-amine (73 mg, 0.56 mmol, 1.2 equiv), TCFH (198 mg, 0.71 mmol, 1.5 equiv) and NMI (116 mg, 1.41 mmol, 3 equiv) in ACN (2 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (method1) to afford 2-chloro-N-[(trans)-4-methoxycyclohexyl]-5,6,7,8-tetrahydroquinazoline-4- carboxamide (60 mg, 39.40%) as a white solid. [000167] A solution of 2-chloro-N-[(trans)-4-methoxycyclohexyl]-5,6,7,8- tetrahydroquinazoline-4-carboxamide (50 mg, 0.154 mmol, 1 equiv), 5-(tributylstannyl)-1,3- thiazole (87 mg, 0.23 mmol, 1.5 equiv) and Pd(PPh3)4(18 mg, 0.02 mmol, 0.1 equiv) in DCE (3 mL) was stirred for 4 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the residue was purified by reverse phase flash chromatography (method 1) to afford N-[(trans)-4-methoxycyclohexyl]-2-(1,3-thiazol-5-yl)- 5,6,7,8-tetrahydroquinazoline-4-carboxamide (21.4 mg, 37.15%) as a white solid. LCMS (ESI) [M+H]+: 373.10.1H NMR (400 MHz, DMSO-d6) δ 9.21 (d, J = 5.1 Hz, 1H), 8.67 (d, J = 5.4 Hz, 1H), 8.57 (d, J = 8.0 Hz, 1H), 3.75 (d, J = 7.8 Hz, 1H), 3.24 (s, 3H), 3.15 – 3.08 (m, 1H), 2.94 – 2.77 (m, 4H), 2.08 – 1.98 (m, 2H), 1.91 – 1.64 (m, 6H), 1.46 – 1.34 (m, 2H), 1.29 – 1.16 (m, 2H). Example 23: Synthesis of 2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]-5,6,7,8- tetrahydroquinazoline-4-carboxamide (Compound 112)[000168] A solution of 2-chloro-N-[(trans)-4-methoxycyclohexyl]-5,6,7,8- tetrahydroquinazoline-4-carboxamide (50 mg, 0.154 mmol, 1.00 equiv), imidazole (13 mg, 0.19 mmol, 1.2 equiv), t-Buxphos (13 mg, 0.03 mmol, 0.2 equiv), Pd2(dba)3(14 mg, 0.02 mmol, 0.1 equiv) and K3PO4(98 mg, 0.462 mmol, 3 equiv) in toluene (2 mL) was stirred for 2 h at 110 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (30 mg) was purified by Prep-HPLC (method 7) to afford 2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]-5,6,7,8-tetrahydroquinazoline-4- carboxamide (9.3 mg, 16.75%) as a white solid. LCMS (ESI) [M+H]+: 356.20.1H NMR (400 MHz, DMSO-d6) δ 8.69 – 8.60 (m, 2H), 7.99 (s, 1H), 7.13 (s, 1H), 3.82 – 3.70 (m, 1H), 3.24 (s, 3H), 3.17 – 3.06 (m, 1H), 2.95 – 2.88 (m, 4H), 2.09 – 1.98 (m, 2H), 1.92 – 1.74 (m, 6H), 1.51 – 1.34 (m, 2H), 1.30 – 1.16 (m, 2H).Example 24: Synthesis of 2-(imidazol-1-yl)-N-[(trans)-4-(2-methoxyethoxy)cyclohexyl]- 5,6,7,8-tetrahydroquinazoline-4-carboxamide (Compound 111)[000169] A solution of 2-chloro-5,6,7,8-tetrahydroquinazoline-4-carboxylic acid (100 mg, 0.47 mmol, 1.0 equiv), trans-4-(2-methoxyethoxy) cyclohexan-1-amine (81 mg, 0.470 mmol, 1 equiv), TCFH (198 mg, 0.71 mmol, 1.5 equiv) and NMI (116 mg, 1.41 mmol, 3 equiv) in ACN (3 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (method 1) to afford 2-chloro-N-[(trans)-4-(2-methoxyethoxy) cyclohexyl]-5,6,7,8- tetrahydroquinazoline-4-carboxamide (60 mg, 30.69%) as a white solid. [000170] A solution of 2-chloro-N-[(trans)-4-(2-methoxyethoxy) cyclohexyl]-5,6,7,8- tetrahydroquinazoline-4-carboxamide (60 mg, 0.16 mmol, 1 equiv), imidazole (13 mg, 0.20 mmol, 1.2 equiv), t-Buxphos (14 mg, 0.03 mmol, 0.2 equiv), Pd2(dba)3(15 mg, 0.02 mmol, 0.1 equiv) and K3PO4(104 mg, 0.49 mmol, 3 equiv) in toluene (2 mL) was stirred for 2 h at 110 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (method 1) to afford 2-(imidazol-1-yl)-N-[(trans)-4-(2-methoxyethoxy)cyclohexyl]-5,6,7,8- tetrahydroquinazoline-4-carboxamide (25.3 mg, 37.94%) as a light yellow solid. LCMS (ESI) [M+H]+: 400.20.1H NMR (400 MHz, DMSO-d6) δ 8.68 – 8.57 (m, 2H), 7.99 (s, 1H), 7.13 (s, 1H), 3.82 – 3.70 (m, 1H), 3.55 – 3.49 (m, 2H), 3.44 – 3.41 (m, 2H), 3.26 – 3.20 (m, 4H), 2.95 – 2.88 (m, 4H), 2.07 – 1.97 (m, 2H), 1.92 – 1.71 (m, 6H), 1.50 – 1.36 (m, 2H), 1.31 – 1.19 (m, 2H). Example 25: Synthesis of 2-(imidazol-1-yl)-N-[(trans)-4-(methylcarbamoyl) cyclohexyl]- 5,6,7,8-tetrahydroquinazoline-4-carboxamide (Compound 104)..[000171] A solution of 2-chloro-5,6,7,8-tetrahydroquinazoline-4-carboxylic acid (150 mg, 0.71 mmol, 1 equiv), (trans)-4-amino-N-methylcyclohexane-1-carboxamide (165 mg, 1.06 mmol, 1.5 equiv), HATU (402 mg, 1.06 mmol, 1.5 equiv) and DIEA (274 mg, 2.12 mmol, 3 equiv) in DMF (5 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (method 1) to afford 2-chloro-N-[(trans)-4-(methylcarbamoyl)cyclohexyl]- 5,6,7,8-tetrahydroquinazoline-4-carboxamide (90 mg, 36.36% yield) as a white solid. [000172] A solution of 2-chloro-N-[(trans)-4-(methylcarbamoyl)cyclohexyl]-5,6,7,8- tetrahydroquinazoline-4-carboxamide (80 mg, 0.23 mmol, 1 equiv), imidazole (23 mg, 0.34 mmol, 1.5 equiv), t-BuBrettphos (22 mg, 0.05 mmol, 0.2 equiv), t-BuBrettPhos Pd G3(19 mg, 0.02 mmol, 0.1 equiv) and Cs2CO3(223 mg, 0.68 mmol, 3 equiv) in dioxane (10 mL) was stirred for 1 h at 120 °C under nitrogen atmosphere. The mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layer was concentrated under reduced pressure. The crude product (48 mg) was purified by Prep-HPLC (method 6) to afford 2-(imidazol-1-yl)-N-[(trans)-4-(methylcarbamoyl)cyclohexyl]-5,6,7,8- tetrahydroquinazoline-4-carboxamide (23 mg, 26.20% yield) as a white solid. LCMS (ESI) [M+H]+: 383.20.1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 9.8 Hz, 2H), 8.00 (s, 1H), 7.70 (s, 1H), 7.13 (s, 1H), 3.80 – 3.63 (m, 1H), 2.91 (t, J = 6.4 Hz, 4H), 2.56 (d, J = 4.6 Hz, 3H), 2.10 – 2.00 (m, 1H), 1.95 – 1.72 (m, 8H), 1.50 – 1.29 (m, 4H). Example 26: Synthesis of N-[(trans)-4-(2-methoxyethoxy)cyclohexyl]-2-(1,3-thiazol-5- yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxamide (Compound 115)[000173] To a stirred solution of 2,4-dichloro-5H,6H,7H-cyclopenta[d]pyrimidine (300 mg, 1.58 mmol, 1 equiv) and oxalic acid (1.43 g, 15.87 mmol, 10 equiv) in DMF were added Pd(OAc)2 (356 mg, 1.58 mmol, 1 equiv), XantPhos (459 mg, 0.79 mmol, 0.5 equiv), Ac2O (324 mg, 3.17 mmol, 2 equiv) and DIEA (1.03 g, 7.93 mmol, 5 equiv) dropwise at room temperature. The resulting mixture was stirred for 3 h at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The crude product was purified by reverse phase flash chromatography (method 2) to afford 2-chloro-5H,6H,7H- cyclopenta[d]pyrimidine-4-carboxylic acid (90 mg, 28.55%) as a light yellow oil. [000174] To a stirred solution of 2-chloro-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylic acid (90 mg, 0.45 mmol, 1 equiv) and trans-4-(2-methoxyethoxy)cyclohexan-1- amine (117 mg, 0.67 mmol, 1.5 equiv) in MeCN (1 mL) were added TCFH (254 mg, 0.90 mmol, 2 equiv) and NMI (185 mg, 2.26 mmol, 5 equiv) dropwise at room temperature under air atmosphere. The resulting mixture was stirred for 1 h at room temperature. The mixture was allowed to cool down to room temperature. The crude product was purified by reverse phase flash chromatography (method 2) to afford 2-chloro-N-[(trans)-4-(2- methoxyethoxy)cyclohexyl]-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxamide (100 mg, 62.36%) as a light yellow oil. [000175] To a stirred mixture of 2-chloro-N-[(trans)-4-(2-methoxyethoxy)cyclohexyl]- 5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxamide (75 mg, 0.21 mmol, 1 equiv) and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (67 mg, 0.31 mmol, 1.5 equiv) in 1,4-dioxane (1 mL) were added Pd(dppf)Cl2(23 mg, 0.03 mmol, 0.15 equiv) and K2CO3(73 mg, 0.530 mmol, 2.5 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The crude product was purified by reverse phaseflash chromatography (method 2) to afford N-[(trans)-4-(2-methoxyethoxy)cyclohexyl]-2- (1,3-thiazol-5-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxamide (12.5 mg, 14.60%) as a white solid. LCMS (ESI) [M+H]+: 403.00.1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.97 (s, 1H), 8.60 (d, J = 8.5 Hz, 1H), 3.80 (s, 1H), 3.55 (s, 3H), 3.46 (s, 1H), 3.26 (d, J = 6.6 Hz, 6H), 3.00 (t, J = 7.8 Hz, 2H), 2.06 (td, J = 14.7, 14.3, 5.7 Hz, 4H), 1.85 (d, J = 12.2 Hz, 2H), 1.54 (q, J = 12.5 Hz, 2H), 1.27 (t, J = 12.7 Hz, 2H). Example 27: Synthesis of 2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]-5H,6H,7H- cyclopenta[d]pyrimidine-4-carboxamide (Compound 108) .[000176] To a stirred solution of ethyl 2-chloro-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylate (300 mg, 1.32 mmol, 1 equiv) in THF (2 mL) and H2O (2 mL) was added LiOH (158 mg, 6.62 mmol, 5 equiv) in portions at room temperature under nitrogen atmosphere. The mixture was stirred for 1 h at room temperature under nitrogen atmosphere and then acidified to pH 6 with 1 M HCl (aq.). The resulting mixture was filtered, the filter cake was washed with THF (3x5 mL). The filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. [000177] To a stirred solution of 2-chloro-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylic acid (100 mg, 0.50 mmol, 1 equiv) and trans-4-methoxycyclohexan-1-amine (65 mg, 0.50 mmol, 1 equiv) in DMF (2.5 mL) were added TCFH (282 mg, 1.00 mmol, 2 equiv) and NMI (206 mg, 2.51 mmol, 5 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The crude product was purified by reversed-phase flash chromatography (method 2) to afford 2-chloro-N-[(trans)-4-methoxycyclohexyl]-5H,6H,7H- cyclopenta[d]pyrimidine-4-carboxamide (117 mg, 75.01% yield) as a light yellow oil.[000178] To a stirred solution of 2-chloro-N-[(trans)-4-methoxycyclohexyl]-5H,6H,7H- cyclopenta [d]pyrimidine-4-carboxamide (50 mg, 0.16 mmol, 1 equiv) and imidazole (32 mg, 0.48 mmol, 3 equiv) in DMF (1 mL) were added CuI (30 mg, 0.16 mmol, 1 equiv) and K2CO3(66 mg, 0.48 mmol, 3.00 equiv) in portions at room temperature under nitrogen atmosphere. The mixture was stirred for 1 h at 120 °C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The crude product (50 mg) was purified by reversed- phase flash chromatography (method 2) to afford 2-(imidazol-1-yl)-N-[(trans)-4-methoxy cyclohexyl]-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxamide (17.1 mg, 30.76% yield) as a white solid. LCMS (ESI) [M+H]+:342.00.1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.74 (d, J = 8.6 Hz, 1H), 8.18 (s, 1H), 7.15 (s, 1H), 3.89 – 3.65 (m, 1H), 3.29 – 3.21 (m, 5H), 3.16 – 3.07 (m, 1H), 3.02 (t, J = 7.8 Hz, 2H), 2.17 – 1.98 (m, 4H), 1.83 (d, J = 12.1 Hz, 2H), 1.63 – 1.48 (m, 2H), 1.28 – 1.14 (m, 2H). Example 28: Synthesis of 2-(imidazol-1-yl)-N-[(trans)-4-(2-methoxyethoxy)cyclohexyl]-5 H,6H,7H-cyclopenta[d]pyrimidine-4-carboxamide (Compound 142) ..[000179] To a stirred mixture of 2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylic acid (50 mg, 0.21 mmol, 1 equiv), NMI (89 mg, 1.08 mmol, 5 equiv), TCFH (121 mg, 0.43 mmol, 2 equiv) in MeCN (0.5 ml) was added (trans)-4-(2- methoxyethoxy)cyclohexan-1-amine (56 mg, 0.32 mmol, 1.5 equiv) at room temperature under nitrogen atmosphere. The mixture was stirred for 15 min at room temperature under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeCN (3 x 1 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 5) to afford 2-(imidazol-1-yl)-N-[(trans)-4-(2- methoxyethoxy)cyclohexyl]-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxamide (20.1 mg, 24.01% yield) as an off-white solid. LCMS (ESI) [M+H]+: 386.20.1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.73 (d, J = 8.6 Hz, 1H), 8.19 (s, 1H), 7.15 (m, 1H), 3.88 – 3.74(m, 1H), 3.58 – 3.51 (m, 2H), 3.46 – 3.39 (m, 2H), 3.29 – 3.20 (m, 6H), 3.05 – 2.98 (m, 2H), 2.17 – 1.99 (m, 4H), 1.82 (d, J = 12.5 Hz, 2H), 1.63 – 1.48 (m, 2H), 1.28 – 1.20 (m, 2H). Example 29: Synthesis of 2-(imidazol-1-yl)-N-[(3S)-oxolan-3-yl]-5H,6H,7H- cyclopenta[d] pyrimidine-4-carboxamide (Compound 139)[000180] To a mixture of 2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylic acid (110 mg, 0.478 mmol, 1 equiv) in DMF (3 mL) was added (3S)-oxolan-3- amine (62 mg, 0.72 mmol, 1.5 equiv), DIEA (93 mg, 0.72 mmol, 1.5 equiv) and HATU (545 mg, 1.43 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was diluted with water and the resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by Prep- HPLC (method 4) to afford 2-(imidazol-1-yl)-N-[(3S)-oxolan-3-yl]-5H,6H,7H- cyclopenta[d]pyrimidine-4-carboxamide (22.5 mg, 15.69% yield) as a white solid. LCMS (ESI) [M+H]+: 300.15.1H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J = 7.4 Hz, 1H), 8.91 (d, J = 1.1 Hz, 1H), 8.19 (d, J = 1.4 Hz, 1H), 7.14 (s, 1H), 4.58 – 4.44 (m, 1H), 4.06 – 3.81 (m, 2H), 3.78 – 3.60 (m, 2H), 3.30 – 3.22 (m, 2H), 3.15 – 2.89 (m, 2H), 2.21 – 1.93 (m, 4H). Example 30: Synthesis of 2-(1H-imidazol-1-yl)-N-((trans)-4-(methoxy-d3)cyclohexyl)- 6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (Compound 137)..[000181] A solution of (trans)-4-aminocyclohexan-1-ol (500 mg, 4.341 mmol, 1 equiv), Cs2CO3(4.24 g, 13.023 mmol, 3 equiv) and BnBr (1.86 g, 10.853 mmol, 2.5 equiv) in acetonitrile (100 ml) was stirred for 1 h at room temperature. The reaction was diluted with water and the resulting mixture was extracted with EtOAc (3 x 100 mL), the combined organic phase was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford (trans)-4-(dibenzylamino)cyclohexan-1-ol (660 mg, 51.46% yield) as a white solid. [000182] To a stirred solution of (trans)-4-(dibenzylamino)cyclohexan-1-ol (640 mg, 2.166 mmol, 1 equiv) in THF (10 ml) was added NaH (173 mg, 4.332 mmol, 2 equiv) in portions at 0 °C under nitrogen atmosphere. The mixture was stirred for 20 mins at 0 °C under nitrogen atmosphere. To the above mixture was added iodomethane-d3(628 mg, 4.332 mmol, 2 equiv) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred for 30 min at 25 °C. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL) and the combined organic phase were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford (trans)-N,N-dibenzyl-4-(methoxy-d3)cyclohexan-1-amine (350 mg, 51.70% yield) as a light yellow oil. [000183] To a stirred solution of (trans)-N,N-dibenzyl-4-(methoxy-d3)cyclohexan-1- amine (330 mg, 1.056 mmol, 1 equiv) in MeOH (5 mL) was added Pd(OH)2 / C (66 mg, 0.095 mmol, 0.09 equiv, 20%) in portions at room temperature. The mixture was stirred for 16 h at25 °C under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure to afford (trans)-4-(methoxy-d3)cyclohexan-1-amine (130 mg, 93.10% yield) as a light yellow solid. [000184] To a stirred solution of (trans)-4-(methoxy-d3)cyclohexan-1-amine (40 mg, 0.303 mmol, 1 equiv), DIEA (100 mg, 0.774 mmol, 2.56 equiv) and 2-(imidazol-1-yl)- 5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxylic acid (60 mg, 0.261 mmol, 0.86 equiv) in DMF (10 mL) was added HATU (150 mg, 0.394 mmol, 1.30 equiv) in portions at room temperature. The mixture was stirred for 1 h at room temperature. The reaction was diluted with water and the resulting mixture was extracted with EtOAc (3 x 50 mL), and the combined organic phase dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (55 mg) was purified by Prep-HPLC (method 9) to afford 2-(1H-imidazol-1-yl)-N-((trans)-4-(methoxy-d3)cyclohexyl)-6,7- dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (23.9 mg, 22.75% yield) as a white solid. LCMS (ESI) [M+H]+: 345.25.1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.70 (d, J = 8.6 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.14 (d, J = 1.4 Hz,1H), 3.88 – 3.74 (m, 1H), 3.30 – 3.21 (m, 2H), 3.19 – 3.07 (m, 1H), 3.06 – 2.97 (m, 2H), 2.16 – 2.10 (m, 3H), 2.05 (d, J = 4.1 Hz, 1H), 1.88 – 1.79 (m, 2H), 1.60 – 1.48 (m, 2H), 1.29 – 1.14 (m, 2H). Example 31: Synthesis of 2-(imidazol-1-yl)-N-[(3R)-1-methyl-6-oxopiperidin-3-yl]- 5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxamide (Compound 136) .[000185] To a stirred solution of 2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylic acid (100 mg, 0.434 mmol, 1 equiv) and (5R)-5-amino-1-methylpiperidin-2-one (83 mg, 0.651 mmol, 1.5 equiv) in MeCN (3 mL) was added NMI (106 mg, 1.302 mmol, 3 equiv) and TCFH (365 mg, 1.302 mmol, 3 equiv) in portions at room temperature. The reaction was stirred for 1 h at room temperature. The mixture was concentrated underreduced pressure and the crude product (57 mg) was purified by Prep-HPLC (method 9) to afford 2-(imidazol-1-yl)-N-[(3R)-1-methyl-6-oxopiperidin-3-yl]-5H,6H,7H- cyclopenta[d]pyrimidine-4-carboxamide (33 mg, 22.46% yield) as a white solid. LCMS (ESI) [M+H]+: 341.20.1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.95(d, J = 8.2 Hz, 1H), 8.27(d, J = 1.7 Hz, 1H), 7.31 (s, 1H), 4.38 – 4.33 (m, 1H), 3.48 – 3.34 (m, 2H), 3.32 – 3.23 (m, 2H), 3.09 – 2.97 (m, 2H), 2.83 (s, 3H), 2.41 – 2.34 (m, 2H), 2.20 – 2.10 (m, 2H), 2.10 – 2.04 (m, 1H), 1.97 – 1.89 (m, 1H). Example 32: Synthesis of 2-(imidazol-1-yl)-N-[(3S)-5-oxopyrrolidin-3-yl]-5H,6H,7H- cyclopenta [d]pyrimidine-4-carboxamide (Compound 135) . .[000186] To a stirred mixture of 2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylic acid (100 mg, 0.43 mmol, 1.0 equiv) in DMF (4 mL) was added (4S)-4- aminopyrrolidin-2-one (52 mg, 0.521 mmol, 1.2 equiv), TCFH (244 mg, 0.87 mmol, 2.0 equiv) and NMI (107 mg, 1.30 mmol, 3.0 equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature. The crude product was purified by Prep-HPLC (method 8) to afford 2-(imidazol-1-yl)-N-[(3S)-5-oxopyrrolidin-3-yl]-5H,6H,7H- cyclopenta [d]pyrimidine-4-carboxamide (24.8 mg, 18.10% yield) as a white solid. LCMS (ESI) [M+H]+: 313.20.1H NMR (400 MHz, DMSO-d6) δ 9.20 (d, J = 7.8 Hz, 1H), 8.90 (d, J = 1.1 Hz, 1H), 8.19 (d, J = 1.4 Hz, 1H), 7.71 (s, 1H), 7.14 (s, 1H), 4.76 – 4.68 (m, 1H), 3.65 – 3.54 (m, 1H), 3.29 – 3.23 (m, 3H), 3.05 – 3.01 (m, 2H), 2.51 – 2.44 (m, 2H), 2.14 – 2.10 (m, 2H). Example 33: Synthesis of 2-(imidazol-1-yl)-N-[(trans)-4-cyanocyclohexyl]-5H,6H,7H- cyclopenta [d]pyrimidine-4-carboxamide (Compound 133)[000187] A solution of 2-chloro-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxylic acid (150 mg, 0.76 mmol, 1.0 equiv), (trans)-4-aminocyclohexane-1-carbonitrile (188 mg, 1.51 mmol, 2.0 equiv), TCFH (424 mg, 1.51 mmol, 2.0 equiv) and NMI (124 mg, 1.51 mmol, 2.0 equiv) in ACN (5 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The crude product was purified by reversed-phase flash chromatography (method 1) to afford 2-chloro-N-[(trans)-4-cyanocyclohexyl]-5H,6H,7H-cyclopenta[d] pyrimidine-4- carboxamide (160 mg, 69.51% yield) as a light yellow solid. [000188] A solution of 2-chloro-N-[(trans)-4-cyanocyclohexyl]-5H,6H,7H-cyclopenta[d] pyrimidine-4-carboxamide (70 mg, 0.23 mmol, 1.0 equiv), imidazole (156 mg, 2.30 mmol, 10.0 equiv) and K2CO3(95 mg, 0.69 mmol, 3.0 equiv) in DMF (4 mL) was stirred for 1 h at 90 °C under nitrogen atmosphere. The mixture was purified by Prep-HPLC (method 6) to afford 2-(imidazol-1-yl)-N-[(trans)-4-cyanocyclohexyl]-5H,6H,7H-cyclopenta[d]pyrimidine- 4-carboxamide (22 mg, 28.19% yield) as a white solid. LCMS (ESI) [M+H]+: 337.25.1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 1.3 Hz, 1H), 8.76 (d, J = 8.5 Hz, 1H), 8.22 – 8.11 (m, 1H), 7.14 (d, J = 1.3 Hz, 1H), 3.91 – 3.78 (m, 1H), 3.29 – 3.21 (m, 2H), 3.10 – 2.90 (m, 2H), 2.71 – 2.59 (m, 1H), 2.21 – 2.01 (m, 4H), 1.91 – 1.78 (m, 2H), 1.72 – 1.46 (m, 4H). Example 34: Synthesis of 2-(imidazol-1-yl)-N-[(trans)-4-(trifluoromethyl)cyclohexyl]- 5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxamide (Compound 132)[000189] To a mixture of 2-chloro-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxylic acid (100 mg, 0.50 mmol, 1.0 equiv) in ACN (5 mL) was added (trans)-4-aminocyclohexane-1- carbonitrile (125 mg, 1.00 mmol, 2.0 equiv), TCFH (283 mg, 1.00 mmol, 2.0 equiv) and NMI (124 mg, 1.51 mmol, 3.0 equiv) in portions at room temperature. The reaction was stirred for1 h at room temperature. The mixture was concentrated under reduced pressure and the residue was purified by reversed-phase flash chromatography (method 1) to afford 2-chloro- N-[(trans)-4-cyanocyclohexyl]-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxamide (80 mg, 52.13% yield) as a yellow solid. [000190] To a mixture of 2-chloro-N-[(trans)-4-(trifluoromethyl)cyclohexyl]-5H,6H,7H- cyclopenta [d]pyrimidine-4-carboxamide (75 mg, 0.22 mmol, 1.0 equiv) in DMF (3 mL) was added imidazole (147 mg, 2.16 mmol, 10.0 equiv) and K2CO3(89 mg, 0.65 mmol, 3.0 equiv) in portions at room temperature. The mixture was stirred for 1 h at 90 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The residue was purified by Prep-HPLC (method 6) to afford 2-(imidazol-1-yl)-N-[(trans)-4- (trifluoromethyl)cyclohexyl]-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxamide (21.3 mg, 25.80% yield) as a white solid. LCMS (ESI) [M+H]+: 380.10.1H NMR (400 MHz, DMSO- d6) δ 8.89 (s, 1H), 8.78 (d, J = 8.5 Hz, 1H), 8.17 (s, 1H), 7.14 (s, 1H), 3.90 – 3.75 (m, 1H), 3.28 – 3.22 (m, 2H), 3.04 – 2.92 (m, 2H), 2.31 – 2.19 (m, 1H), 2.19 – 2.03 (m, 2H), 1.98 – 1.88 (m, 4H), 1.68 – 1.50 (m, 2H), 1.50 – 1.29 (m, 2H). Example 35: Synthesis of 2-(1H-imidazol-1-yl)-N-((trans)-3- (methylcarbamoyl)cyclobutyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (Compound 131)[000191] To a stirred solution of 2-chloro-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylic acid (300 mg, 1.510 mmol, 1.0 equiv) and methyl (trans)-3-aminocyclobutane-1- carboxylate (292 mg, 2.265 mmol, 1.5 equiv) in MeCN (10 mL) were added NMI (372 mg,4.530 mmol, 3.0 equiv) and TCFH (1271 mg, 4.530 mmol, 3.0 equiv) at 25 °C. The reaction was stirred for 1 h at room temperature. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl (trans)-3-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidine-4- amido}cyclobutane-1-carboxylate (200 mg, 42.75% yield) as a colorless oil. [000192] A solution of methyl (trans)-3-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidine-4- amido} cyclobutane-1-carboxylate (200 mg, 0.646 mmol, 1.0 equiv), imidazole (87 mg, 1.292 mmol, 2.0 equiv) and K2CO3(267 mg, 1.938 mmol, 3.0 equiv) in DMF (10 mL) was stirred for 3 h at 100 °C under nitrogen atmosphere. The reaction was diluted with water and the resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic phase were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford (trans)-3-[2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4- amido]cyclobutane-1-carboxylic acid (150 mg, 61.51% yield) as a light green solid. [000193] To a stirred solution of (trans)-3-[2-(imidazol-1-yl)-5H,6H,7H- cyclopenta[d]pyrimidine-4-amido]cyclobutane-1-carboxylic acid (145 mg, 0.443 mmol, 1.0 equiv) and methanamine hydrochloride (134 mg, 0.886 mmol, 2.0 equiv) in MeCN (10 mL) was added TCFH (372 mg, 1.329 mmol, 3.0 equiv) and NMI (109 mg, 1.329 mmol, 3.0 equiv) at room temperature. The reaction was stirred for 1 h at room temperature. The mixture was concentrated under reduced pressure and the crude product (200 mg) was purified by Prep-HPLC (method 8) to afford 2-(1H-imidazol-1-yl)-N-((trans)-3- (methylcarbamoyl)cyclobutyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (21.8 mg, 14.26% yield) as a light yellow solid. LCMS (ESI) [M+H]+: 341.15.1H NMR (400 MHz, DMSO-d6) δ 9.12 (d, J = 8.3 Hz, 1H), 8.92 (s, 1H), 8.20 (s, 1H), 7.79 – 7.71 (m, 1H), 7.15 (s, 1H), 4.74 – 4.59 (m, 1H), 3.29 – 3.21 (m, 2H), 3.06 – 2.98 (m, 2H), 2.96 – 2.86 (m, 1H), 2.63 – 2.57 (m, 3H), 2.49 – 2.28 (m, 4H), 2.18 – 2.06 (m, 2H). Example 36: Synthesis of 2-(imidazol-1-yl)-N-[(trans)-4-(methylcarbamoyl)cyclohexyl]- 5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxamide & 2-(imidazol-1-yl)-N-[(cis)-4- (methyl carbamoyl)cyclohexyl]-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxamide (Compounds 129 and 130)[000194] To a mixture of 2-chloro-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxylic acid (300 mg, 1.51 mmol, 1.0 equiv) in ACN (5 mL) was added methyl (trans)-4- aminocyclohexane-1-carbo xylate (356 mg, 2.27 mmol, 1.5 equiv), NMI (248 mg, 3.02 mmol, 2.0 equiv) and TCFH (1271 mg, 4.53 mmol, 3.0 equiv) in portions at room temperature under nitrogen atmosphere and the mixture was stirred for 1h. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford methyl (trans)-4-{2-chloro- 5H,6H,7H-cyclopenta[d]pyrimidine-4-amido}cyclohexane-1-carboxylate (280 mg, 54.88% yield) as a yellow solid. [000195] To a mixture of methyl (trans)-4-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidine- 4-amido} cyclohexane-1-carboxylate (270 mg, 0.80 mmol, 1.0 equiv) in DMF (5 mL) was added imidazole (544 mg, 7.99 mmol, 10.0 equiv) and K2CO3(331 mg, 2.40 mmol, 3.0 equiv) in portions at room temperature under nitrogen atmosphere. The mixture was stirred for 12 h at 90 °C under nitrogen atmosphere and then allowed to cool down to room temperature. The residue was purified by reversed-phase flash chromatography (method 1) to afford methyl (trans)-4-[2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4- amido]cyclohexane-1-carboxylate & methyl (cis)-4-[2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4-amido]cyclohexane-1-carboxylic acid (mix) (160 mg, 54.19% yield) as a brown solid. [000196] To a mixture of methyl (trans)-4-[2-(imidazol-1-yl)-5H,6H,7H- cyclopenta[d]pyrimidine-4-amido]cyclohexane-1-carboxylate & methyl (cis)-4-[2-(imidazol- 1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4-amido]cyclohexane-1-carboxylic acid (mix) (110 mg, 0.31 mmol, 1.0 equiv) in ACN (4 mL) was added 2 M Methylamine in THF (0.75 mL, 0.465 mmol, 1.5 equiv), TCFH (174 mg, 0.62 mmol, 2.0 equiv) and NMI (76 mg, 0.93 mmol, 3.0 equiv) in portions at room temperature. The mixture was stirred for 1 h at room temperature under nitrogen atmosphere and then concentrated under reduced pressure. The crude product (110 mg) was purified by Prep-HPLC (method 6) to afford 2-(imidazol-1-yl)- N-[(trans)-4-(methylcarbamoyl)cyclohexyl]-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxamide (27.6 mg, 24.17%) and 2-(imidazol-1-yl)-N-[(cis)-4- (methylcarbamoyl)cyclohexyl]-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxamide (17.0 mg, 14.96%) as a white solid. Compound 130: LCMS (ESI) [M+H]+: 369.25.1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.74 (s, 1H), 8.19 (s, 1H), 7.72 (s, 1H), 7.14 (s, 1H), 3.93 – 3.62 (m, 1H), 3.31 – 3.21 (m, 2H), 3.08 – 3.02 (m, 2H), 2.57 (d, J = 4.5 Hz, 3H), 2.18 – 2.04 (m, 3H), 1.89 – 1.74 (m, 4H), 1.62 – 1.37 (m, 4H). Compound 129: LCMS (ESI) [M+H]+: 369.15.1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.74 (s, 1H), 8.25 – 8.14 (m, 1H), 7.72 (s, 1H), 7.14 (s, 1H), 3.89 – 3.73 (m, 1H), 3.25 – 3.24 (m, 2H), 3.02 (d, J = 7.8 Hz, 2H), 2.57 (d, J = 4.6 Hz, 3H), 2.18 – 2.04 (m, 3H), 1.90 – 1.76 (m, 4H), 1.61 – 1.38 (m, 4H). Example 37: Synthesis of 7-hydroxy-2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]- 5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxamide and 2-(imidazol-1-yl)-4-{[(trans)-4- methoxycyclohexyl]carbamoyl}-5H,6H, 7H-cyclopenta[d]pyrimidin-7-yl acetate (Compounds 124 and 144)[000197] A solution of 2,4-dichloro-5H, 6H, 7H-cyclopenta[d]pyrimidine (2 g, 10.580 mmol, 1.0 equiv) and Pb(OAc)4(9.38 g, 21.160 mmol, 2.0 equiv) in AcOH (40 mL) was stirred for 28 h at 120 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the crude product purified by reversed-phase flash chromatography (method 1) to afford 2,4-dihydroxy-5H, 6H, 7H-cyclopenta [d]pyrimidin-7- yl acetate (700 mg, 31.48% yield) as a light yellow solid. [000198] To a stirred mixture of 2,4-dihydroxy-5H, 6H, 7H-cyclopenta[d]pyrimidin-7-yl acetate (580 mg, 2.76 mmol, 1.0 equiv) in ACN (5 mL) was added POCl3(1.27 g, 8.27 mmol, 3.0 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 80 °C under nitrogen atmosphere and then allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford 2,4-dichloro-5H, 6H, 7H-cyclopenta[d] pyrimidin-7-yl acetate (280 mg, 41.07% yield) as a light yellow oil. [000199] A solution of 2,4-dichloro-5H, 6H, 7H-cyclopenta[d]pyrimidin-7-yl acetate (270 mg, 1.09 mmol, 1.0 equiv), tributyl(1-ethoxyethenyl)stannane (395 mg, 1.09 mmol, 1.0 equiv) and Pd(PPh3)2Cl2(77 mg, 0.11 mmol, 0.1 equiv) in DMF (20 mL) was stirred for 1 h at 65 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched with KF (aq). And the mixture was diluted with water. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organiclayers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford 2-chloro-4-(1-ethoxyethenyl)-5H, 6H, 7H-cyclopenta[d]pyrimidin-7-yl acetate (200 mg, 64.74% yield) as a light yellow oil. [000200] To a stirred mixture of 2-chloro-4-(1-ethoxyethenyl)-5H, 6H, 7H- cyclopenta[d]pyrimidin-7-yl acetate (190 mg, 0.67 mmol, 1.0 equiv) in dioxane (5 mL) and H2O (5 mL) was added NaIO4(287 mg, 1.34 mmol, 2.0 equiv) and KMnO4(53 mg, 0.34 mmol, 0.5 equiv) in portions at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with Na2S2O3(aq) and NaHCO3(aq) at 0 °C. The mixture was diluted with water and the resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 7-(acetyloxy)-2- chloro-5H, 6H, 7H-cyclopenta[d]pyrimidine-4-carboxylic acid (100 mg, 57.98% yield) as a light yellow oil. [000201] To a mixture of 7-(acetyloxy)-2-chloro-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylic acid (670 mg, 2.61 mmol, 1.0 equiv) in ACN (10 mL) was added (trans)-4- methoxycyclohexan-1-amine (506 mg, 3.92 mmol, 1.5 equiv), TCFH (1.10 g, 3.92 mmol, 1.5 equiv) and NMI (643 mg, 7.83 mmol, 3.0 equiv) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography (method 1) to afford 2-chloro-4-{[(trans)-4- methoxycyclohexyl]carbamoyl}-5H,6H,7H-cyclopenta[d]pyrimidin-7-yl acetate (580 mg, 60.40% yield) as a light yellow solid. [000202] A mixture of 2-chloro-4-{[(trans)-4-methoxycyclohexyl]carbamoyl}- 5H,6H,7H-cyclopenta[d]pyrimidin-7-yl acetate (570 mg, 1.55 mmol, 1.0 equiv) and imidazole (316 mg, 4.65 mmol, 3.0 equiv) in DMF (8 mL) was stirred for overnight at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and the crude product was purified by reversed-phase flash chromatography (method 1) to afford 2-(imidazol-1-yl)-4-{[(trans)-4-methoxycyclohexyl]carbamoyl}- 5H,6H,7H-cyclopenta[d]pyrimidin-7-yl acetate (380 mg, 61.39% yield) as a light yellow solid. LCMS (ESI) [M+H]+: 400.20.1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H),8.80 (d, J = 8.5 Hz, 1H), 8.15 (s, 1H), 7.16 (s, 1H), 6.17 – 6.09 (m, 1H), 3.88 – 3.73 (m, 1H), 3.41 (s, 1H), 3.26 (s, 3H), 3.20 – 3.10 (m, 2H), 2.66 – 2.57 (m, 1H), 2.12 (s, 3H), 2.10 – 1.96 (m, 3H), 1.91 – 1.76 (m, 2H), 1.62 – 1.49 (m, 2H), 1.29 – 1.21 (m, 2H). [000203] To a mixture of 2-(imidazol-1-yl)-4-{[(trans)-4- methoxycyclohexyl]carbamoyl}-5H,6H, 7H-cyclopenta[d]pyrimidin-7-yl acetate (370 mg, 0.93 mmol, 1.0 equiv) in MeOH (4 mL) and H2O (1 mL) was added LiOH (222 mg, 9.26 mmol, 10.0 equiv) in portions at 0 °C. The mixture was stirred for 1 h at room temperature and then acidified to pH 5 with 1 M HCl (aq). The resulting mixture was concentrated under reduced pressure and the crude product was purified by Prep-HPLC (method 8) to afford 7- hydroxy-2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]-5H,6H,7H- cyclopenta[d]pyrimidine-4-carboxamide (17.1 mg, 5.05% yield) as a white solid. LCMS (ESI) [M+H]+: 358.15.1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.75 (d, J = 8.6 Hz, 1H), 8.19 (s, 1H), 7.16 (s, 1H), 5.82 (d, J = 6.2 Hz, 1H), 5.03 (d, J = 6.9 Hz, 1H), 3.92 – 3.74 (m, 1H), 3.41 (s, 1H), 3.26 (s, 3H), 3.19 – 2.98 (m, 2H), 2.47 – 2.39 (m, 1H), 2.06 (d, J = 12.1 Hz, 2H), 1.96 – 1.70 (m, 3H), 1.69 – 1.40 (m, 2H), 1.38 – 1.07 (m, 2H). Example 38: Synthesis of N-((trans)-4-methoxycyclohexyl)-2-(1-methyl-1H-imidazol-5- yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (Compound 127)[000204] A solution of methyl 2-chloro-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylate (500 mg, 2.352 mmol, 1.0 equiv), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)imidazole (733 mg, 3.528 mmol, 1.5 equiv), Pd(dppf)Cl2(172 mg, 0.235 mmol, 0.1 equiv) and K2CO3(974 mg, 7.056 mmol, 3.0 equiv) in dioxane (10 mL) and H2O (2 mL) was stirred for 1 h at 90 °C under nitrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by reversed-phase flash chromatography (method1 ) to afford methyl 2-(3-methylimidazol-4-yl)-5H,6H,7H- cyclopenta[d]pyrimidine-4-carboxylate (350 mg, 57.63% yield) as a yellow solid.[000205] A solution of methyl 2-(3-methylimidazol-4-yl)-5H,6H,7H- cyclopenta[d]pyrimidine-4-carboxylate (340 mg, 1.316 mmol, 1.0 equiv) and LiOH (315 mg, 13.160 mmol, 10 equiv) in THF (10 mL) and H2O (2.5 mL) was stirred for 1 h at room temperature. The mixture was acidified to pH 6 with 1 M HCl (aq.) and then concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford 2-(3-methylimidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylic acid (280 mg, 87.08% yield) as a light yellow solid. [000206] A solution of 2-(3-methylimidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylic acid (80 mg, 0.328 mmol, 1 equiv), (trans)-4-methoxycyclohexan-1-amine (63 mg, 0.492 mmol, 1.5 equiv), TCFH (275 mg, 0.984 mmol, 3 equiv) and NMI (80 mg, 0.984 mmol, 3 equiv) in ACN (5 mL) was stirred for 2 h at room temperature. The mixture was concentrated under reduced pressure and the crude product (80 mg) was purified by Prep- HPLC (method 8) to afford N-((trans)-4-methoxycyclohexyl)-2-(1-methyl-1H-imidazol-5- yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (25.8 mg, 22.14% yield) as a white solid. LCMS (ESI) [M+H]+: 356.15.1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 1.2 Hz, 1H), 7.82 (s, 1H), 4.03 (s, 3H), 3.83 – 3.69 (m, 1H), 3.28 – 3.19 (m, 5H), 3.16 – 3.07(m, 1H), 3.05 – 2.92 (m, 2H), 2.13 – 1.95 (m, 4H), 1.86 (d, J = 10.4 Hz, 2H), 1.59 – 1.40 (m, 2H), 1.32 – 1.14 (m, 2H). Example 39: Synthesis of N-((trans)-4-hydroxycyclohexyl)-2-(1-methyl-1H-imidazol-5- yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (Compound 126) .[000207] A solution of 2-(3-methylimidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxy lic acid (80 mg, 0.328 mmol, 1.0 equiv), (trans)-4-aminocyclohexan-1-ol (56 mg, 0.492 mmol, 1.5 equiv), TCFH (275 mg, 0.984 mmol, 3.0 equiv) and NMI (80 mg, 0.984 mmol, 3 equiv) in ACN (5 mL) was stirred for 2 h at room temperature. The mixture was concentrated under reduced pressure and the crude product (60 mg) was purified by Prep- HPLC (method 6) to afford N-((trans)-4-hydroxy cyclohexyl)-2-(1-methyl-1H-imidazol-5-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (35 mg, 31.11% yield) as a white solid. LCMS (ESI) [M+H]+: 342.10.1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.52 (s, 1H), 8.46 (d, J = 8.5 Hz, 1H), 4.19 (s, 3H), 3.82 – 3.69 (m, 1H), 3.48 – 3.36 (m, 1H), 3.31 – 3.22 (m, 2H), 3.07 – 2.99 (m, 2H), 2.17 – 2.05 (m, 2H), 1.91 – 1.77 (m, 4H), 1.57 – 1.42 (m, 2H), 1.34 – 1.20 (m, 2H). Example 40: Synthesis of 2-(1H-imidazol-1-yl-d3)-N-((trans)-4-methoxycyclohexyl)-6,7- dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (Compound 125)A solution of methyl 2-chloro-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxylate (150 mg, 0.705 mmol, 1 equiv), 1H-imidazole-d4(76 mg, 1.057 mmol, 1.5 equiv) and K2CO3(292 mg, 2.115 mmol, 3 equiv) in DMF (10 mL) was stirred for 2 h at 90 °C. The crude product was purified by reversed-phase flash chromatography (method 1) to afford 2-(1H-imidazol-1- yl-d3)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxylic acid (90 mg, 54.70% yield) as a light yellow solid. [000208] A solution of 2-(1H-imidazol-1-yl-d3)-6,7-dihydro-5H-cyclopenta[d]pyrimidine- 4-carboxylic acid (80 mg, 0.343 mmol, 1.0 equiv), (trans)-4-methoxycyclohexan-1-amine (66 mg, 0.515 mmol, 1.5 equiv), TCFH (288 mg, 1.029 mmol, 3 equiv) and NMI (84 mg, 1.029 mmol, 3 equiv) in ACN (5 mL) was stirred for 2 h at room temperature. The mixture was concentrated under reduced pressure and the crude product (60 mg) was purified by Prep- HPLC (method 5) to afford 2-(1H-imidazol-1-yl-d3)-N-((trans)-4-methoxycyclohexyl)-6,7- dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (32.3 mg, 27.34% yield) as a white solid. LCMS (ESI) [M+H]+: 345.40.1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 8.6 Hz, 1H), 3.87 – 3.74 (m, 1H), 3.31 – 3.22 (m, 5H), 3.18 – 3.12 (m, 1H), 3.12 – 2.96 (m, 2H), 2.12 – 2.02 (m, 4H), 1.88 – 1.79 (m, 2H), 1.63 –1.48 (m, 2H), 1.29 – 1.15 (m, 2H). Example 41: Synthesis of N-((trans)-4-hydroxycyclohexyl)-2-(1H-imidazol-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (Compound 123)[000209] A solution of 2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylic acid (100 mg, 0.434 mmol, 1.0 equiv), (trans)-4-aminocyclohexan-1-ol (75 mg, 0.651 mmol, 1.5 equiv), TCFH (365 mg, 1.302 mmol, 3 equiv) and NMI (106 mg, 1.302 mmol, 3.0 equiv) in ACN (5 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure and the crude product (80 mg) was purified by Prep-HPLC (method 6) to afford N-((trans)-4-hydroxycyclohexyl)-2-(1H-imidazol-1-yl)- 6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (21.2 mg, 14.58% yield) as an off- white solid. LCMS (ESI) [M+H]+: 328.15.1H NMR (400 MHz, DMSO-d6) δ 8.90 (d, J = 1.2 Hz, 1H), 8.69 (d, J = 8.7 Hz, 1H), 8.19 (s, 1H), 7.14 (s, 1H), 4.60 (d, J = 4.4 Hz, 1H), 3.78 (d, J = 7.2 Hz, 1H), 3.42 (d, J = 4.4 Hz, 1H), 3.29 – 3.20 (m, 2H), 3.08 – 2.94 (m, 2H), 2.20 – 2.03 (m, 2H), 1.88 (d, J = 12.3 Hz, 2H), 1.77 (d, J = 12.7 Hz, 2H), 1.63 – 1.45 (m, 2H), 1.34 – 1.17 (m, 2H). Example 42: Synthesis of N-((trans)-4-(2-hydroxypropan-2-yl)cyclohexyl)-2-(1H- imidazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (Compound 122) . .[000210] A solution of 2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylic acid (100 mg, 0.434 mmol, 1 equiv), 2-[(trans)-4-aminocyclohexyl]propan-2-ol (102 mg, 0.651 mmol, 1.5 equiv), TCFH (365 mg, 1.302 mmol, 3 equiv) and NMI (106 mg, 1.302 mmol, 3 equiv) in ACN (1 mL) was stirred for 1 h at room temperature. The mixture was concentrated under reduced pressure and the crude product (80 mg) was purified by Prep-HPLC (method 8) to afford N-((trans)-4-(2-hydroxypropan-2-yl) cyclohexyl)-2-(1H- imidazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (24.1 mg, 14.64%yield) as an off-white solid. LCMS (ESI) [M+H]+: 370.20.1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.72 (d, J = 8.7 Hz, 1H), 8.19 (s, 1H), 7.14 (s, 1H), 4.08 (s, 1H), 3.88 – 3.52 (m, 1H), 3.30 – 3.21 (m, 2H), 3.07 – 2.96 (m, 2H), 2.18 – 2.05 (m, 2H), 1.92 – 1.78 (m, 4H), 1.59 – 1.40 (m, 2H), 1.26 – 1.07 (m, 3H), 1.05 (s, 6H). Example 43: Synthesis of N-[(trans)-4-methoxycyclohexyl]-2-(1,3-thiazol-5-yl)-5H,6H,7 H-cyclopenta[b]pyridine-4-carboxamide (Compound 107)[000211] To a stirred solution of 2-(1,3-thiazol-5-yl)-5H,6H,7H-cyclopenta[b]pyridine-4- carboxylic acid (80 mg, 0.32 mmol, 1 equiv) and trans-4-methoxycyclohexan-1-amine (83 mg, 0.65 mmol, 2 equiv) in DMF (2.5 mL) were added TCFH (136 mg, 0.48 mmol, 1.5 equiv) and NMI (80 mg, 0.97 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 5 mL). The filtrate was concentrated under reduced pressure. The crude product (80 mg) was purified by Prep-HPLC (method 8) to afford N-[(trans)-4-methoxycyclohexyl]-2-(1,3-thiazol-5-yl)- 5H,6H,7H-cyclopenta[b]pyridine-4-carboxamide (22.6 mg, 19.28% yield) as a white solid. LCMS (ESI) [M+H]+:358.00.1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.58 (s, 1H), 8.37 (d, J = 7.7 Hz, 1H), 7.84 (s, 1H), 3.78 – 3.72 (m, 1H), 3.24 (s, 3H), 3.17 – 3.08 (m, 1H), 3.04 (t, J = 7.4 Hz, 2H), 2.96 (t, J = 7.7 Hz, 2H), 2.13 – 1.99 (m, 4H), 1.90 (d, J = 12.6 Hz, 2H), 1.42 – 1.30 (m, 2H), 1.30 – 1.15 (m, 2H). Example 44: Synthesis of 2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]-5H,6H,7H- cyclopenta[b]pyridine-4-carboxamide (Compound 138).[000212] To a stirred mixture of methyl 2-chloro-5H,6H,7H-cyclopenta[b]pyridine-4- carboxylate (200 mg, 0.95 mmol, 1.0 equiv) in THF (5 mL) and H2O (2 mL) was added NaOH (19 mg, 0.47 mmol, 0.5 equiv) in portions at 0 °C. The resulting mixture was stirred for additional 1 h at room temperature. The reaction was acidified to pH 6 with 1 M HCl (aq.). The resulting mixture was concentrated under reduced pressure and the residue was purified by reversed-phase flash chromatography (method 1) to afford 2-chloro- 5H,6H,7H-cyclopenta[b]pyridine-4-carboxylic acid (140 mg, 74.97% yield) as a yellow solid. [000213] To a stirred mixture of 2-chloro-5H,6H,7H-cyclopenta[b]pyridine-4-carboxylic acid (130 mg, 0.66 mmol, 1.0 equiv) in DMF (3 mL) were added (trans)-4- methoxycyclohexan-1-amine (127 mg, 0.99 mmol, 1.5 equiv), HATU (375 mg, 0.99 mmol, 1.5 equiv) and DIEA (255 mg, 1.97 mmol, 3.0 equiv) in portions at room temperature. The reaction was stirred for 1 h at room temperature under nitrogen atmosphere. The mixture was diluted with water and the resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford 2-chloro-N-((trans)-4- methoxycyclohexyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-carboxamide (80 mg, 33.05% yield) as a yellow solid. [000214] A mixture of 2-chloro-N-((trans)-4-methoxycyclohexyl)-6,7-dihydro-5H- cyclopenta[b] pyridine-4-carboxamide (80 mg, 0.26 mmol, 1.0 equiv), imidazole (353 mg, 5.18 mmol, 20.0 equiv), t-BuBrettphos (25 mg, 0.05 mmol, 0.2 equiv), t-BuBrettPhos Pd G3(22 mg, 0.03 mmol, 0.1 equiv) and Cs2CO3(253 mg, 0.78 mmol, 3.0 equiv) in dioxane (4 mL) was stirred for 1 h at 120 °C under nitrogen atmosphere. The mixture was allowed tocool down to room temperature. After filtration, the filtrate was concentrated under reduced pressure. The crude product (35 mg) was purified by Prep-HPLC (method 8) to afford 2- (imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]-5H,6H,7H-cyclopenta[b]pyridine-4- carboxamide (20.3 mg, 23.00% yield) as a white solid. LCMS (ESI) [M+H]+: 341.20.1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 1.2 Hz, 1H), 8.35 (d, J = 7.7 Hz, 1H), 7.94 (d, J = 1.5 Hz, 1H), 7.62 (s, 1H), 7.11 (d, J = 1.2 Hz, 1H), 3.89 – 359 (m, 1H), 3.24 (s, 3H), 3.20 – 3.19 (m, 1H), 3.01 – 2.92 (m, 2H), 2.97 (d, J = 7.7 Hz, 2H), 2.25 – 2.08 (m, 2H), 2.06 – 1.98 (m, 2H), 1.95 – 1.87 (m, 2H), 1.42 – 1.29 (m, 2H), 1.29 – 1.17 (m, 2H). Example 45: Synthesis of N-((trans)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-2-(1H- imidazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (Compound 176)[000215] A mixture of 2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylic acid (90 mg, 0.391 mmol, 1 equiv), (trans)-4-amino-1- (trifluoromethyl)cyclohexan-1-ol (107 mg, 0.587 mmol, 1.5 equiv), TCFH (329 mg, 1.173 mmol, 3 equiv) and NMI (96 mg, 1.173 mmol, 3 equiv) in ACN (5 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 6) to afford N- ((trans)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine-4-carboxamide (36.9 mg, 23% yield) as a white solid. LCMS (ESI) [M+H]+: 396.20.1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.59 (d, J = 6.7 Hz, 1H), 8.15 (s, 1H), 7.22 (s, 1H), 5.83 (s, 1H), 4.11 – 3.98 (m, 1H), 3.28 – 3.15 (m, 2H), 3.10 – 2.97 (m, 2H), 2.19 – 2.05 (m, 2H), 1.98 – 1.73 (m, 6H), 1.68 – 1.53 (m, 2H). Example 46: Synthesis of N-((trans)-4-hydroxy-4-methylcyclohexyl)-2-(1H-imidazol-1- yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (Compound 189)[000216] A solution of^2,4-dichloro-5H,6H,7H-cyclopenta[d]pyrimidine (10 g, 52.899 mmol, 1 equiv), tributyl(1-ethoxyethenyl)stannane (19.10 g, 52.899 mmol, 1. equiv)^and^Pd(PPh3)2Cl2(3.71 g, 5.290 mmol, 0.1 equiv)^in^DMF (40 mL)^was stirred for 12 h^at 65 °C under nitrogen atmosphere. The reaction was quenched with^KF (aq). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with^PE / EA^(5:1) to afford^2-chloro-4-(1-ethoxyethenyl)-5H,6H,7H- cyclopenta[d]pyrimidine (6 g, 51% yield)^as a^brown^solid. [000217] To a stirred solution of^2-chloro-4-(1-ethoxyethenyl)-5H,6H,7H- cyclopenta[d]pyrimidine (6 g, 26.703 mmol, 1 equiv)^in^dioxane (50 mL) and water (20 mL)^was added^NaIO4(11.42 g, 53.406 mmol, 2.00 equiv)^and^KMnO4(2.11 g, 13.351 mmol, 0.5 equiv)^in portions at 0 °C. The mixture was stirred^for 12 h^at^room temperature. The reaction was quenched with^Na2S2O3(aq)^at 0 °C. The resulting mixture was extracted with^EtOAc^(3^x 300 mL), dried over anhydrous^Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in^ethyl 2-chloro-5H,6H,7H- cyclopenta[d]pyrimidine-4-carboxylate (3.2 g, 53% yield)^as a^brown^solid. [000218] A mixture of^ethyl 2-chloro-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxylate (1.5 g, 6.618 mmol, 1 equiv), imidazole (0.90 g, 13.236 mmol, 2 equiv)^and^K2CO3(2.74 g, 19.854 mmol, 3 equiv)^in^DMF (10 mL)^was stirred for 4 h^at 100 °C^under^nitrogen^atmosphere. The residue was purified by reversed-phase flash chromatography (method 1). This resulted in^2-(imidazol-1-yl)-5H,6H,7H- cyclopenta[d]pyrimidine-4-carboxylic acid (800 mg, 53% yield)^as an^off-white^solid.[000219] A solution of^2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylic acid (70 mg, 0.304 mmol, 1 equiv), (trans)-4-amino-1-methylcyclohexan-1-ol (58 mg, 0.456 mmol, 1.5 equiv), TCFH (255 mg, 0.912 mmol, 3 equiv)^and^NMI (74 mg, 0.912 mmol, 3 equiv)^in^ACN (5 mL)^was stirred for 1 h^at^room temperature. The mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 7) to afford^2-(imidazol-1-yl)-N-[(trans)-4-hydroxy-4-methylcyclohexyl]-5H,6H,7H- cyclopenta[d]pyrimidine-4-carboxamide (36.4 mg, 34% yield)^as a^white^solid. LCMS (ESI) [M+H]+: 342.15.1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.65 (d, J = 8.5 Hz, 1H), 8.16 (s, 1H), 7.15 (s, 1H), 4.34 (s, 1H), 3.88 – 3.77 (m, 1H), 3.29 – 3.22 (m, 2H), 3.08 – 2.98 (m, 2H), 2.18 – 2.05 (m, 2H), 1.78 – 1.65 (m, 2H), 1.69 – 1.55 (m, 4H), 1.51 – 1.39 (m, 2H), 1.21 (s, 3H). Example 47: Synthesis of N-((cis)-4-hydroxy-4-methylcyclohexyl)-2-(1H-imidazol-1-yl)- 6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (Compound 188)[000220] A mixture of 2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylic acid (50 mg, 0.217 mmol, 1 equiv), (cis)-4-amino-1-methylcyclohexan-1-ol (42 mg, 0.326 mmol, 1.5 equiv), TCFH (182 mg, 0.651 mmol, 3 equiv) and NMI (53 mg, 0.651 mmol, 3 equiv) in ACN (5 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 6) to afford N-((cis)-4-hydroxy-4- methylcyclohexyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4- carboxamide (32.5 mg, 43% yield) as a white solid. LCMS (ESI) [M+H]+: 342.10.1H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J = 1.2 Hz, 1H), 8.80 (d, J = 8.7 Hz, 1H), 8.21 (s, 1H), 7.18 (s, 1H), 4.13 (s, 1H), 3.87 – 3.66 (m, 1H), 3.28 – 3.18 (m, 2H), 3.10 – 2.95 (m, 2H), 2.19 – 2.03 (m, 2H), 1.98 – 1.83 (m, 2H), 1.67 – 1.56 (m, 2H), 1.51– 1.45 (m, 2H), 1.44 – 1.31 (m, 2H), 1.14 (s, 3H). Example 48: Synthesis of N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-2-(1H-imidazol-1-yl)- 6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (Compound 187)[000221] A solution of^2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylic acid (60 mg, 0.261 mmol, 1 equiv), 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (69 mg, 0.392 mmol, 1.5 equiv), TCFH (219 mg, 0.783 mmol, 3 equiv)^and^NMI (64 mg, 0.783 mmol, 3 equiv)^in^ACN (5 mL)^was stirred for 1 h^at^room temperature. The mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 8) to afford^N-{4-hydroxybicyclo[2.2.2]octan-1-yl}-2- (imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxamide (15.1 mg, 16% yield)^as a^white^solid. LCMS (ESI) [M+H]+: 354.10.1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.08 (s, 1H), 8.01 (s, 1H), 7.13 (s, 1H), 4.33 (s, 1H), 3.27 – 3.18 (m, 2H), 3.04 – 2.97 (m, 2H), 2.17 – 2.03 (m, 8H), 1.68 – 1.59(m, 6H). Example 49: Synthesis of N-((trans)-4-ethyl-4-hydroxycyclohexyl)-2-(1H-imidazol-1-yl)- 6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (Compound 185)[000222] To a stirred solution of^4-(dibenzylamino)cyclohexan-1-one (1 g, 3.408 mmol, 1 equiv) in Toluene (20 mL) was added triethylaluminium (17 mL, 17 mmol, 5 equiv, 1 M) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred for 1 h at room temperature. The reaction was quenched with 1 M NaOH (aq). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford (trans)-4-(dibenzylamino)-1-ethylcyclohexan-1-ol (assumed) (120 mg, 11% yield) &(cis)-4-(dibenzylamino)-1-ethylcyclohexan-1-ol (assumed) (75 mg, 6.8% yield) as white solid. [000223] A solution of (trans)-4-(dibenzylamino)-1-ethylcyclohexan-1-ol (assumed) (110 mg, 0.340 mmol, 1 equiv) and Pd / C (36 mg, 0.034 mmol, 0.1 equiv, 10% purity) in MeOH (2 mL) was stirred for 5 h at room temperature under hydrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford (trans)-4-amino-1- ethylcyclohexan-1-ol (assumed) (50 mg, 82% yield) as a white solid. [000224] A mixture of (trans)-4-amino-1-ethylcyclohexan-1-ol (assumed) (50 mg, 0.349 mmol, 1.5 equiv), 2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxylic acid (53 mg, 0.233 mmol, 1.00 equiv), TCFH (195 mg, 0.698 mmol, 3 equiv) and NMI (57 mg, 0.698 mmol, 3 equiv) in ACN (5 mL) was stirred for 1 h at room temperature. The mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 6) to afford N-((trans)-4-ethyl-4-hydroxycyclohexyl)-2-(1H-imidazol-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (assumed) (14.1 mg, 16.5% yield) as a white solid. LCMS (ESI) [M+H]+: 356.20.1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.63 (d, J = 8.5 Hz, 1H), 8.17 (s, 1H), 7.17 (s, 1H), 4.09 (s, 1H), 3.88 – 3.78 (m, 1H), 3.30 – 3.21 (m, 2H), 3.06 – 2.95 (m, 2H), 2.16 – 2.07 (m, 2H), 1.78 – 1.50 (m, 8H), 1.46 – 1.35 (m, 2H), 0.91 – 0.81 (m, 3H). Example 50: Synthesis of N-((cis)-4-ethyl-4-hydroxycyclohexyl)-2-(1H-imidazol-1-yl)- 6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (Compound 184)[000225] A mixture of (cis)-4-(dibenzylamino)-1-ethylcyclohexan-1-ol (assumed) (76 mg, 0.235 mmol, 1 equiv) and Pd / C (24 mg, 0.023 mmol, 0.1 equiv, 10% purity) in MeOH (5 mL)^was stirred for 5 h at room temperature under hydrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phaseflash chromatography (method 1) to afford (cis)-4-amino-1-ethylcyclohexan-1-ol (assumed) (45 mg, 94% yield) as a white solid. [000226] A solution of (cis)-4-amino-1-ethylcyclohexan-1-ol (assumed) (45 mg, 0.314 mmol, 1 equiv), 2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxylic acid (144 mg, 0.628 mmol, 2 equiv), TCFH (264 mg, 0.942 mmol, 3 equiv) and NMI (77 mg, 0.942 mmol, 3 equiv) in ACN (5 mL) was stirred for 1 h at room temperature. The mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 6) to afford N-((cis)-4-ethyl-4-hydroxycyclohexyl)-2-(1H-imidazol-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (assumed) (13.0 mg, 12% yield) as a white solid. LCMS (ESI) [M+H]+: 356.15.1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.81 (d, J = 8.7 Hz, 1H), 8.22 (s, 1H), 7.14 (s, 1H), 3.89 (s, 1H), 3.85 – 3.70 (m, 1H), 3.29 – 3.24 (m, 2H), 3.05 – 2.97 (m, 2H), 2.17 – 2.05 (m, 2H), 1.97 – 1.83 (m, 2H), 1.63 – 1.49 (m, 4H), 1.44 – 1.21 (m, 4H), 0.90 – 0.80 (m, 3H). Example 51: Synthesis of 2-(imidazol-1-yl)-N-[(trans)-3-methoxycyclobutyl]-5H,6H,7H- cyclopenta[d]pyrimidine-4-carboxamide (Compound 167)[000227] To a stirred solution of 2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylic acid (100 mg, 0.434 mmol, 1 equiv) and (trans)-3-methoxycyclobutan-1-amine hydrochloride (68 mg, 0.494 mmol, 1.14 equiv) in ACN (3 mL) was added TCFH (200 mg, 0.713 mmol, 1.64 equiv) and NMI (300 mg, 3.654 mmol, 8.41 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 2) to afford 2-(imidazol-1-yl)-N-[(trans)-3-methoxycyclobutyl]-5H,6H,7H- cyclopenta[d]pyrimidine-4-carboxamide (52.4 mg, 38% yield) as a white solid. LCMS (ESI) [M+H]+: 314.10.1H NMR (400 MHz, DMSO-d6) δ 9.12 (d, J = 7.7 Hz, 1H), 8.91 (s, 1H), 8.19 (s, 1H), 7.15 (s, 1H), 4.69 – 4.38 (m, 1H), 4.18 – 4.89 (m, 1H), 3.29 – 3.20 (m, 2H), 3.18 (s, 3H), 3.09 – 2.90 (m, 2H), 2.48 – 2.34 (m, 2H), 2.34 – 2.20 (m, 2H), 2.20 – 1.92 (m, 2H).Example 52: Synthesis of N-((trans)-4-(dimethylcarbamoyl)cyclohexyl)-2-(1H-imidazol- 1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (Compound 183)[000228] A mixture of 2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylic acid (200 mg, 0.869 mmol, 1 equiv), methyl (trans)-4-aminocyclohexane-1- carboxylate (205 mg, 1.304 mmol, 1.5 equiv), TCFH (732 mg, 2.607 mmol, 3 equiv) and NMI (214 mg, 2.607 mmol, 3 equiv) in ACN (5 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford methyl (trans)-4-[2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4- amido]cyclohexane-1-carboxylate (130 mg, 41% yield) as a yellow solid. [000229] A mixture of methyl (trans)-4-[2-(imidazol-1-yl)-5H,6H,7H- cyclopenta[d]pyrimidine-4-amido]cyclohexane-1-carboxylate (120 mg, 0.541 mmol, 1 equiv), dimethylamine (0.8 mL, 1.6 mmol, 3 equiv, 2 M) and 1H,2H,3H,4H,6H,7H,8H- [1,3]diazino[1,2-a]pyrimidine (150 mg, 1.082 mmol, 2 equiv) in THF (10 mL) was stirred for 12 h at 110 °C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 7) to afford N-((trans)-4- (dimethylcarbamoyl)cyclohexyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine-4-carboxamide (44.1 mg, 21% yield) as a light yellow solid. LCMS (ESI) [M+H]+: 383.15.1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.74 (d, J = 8.6 Hz, 1H), 8.18 (d, J = 1.5 Hz, 1H), 7.16 (s, 1H), 3.85 – 3.71 (m, 1H), 3.29 – 3.24 (m, 2H), 3.03 (d, J = 2.4 Hz, 5H), 2.82 (s, 3H), 2.60 – 2.54 (m, 1H), 2.20 – 2.05 (m, 2H), 1.91 – 1.83 (m, 2H), 1.81 – 1.70 (m, 2H), 1.67 – 1.53 (m, 2H), 1.51 – 1.38 (m, 2H). Example 53: Synthesis of 2-(imidazol-1-yl)-N-[(trans)-4-[(2,2,2-trifluoroethyl)amino] cyclohexyl]-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxamide (Compound 165)[000230] A solution of 2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylic acid (130 mg, 0.565 mmol, 1 equiv), tert-butyl N-[(trans)-4- aminocyclohexyl]carbamate (181 mg, 0.847 mmol, 1.5 equiv), TCFH (317 mg, 1.130 mmol, 2.0 equiv) and NMI (232 mg, 2.825 mmol, 5.0 equiv) in MeCN (8 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford tert-butyl N-[(trans)-4-[2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4- amido]cyclohexyl]carbamate (120 mg, 50% yield) as a grey white solid. [000231] A solution of tert-butyl N-[(trans)-4-[2-(imidazol-1-yl)-5H,6H,7H- cyclopenta[d]pyrimidine-4-amido]cyclohexyl]carbamate (106 mg, 0.249 mmol, 1 equiv) in 4 M HCl in dioxane (5 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in 2-(imidazol-1-yl)-N-[(trans)-4- aminocyclohexyl]-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxamide (132 mg, crude) as a brown solid. [000232] A solution of 2-(imidazol-1-yl)-N-[(trans)-4-aminocyclohexyl]-5H,6H,7H- cyclopenta[d]pyrimidine-4-carboxamide (120 mg, 0.368 mmol, 1 equiv),^2,2,2-trifluoroethyl trifluoromethanesulfonate (127 mg, 0.552 mmol, 1.5 equiv)^and^TEA (186 mg, 1.840 mmol, 5 equiv)^in^ACN (3 mL)^was stirred for 16 h^at 70 °C^under^nitrogen^atmosphere.^The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 5) to afford^2-(imidazol-1-yl)-N-[(trans)-4-[(2,2,2- trifluoroethyl)amino]cyclohexyl]-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxamide (24.4 mg, 16% yield)^as a^white^solid. LCMS (ESI) [M+H]+: 409.20.1H NMR (400 MHz, DMSO- d6) δ 8.89 (s, 1H), 8.70 (d, J = 8.6 Hz, 1H), 8.17 (s, 1H), 7.14 (s, 1H), 3.86 – 3.71 (m, 1H),3.29 – 3.20 (m, 4H), 3.02 (t, J = 7.7 Hz, 2H), 2.48 – 2.39 (m, 1H), 2.22 (q, J = 7.4 Hz, 1H), 2.11 (p, J = 7.7 Hz, 2H), 1.95 (d, J = 12.8 Hz, 2H), 1.81 (d, J = 12.4 Hz, 2H), 1.54 (q, J = 12.5 Hz, 2H), 1.12 (q, J = 12.4 Hz, 2H). Example 54: Synthesis of 2-(imidazol-1-yl)-N-[(trans)-4-(3,3-difluoropyrrolidin-1- yl)cyclohexyl] -5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxamide (Compound 162)[000233] A solution of 4-(dibenzylamino)cyclohexan-1-one (1 g, 3.408 mmol, 1 equiv), AcOH (200 mg, 3.408 mmol, 1 equiv) and 3,3-difluoropyrrolidine hydrochloride (540 mg, 3.749 mmol, 1.1 equiv) in DCM (50 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. To the above mixture was added NaBH3CN (430 mg, 6.816 mmol, 2 equiv) in portions at 0 °C. The resulting mixture was stirred for 3 h at room temperature under air atmosphere. The reaction was quenched with 1 M NaOH(aq) at 0 °C. The MeOH was concentrated under reduced pressure. The aqueous layer was extracted with CH2Cl2(3 x 150 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford (trans)-N,N- dibenzyl-4-(3,3-difluoropyrrolidin-1-yl)cyclohexan-1-amine (430 mg, 33% yield) as a white solid. [000234] A solution of (trans)-N,N-dibenzyl-4-(3,3-difluoropyrrolidin-1-yl)cyclohexan- 1-amine (420 mg, 1.092 mmol, 1 equiv) and Pd(OH)2 / C (153 mg, 0.109 mmol, 0.1 equiv 10% purity) in methanol (10 mL) was stirred for 3 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. This resulted in (trans)-4-(3,3- difluoropyrrolidin-1-yl)cyclohexan-1-amine (200 mg, 90% yield) as an off-white solid.[000235] A solution of (trans)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexan-1-amine (80 mg, 0.392 mmol, 1 equiv), 2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylic acid (99 mg, 0.431 mmol, 1.1 equiv), TCFH (219 mg, 0.784 mmol, 2 equiv) and NMI (160 mg, 1.960 mmol, 5 equiv) in ACN (2 mL) was stirred for 1 h at room temperature under air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 10) to afford 2-(imidazol-1-yl)-N- [(trans)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl]-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxamide (14.6 mg, 9% yield) as a white solid. LCMS (ESI) [M+H]+: 417.20.1H NMR (400 MHz, Methanol-d4) δ 8.87 (s, 1H), 8.15 (d, J = 1.8 Hz, 1H), 7.13 (d, J = 1.7 Hz, 1H), 4.05 – 3.74 (m, 1H), 3.36 (t, J = 7.6 Hz, 2H), 3.17 – 2.94 (m, 4H), 2.86 (t, J = 7.1 Hz, 2H), 2.31 – 2.19 (m, 5H), 2.15 – 1.91 (m, 4H), 1.58 (q, J = 12.5 Hz, 2H), 1.38 (q, J = 11.4 Hz, 2H). Example 55: Synthesis of 2-(imidazol-1-yl)-N-[(trans)-3-[(2,2,2- trifluoroethyl)amino]cyclobutyl]-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxamide (Compound 159)[000236] To a stirred mixture of methyl 2-chloro-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylate (800 mg, 3.762 mmol, 1 equiv) and imidazole (500 mg, 7.344 mmol, 1.95 equiv) in 1,4-dioxane were added t-BuBrettphos Pd G3 (321 mg, 0.376 mmol, 0.10 equiv), t- BuBrettphos (360 mg, 0.743 mmol, 0.20 equiv) and Cs2CO3(3.7 g, 11.356 mmol, 3.02 equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at 120 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12:1) to afford methyl 2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxylate (550 mg, 60% yield) as a yellow solid.[000237] To a stirred mixture of methyl 2-(imidazol-1-yl)-5H,6H,7H- cyclopenta[d]pyrimidine-4-carboxylate (500 mg, 2.047 mmol, 1 equiv) and tert-butyl N- [(trans)-3-aminocyclobutyl]carbamate (600 mg, 3.221 mmol, 1.57 equiv) in DMF (10 mL) were added HATU (1.3 g, 3.419 mmol, 1.67 equiv) and 2,4,6-trimethylpyridine (750 mg, 6.189 mmol, 3.02 equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature. The mixture was diluted with water. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl N-[(trans)-3-[2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine- 4-amido]cyclobutyl]carbamate (420 mg, 52% yield) as a yellow solid. [000238] To a stirred mixture of tert-butyl N-[(trans)-3-[2-(imidazol-1-yl)-5H,6H,7H- cyclopenta[d]pyrimidine-4-amido]cyclobutyl]carbamate (220 mg, 0.552 mmol, 1 equiv) in dioxane (2 mL) was added 4 M HCl(gas) in 1,4-dioxane (2 mL) dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in 2-(imidazol-1-yl)-N- [(trans)-3-aminocyclobutyl]-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxamide (150 mg, 91% yield) as a yellow solid. [000239] To a stirred solution of 2-(imidazol-1-yl)-N-[(trans)-3-aminocyclobutyl]- 5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxamide (100 mg, 0.335 mmol, 1 equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (120 mg, 0.517 mmol, 1.54 equiv) in ACN (3 mL) was added TEA (170 mg, 1.680 mmol, 5.01 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (method 5) to afford 2-(imidazol-1-yl)-N-[(trans)-3- [(2,2,2-trifluoroethyl)amino]cyclobutyl]-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxamide (42.4 mg, 33% yield) as a white solid. LCMS (ESI) [M+H]+: 381.20.1H NMR (400 MHz, DMSO-d6) δ 9.09 (d, J = 7.8 Hz, 1H), 8.92 (s, 1H), 8.20 (d, J = 1.4 Hz, 1H), 7.15 (d, J = 1.2 Hz, 1H), 4.62 – 4.48 (m, 1H), 3.46 – 3.40 (m, 1H), 3.30 – 3.21 (m, 2H), 3.21 – 3.15 (m, 2H), 3.08 – 2.96 (m, 2H), 2.82 – 2.71 (m, 1H), 2.41 – 2.30 (m, 2H), 2.17 – 2.05 (m, 4H). Example 56: Synthesis of N-((trans)-3-(3,3-difluoropyrrolidin-1-yl)cyclobutyl)-2-(1H- imidazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (Compound150) and N-((cis)-3-(3,3-difluoropyrrolidin-1-yl)cyclobutyl)-2-(1H-imidazol-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (Compound 149)[000240] A mixture of benzyl N-(3-oxocyclobutyl)carbamate (300 mg, 1.368 mmol, 1 equiv), 3,3-difluoropyrrolidine (175.87 mg, 1.642 mmol, 1.2 equiv), NaBH3CN (128.98 mg, 2.052 mmol, 1.5 equiv) and AcOH (98.61 mg, 1.642 mmol, 1.2 equiv) in DCM (3 mL) was stirred for 3h at room temperature. The reaction was quenched with sat. NH4Cl (aq.) at 0°C. The aqueous layer was extracted with EtOAc. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford benzyl (3-(3,3-difluoropyrrolidin-1-yl)cyclobutyl)carbamate (300 mg, 71% yield) as a colorless oil. [000241] To a solution of (3-(3,3-difluoropyrrolidin-1-yl)cyclobutyl)carbamate (135 mg, 0.435 mmol, 1 equiv) in MeOH (10 mL) was added Pd / C (47.7 mg, 0.045 mmol, 0.1 equiv, 10% purity) in a pressure tank at room temperature. The resulting mixture was stirred for 16 h at 50 °C under 30 psi of hydrogen pressure. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. This resulted in 3-(3,3-difluoropyrrolidin-1-yl)cyclobutan-1-amine (70 mg, 92% yield) as a white solid. [000242] A mixture of 3-(3,3-difluoropyrrolidin-1-yl)cyclobutan-1-amine (60 mg, 0.341 mmol, 1 equiv), 2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxylic acid (78.39 mg, 0.341 mmol, 1 equiv), NMI (83.87 mg, 1.023 mmol, 3 equiv) and TCFH (191.08 mg, 0.682 mmol, 2 equiv) in DMF (2.5 mL) was stirred for 2 h at room temperature. The residue was purified by reverse phase (method 7) to afford N-((trans)-3-(3,3- difluoropyrrolidin-1-yl)cyclobutyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (4.5 mg, 3.3% yield) as a white solid. LCMS (ESI) [M+H]+: 389.10.1H NMR (400 MHz, DMSO-d6) δ 9.22 – 9.08 (m, 1H), 8.92 (s, 1H), 8.20 (d, J = 1.9 Hz, 1H), 7.15 (s, 1H), 4.67 – 4.41 (m, 1H), 3.28 – 3.18 (m, 2H), 3.08 – 2.96 (m, 3H), 2.88 (t, J = 13.4 Hz, 2H), 2.68 (t, J = 6.9 Hz, 2H), 2.38 – 2.19 (m, 6H), 2.17 – 1.99 (m, 2H). And N-((cis)-3-(3,3-difluoropyrrolidin-1-yl)cyclobutyl)-2-(1H-imidazol-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidine-4-carboxamide (9.1 mg, 7% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.16 – 9.03 (m, 1H), 8.93 (s, 1H), 8.28 – 8.14 (m, 1H), 7.22 – 7.03 (m, 1H), 4.23 (h, J = 8.5 Hz, 1H), 3.29 – 3.19 (m, 2H), 3.08 – 2.94 (m, 2H), 2.89 – 2.79 (m, 2H), 2.76 – 2.60 (m, 3H), 2.44 – 2.32 (m, 2H), 2.32 – 2.19 (m, 2H), 2.19 – 2.03 (m, 4H). Example 57: Synthesis of 2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]-5H,7H- furo[3,4-d]pyrimidine-4-carboxamide (Compound 157)[000243] A solution of malononitrile (1 g, 15.137 mmol, 1.45 equiv) in THF (10 mL) was treated with NaH (750 mg, 60% purity) for 10 min at 0 °C under nitrogen atmosphere. To the above mixture was added 2,4-dichloro-5H,7H-furo[3,4-d]pyrimidine (2 g, 10.471 mmol, 1 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched with NH4Cl(aq) (10 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (7:1) to afford 2-{2-chloro-5H,7H- furo[3,4-d]pyrimidin-4-yl}propanedinitrile (1.8 g, 74% yield) as a yellow solid. [000244] To a stirred solution of 2-{2-chloro-5H,7H-furo[3,4-d]pyrimidin-4- yl}propanedinitrile (1.8 g, 8.159 mmol, 1 equiv) in MeOH (40 mL) was added m-CPBA (3.53 g, 17.385 mmol, 2.13 equiv, 85% purity) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched by the addition of saturated Na2S2O3(aq) at room temperature. The resulting mixture was extracted withEtOAc (3 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford methyl 2-chloro-5H,7H-furo[3,4-d]pyrimidine-4-carboxylate (1.2 g, 68% yield) as a yellow solid. [000245] To a stirred solution of methyl 2-chloro-5H,7H-furo[3,4-d]pyrimidine-4- carboxylate (1.2 g, 5.592 mmol, 1 equiv) and imidazole (0.76 g, 11.184 mmol, 2 equiv) in dioxane (40 mL) were added Cs2CO3(5.47 g, 16.776 mmol, 3 equiv) and t-BuBrettphos Pd G3 (0.48 g, 0.559 mmol, 0.1 equiv) and t-BuBrettphos (0.54 g, 1.118 mmol, 0.2 equiv) in portions at room temperature. The resulting mixture was stirred for 2 h at 120 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12:1) to afford methyl 2-(imidazol-1-yl)-5H,7H-furo[3,4-d]pyrimidine-4-carboxylate (500 mg, 36% yield) as a yellow solid. [000246] To a stirred solution of methyl 2-(imidazol-1-yl)-5H,7H-furo[3,4-d]pyrimidine- 4-carboxylate (50 mg, 0.203 mmol, 1 equiv) and (trans)-4-methoxycyclohexan-1-amine (40 mg, 0.310 mmol, 1.52 equiv) in THF (2 mL) was added TBD (60 mg, 0.431 mmol, 2.12 equiv) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (method 10) to afford 2-(imidazol- 1-yl)-N-[(trans)-4-methoxycyclohexyl]-5H,7H-furo[3,4-d]pyrimidine-4-carboxamide (22.3 mg, 32% yield) as a white solid. LCMS (ESI) [M+H]+: 344.05.1H NMR (400 MHz, DMSO- d6) δ 8.97 – 8.88 (m, 2H), 8.23 (s, 1H), 7.17 (s, 1H), 5.33 (s, 2H), 5.03 (d, J = 1.6 Hz, 2H), 3.99 – 3.69 (m, 1H), 3.26 (s, 3H), 3.20 – 2.99 (m, 1H), 2.11 – 2.03 (m, 2H), 1.88 – 1.79 (m, 2H), 1.61 – 1.54 (m, 2H), 1.29 – 1.14 (m, 2H). Example 58: Synthesis of 2-(1H-imidazol-1-yl)-N-(trans-4-(trifluoromethyl)cyclohexyl)- 5,7-dihydrofuro[3,4-d]pyrimidine-4-carboxamide (Compound 153)[000247] To a stirred mixture of methyl 2-(imidazol-1-yl)-5H,7H-furo[3,4-d]pyrimidine- 4-carboxylate (400 mg, 1.625 mmol, 1 equiv) in THF (3 mL) and H2O (3 mL) was added LiOH (160 mg, 6.681 mmol, 4.11 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford 2-(imidazol-1-yl)-5H,7H-furo[3,4-d]pyrimidine-4-carboxylic acid (300 mg, 80% yield) as a white solid. [000248] To a stirred solution of 2-(imidazol-1-yl)-5H,7H-furo[3,4-d]pyrimidine-4- carboxylic acid (50 mg, 0.215 mmol, 1 equiv) and trans-4-(trifluoromethyl)cyclohexan-1- amine (50 mg, 0.300 mmol, 1.40 equiv) in ACN (3 mL) were added NMI (55 mg, 0.670 mmol, 3.00 equiv) and TCFH (120 mg, 0.430 mmol, 2.00 equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography (method 10) to afford 2-(1H-imidazol-1-yl)-N-(trans-4- (trifluoromethyl)cyclohexyl)-5,7-dihydrofuro[3,4-d]pyrimidine-4-carboxamide (40.6 mg, 48% yield) as a white solid. LCMS (ESI) [M+H]+: 382.10.1H NMR (400 MHz, DMSO-d6) δ 9.00 – 8.93 (m, 2H), 8.23 (d, J = 1.4 Hz, 1H), 7.18 (d, J = 1.2 Hz, 1H), 5.34 (d, J = 1.7 Hz, 2H), 5.04 (d, J = 1.5 Hz, 2H), 3.91 – 3.78 (m, 1H), 2.26 (s, 1H), 2.00 – 1.88 (m, 4H), 1.68 – 1.57 (m, 2H), 1.41 (d, J = 6.6 Hz, 2H). Example 59: Synthesis of 2-(imidazol-1-yl)-N-[(trans)-4-(3,3-difluoropyrrolidin-1- yl)cyclohexyl]-5H,7H-furo[3,4-d]pyrimidine-4-carboxamid (Compound 156)[000249] To a stirred mixture of methyl 2-(imidazol-1-yl)-5H,7H-furo[3,4-d]pyrimidine- 4-carboxylate (50 mg, 0.203 mmol, 1 equiv) and (trans)-4-(3,3-difluoropyrrolidin-1- yl)cyclohexan-1-amine (80 mg, 0.392 mmol, 1.93 equiv) in THF (3 mL) was added TBD (60 mg, 0.431 mmol, 2.12 equiv) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. [000250] The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (method 10) to afford 2-(imidazol-1-yl)-N-[(trans)-4-(3,3- difluoropyrrolidin-1-yl)cyclohexyl]-5H,7H-furo[3,4-d]pyrimidine-4-carboxamide (16.6 mg, 19% yield) as a white solid. LCMS (ESI) [M+H]+: 419.10.1H NMR (400 MHz, DMSO-d6) δ 8.98 – 8.89(m, 2H), 8.23 (d, J = 1.4 Hz, 1H), 7.17 (d, J = 1.2 Hz, 1H), 5.33 (d, J = 1.6 Hz, 2H), 5.03 (d, J = 1.6 Hz, 2H), 3.98 – 3.65 (m, 1H), 3.11 – 2.86 (m, 2H), 2.86 – 2.63 (m, 2H), 2.30 – 2.05 (m, 3H), 2.02 – 1.93 (m, 2H), 1.88 – 1.79 (m, 2H), 1.60 – 1.53(m, 2H), 1.40 – 1.08 (m, 2H). Example 61: Synthesis of N-[(1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl]-2-(1,3- thiazol-5-yl)-5H,7H-furo[3,4-d]pyrimidine-4-carboxamide (Compound 155)[000251] A mixture of methyl 2-chloro-5H,7H-furo[3,4-d]pyrimidine-4-carboxylate (300 mg, 1.398 mmol, 1 equiv), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (295 mg, 1.398 mmol, 1 equiv), Pd(dppf)Cl2(102 mg, 0.140 mmol, 0.1 equiv) and K2CO3(580 mg, 4.194 mmol, 3 equiv) in dioxane (10 mL) and H2O (2 mL) was stirred for 1 h at 90 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 2) to afford 2- (1,3-thiazol-5-yl)-5H,7H-furo[3,4-d]pyrimidine-4-carboxylic acid (100 mg, 28% yield) as a white solid. [000252] A mixture of 2-(1,3-thiazol-5-yl)-5H,7H-furo[3,4-d]pyrimidine-4-carboxylic acid (40 mg, 0.160 mmol, 1 equiv), (1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexan-1- amine (32.78 mg, 0.160 mmol, 1 equiv), TCFH (90.06 mg, 0.320 mmol, 2 equiv) and NMI(39.53 mg, 0.480 mmol, 3 equiv) in DMF (1.5 mL) was stirred for 1h at room temperature. The solution was purified by Prep-HPLC (method 5) to afford N-[(1r,4r)-4-(3,3- difluoropyrrolidin-1-yl)cyclohexyl]-2-(1,3-thiazol-5-yl)-5H,7H-furo[3,4-d]pyrimidine-4- carboxamide (24.3 mg, 34% yield) as a white solid. LCMS (ESI) [M+H]+: 436.05.1H NMR (400 MHz, DMSO-d6) δ 9.29 (d, J = 0.8 Hz, 1H), 9.12 (d, J = 0.8 Hz, 1H), 8.77 (s, 1H), 5.34 (t, J = 1.7 Hz, 2H), 5.03 (dd, J = 2.2, 1.2 Hz, 2H), 3.89 – 3.70 (m, 1H), 2.95 (t, J = 13.8 Hz, 2H), 2.76 (t, J = 7.0 Hz, 2H), 2.29 – 2.16 (m, 2H), 2.15 – 2.06 (m, 1H), 2.04 – 1.91 (m, 2H), 1.91 – 1.76 (m, 2H), 1.67 – 1.48 (m, 2H), 1.36 – 1.13 (m, 2H). Example 62: Synthesis of N-((1r,4r)-4-methoxycyclohexyl)-2-(thiazol-5-yl)-5,7- dihydrofuro[3,4-d]pyrimidine-4-carboxamide (Compound 154)[000253] A mixture of 2-(1,3-thiazol-5-yl)-5H,7H-furo[3,4-d]pyrimidine-4-carboxylic acid (40 mg, 0.160 mmol, 1 equiv), (1r,4r)-4-methoxycyclohexan-1-amine (21 mg, 0.160 mmol, 1 equiv), TCFH (68 mg, 0.240 mmol, 1.5 equiv) and NMI (66 mg, 0.800 mmol, 5 equiv) in ACN (1 mL) was stirred for 1 h at room temperature. The mixture was purified by Prep-HPLC (method 5) to afford N-((1r,4r)-4-methoxycyclohexyl)-2-(thiazol-5-yl)-5,7- dihydrofuro[3,4-d]pyrimidine-4-carboxamide (20.5 mg, 35% yield) as a white solid. LCMS (ESI) [M+H]+:361.05.1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 9.14 – 9.08 (s, 1H), 8.79 – 8.72 (m, 1H), 5.34 (s, 2H), 5.02 (s, 2H), 3.89 – 3.76 (m, 1H), 3.26 (s, 3H), 3.20 – 3.08 (m, 1H), 2.10 – 2.02 (m, 2H), 1.89 – 1.81 (m, 2H), 1.66 – 1.52 (m, 2H), 1.30 – 1.16 (m, 2H). Example 63: Synthesis of 1-(1H-imidazol-1-yl)-N-((trans)-4-methoxycyclohexyl)-6,7- dihydro-5H-cyclopenta[c]pyridine-3-carboxamide (Compound 182)..[000254] Into a 30 mL sealed tube were added trichloro-1,2,4-triazine (3 g, 16.269 mmol, 1 equiv) and cyclopentene (1.11 g, 16.269 mmol, 1 equiv) at room temperature. The final reaction mixture was stirred for 12 h at 70 °C. The residue was purified by reversed-phase flash chromatography (method 1) to afford 1,3-dichloro-5H,6H,7H-cyclopenta[c]pyridine (610 mg, 20% yield) as a brown oil. [000255] A solution of 1,3-dichloro-5H,6H,7H-cyclopenta[c]pyridine (600 mg, 3.191 mmol, 1 equiv), imidazole (434 mg, 6.382 mmol, 2 equiv) and K2CO3(1.32 g, 9.573 mmol, 3 equiv) in DMF (10 mL) was stirred for 24 h at 100 °C under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography (Method 1) to afford 1-{3- chloro-5H,6H,7H-cyclopenta[c]pyridin-1-yl}imidazole (300 mg, 43% yield) as a light brown oil. [000256] A mixture of 1-{3-chloro-5H,6H,7H-cyclopenta[c]pyridin-1-yl}imidazole (290 mg, 1.320 mmol, 1 equiv), zinc cyanide (310 mg, 2.640 mmol, 2 equiv) and Pd(PPh3)4(152 mg, 0.132 mmol, 0.1 equiv) in DMF (5 mL) was stirred for 16 h at 120 °C under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography (Method 1) to afford 1-(imidazol-1-yl)-5H,6H,7H-cyclopenta[c]pyridine-3-carbonitrile (150 mg, 54% yield) as a brown oil. [000257] A solution of 1-(imidazol-1-yl)-5H,6H,7H-cyclopenta[c]pyridine-3-carbonitrile (140 mg, 0.571 mmol, 1 equiv) in 6 M HCl (aq) (1 mL) was stirred for 1 h at 90 ℃ under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford 1-(imidazol-1-yl)- 5H,6H,7H-cyclopenta[c]pyridine-3-carboxylic acid (80 mg, 21% yield) as a yellow oil.[000258] A solution of 1-(imidazol-1-yl)-5H,6H,7H-cyclopenta[c]pyridine-3-carboxylic acid (70 mg, 0.305 mmol, 1 equiv), (trans)-4-methoxycyclohexan-1-amine (78 mg, 0.610 mmol, 2 equiv), TCFH (257 mg, 0.915 mmol, 3 equiv) and NMI (75 mg, 0.915 mmol, 3 equiv) in ACN (1 mL) was stirred for 1 h at room temperature. The mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 7) to afford 1-(1H-imidazol-1-yl)-N-((trans)-4-methoxycyclohexyl)-6,7-dihydro-5H- cyclopenta[c]pyridine-3-carboxamide (16.5 mg, 16% yield) as a white solid. LCMS (ESI) [M+H]+: 341.20.1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.38 (d, J = 8.6 Hz, 1H), 8.01 (s, 1H), 7.91 (s, 1H), 7.15 (s, 1H), 3.87 – 3.74 (m, 1H), 3.25 (s, 3H), 3.21 – 3.06 (m, 3H), 3.09 – 2.99 (m, 2H), 2.18 – 2.05 (m, 2H), 2.10 – 1.99 (m, 2H), 1.88 – 1.77 (m, 2H), 1.60 – 1.45 (m, 2H), 1.29 – 1.14 (m, 2H). Example 64: Synthesis of 3-(imidazol-1-yl)-N-[(trans)-4-hydroxy-4-methylcyclohexyl]- 5H,6H,7H-cyclopenta[c]pyridine-1-carboxamide (Compound 179)[000259] A mixture of^ethyl 1,2,4-triazine-3-carboxylate (1 g, 6.53 mmol, 1.0 equiv), pyrrolidine (930 mg, 13.06 mmol, 2.0 equiv)^and^cyclopentanone (1 g, 13.06 mmol, 2.0 equiv)^in^toluene (20 mL)^was stirred for 16 h^at 160 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with^PE / EA^(1:1) to afford^ethyl 5H,6H,7H-cyclopenta[c]pyridine- 1-carboxylate (500 mg, 40% yield)^as a^yellow^oil. [000260] To a mixture of^ethyl 5H,6H,7H-cyclopenta[c]pyridine-1-carboxylate (400 mg, 2.09 mmol, 1.0 equiv)^in^DCM (5 mL)^was added^m-CPBA (722 mg, 4.18 mmol, 2.0 equiv) in portions at room temperature. The mixture was stirred for 2 h^at^room temperature^under^nitrogen^atmosphere. The reaction was quenched by the addition of^Na2S2O3(aq) and NaHCO3(aq) at 0 °C. The resulting mixture was extracted with EtOAc (3x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with^PE / EA^(1:1) to afford^1- (ethoxycarbonyl)-5H,6H,7H-cyclopenta[c]pyridin-2-ium-2-olate (390 mg, 90% yield)^as a^light yellow^solid. [000261] To a mixture of^1-(ethoxycarbonyl)-5H,6H,7H-cyclopenta[c]pyridin-2-ium-2- olate (310 mg, 1.50 mmol, 1.0 equiv)^in^ACN (5 mL)^was added^POCl3(5 mL) dropwise at 0 °C. The reaction was stirred for^2 h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to^room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with^PE / EA^(5:1) to afford^ethyl 3-chloro-5H,6H,7H-cyclopenta[c]pyridine-1-carboxylate (200 mg, 59% yield)^as a^yellow^solid. [000262] To a mixture of^ethyl 3-chloro-5H,6H,7H-cyclopenta[c]pyridine-1-carboxylate (190 mg, 0.84 mmol, 1.0 equiv)^in^DMF (5 mL)^was added^imidazole (287 mg, 4.21 mmol, 5.0 equiv) and^K2CO3(349 mg, 2.53 mmol, 3.0 equiv) in portions at room temperature. The mixture was stirred for 2 h^at 120 °C under nitrogen^atmosphere. The mixture was allowed to cool down to^room temperature. The residue was purified by reversed-phase flash chromatography (method 1) to afford^ethyl 3-(imidazol-1-yl)-5H,6H,7H- cyclopenta[c]pyridine-1-carboxylate (120 mg, 55% yield)^as a^yellow^solid. [000263] To a mixture of^ethyl 3-(imidazol-1-yl)-5H,6H,7H-cyclopenta[c]pyridine-1- carboxylate (110 mg, 0.43 mmol, 1.0 equiv)^in^THF (1.6 mL)^and^H2O (0.4 mL) was added^LiOH (102 mg, 4.28 mmol, 10.0 equiv)^in portions at 0 °C. The mixture was stirred for 1 h^at^room temperature. The mixture was neutralized to pH^6^with^1 M HCl (aq.). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford^3-(imidazol-1-yl)-5H,6H,7H- cyclopenta[c]pyridine-1-carboxylic acid (80 mg, 82% yield)^as a^yellow^solid. [000264] A mixture of^3-(imidazol-1-yl)-5H,6H,7H-cyclopenta[c]pyridine-1-carboxylic acid (30 mg, 0.13 mmol, 1.0 equiv),^(trans)-4-amino-1-methylcyclohexan-1-ol (25 mg, 0.20 mmol, 1.5 equiv), TCFH (55 mg, 0.2 mmol, 1.5 equiv)^and^NMI (32 mg, 0.39 mmol, 3.0 equiv) in^ACN (1 mL) was stirred for 1 h^at^room temperature^under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product waspurified by Prep-HPLC (method 10) to afford^3-(imidazol-1-yl)-N-[(trans)-4-hydroxy-4- methylcyclohexyl]-5H,6H,7H-cyclopenta[c]pyridine-1-carboxamide (8.6 mg, 19% yield)^as a^light yellow^solid. LCMS (ESI) [M+H]+: 341.15.1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.39 (d, J = 8.6 Hz, 1H), 8.15 (s, 1H), 7.89 (s, 1H), 7.14 (s, 1H), 3.81 (d, J = 10.3 Hz, 2H), 3.27 (d, J = 7.6 Hz, 2H), 2.97 (d, J = 7.6 Hz, 2H), 2.07 (d, J = 7.6 Hz, 2H), 1.75 – 1.42 (m, 8H), 1.21 (s, 3H). Example 65: Synthesis of 3-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]-5H,6H,7H- cyclopenta[c]pyridine-1-carboxamide (Compound 181)[000265] Into a 30 mL sealed tube were added trichloro-1,2,4-triazine (5 g, 27.115 mmol, 1 equiv) and cyclopentene (1.85 g, 27.115 mmol, 1 equiv) at room temperature. The final reaction mixture was stirred for 12 h at 70 °C. The residue was purified by reversed-phase flash chromatography (method 1) to afford 1,3-dichloro-5H,6H,7H-cyclopenta[c]pyridine (1.8 g, 35% yield) as a brown oil. [000266] A solution of 1,3-dichloro-5H,6H,7H-cyclopenta[c]pyridine (1.7 g, 9.040 mmol, 1 equiv) and TBACN (3.64 g, 13.560 mmol, 1.5 equiv) in DMF (50 mL) was stirred for 12 h at 120 °C. The residue was purified by reversed-phase flash chromatography (method 1) to afford 3-chloro-5H,6H,7H-cyclopenta [c]pyridine-1-carbonitrile (200 mg, 12% yield) as a brown oil. [000267] A solution of 3-chloro-5H,6H,7H-cyclopenta[c]pyridine-1-carbonitrile (120 mg, 0.672 mmol, 1 equiv), imidazole (91 mg, 1.344 mmol, 2 equiv) and K2CO3(278 mg, 2.016 mmol, 3 equiv) in DMF (1 mL) was stirred for 4 h at 100 °C under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography (method 1) toafford 3-(imidazol-1-yl)-5H,6H,7H-cyclopenta[c]pyridine-1-carbonitrile (50 mg, 35% yield) as a white solid. [000268] A solution of 3-(imidazol-1-yl)-5H,6H,7H-cyclopenta[c]pyridine-1-carbonitrile (40 mg, 0.190 mmol, 1 equiv) in HCl (aq) (1 mL, 6 N) was stirred for 1 h at 90 °C under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford 3-(imidazol-1-yl)- 5H,6H,7H-cyclopenta[c]pyridine-1-carboxylic acid (23 mg, 53% yield) as a white solid. [000269] To a stirred mixture of [3-(imidazol-1-yl)-5H,6H,7H-cyclopenta[c]pyridin-1- yl]methanediol (23 mg, 0.099 mmol, 1 equiv) and (trans)-4-methoxycyclohexan-1-amine (19 mg, 0.149 mmol, 1.5 equiv) in ACN (4 mL) were added TCFH (56 mg, 0.198 mmol, 2 equiv) and NMI (16 mg, 0.199 mmol, 2.00 equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 8) to afford 3-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]-5H,6H,7H-cyclopenta[c]pyridine-1- carboxamide (3.5 mg, 10% yield) as a colorless oil. LCMS (ESI) [M+H]+: 341.19.1H NMR (400 MHz, Methanol-d4) δ 8.71 (s, 1H), 7.99 (s, 1H), 7.75 (s, 1H), 7.15 (s, 1H), 4.59 (s, 1H), 3.92 – 3.83 (m, 1H), 3.36 (d, J = 3.2 Hz, 5H), 3.27 – 3.21 (m, 1H), 3.08 – 2.99 (m, 2H), 2.21 – 2.10 (m, 4H), 2.05 – 1.97 (m, 2H), 1.63 – 1.49 (m, 2H), 1.39 – 1.29 (m, 2H). Example 66: Synthesis of 3-(imidazol-1-yl)-N-[(cis)-4-hydroxy-4-methylcyclohexyl]- 5H,6H,7H-cyclopenta[c]pyridine-1-carboxamide (Compound 178)[000270] To a stirred mixture of 3-(imidazol-1-yl)-5H,6H,7H-cyclopenta[c]pyridine-1- carboxylic acid (80 mg, 0.35 mmol, 1.0 equiv) in ACN (2 mL) was added (cis)-4-amino-1- methylcyclohexan-1-ol (68 mg, 0.52 mmol, 1.5 equiv), TCFH (147 mg, 0.52 mmol, 1.5 equiv) and NMI (86 mg, 1.05 mmol, 3.0 equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep HPLC (method 6) to afford 3 (imidazol 1 yl) N [(cis) 4 hydroxy-4-methylcyclohexyl]-5H,6H,7H-cyclopenta[c]pyridine-1-carboxamide (12.2 mg, 10% yield) as a white solid. LCMS (ESI) [M+H]+: 341.10.1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.48 (d, J = 8.7 Hz, 1H), 8.21 (s, 1H), 7.88 (s, 1H), 7.12 (s, 1H), 4.09 (s, 1H), 3.83 – 3.70 (m, 1H), 3.29 – 3.24 (m, 2H), 3.01 – 2.92 (m, 2H), 2.12 – 2.00 (m, 2H), 1.92 – 1.81 (m, 2H), 1.64 – 1.47 (m, 4H), 1.42 – 1.32 (m, 2H), 1.13 (s, 3H). Example 67: Synthesis of 3-(imidazol-1-yl)-N-[(trans)-4-ethyl-4-hydroxycyclohexyl]- 5H,6H,7H-cyclopenta[c]pyridine-1-carboxamide (Compound 174)[000271] To a mixture of ethyl 1,2,4-triazine-3-carboxylate (1 g, 6.53 mmol, 1.0 equiv) in Toluene (25 mL) was added cyclopentanone (0.82 g, 9.79 mmol, 1.5 equiv) and pyrrolidine (0.70 g, 9.79 mmol, 1.5 equiv) in portions at room temperature. The resulting mixture was stirred for 16 h at 160 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford ethyl 5H,6H,7H-cyclopenta[c]pyridine-1-carboxylate (600 mg, 48% yield) as a black oil. [000272] To a mixture of ethyl 5H,6H,7H-cyclopenta[c]pyridine-1-carboxylate (600 mg, 3.14 mmol, 1.0 equiv) in DCM (5 mL) was added m-CPBA (1.08 g, 6.28 mmol, 2.0 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was quenched with sat. sodium hyposulfite (aq.) at 0 °C. The aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (5:1) to afford (160 mg, 74% yield) as a yellow oil.[000273] To a mixture of ethyl 2-hydroxy-5H,6H,7H-2lambda4-cyclopenta[c]pyridine-1- carboxylate (350 mg, 1.68 mmol, 1.0 equiv) in ACN (2 mL) was added POCl3(4 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction was stirred for 2 h at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was quenched with water at 0 °C. The aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (5:1) to afford ethyl 3-chloro- 5H,6H,7H-cyclopenta[c]pyridine-1-carboxylate (230 mg, 61% yield) as a yellow solid. [000274] A solution of ethyl 3-chloro-5H,6H,7H-cyclopenta[c]pyridine-1-carboxylate (130 mg, 0.58 mmol, 1.0 equiv), imidazole (78 mg, 1.15 mmol, 2.0 equiv) and K2CO3(398 mg, 2.88 mmol, 5.0 equiv) in DMF (5 mL) was stirred for 2 h at 120 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The residue was purified by reversed-phase flash chromatography (method 1) to afford ethyl 3-(imidazol-1- yl)-5H,6H,7H-cyclopenta[c]pyridine-1-carboxylate (85 mg, 57% yield) as a yellow solid. [000275] To a mixture of ethyl 3-(imidazol-1-yl)-5H,6H,7H-cyclopenta[c]pyridine-1- carboxylate (85 mg, 0.33 mmol, 1.0 equiv) in THF (2 mL) and H2O (2 mL) was added LiOH (79 mg, 3.30 mmol, 10.0 equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The mixture was neutralized to pH 6 with 1 M HCl (aq.). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford 3- (imidazol-1-yl)-5H,6H,7H-cyclopenta[c]pyridine-1-carboxylic acid (80 mg, 96% yield) as a light yellow solid. [000276] To a mixture of 3-(imidazol-1-yl)-5H,6H,7H-cyclopenta[c]pyridine-1- carboxylic acid (80 mg, 0.35 mmol, 1.0 equiv) in ACN (5 mL) was added (trans)-4-amino-1- ethylcyclohexan-1-ol (assumed）(75 mg, 0.52 mmol, 1.5 equiv), TCFH (147 mg, 0.523 mmol, 1.5 equiv) and NMI (86 mg, 1.05 mmol, 3.0 equiv) in portions at room temperature. The mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 7) to afford 3-(imidazol-1-yl)-N-[(trans)-4-ethyl-4-hydroxycyclohexyl]-5H,6H,7H- cyclopenta[c] pyridine-1-carboxamide (344 mg 28% yield) as a white solid. LCMS (ESI)[M+H]+: 355.25.1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.37 (d, J = 8.6 Hz, 1H), 8.15 (s, 1H), 7.89 (s, 1H), 7.13 (s, 1H), 4.07 (s, 1H), 3.90 – 3.77 (m, 1H), 3.29 – 3.25 (m, 2H), 3.02 – 2.94 (m, 2H), 2.12 – 2.02 (m, 2H), 1.92 – 1.50 (m, 8H), 1.46 – 1.33 (m, 2H), 0.90 – 0.81 (m, 3H). Example 68: Synthesis of 3-(1H-imidazol-1-yl)-N-((trans)-4-(methoxy-d3)cyclohexyl)- 6,7-dihydro-5H-cyclopenta[c]pyridine-1-carboxamide (Compound 172)[000277] To a stirred solution of (trans)-4-aminocyclohexan-1-ol hydrochloride (5 g, 32.975 mmol, 1 equiv) and Cs2CO3(32.23 g, 98.925 mmol, 3 equiv) in ACN (50 mL) was added BnBr (11.28 g, 65.950 mmol, 2 equiv) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred for 1 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford (trans)-4-(dibenzylamino) cyclohexan-1-ol (8 g, 82% yield) as a white solid. [000278] A solution of (trans)-4-(dibenzylamino)cyclohexan-1-ol (5 g, 16.925 mmol, 1 equiv) in THF (100 mL) was treated with NaH (1.35 g, 33.850 mmol, 2 equiv, 60% purity) for 20 min at 0 °C under nitrogen atmosphere. To the above mixture was added CD3I (4.91 g, 33.850 mmol, 2 equiv) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred for 1 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The reaction was quenched with sat. NH4Cl (aq.) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA(1:1) to afford (trans)-N,N-dibenzyl-4-(methoxy-d3)cyclohexan-1-amine (3.3 g, 62% yield) as a white solid. [000279] A mixture of (trans)-N,N-dibenzyl-4-(methoxy-d3)cyclohexan-1-amine (1.5 g, 4.800 mmol, 1 equiv) and Pd(OH)2 / C (336 mg, 0.480 mmol, 0.1 equiv, 20% purity) in MeOH (40 mL) was stirred for 5 h at room temperature under hydrogen atmosphere. Desired product could be detected by LCMS. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford (trans)-4-(methoxy-d3)cyclohexan-1-amine (400 mg, 63% yield) as a white oil. [000280] A mixture of (trans)-4-(methoxy-d3)cyclohexan-1-amine (70 mg, 0.529 mmol, 1 equiv) , 3-(imidazol-1-yl)-5H,6H,7H-cyclopenta[c]pyridine-1-carboxylic acid (121 mg, 0.529 mmol, 1 equiv), TCFH (445 mg, 1.587 mmol, 3 equiv) and NMI (260 mg, 3.174 mmol, 6.00 equiv) in ACN (2 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (method 5) to afford 3-(1H- imidazol-1-yl)-N-((trans)-4-(methoxy-d3)cyclohexyl)-6,7-dihydro-5H-cyclopenta[c]pyridine- 1-carboxamide (38.4 mg, 21% yield) as a white solid. LCMS (ESI) [M+H]+: 344.20.1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.43 (d, J = 8.6 Hz, 1H), 8.19 (s, 1H), 7.89 (s, 1H), 7.15 (s, 1H), 3.88 – 3.72 (m, 1H), 3.29 – 3.22 (m, 2H), 3.17 – 3.08 (m, 1H), 3.01 – 2.93 (m, 2H), 2.13 – 2.00 (m, 4H), 1.87 – 1.76 (m, 2H), 1.63 – 1.47 (m, 2H), 1.29 – 1.14 (m, 2H). Example 69: Synthesis of 3-(1H-imidazol-1-yl)-N-((trans)-4-methoxy-4- methylcyclohexyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-1-carboxamide (Compound 170)[000281] A mixture of (trans)-4-methoxy-4-methylcyclohexan-1-amine (75 mg, 0.524 mmol, 1 equiv), 3-(imidazol-1-yl)-5H,6H,7H-cyclopenta[c]pyridine-1-carboxylic acid (180 mg, 0.786 mmol, 1.5 equiv), TCFH (440 mg, 1.572 mmol, 3 equiv) and NMI (129 mg, 1.572mmol, 3 equiv) in ACN (5 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Column: Kinetex EVO C18 Column, 30*150, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Wave Length: 254 nm / 220 nm) to afford 3-(1H-imidazol-1-yl)-N-((trans)-4- methoxy-4-methylcyclohexyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-1-carboxamide (25.8 mg, 14% yield) as a light yellow solid. LCMS (ESI) [M+H]+: 355.20.1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.40 (d, J = 8.5 Hz, 1H), 8.23 (s, 1H), 7.90 (s, 1H), 7.14 (s, 1H), 3.99 – 3.75 (m, 1H), 3.29 – 3.22 (m, 2H), 3.13 (s, 3H), 3.01 – 2.92 (m, 2H), 2.16 – 2.03 (m, 2H), 1.84 – 1.57 (m, 6H), 1.56 – 1.43 (m, 2H), 1.21 (s, 3H). Example 70: Synthesis of N-((trans)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-3-(1H- imidazol-1-yl)-6,7-dihydro-5H-cyclopenta[c]pyridine-1-carboxamide (Compound 161)[000282] To a mixture of ethyl 1,2,4-triazine-3-carboxylate (1 g, 6.530 mmol, 1 equiv) in toluene (25 mL) was added cyclopentanone (0.82 g, 9.795 mmol, 1.5 equiv) and pyrrolidine (0.70 g, 9.795 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for 16 h at 150 °C. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford ethyl 5H,6H,7H- cyclopenta[c]pyridine-1-carboxylate (600 mg, 48% yield) as a black oil. [000283] To a stirred solution of ethyl 5H,6H,7H-cyclopenta[c]pyridine-1-carboxylate (500 mg, 2.615 mmol, 1 equiv) in DCM (15 mL) was added m-CPBA (1.06 g, 5.216 mmol, 1.99 equiv, 85% purity) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with sat. NaHCO3(aq.) (15 mL) and Na2S2O3(aq.) (15 mL) at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with NaHCO dried over anhydrous Na2SO4. Afterfiltration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 1-(ethoxycarbonyl)- 5H,6H,7H-2lambda4-cyclopenta[c]pyridin-2-olate (360 mg, 66% yield) as a white solid. [000284] To a stirred solution of 1-(ethoxycarbonyl)-5H,6H,7H-2lambda4- cyclopenta[c]pyridin-2-olate (350 mg, 1.689 mmol, 1 equiv) in DCM (10 mL) was added POCl3(520 mg, 3.392 mmol, 2.01 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to afford ethyl 3-chloro-5H,6H,7H- cyclopenta[c]pyridine-1-carboxylate (230 mg, 60% yield) as a yellow solid. [000285] To a stirred solution of ethyl 3-chloro-5H,6H,7H-cyclopenta[c]pyridine-1- carboxylate (210 mg, 0.931 mmol, 1 equiv) and imidazole (130 mg, 1.910 mmol, 2.05 equiv) in dioxane (10 mL) were added t-BuBrettphos Pd G3(80 mg, 0.094 mmol, 0.10 equiv), t- BuBrettphos (90 mg, 0.186 mmol, 0.20 equiv) and Cs2CO3(910 mg, 2.793 mmol, 3.00 equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:10) to afford ethyl 3-(imidazol-1-yl)-5H,6H,7H-cyclopenta[c]pyridine-1-carboxylate (200 mg, 83% yield) as a brown solid. [000286] To a stirred solution of ethyl 3-(imidazol-1-yl)-5H,6H,7H- cyclopenta[c]pyridine-1-carboxylate (100 mg, 0.389 mmol, 1 equiv) in THF (1 mL) and H2O (1 mL) was added LiOH (28 mg, 1.169 mmol, 3.01 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford 3-(imidazol-1-yl)-5H,6H,7H-cyclopenta[c]pyridine-1-carboxylic acid (60 mg, 67% yield) as a white solid. [000287] To a stirred solution of 3-(imidazol-1-yl)-5H,6H,7H-cyclopenta[c]pyridine-1- carboxylic acid (60 mg, 0.262 mmol, 1 equiv) and (trans)-4-(3,3-difluoropyrrolidin-1- yl)cyclohexan-1-amine (80 mg, 0.392 mmol, 1.50 equiv) in ACN (5 mL) were added TCFH (140 mg, 0.499 mmol, 1.91 equiv) and NMI (65 mg, 0.792 mmol, 3.02 equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature. Theresulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 8) to afford N-((trans)-4-(3,3- difluoropyrrolidin-1-yl)cyclohexyl)-3-(1H-imidazol-1-yl)-6,7-dihydro-5H- cyclopenta[c]pyridine-1-carboxamide (45.6 mg, 41% yield) as a white solid. LCMS (ESI) [M+H]+: 416.20.1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.43 (d, J = 8.6 Hz, 1H), 8.17 (t, J = 1.4 Hz, 1H), 7.89 (s, 1H), 7.12 (t, J = 1.2 Hz, 1H), 3.86 – 3.67 (m, 1H), 3.29 – 3.19 (m, 2H), 3.02 – 2.88 (m, 4H), 2.81 – 2.69 (m, 2H), 2.30 – 2.15 (m, 2H), 2.14 – 2.02 (m, 3H), 2.00 – 1.89 (m, 2H), 1.87 – 1.77 (m, 2H), 1.63 – 1.46 (m, 2H), 1.31 – 1.14 (m, 2H). Example 71: Synthesis of 8-amino-2-(1H-imidazol-1-yl)-N-((trans)-4- methoxycyclohexyl) quinazoline-4-carboxamide (Compound 186)[000288] A solution of malononitrile (1.78 g, 26.985 mmol, 1.5 equiv) in THF (100 mL) was treated with NaH (1.22 g, 30.583 mmol, 1.7 equiv, 60% purity) for 30 min at 0 °C under nitrogen atmosphere. To the above mixture was added 8-bromo-2,4-dichloroquinazoline (5 g, 17.990 mmol, 1 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was quenched with NH4Cl (aq) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA^(1:1) to afford 2-(8-bromo-2-chloroquinazolin-4-yl) vpropanedinitrile (3.8 g, 69% yield) as a yellow solid. [000289] To a stirred solution of 2-(8-bromo-2-chloroquinazolin-4-yl)propanedinitrile (3.8 g, 12.356 mmol, 1 equiv) in MeOH (100 mL) was added m-CPBA (4.26 g, 24.712 mmol,2 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0 °C under nitrogen atmosphere. The reaction was quenched with sat. Na2S2O3(aq.) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with^PE / EA^(1:1) to afford^methyl 8-bromo-2-chloroquinazoline-4-carboxylate (2.5 g, 67% yield) as a white solid. [000290] A mixture of methyl 8-bromo-2-chloroquinazoline-4-carboxylate (1 g, 3.317 mmol, 1 equiv), K2CO3(1.38 g, 9.951 mmol, 3 equiv) and imidazole (450 mg, 6.634 mmol, 2 equiv) in DMF (20 mL) was stirred for 6 h at 100 °C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 10^mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford 8-bromo-2-(imidazol-1-yl)quinazoline-4- carboxylic acid (720 mg, 68% yield) as a brown solid. [000291] To a stirred mixture of 8-bromo-2-(imidazol-1-yl)quinazoline-4-carboxylic acid (350 mg, 1.097 mmol, 1 equiv) and (trans)-4-methoxycyclohexan-1-amine (283 mg, 2.194 mmol, 2 equiv) in DMF (10 mL) were added DIEA (425 mg, 3.291 mmol, 3 equiv) and HATU (834 mg, 2.194 mmol, 2 equiv) in portions at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The mixture was diluted with water. The resulting mixture was extracted with EtOAc (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford 8-bromo-2-(imidazol-1-yl)-N-[(trans)-4- methoxycyclohexyl]quinazoline-4-carboxamide (200 mg, 42% yield) as a brown solid. [000292] A mixture of 8-bromo-2-(imidazol-1-yl)-N-[(trans)-4- methoxycyclohexyl]quinazoline-4-carboxamide (190 mg, 0.442 mmol, 1 equiv), tert-butyl carbamate (103 mg, 0.884 mmol, 2 equiv), Xantphos (51 mg, 0.088 mmol, 0.2 equiv), Pd2(dba)3(40 mg, 0.044 mmol, 0.1 equiv) and K2CO3(183 mg, 1.326 mmol, 3 equiv)^in^dioxane (2 mL) was stirred for 1 h at 120 °C under nitrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford tert-butyl N-[2-(imidazol-1-yl)-4- {[(trans)-4-methoxycyclohexyl]carbamoyl}quinazolin-8-yl]carbamate (150 mg, 73% yield) as a yellow solid.[000293] A solution of tert-butyl N-[2-(imidazol-1-yl)-4-{[(trans)-4- methoxycyclohexyl]carbamoyl} quinazolin-8-yl]carbamate (140 mg, 0.300 mmol, 1 equiv) in HCl / 1,4-dioxane (10 mL, 4 M) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 6) to afford^8-amino-2-(imidazol-1-yl)-N-[(trans)-4- methoxycyclohexyl]quinazoline-4-carboxamide (13.6 mg, 12% yield) as an orange solid. LCMS (ESI) [M+H]+: 367.15.1H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J = 1.1 Hz, 1H), 8.89 (d, J = 8.0 Hz, 1H), 8.35 (s, 1H), 7.64 (dd, J = 8.3, 1.1 Hz, 1H), 7.44 – 7.37 (m, 1H), 7.19 – 7.15 (m, 1H), 7.08 (dd, J = 7.8, 1.2 Hz, 1H), 6.37 (s, 2H), 3.93 – 3.81(m, 1H), 3.26 (s, 3H), 3.18 – 3.08 (m, 1H), 2.10 – 2.01 (m, 2H), 2.01 – 1.88 (m, 2H), 1.53 – 1.36 (m, 2H), 1.35 – 1.23 (m, 2H). Example 72: Synthesis of 8-cyano-2-(imidazol-1-yl)-N-[(trans)-4-(2-hydroxypropan-2- yl) cyclohexyl]quinazoline-4-carboxamide (Compound 190)[000294] A mixture of 8-bromo-2-(imidazol-1-yl)quinazoline-4-carboxylic acid (300 mg, 0.940 mmol, 1 equiv), 2-[(trans)-4-aminocyclohexyl]propan-2-ol (177 mg, 1.128 mmol, 1.2 equiv), TCFH (791 mg, 2.820 mmol, 3 equiv) and^NMI (463 mg, 5.640 mmol, 6 equiv) in^ACN (10 mL) was stirred for 1 h at room temperature under nitrogen atmosphere.^Desired product could be detected by LCMS. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford 8- bromo-2-(imidazol-1-yl)-N-[(trans)-4-(2-hydroxypropan-2-yl)cyclohexyl]quinazoline-4- carboxamide (240 mg, 56% yield) as a white solid. [000295] A mixture of 8-bromo-2-(imidazol-1-yl)-N-[(trans)-4-(2-hydroxypropan-2- yl)cyclohexyl] quinazoline-4-carboxamide (200 mg, 0.436 mmol, 1 equiv), cuprous cyanide (78 mg, 0.872 mmol, 2 equiv) and Pd(PPh3)2Cl2(61 mg, 0.087 mmol, 0.2 equiv)^in^DMSO (10 mL) was stirred for 10 h at 140 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The residue was purified by Prep-HPLC (method 6) to afford 8-cyano-2- (imidazol-1-yl)-N-[(trans)-4-(2-hydroxypropan-2-yl)cyclohexyl]quinazoline-4-carboxamide(50.9 mg, 2% yield) as a white solid. LCMS (ESI) [M+H]+: 405.05.1H NMR (400 MHz, DMSO-d6) δ 9.21 – 9.10 (m, 1H), 9.08 (d, J = 8.3 Hz, 1H), 8.96 (d, J = 1.1 Hz, 1H), 8.72 – 8.65 (m, 1H), 8.16 (d, J = 1.4 Hz ,1H), 7.94 – 7.83 (m, 1H), 7.26 (d, J = 1.2 Hz ,1H), 4.07 (s, 1H), 3.91 – 3.78 (m, 1H), 2.03 – 1.94 (m, 2H), 1.89 (d, J = 12.0 Hz, 2H), 1.55 – 1.39 (m, 2H), 1.29 – 1.08 (m, 3H), 1.07 (s, 6H). Example 73: Synthesis of 5-cyano-3-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl] isoquinoline-1-carboxamide (Compound 180)[000296] A solution of malononitrile (4.77 g, 72.218 mmol, 2 equiv) in THF (150 mL) was treated with NaH (2.88 g, 72.218 mmol, 2 equiv, 60% purity) for 30 min at 0 °C under nitrogen atmosphere. To the above mixture was added 5-bromo-1,3-dichloroisoquinoline (10 g, 36.109 mmol, 1 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The reaction was quenched with sat. NH4Cl (aq.) at 0 °C. The aqueous layer was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 2-(5-bromo-3-chloroisoquinolin-1- yl)propanedinitrile (11 g, 99% yield) as a yellow solid. [000297] A solution of 2-(5-bromo-3-chloroisoquinolin-1-yl)propanedinitrile (11 g, 35.883 mmol, 1 equiv) in MeOH (150 mL) was treated with m-CPBA (12.38 g, 71.766 mmol, 2 equiv) for 1 h at 0 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The reaction was quenched with sat. Na2S2O3(aq.) at 0 °C. The aqueous layer was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 5-bromo-3-chloroisoquinoline-1-carboxylate (9 g, 83% yield) as a white solid. [000298] A solution of methyl 5-bromo-3-chloroisoquinoline-1-carboxylate (5 g, 16.637 mmol, 1 equiv) and CuCN (2.98 g, 33.274 mmol, 2 equiv) in DMSO (60 mL) was stirred for 16 h at 150 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The residue was purified by reversed-phase flash chromatography (method 1) to afford methyl 3- chloro-5-cyanoisoquinoline-1-carboxylate (2 g, 49% yield) as a yellow solid. [000299] To a stirred solution of methyl 5-bromo-3-chloroisoquinoline-1-carboxylate (2 g, 6.655 mmol, 1 equiv) in THF (10 mL) and H2O (10 mL) was added LiOH (800 mg, 33.275 mmol, 5 equiv) in portions at 0 °C. The reaction was stirred for 1 h at room temperature. Desired product could be detected by LCMS. The mixture was acidified neutralized to pH 6 with 1 M HCl (aq). The resulting mixture was concentrated under reduced pressure. This resulted in 3-chloro-5-cyanoisoquinoline-1-carboxylic acid (1.5 g, 97%, yield) as a white solid. [000300] To a stirred solution of bis(3-chloro-5-cyanoisoquinoline-1-carboxylic acid) (1.5 g, 3.224 mmol, 1 equiv) and (trans)-4-methoxycyclohexan-1-amine (500 mg, 3.869 mmol, 1.2 equiv) in DMF (20 mL) was added DIEA (2.08 g, 16.120 mmol, 5 equiv) and HATU (1.84 g, 4.836 mmol, 1.5 equiv) in portions at room temperature. The reaction was stirred for 1 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The residue was purified by reversed-phase flash chromatography (method 1) to afford bis(3-chloro-5-cyano-N-[(trans)-4-methoxycyclohexyl]isoquinoline-1-carboxamide) (700 mg, 32%, yield) as a white solid. [000301] A solution of 3-chloro-5-cyano-N-[(trans)-4-methoxycyclohexyl]isoquinoline-1- carboxamide (700 mg, 2.036 mmol, 1 equiv), imidazole (693 mg, 10.180 mmol, 5 equiv), t- BuBrettphos (197 mg, 0.407 mmol, 0.2 equiv), Cs2CO3(2 g, 6.138 mmol, 3.01 equiv) and t- BuBrettPhos Pd G3 (173 mg, 0.204 mmol, 0.1 equiv) in dioxane (15 mL) was stirred for 1 h at 120 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The residue was purified by Prep-HPLC (method 9) to afford 5-cyano-3-(imidazol-1-yl)-N- [(trans)-4-methoxycyclohexyl]isoquinoline-1-carboxamide (308 mg, 40% yield) as a white solid. LCMS (ESI) [M+H]+: 376.10.1H NMR (400 MHz, DMSO-d6) δ 9.15 – 9.09 (m, 1H),8.92 – 8.86 (m, 2H), 8.55 – 8.50 (m, 1H), 8.28 (s, 1H), 8.23 (s, 1H), 7.88 – 7.81 (m, 1H), 7.21 (s, 1H), 3.93 – 3.83 (m, 1H), 3.26 (s, 3H), 3.20 – 3.09 (m, 1H), 2.11 – 2.02 (m, 2H), 2.00 – 1.91 (m, 2H), 1.58 – 1.44 (m, 2H), 1.34 – 1.20 (m, 2H). Example 74: Synthesis of 5-cyano-3-(3-methylimidazol-4-yl)-N-[(trans)-4- methoxycyclohexyl]isoquinoline-1-carboxamide (Compound 177)[000302] A mixture of methyl 3-chloro-5-cyanoisoquinoline-1-carboxylate (115 mg, 0.466 mmol, 1 equiv), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazole (116 mg, 0.559 mmol, 1.2 equiv), K2CO3(193 mg, 1.398 mmol, 3 equiv) and Pd(dppf)Cl2(68 mg, 0.093 mmol, 0.2 equiv) in dioxane (6 mL) and H2O (2 mL) was stirred for 2 h at 90 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The residue was purified by reversed-phase flash chromatography (method 1) to afford 5-cyano-3-(3- methylimidazol-4-yl)isoquinoline-1-carboxylic acid (90 mg, 69% yield) as a brown solid. [000303] A mixture of 5-cyano-3-(3-methylimidazol-4-yl)isoquinoline-1-carboxylic acid (115 mg, 0.413 mmol, 1 equiv), (trans)-4-methoxycyclohexan-1-amine (64 mg, 0.496 mmol, 1.2 equiv), TCFH (347 mg, 1.239 mmol, 3 equiv) and NMI (203 mg, 2.478 mmol, 6 equiv) in ACN (10 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The residue was purified by Prep-HPLC (method 7) to afford 5-cyano-3-(3-methylimidazol-4-yl)-N-[(trans)-4-methoxycyclohexyl]isoquinoline-1- carboxamide (26.6 mg, 17% yield) as a green solid. LCMS (ESI) [M+H]+: 390.20.1H NMR (400 MHz, DMSO-d6) δ 9.01 – 8.94 (m, 1H), 8.73 (d, J = 8.2 Hz, 1H), 8.49 (d, J = 7.2, 1.2 Hz, 1H), 8.24 (d, J = 0.9 Hz, 1H), 8.11 (s, 1H), 7.90 – 7.81 (m, 2H), 4.04 (s, 3H), 3.95 – 3.83 (m, 1H), 3.25 (s, 3H), 3.20 – 3.08 (m, 1H), 2.10 – 2.01 (m, 2H), 2.00 – 1.92 (m, 2H), 1.51 – 1.37 (m, 2H), 1.35 – 1.21 (m, 2H). Example 75: Synthesis of 3-(1H-imidazol-1-yl)-N-((trans)-4- methoxycyclohexyl)isoquinoline-1-carboxamide (Compound 185)[000304] A solution of methyl isoquinoline-1-carboxylate (2 g, 10.684 mmol, 1 equiv) and mCPBA (2.7 g, 16.026 mmol, 1.5 equiv) in DCM (20 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched with Na2S2O3(aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to afford 1-(methoxycarbonyl)isoquinolin-2-ium-2-olate (1.8 g, 83% yield) as a yellow oil. [000305] A mixture of 1-(methoxycarbonyl)isoquinolin-2-ium-2-olate (1.8 g, 8.858 mmol, 1 equiv) in POCl3(10 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 200 mL). Dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 3-chloroisoquinoline-1-carboxylate (1.5 g, 76% yield) as a yellow solid. [000306] A mixture of methyl 3-chloroisoquinoline-1-carboxylate (1.5 g, 6.768 mmol, 1 equiv), K2CO3(2.8 g, 20.304 mmol, 3 equiv), CuI (2.6 g, 13.536 mmol, 2 equiv) and imidazole (0.7 g, 10.152 mmol, 1.5 equiv) in DMF (5 mL) was stirred for 2 h at 100 °C under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography (method 1) to afford 3-(imidazol-1-yl)isoquinoline-1-carboxylic acid (950 mg, 59% yield) as a yellow solid. [000307] A solution of 3-(imidazol-1-yl)isoquinoline-1-carboxylic acid (160 mg, 0.669 mmol, 1 equiv), (trans)-4-methoxycyclohexan-1-amine (130 mg, 1.004 mmol, 1.5 equiv), TCFH (563 mg, 2.007 mmol, 3 equiv) and NMI (83 mg, 2.007 mmol, 3 equiv) in ACN (2 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resultingmixture was concentrated under reduced pressure. The crude product was purified by Prep- HPLC (method 7) to afford 3-(1H-imidazol-1-yl)-N-((trans)-4- methoxycyclohexyl)isoquinoline-1-carboxamide (56.9 mg, 24% yield) as a white solid. LCMS (ESI) [M+H]+: 351.05.1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J = 8.6 Hz, 1H), 8.75 (d, J = 9.5 Hz, 2H), 8.39 (s, 1H), 8.14 (d, J = 1.6 Hz, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.91 – 7.80 (m, 1H), 7.75 – 7.65 (m, 1H), 7.19 (s, 1H), 3.98 – 3.82 (m, 1H), 3.26 (s, 3H), 3.21 – 3.05 (m, 1H), 2.15 – 2.01 (m, 2H), 2.00 – 1.90 (m, 2H), 1.56 – 1.38 (m, 2H), 1.36 – 1.01 (m, 2H). Example 76: Synthesis of 5-cyano-3-(1H-imidazol-1-yl)-N-((trans)-4-methoxy-4- methylcyclohexyl)isoquinoline-1-carboxamide (Compound 171)[000308] A solution of (trans)-4-amino-1-methylcyclohexan-1-ol (500 mg, 3.870 mmol, 1 equiv), benzyl bromide (1.38 g, 8.127 mmol, 2.1 equiv) and K2CO3(1.6 g, 11.610 mmol, 3 equiv) in DMF (15 mL) was stirred for 1 h at 70 °C under nitrogen atmosphere. The mixture was diluted with water. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford (trans)-4- (dibenzylamino)-1-methylcyclohexan-1-ol (750 mg, 63% yield) as a yellow solid. [000309] To a stirred mixture of (trans)-4-(dibenzylamino)-1-methylcyclohexan-1-ol (750 mg, 2.424 mmol, 1 equiv) in THF (10 mL) was added NaH (291 mg, 7.272 mmol, 3 equiv, 60% purity) in portions at 0 °C under nitrogen atmosphere. The mixture was stirred for 30 mins at 0 °C under nitrogen atmosphere. To the above mixture was added CH3I (688 mg, 4.848 mmol, 2 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for additional 2 h at room temperature. The reaction was quenched with sat. NH4Cl(aq.) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford (trans)-N,N-dibenzyl-4- methoxy-4-methylcyclohexan-1-amine (650 mg, 83% yield) as a white solid. [000310] A solution of (trans)-N,N-dibenzyl-4-methoxy-4-methylcyclohexan-1-amine (650 mg, 2.009 mmol, 1 equiv) and Pd(OH)2 / C (28 mg, 0.020 mmol, 0.01 equiv, 10% purity) in MeOH (10 mL) was stirred for 12 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. This resulted in (trans)-4-methoxy-4- methylcyclohexan-1-amine (200 mg, 70% yield) as a dark oil. [000311] A solution of (trans)-4-methoxy-4-methylcyclohexan-1-amine (200 mg, 1.396 mmol, 1 equiv), 3-chloro-5-cyanoisoquinoline-1-carboxylic acid (487 mg, 2.094 mmol, 1.5 equiv), DIEA (541 mg, 4.188 mmol, 3 equiv) and HATU (1.6 g, 4.188 mmol, 3 equiv) in DMF (5 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography (method 1) to afford 3-chloro-5-cyano- N-[(trans)-4-methoxy-4-methylcyclohexyl]isoquinoline-1-carboxamide (270 mg, 54% yield) as a white solid. [000312] A solution of 3-chloro-5-cyano-N-[(trans)-4-methoxy-4- methylcyclohexyl]isoquinoline-1-carboxamide (270 mg, 0.755 mmol, 1 equiv), imidazole (102 mg, 1.510 mmol, 2 equiv), t-BuBrettPhos (73 mg, 0.151 mmol, 0.2 equiv), t- BuBrettPhos Pd G3 (64 mg, 0.076 mmol, 0.1 equiv) and Cs2CO3(738 mg, 2.265 mmol, 3 equiv) in dioxane (10 mL) was stirred for 1 h at 120 °C under nitrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 7) to afford 5-cyano-3-(1H-imidazol-1-yl)-N-((trans)-4- methoxy-4-methylcyclohexyl)isoquinoline-1-carboxamide (139 mg, 46% yield) as a light yellow solid. LCMS (ESI) [M+H]+: 390.10.1H NMR (300 MHz, DMSO-d6) δ 9.07 (d, J = 8.7 Hz, 1H), 8.85 (d, J = 6.7 Hz, 2H), 8.53 (d, J = 7.3 Hz, 1H), 8.36 – 8.16 (m, 2H), 7.91 – 7.81 (m, 1H), 7.22 (s, 1H), 4.02 (s, 1H), 3.13 (s, 3H), 1.84 (d, J = 9.1 Hz, 2H), 1.76 – 1.40 (m, 6H), 1.16 (s, 3H).Example 77: Synthesis of N-((trans)-4-ethyl-4-hydroxycyclohexyl)-3-(1H-imidazol-1- yl)isoquinoline-1-carboxamide (Compound 173)[000313] A solution of 3-(imidazol-1-yl)isoquinoline-1-carboxylic acid (200 mg, 0.836 mmol, 1 equiv), (trans)-4-amino-1-ethylcyclohexan-1-ol (assumed) (179 mg, 1.254 mmol, 1.5 equiv), TCFH (703 mg, 2.508 mmol, 3 equiv) and NMI (205 mg, 2.508 mmol, 3 equiv) in ACN (10 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 6) to afford N-((trans)-4-ethyl-4-hydroxycyclohexyl)-3-(1H- imidazol-1-yl)isoquinoline-1-carboxamide (10.6 mg, 3.4% yield) as a white solid. LCMS (ESI) [M+H]+: 365.25.1H NMR (400 MHz, DMSO-d6) δ 8.90 – 8.67 (m, 3H), 8.37 (s, 1H), 8.15 (s, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.93 – 7.79 (m, 1H), 7.77 – 7.63 (m, 1H), 7.18 (s, 1H), 3.96 – 3.76 (m, 2H), 1.92 – 1.73 (m, 2H), 1.75 – 1.51 (m, 4H), 1.49 – 1.22 (m, 4H), 0.91 – 0.81 (m, 3H). Example 78: Synthesis of 5-cyano-3-(imidazol-1-yl)-N-{6-methoxyspiro[3.3]heptan-2- yl} isoquinoline-1-carboxamide (Compound 169)[000314] To a mixture of {6-hydroxyspiro[3.3]heptan-2-yl}aminyl hydrochloride (500 mg, 3.07 mmol, 1.0 equiv) and Cs2CO3(3 g, 9.22 mmol, 3.0 equiv) in ACN (20 mL) was added BnBr (789 mg, 4.61 mmol, 1.5 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure The residue was purified by silicagel column chromatography, eluted with PE / EA (10:1) to afford 6- (dibenzylamino)spiro[3.3]heptan-2-ol (680 mg, 72% yield) as a colorless oil. [000315] To a mixture of 6-(dibenzylamino)spiro[3.3]heptan-2-ol (660 mg, 2.15 mmol, 1.0 equiv) in THF (20 mL) was added NaH (129 mg, 3.225 mmol, 1.5 equiv, 60% purity) in portions at 0 °C under nitrogen atmosphere. The mixture was stirred for 30 min at 0 °C under nitrogen atmosphere. To the above mixture was added methyl iodide (914 mg, 6.44 mmol, 3.0 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 0 °C under nitrogen atmosphere. The reaction was quenched with NH4Cl(aq) at 0 °C. The aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford N,N-dibenzyl-6- methoxyspiro[3.3]heptan-2-amine (610 mg, 88% yield) as a colorless oil. [000316] To a mixture of N,N-dibenzyl-6-methoxyspiro[3.3]heptan-2-amine (600 mg, 1.87 mmol, 1.0 equiv) in MeOH (10 mL) was added Pd(OH)2 / C (198 mg, 0.187 mmol, 0.1 equiv, 10% purity) in portions at room temperature. The resulting mixture was stirred for 12 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. This resulted in 6-methoxyspiro[3.3]heptan-2-amine (160 mg, 61% yield) as a light yellow oil. [000317] To a mixture of 3-chloro-5-cyanoisoquinoline-1-carboxylic acid (150 mg, 0.56 mmol, 1.0 equiv) in ACN (5 mL) was added 6-methoxyspiro[3.3]heptan-2-amine (118 mg, 0.84 mmol, 1.5 equiv), TCFH (235 mg, 0.84 mmol, 1.5 equiv) and NMI (138 mg, 1.68 mmol, 3.0 equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford 3-chloro-5-cyano-N-{6- methoxyspiro[3.3]heptan-2-yl}isoquinoline-1-carboxamide (120 mg, 60% yield) as a yellow solid. [000318] A solution of 3-chloro-5-cyano-N-{6-methoxyspiro[3.3]heptan-2- yl}isoquinoline-1-carboxamide (110 mg, 0.31 mmol, 1.0 equiv), imidazole (32 mg, 0.46 mmol, 1.5 equiv), t-BuBrettphos (30 mg, 0.06 mmol, 0.2 equiv), t-BuBrettPhos Pd G3(26mg, 0.03 mmol, 0.1 equiv) and Cs2CO3(302 mg, 0.93 mmol, 3.0 equiv) in dioxane (4 mL) was stirred for 1 h at 120 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 9) to afford 5-cyano-3-(imidazol-1-yl)-N-{6- methoxyspiro[3.3]heptan-2-yl}isoquinoline-1-carboxamide (40.8 mg, 34% yield) as a white solid. LCMS (ESI) [M+H]+: 388.15.1H NMR (400 MHz, DMSO-d6) δ 9.25 – 9.17 (m, 2H), 8.93 (s, 1H), 8.52 (d, J = 7.2, 1.2 Hz, 1H), 8.31 (s, 1H), 8.24 (s, 1H), 7.88 – 7.80 (m, 1H), 7.21 (s, 1H), 4.53 – 4.41 (m, 1H), 3.82 – 3.73 (m, 1H), 3.11 (s, 3H), 2.47 – 2.35 (m, 2H), 2.31 – 2.22 (m, 4H), 1.95 – 1.81 (m, 2H). Example 79: Synthesis of 3-(1H-imidazol-1-yl)-5-methoxy-N-((trans)-4- methoxycyclohexyl)isoquinoline-1-carboxamide (Compound 168)[000319] A mixture of methyl 5-bromo-3-chloroisoquinoline-1-carboxylate (700 mg, 2.329 mmol, 1 equiv), B(OH)2(1.49 g, 11.645 mmol, 5 equiv), Pd(OAc)2(261 mg, 1.165 mmol, 0.5 equiv), t-BuBrettPhos (225 mg, 0.466 mmol, 0.2 equiv) and Cs2CO3(2.28 g, 6.987 mmol, 3 equiv) in NMP (10 mL) was stirred for 16 h at 80 °C under nitrogen atmosphere. The mixture was diluted with water. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford methyl 3-chloro- 5-hydroxyisoquinoline-1-carboxylate (280 mg, 51% yield) as a brown solid. [000320] To a stirred solution of methyl 3-chloro-5-hydroxyisoquinoline-1-carboxylate (270 mg, 1.136 mmol, 1 equiv) in THF (10 mL) was added NaH (91 mg, 2.272 mmol, 2 equiv, 60% purity) in portions at 0 °C under nitrogen atmosphere. The mixture was stirred for 30 min at 0 °C under nitrogen atmosphere. To the above mixture was added CH3I (322 mg, 2.272 mmol, 2 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for additional 1 h at room temperature. The reaction was quenched with sat. NH4Cl(aq.) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford methyl 3-chloro-5- methoxyisoquinoline-1-carboxylate (150 mg, 52% yield) as a yellow oil. [000321] To a stirred solution of methyl 3-chloro-5-methoxyisoquinoline-1-carboxylate (140 mg, 0.556 mmol, 1 equiv) in THF (3 mL) was added LiOH (40 mg, 1.668 mmol, 3 equiv) in H2O (3 mL) dropwise 0 °C. The mixture was stirred for 1 h at room temperature. The mixture was acidified to pH 5 with 1 M HCl(aq). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-chloro-5-methoxyisoquinoline-1-carboxylic acid (100 mg, 76% yield) as a yellow solid. [000322] A solution of 3-chloro-5-methoxyisoquinoline-1-carboxylic acid (90 mg, 0.379 mmol, 1 equiv), (trans)-4-methoxycyclohexan-1-amine (73 mg, 0.569 mmol, 1.5 equiv), DIEA (147 mg, 1.137 mmol, 3 equiv) and HATU (432 mg, 1.137 mmol, 3 equiv) in DMF (3 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography (method 1) to afford 3-chloro-5-methoxy- N-[(trans)-4-methoxycyclohexyl]isoquinoline-1-carboxamide (60 mg, 45% yield) as a brown solid. [000323] A solution of 3-chloro-5-methoxy-N-[(trans)-4- methoxycyclohexyl]isoquinoline-1-carboxamide (50 mg, 0.143 mmol, 1 equiv), imidazole (20 mg, 0.286 mmol, 2 equiv), t-BuBrettPhos (14 mg, 0.029 mmol, 0.2 equiv), t-BuBrettPhos Pd G3 (12 mg, 0.014 mmol, 0.1 equiv) and Cs2CO3(140 mg, 0.429 mmol, 3 equiv) in dioxane (5 mL) was stirred for 1 h at 120 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep- HPLC (method 7) to afford 3-(1H-imidazol-1-yl)-5-methoxy-N-((trans)-4- methoxycyclohexyl)isoquinoline-1-carboxamide (25.8 mg, 47% yield) as a brown solid. LCMS (ESI) [M+H]+: 381.05.1H NMR (400 MHz, DMSO-d6) δ 8.79 – 8.69 (m, 2H), 8.37 – 8.26 (m, 2H), 8.18 (d, J = 1.4 Hz, 1H), 7.68 – 7.57 (m, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.19 (s, 1H), 4.05 (s, 3H), 3.93 – 3.80 (m, 1H), 3.26 (s, 3H), 3.18 – 3.10 (m, 1H), 2.13 – 2.02 (m, 2H), 2.02 – 1.89 (m, 2H), 1.56 – 1.41 (m, 2H), 1.34 – 1.16 (m, 2H)Example 80: Synthesis of 5-cyano-3-(imidazol-1-yl)-N-[(trans)-3-methoxycyclobutyl] isoquinoline-1-carboxamide (Compound 166)[000324] To a stirred solution of 3-chloro-5-cyanoisoquinoline-1-carboxylic acid (200 mg, 0.430 mmol, 1 equiv) and (trans)-3-methoxycyclobutan-1-amine (60 mg, 0.593 mmol, 1.38 equiv) in ACN (5 mL) was added TCFH (220 mg, 0.784 mmol, 1.82 equiv) and NMI (150 mg, 1.827 mmol, 4.25 equiv) in portions at room temperature. The resulting mixture was stirred for 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12:1) to afford 3-chloro-5-cyano-N-((trans)-3- methoxycyclobutyl)isoquinoline-1-carboxamide (180 mg, 66% yield) as a yellow solid. [000325] A solution of 3-chloro-5-cyano-N-[(trans)-3-methoxycyclobutyl]isoquinoline-1- carboxamide (50 mg, 0.158 mmol, 1 equiv), t-BuBrettphos Pd G3 (13 mg, 0.015mmol, 0.1 equiv); t-BuBrettphos (15 mg, 0.032 mmol, 0.2 equiv), Cs2CO3(150 mg, 0.460 mmol, 2.91 equiv) and imidazole (25 mg, 0.367 mmol, 2.32 equiv) in dioxane (3 mL) was stirred for 30 min at 120 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 7) to afford 5- cyano-3-(imidazol-1-yl)-N-[(trans)-3-methoxycyclobutyl]isoquinoline-1-carboxamide (8.5 mg, 10% yield) as a white solid. LCMS (ESI) [M+H]+: 348.10.1H NMR (400 MHz, DMSO- d6) δ 9.42 – 9.09 (m, 2H), 8.91 (s, 1H), 8.51 (d, J = 7.2 Hz, 1H), 8.35 – 8.16 (m, 2H), 7.89 – 7.80 (m, 1H), 7.21 (s, 1H), 4.66 – 4.52 (m, 1H), 4.10 – 4.01 (m, 1H), 3.19 (s, 3H), 2.48 – 2.29 (m, 4H). Example 81: Synthesis of 5-cyano-3-(imidazol-1-yl)-N-[(trans)-4-(3,3- difluoropyrrolidin-1-yl) cyclohexyl]isoquinoline-1-carboxamide (Compound 165)[000326] A solution of (trans)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexan-1-amine (50 mg, 0.245 mmol, 1 equiv), 5-cyano-3-(imidazol-1-yl)isoquinoline-1-carboxylic acid (71 mg, 0.270 mmol, 1.1 equiv), TCFH (137 mg, 0.490 mmol, 2 equiv) and NMI (100 mg, 1.225 mmol, 5 equiv) in ACN (2 mL) was stirred for 1 h at room temperature under air atmosphere. The mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 5) to afford 5-cyano-3-(imidazol-1-yl)-N-[(trans)-4-(3,3- difluoropyrrolidin-1-yl)cyclohexyl]isoquinoline-1-carboxamide (12.3 mg, 11% yield) as a white solid. LCMS (ESI) [M+H]+: 451.20.1H NMR (400 MHz, DMSO-d6) δ 9.13 (dt, J = 8.7, 1.1 Hz, 1H), 8.95 – 8.79 (m, 2H), 8.52 (dd, J = 7.2, 1.2 Hz, 1H), 8.35 – 8.16 (m, 2H), 7.84 (dd, J = 8.7, 7.2 Hz, 1H), 7.21 (t, J = 1.3 Hz, 1H), 4.01 – 3.75 (m, 1H), 2.95 (t, J = 13.7 Hz, 2H), 2.76 (t, J = 6.9 Hz, 2H), 2.32 – 2.06 (m, 3H), 1.97 (d, J = 11.2 Hz, 4H), 1.49 (q, J = 11.9 Hz, 2H), 1.28 (q, J = 13.2, 12.4 Hz, 2H). Example 82: Synthesis of 5-cyano-3-(1H-imidazol-1-yl)-N-((trans)-4-((2,2,2- trifluoroethyl) amino)cyclohexyl)isoquinoline-1-carboxamide (Compound 163)[000327] A mixture of 3-chloro-5-cyanoisoquinoline-1-carboxylic acid (300 mg, 1.290 mmol, 1 equiv), tert-butyl N-[(trans)-4-aminocyclohexyl]carbamate (331 mg, 1.548 mmol, 1.2 equiv), TCFH (1.085 g, 3.870 mmol, 3 equiv) and NMI (317 mg, 3.870 mmol, 3 equiv) in ACN (10 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford tert-butyl N-[(trans)-4-(3-chloro-5-cyanoisoquinoline- 1-amido)cyclohexyl]carbamate (220 mg, 40% yield) as a yellow solid. [000328] A mixture of tert-butyl N-[(trans)-4-(3-chloro-5-cyanoisoquinoline-1- amido)cyclohexyl] carbamate (210 mg, 0.490 mmol, 1 equiv), imidazole (40 mg, 0.588 mmol, 1.2 equiv), t-BuBrettPhos (23 mg, 0.049 mmol, 0.1 equiv), t-BuBrettPhos Pd G3 (83 mg, 0.098 mmol, 0.2 equiv) and Cs2CO3(478 mg, 1.470 mmol, 3 equiv) in 1,4-dioxane (7 mL) was stirred for 1 h at 120 °C under nitrogen atmosphere. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:3) to afford tert-butyl N-[(trans)-4-[5-cyano-3- (imidazol-1-yl)isoquinoline-1-amido]cyclohexyl]carbamate (160 mg, 71% yield) as a light yellow solid. [000329] A solution of tert-butyl N-[(trans)-4-[5-cyano-3-(imidazol-1-yl)isoquinoline-1- amido] cyclohexyl]carbamate (150 mg, 0.326 mmol, 1 equiv) in 4 M HCl(gas) in 1,4-dioxane (10 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in 5-cyano-3-(imidazol-1-yl)-N-[(trans)-4- aminocyclohexyl]isoquinoline-1-carboxamide (100 mg, 68% yield) as a yellow solid. [000330] A mixture of 5-cyano-3-(imidazol-1-yl)-N-[(trans)-4- aminocyclohexyl]isoquinoline-1-carboxamide (46 mg, 0.128 mmol, 1 equiv), 2,2,2- trifluoroethyl trifluoromethanesulfonate (35 mg, 0.154 mmol, 1.2 equiv) and TEA (64 mg, 0.640 mmol, 5 equiv) in ACN (3 mL) was stirred for 16 h at 70 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 8) to afford 5-cyano-3-(1H-imidazol-1-yl)-N- ((trans)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)isoquinoline-1-carboxamide (21.1 mg, 37% yield) as a light yellow solid. LCMS (ESI) [M+H]+: 443.15.1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 9.20 (d, J = 8.7 Hz, 1H), 8.99 (d, J = 8.2 Hz, 1H), 8.57 (d, J = 7.2 Hz, 1H), 8.49 (s, 1H), 8.38 (s, 1H), 7.94 – 7.85 (m, 1H), 7.48 (s, 1H), 4.01 – 3.88 (m, 3H), 3.13 – 2.90 (m, 2H), 2.31 – 2.10 (m, 2H), 2.10 – 1.89 (m, 2H), 1.58 – 1.46 (m, 4H). Example 83: Synthesis of 7-cyano-3-(1H-imidazol-1-yl)-N-((trans)-4- methoxycyclohexyl) isoquinoline-1-carboxamide (Compound 161)[000331] To a stirred mixture of malononitrile (570 mg, 8.666 mmol, 1.2 equiv) in THF (10 mL) was added NaH (583 mg, 14.444 mmol, 2 equiv, 60% purity) in portions at 0 °Cunder nitrogen atmosphere. The mixture was stirred for 30 min at 0 °C under nitrogen atmosphere. To the above mixture was added 7-bromo-1,3-dichloroisoquinoline (2 g, 7.222 mmol, 1 equiv) in portions at 0 °C under nitrogen atmosphere. The mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched with NH4Cl(aq) at 0 °C. The aqueous layer was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to afford 2-(7-bromo-3- chloroisoquinolin-1-yl)propanedinitrile (820 mg, 37% yield) as a light yellow solid. [000332] A mixture of 2-(7-bromo-3-chloroisoquinolin-1-yl)propanedinitrile (800 mg, 2.610 mmol, 1 equiv) and m-CPBA (1.06 g, 5.220 mmol, 2 equiv, 85% purity) in MeOH (20 mL) was stirred for 1 h at 0 °C. The reaction was quenched by the addition of sat. sodium thiosulfate (aq.) at 0 °C. The aqueous layer was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 7-bromo-3- chloroisoquinoline-1-carboxylate (430 mg, 55% yield) as a yellow solid. [000333] A mixture of methyl 7-bromo-3-chloroisoquinoline-1-carboxylate (410 mg, 1.364 mmol, 1 equiv), CuCN (244 mg, 2.728 mmol, 2 equiv) and Pd(PPh3)2Cl2(95 mg, 0.136 mmol, 0.1 equiv) in DMSO (10 mL) was stirred for 1 h at 150 °C under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography (method 1) to afford methyl 3-chloro-7-cyanoisoquinoline-1-carboxylate (230 mg, 68% yield) as a yellow solid. [000334] A solution of methyl 3-chloro-7-cyanoisoquinoline-1-carboxylate (220 mg, 0.892 mmol, 1 equiv) and trimethyltin hydroxide (322 mg, 1.784 mmol, 2 equiv) in DCE (10 mL) was stirred for 16 h at room temperature. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford 3-chloro-7-cyanoisoquinoline-1-carboxylic acid (100 mg, 48% yield) as a yellow solid. [000335] A mixture of 3-chloro-7-cyanoisoquinoline-1-carboxylic acid (90 mg, 0.387 mmol, 1 equiv), (trans)-4-methoxycyclohexan-1-amine (59 mg, 0.464 mmol, 1.2 equiv), DIEA (150 mg, 1.161 mmol, 3 equiv)^and HATU (220 mg, 0.581 mmol, 1.5 equiv) in DMF(5 mL) was stirred for 1 h at room temperature. The reaction was diluted with water at room temperature. The aqueous layer was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:3) to afford 3-chloro-7-cyano-N-[(trans)-4- methoxycyclohexyl]isoquinoline-1-carboxamide (70 mg, 53% yield) as a yellow solid. [000336] A mixture of 3-chloro-7-cyano-N-[(trans)-4-methoxycyclohexyl]isoquinoline- 1-carboxamide (60 mg, 0.175 mmol, 1 equiv), imidazole (47 mg, 0.700 mmol, 4 equiv), t- BuBrettPhos Pd G3 (29 mg, 0.035 mmol, 0.2 equiv), t-BuBrettPhos (8 mg, 0.017 mmol, 0.1 equiv)^and Cs2CO3(170 mg, 0.525 mmol, 3 equiv) in dioxane (5 mL) was stirred for 1 h at 120 °C under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Column: XBridge BEH C18 OBD Prep Column 19*250 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Wave Length: 254 / 220 nm) to afford 7-cyano-3-(1H- imidazol-1-yl)-N-((trans)-4-methoxycyclohexyl)isoquinoline-1-carboxamide (12.8 mg, 19% yield) as a white solid. LCMS (ESI) [M+H]+: 376.15.1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.95 – 8.82 (m, 2H), 8.52 (s, 1H), 8.21 – 8.14 (m, 2H), 8.14 – 8.09 (m, 1H), 7.22 (d, J = 1.2 Hz, 1H), 3.95 – 3.89 (m, 1H), 3.27 (d, J = 1.8 Hz, 3H), 3.21 – 2.90 (m, 1H), 2.08 (d, J = 6.8 Hz, 2H), 1.95 (d, J = 12.7 Hz, 2H), 1.62 – 1.44 (m, 2H), 1.30 – 1.19 (m, 2H). Example 84: Synthesis of 6-cyano-3-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl] isoquinoline-1-carboxamide (Compound 160)[000337] To a stirred solution of malononitrile (954 mg, 14.44 mmol, 2.0 equiv) in THF (20 mL) was added NaH (867 mg, 21.67 mmol, 3.0 equiv, 60% purity) in portions at 0 °C under nitrogen atmosphere. The mixture was stirred for 10 min at 0 °C under nitrogen atmosphere. To the above mixture was added 6-bromo-1,3-dichloroisoquinoline (2 g, 7.22 mmol, 1.0 equiv) in portions at 0 °C under nitrogen atmosphere. The mixture was stirred for2 h at room temperature. The reaction was quenched with sat. NH4Cl (aq.) at room temperature. The resulting mixture was diluted with water. The aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (7:3) to afford 2-(6-bromo-3-chloroisoquinolin-1-yl) propanedinitrile (1.91 g, 86% yield) as a yellow solid. [000338] To a stirred mixture of 2-(6-bromo-3-chloroisoquinolin-1-yl)propanedinitrile (1 g, 3.26 mmol, 1.0 equiv) in MeOH (10 mL) was added m-CPBA (1.33 g, 6.52 mmol, 2.0 equiv, 85% purity) in portions at 0 °C under nitrogen atmosphere. The mixture was stirred for 1 h at 0 °C under nitrogen atmosphere. The reaction was quenched with sat. sodium hyposulfite (aq.) at 0 °C. The aqueous layer was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 6-bromo-3- chloroisoquinoline-1-carboxylate (700 mg, 71% yield) as a yellow solid. [000339] To a stirred mixture of methyl 6-bromo-3-chloroisoquinoline-1-carboxylate (400 mg, 1.33 mmol, 1.0 equiv) in dioxane (5 mL) was added KOAc (261 mg, 2.66 mmol, 2.0 equiv), H2O (1 mL), K4Fe(CN)6(562 mg, 1.33 mmol, 1.0 equiv) and Pd(dpephos)Cl2(191 mg, 0.27 mmol, 0.2 equiv) in portions at room temperature. The mixture was stirred for 4 h at 80 °C under nitrogen atmosphere. The reaction was allowed to cool down to room temperature. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford methyl 3-chloro-6-cyanoisoquinoline-1-carboxylate (200 mg, 33% yield) as a yellow solid. [000340] To a mixture of methyl 3-chloro-6-cyanoisoquinoline-1-carboxylate (180 mg, 0.73 mmol, 1 equiv) in DCE (3 mL) was added trimethylstannanol (264 mg, 1.46 mmol, 2.0 equiv) in portions at room temperature. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in 3-chloro-6-cyanoisoquinoline-1-carboxylic acid (150 mg, 88% yield) as a yellow solid. [000341] To a stirred mixture of 3-chloro-6-cyanoisoquinoline-1-carboxylic acid (85 mg, 0.37 mmol, 1.0 equiv) in DMF (5 mL) was added (trans)-4-methoxycyclohexan-1-amine (71 mg, 0.55 mmol, 1.5 equiv), DIEA (142 mg, 1.10 mmol, 3.0 equiv) and HATU (208 mg, 0.55mmol, 1.5 equiv) in portions at room temperature. The mixture was stirred for 1 h at room temperature. The residue was purified by reversed-phase flash chromatography (method 1) to afford 3-chloro-6-cyano-N-[(trans)-4-methoxycyclohexyl]isoquinoline-1-carboxamide (85 mg, 68% yield) as a white solid. [000342] To a stirred mixture of 3-chloro-6-cyano-N-[(trans)-4- methoxycyclohexyl]isoquinoline-1-carboxamide (80 mg, 0.23 mmol, 1.0 equiv) in dioxane (2 mL) was added imidazole (48 mg, 0.70 mmol, 3.0 equiv), t-BuBrettphos (23 mg, 0.05 mmol, 0.2 equiv), t-BuBrettPhos Pd G3 (20 mg, 0.02 mmol, 0.1 equiv) and Cs2CO3(227 mg, 0.7 mmol, 3.0 equiv) in portions at room temperature. The mixture was stirred for 1 h at 120 °C under nitrogen atmosphere. The reaction was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge BEH C18 OBD Prep Column 19*250 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3+ 0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Wave Length: 254 / 220 nm) to afford 6-cyano-3-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]isoquinoline-1- carboxamide (14.7 mg, 17% yield) as a light yellow solid. LCMS (ESI) [M+H]+: 376.10.1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 8.9 Hz, 1H), 8.88 – 8.79 (m, 2H), 8.60 (s, 1H), 8.48 (s, 1H), 8.14 (s, J = 1.4 Hz, 1H), 7.99 – 7.95 (m, 1H), 7.22 (d, J = 1.3 Hz, 1H), 3.94 – 3.87 (m, 1H), 3.26 (s, 3H), 3.19 – 3.12 (m, 1H), 2.07 (d, J = 10.8 Hz, 2H), 1.95 (d, J = 12.7 Hz, 2H), 1.58 – 1.49 (m, 2H), 1.35 – 1.32 (m, 2H). Example 85: Synthesis of 5-cyano-3-(imidazol-1-yl)-N-[(trans)-3-[(2,2,2- trifluoroethyl)amino]cyclobutyl]isoquinoline-1-carboxamide (Compound 158)[000343] A solution of^3-chloro-5-cyanoisoquinoline-1-carboxylic acid (150 mg, 0.645 mmol, 1 equiv),^tert-butyl N-[(trans)-3-aminocyclobutyl]carbamate (144 mg, 0.774 mmol,1.2 equiv),^HATU (367 mg, 0.968 mmol, 1.5 equiv)^and^2,4,6-trimethylpyridine (234 mg, 1.935 mmol, 3 equiv)^in^DMF (5 mL)^was stirred for 1 h^at^room temperature^under^air^atmosphere.^The residue was purified by reversed-phase flash chromatography (method 2) to afford tert-butyl N-[(trans)-3-(3-chloro-5-cyanoisoquinoline- 1-amido)cyclobutyl]carbamate (140 mg, 54% yield)^as an^off-white^solid. [000344] A solution of^tert-butyl N-[(trans)-3-(3-chloro-5-cyanoisoquinoline-1- amido)cyclobutyl]carbamate (130 mg, 0.324 mmol, 1 equiv),^imidazole (66 mg, 0.972 mmol, 3 equiv),^t-BuBrettphos (32 mg, 0.065 mmol, 0.2 equiv), t-BuBrettphos Pd G 3 (27 mg, 0.032 mmol, 0.1 equiv)^and^Cs2CO3(316 mg, 0.972 mmol, 3 equiv)^in^dioxane (5 mL)^was stirred for 1 h^at 120 °C^under^nitrogen^atmosphere.^After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with^CH2Cl2 / MeOH^(8:1) to afford^tert-butyl N-[(trans)-3-[5-cyano-3-(imidazol-1- yl)isoquinoline-1-amido]cyclobutyl]carbamate (80 mg, 57% yield)^as a^white^solid. [000345] A solution of^tert-butyl N-[(trans)-3-[5-cyano-3-(imidazol-1-yl)isoquinoline-1- amido]cyclobutyl]carbamate (70 mg, 0.162 mmol, 1 equiv)^in^4 M HCl(gas) in 1,4-dioxane (5 mL)^was stirred for 1 h^at^room temperature^under^air^atmosphere.^The resulting mixture was concentrated under reduced pressure. The crude product (50 mg) was used in the next step directly without further purification. [000346] A solution of^5-cyano-3-(imidazol-1-yl)-N-[(trans)-3- aminocyclobutyl]isoquinoline-1-carboxamide (40 mg, 0.120 mmol, 1 equiv),^2,2,2- trifluoroethyl trifluoromethanesulfonate (55 mg, 0.240 mmol, 2 equiv)^and^TEA (60 mg, 0.600 mmol, 5 equiv)^in^ACN (2 mL)^was stirred for 16 h^at 70 °C^under^nitrogen^atmosphere.^The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 10) to afford^5-cyano-3- (imidazol-1-yl)-N-[(trans)-3-[(2,2,2-trifluoroethyl)amino]cyclobutyl]isoquinoline-1- carboxamide (20.8 mg, 42% yield)^as a^light yellow^solid. LCMS (ESI) [M+H]+: 415.15.1H NMR (400 MHz, DMSO-d6) δ 9.27 (d, J = 7.5 Hz, 1H), 9.18 (dt, J = 8.8, 1.1 Hz, 1H), 8.92 (s, 1H), 8.52 (dd, J = 7.3, 1.2 Hz, 1H), 8.37 – 8.19 (m, 2H), 7.85 (dd, J = 8.7, 7.2 Hz, 1H), 7.22 (s, 1H), 4.61 (h, J = 7.2 Hz, 1H), 3.45 (dt, J = 7.9, 4.2 Hz, 1H), 3.27 – 3.10 (m, 2H), 2.80 (q, J = 7.3 Hz, 1H), 2.45 – 2.28 (m, 2H), 2.27 – 2.05 (m, 2H).Example 88: Synthesis of N-((trans)-4-(4,4-difluoro-2-oxopyrrolidin-1-yl)cyclohexyl)-2- (1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4- carboxamide (Compound 198)[000347] A solution of (trans)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexan-1-amine (200 mg, 0.979 mmol, 1 equiv), di-tert-butyl dicarbonate (320 mg, 1.468 mmol, 1.5 equiv), TEA (297 mg, 2.937 mmol, 3 equiv) and DMAP (11 mg, 0.098 mmol, 0.1 equiv) in DCM (5 mL) was stirred for 1h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl N-[(trans)-4-(3,3-difluoropyrrolidin-1- yl)cyclohexyl]carbamate (110 mg, 37% yield) as a white solid. [000348] To a stirred solution of tert-butyl N-[(trans)-4-(3,3-difluoropyrrolidin-1- yl)cyclohexyl]carbamate (100 mg, 0.329 mmol, 1 equiv) and Ruthenium(III) chloride (4 mg, 0.020 mmol, 0.06 equiv) in EA (3 mL) and H2O (3 mL) was added NaIO4(267 mg, 1.250 mmol, 3.8 equiv) in portions at 0°C. The resulting mixture was stirred for 16h at room temperature. The resulting mixture was extracted with EtOAc (3 x 10mL). The combined organic layers were washed with brine (2x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (Method 2) to afford tert-butyl ((trans)-4-(4,4-difluoro- 2-oxopyrrolidin-1-yl)cyclohexyl)carbamate (40 mg, 38% yield) as a white solid. [000349] A solution of tert-butyl ((trans)-4-(4,4-difluoro-2-oxopyrrolidin-1- yl)cyclohexyl)carbamate (40 mg, 0.126 mmol, 1 equiv) in HCl in 1,4-dioxane(4.0 M) (3 mL) was stirred for 1h at room temperature. The resulting mixture was concentrated underreduced pressure. This resulted in 4,4-difluoro-1-[(trans)-4-aminocyclohexyl]pyrrolidin-2- one (20 mg, crude) as a white solid. [000350] A solution of 4,4-difluoro-1-[(trans)-4-aminocyclohexyl]pyrrolidin-2-one (20 mg, 0.092 mmol, 1 equiv), 2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylic acid (25 mg, 0.110 mmol, 1.2 equiv), TCFH (51 mg, 0.184 mmol, 2 equiv) and NMI (37 mg, 0.460 mmol, 5 equiv) in ACN (2 mL) was stirred for 1h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 7) to afford N-((trans)-4-(4,4-difluoro-2-oxopyrrolidin-1- yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4- carboxamide (3.5 mg, 9% yield) as a white solid. LCMS (ESI) [M+H]+: 431.20.1H NMR (400 MHz, Chloroform-d) δ 9.15 (s, 1H), 8.03 – 7.83 (m, 2H), 7.30 (s, 1H), 4.30 – 4.11 (m, 1H), 3.92 (m, 3.97 – 3.88, 1H), 3.70 (t, J = 13.3 Hz, 2H), 3.45 (t, J = 7.6 Hz, 2H), 3.09 (t, J = 7.9 Hz, 2H), 2.95 (t, J = 14.4 Hz, 2H), 2.22 (m, 2.28 – 2.17, 4H), 1.90 (d, J = 11.4 Hz, 2H), 1.74 – 1.45 (m, 4H). Example 86: Synthesis of N-((trans)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-2-(1H- imidazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (Compound 152)[000351] A solution of benzyl N-(4-oxocyclohexyl)carbamate (1 g, 4.044 mmol, 1 equiv) in DCM (16 mL) was treated with 3,3-difluoroazetidine (0.45 g, 4.853 mmol, 1.2 equiv) at room temperature followed by the addition of AcOH (0.24 g, 4.044 mmol, 1 equiv) dropwise at room temperature. To the above mixture was added NaBH3CN (0.51 g, 8.088 mmol, 2 equiv) in portions at 0°C. The resulting mixture was stirred for 1h at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with DCM (3 x 60mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford benzyl ((trans)-4- (3,3-difluoroazetidin-1-yl)cyclohexyl)carbamate (400 mg, 31% yield) as a white solid.[000352] To a solution of benzyl ((trans)-4-(3,3-difluoroazetidin-1- yl)cyclohexyl)carbamate (380 mg, 1.171 mmol, 1 equiv) in 10 mL MeOH was added Pd(OH)2 / C (380 mg) in a pressure tank. The mixture was hydrogenated at 50 °C for 16 h under 4 atm of hydrogen pressure, filtered through a Celite pad and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: isocratic 2% to 6% B in 8 min; Wave Length: 254 nm / 220 nm; RT1(min): 5.75) to afford (trans)-4-(3,3-difluoroazetidin-1-yl)cyclohexan-1-amine (150 mg, 67% yield) as a white solid. [000353] To a stirred solution of (trans)-4-(3,3-difluoroazetidin-1-yl)cyclohexan-1-amine (60 mg, 0.315 mmol, 1 equiv) and 2-(1H-imidazol-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine-4-carboxylic acid (73 mg, 0.315 mmol, 1 equiv) in ACN (2 mL) were added NMI (78 mg, 0.945 mmol, 3 equiv) and TCFH (133 mg, 0.473 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred for 1h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 8) to afford N-((trans)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-2- (1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamide (33.1 mg, 26% yield) as a white solid. LCMS (ESI) [M+H]+: 403.25.1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.75 (d, J = 8.6 Hz, 1H), 8.18 (t, J = 1.4 Hz, 1H), 7.15 (t, J = 1.3 Hz, 1H), 3.86 – 3.72 (m, 1H), 3.57 (t, J = 12.2 Hz, 4H), 3.26 (t, J = 7.6 Hz, 2H), 3.02 (t, J = 7.8 Hz, 2H), 2.21 – 2.01 (m, 3H), 1.88 – 1.73 (m, 4H), 1.62 – 1.43 (m, 2H), 1.17 – 0.97 (m, 2H). Example 87: Synthesis of N-((trans)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-6-(1H- imidazol-1-yl)-1,3-dihydrofuro[3,4-c]pyridine-4-carboxamide (Compound 194)[000354] A solution of 4,6-dichloro-1H,3H-furo[3,4-c]pyridine (1.5 g, 7.894 mmol, 1 equiv), tributyl(2-methoxyprop-2-en-1-yl)stannane (2.57 g, 7.105 mmol, 0.9 equiv) and Pd(PPh3)2Cl2(554 mg, 0.789 mmol, 0.1 equiv) in DMF (15 mL) was stirred for 2 h at 70 ℃ under nitrogen atmosphere. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (9:1) to afford 6-chloro-4-(1-ethoxyethenyl)-1H,3H- furo[3,4-c]pyridine (420 mg, 24% yield) as an off-white solid. [000355] A solution of 6-chloro-4-(1-ethoxyethenyl)-1H,3H-furo[3,4-c]pyridine (410 mg, 1.817 mmol, 1 equiv) in dioxane (5 mL) and NaIO4(777 mg, 3.634 mmol, 2.0 equiv) in H2O (2 mL) was stirred for 5 min at room temperature. To the above mixture was added KMnO4(43 mg, 0.273 mmol, 0.15 equiv) at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. The resulting mixture was filtered, the filter cake was washed with dioxane (5 mL) (3 x 10 mL). The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford ethyl 6-chloro-1H,3H-furo[3,4- c]pyridine-4-carboxylate (110 mg, 27% yield) as a white solid. [000356] A solution of ethyl 6-chloro-1H,3H-furo[3,4-c]pyridine-4-carboxylate (100 mg, 0.439 mmol, 1 equiv) and LiOH.H2O (37 mg, 0.878 mmol, 2.0 equiv) in THF (1.2 mL) and H2O (0.4 mL) was stirred for 1 h at room temperature. The mixture was acidified to pH 5 with 1 M HCl (aq.). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (method 1) to afford 6-chloro- 1H,3H-furo[3,4-c]pyridine-4-carboxylic acid (50 mg, 57% yield) as a white solid. [000357] A solution of 6-chloro-1H,3H-furo[3,4-c]pyridine-4-carboxylic acid (20 mg, 0.100 mmol, 1 equiv), (trans)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexan-1-amine (25 mg, 0.120 mmol, 1.2 equiv), TCFH (56 mg, 0.200 mmol, 2.0 equiv) and NMI (41 mg, 0.500 mmol, 5.0 equiv) in ACN (1 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:2) to afford 6-chloro-N-[(trans)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl]-1H,3H-furo [3,4-c]pyridine-4-carboxamide (28 mg, 72% yield) as a white solid. [000358] A solution of 6-chloro-N-[(trans)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl]- 1H,3H-furo [3,4-c]pyridine-4-carboxamide (25 mg, 0.065 mmol, 1 equiv), imidazole (11 mg, 0.163 mmol, 2.5 equiv), t-BuBrettphos Pd G3(5 mg, 0.007 mmol, 0.1 equiv), t-BuBrettphos (6 mg, 0.013 mmol, 0.2 equiv) and Cs2CO3(63 mg, 0.195 mmol, 3.0 equiv) in dioxane (1.0 mL) was stirred for 1 h at 100 ℃ under nitrogen atmosphere. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 4) to afford N-((trans)-4-(3,3- difluoropyrrolidin-1-yl)cyclohexyl)-6-(1H-imidazol-1-yl)-1,3-dihydrofuro[3,4-c]pyridine-4- carboxamide (7.6 mg, 28% yield) as a white solid. LCMS (ESI) [M+H]+: 418.20.1H NMR (400 MHz, DMSO-d6) δ 8.94 (t, J = 1.0 Hz, 1H), 8.59 (d, J = 8.7 Hz, 1H), 8.23 (t, J = 1.4 Hz, 1H), 7.99 (s, 1H), 7.20 – 7.09 (m, 1H), 5.29 (s, 2H), 5.08 (s, 2H), 3.89 – 3.70 (m, 1H), 2.95 (t, J = 13.7 Hz, 2H), 2.75 (t, J = 6.9 Hz, 2H), 2.33 – 2.16 (m, 2H), 2.16 – 2.04 (m, 1H), 1.96 (d, J = 12.5 Hz, 2H), 1.82 (dd, J = 13.4, 4.0 Hz, 2H), 1.63 – 1.50 (m, 2H), 1.30 – 1.16 (m, 2H). Example 88: Synthesis of N-((trans)-4-(4,4-difluoro-2-oxopyrrolidin-1-yl)cyclohexyl)-2- (1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4- carboxamide (Compound 198)[000359] A solution of (trans)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexan-1-amine (200 mg, 0.979 mmol, 1 equiv), di-tert-butyl dicarbonate (320 mg, 1.468 mmol, 1.5 equiv), TEA (297 mg, 2.937 mmol, 3 equiv) and DMAP (11 mg, 0.098 mmol, 0.1 equiv) in DCM (5 mL)was stirred for 1h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl N-[(trans)-4-(3,3-difluoropyrrolidin-1- yl)cyclohexyl]carbamate (110 mg, 37% yield) as a white solid. [000360] To a stirred solution of tert-butyl N-[(trans)-4-(3,3-difluoropyrrolidin-1- yl)cyclohexyl]carbamate (100 mg, 0.329 mmol, 1 equiv) and Ruthenium(III) chloride (4 mg, 0.020 mmol, 0.06 equiv) in EA (3 mL) and H2O (3 mL) was added NaIO4(267 mg, 1.250 mmol, 3.8 equiv) in portions at 0°C. The resulting mixture was stirred for 16h at room temperature. The resulting mixture was extracted with EtOAc (3 x 10mL). The combined organic layers were washed with brine (2x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (Method 2) to afford tert-butyl ((trans)-4-(4,4-difluoro- 2-oxopyrrolidin-1-yl)cyclohexyl)carbamate (40 mg, 38% yield) as a white solid. [000361] A solution of tert-butyl ((trans)-4-(4,4-difluoro-2-oxopyrrolidin-1- yl)cyclohexyl)carbamate (40 mg, 0.126 mmol, 1 equiv) in HCl in 1,4-dioxane(4.0 M) (3 mL) was stirred for 1h at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in 4,4-difluoro-1-[(trans)-4-aminocyclohexyl]pyrrolidin-2- one (20 mg, crude) as a white solid. [000362] A solution of 4,4-difluoro-1-[(trans)-4-aminocyclohexyl]pyrrolidin-2-one (20 mg, 0.092 mmol, 1 equiv), 2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4- carboxylic acid (25 mg, 0.110 mmol, 1.2 equiv), TCFH (51 mg, 0.184 mmol, 2 equiv) and NMI (37 mg, 0.460 mmol, 5 equiv) in ACN (2 mL) was stirred for 1h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (method 7) to afford N-((trans)-4-(4,4-difluoro-2-oxopyrrolidin-1- yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4- carboxamide (3.5 mg, 9% yield) as a white solid. LCMS (ESI) [M+H]+: 431.20.1H NMR (400 MHz, Chloroform-d) δ 9.15 (s, 1H), 8.03 – 7.83 (m, 2H), 7.30 (s, 1H), 4.30 – 4.11 (m, 1H), 3.92 (m, 3.97 – 3.88, 1H), 3.70 (t, J = 13.3 Hz, 2H), 3.45 (t, J = 7.6 Hz, 2H), 3.09 (t, J = 7.9 Hz, 2H), 2.95 (t, J = 14.4 Hz, 2H), 2.22 (m, 2.28 – 2.17, 4H), 1.90 (d, J = 11.4 Hz, 2H), 1.74 – 1.45 (m, 4H).[000363] Example 89: Synthesis of N-((trans)-4-(3,3-difluoro-2-oxopyrrolidin-1- yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4- carboxamide (Compound 199)[000364] A solution of tert-butyl ((cis)-4-hydroxycyclohexyl)carbamate (5 g, 23.22 mmol, 1 equiv) and TEA (7.05 g, 69.67 mmol, 3 equiv) in DCM (50 mL) were added TsCl (6.64 g, 34.83 mmol, 1.5 equiv) and DMAP (0.57 g, 4.64 mmol, 0.2 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The reaction was quenched with Water at 0°C. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl N-[(cis)-4-[(4-methylbenzenesulfonyl)oxy]cyclohexyl]carbamate (3 g, 35% yield) as a white solid. [000365] To a solution of tert-butyl N-[(cis)-4-[(4- methylbenzenesulfonyl)oxy]cyclohexyl] carbamate (3 g, 8.12 mmol, 1 equiv) in DMF (30 mL) was added sodium hydride (60% in oil, 290 mg) at 0 degrees C. The mixture was stirred for 15 min.1-(Chloromethyl)-4-methoxybenzene (2.54 g, 16.24 mmol, 2 equiv) was added and the mixture was allowed to warm to RT and stirred for 2h. The reaction was quenched with sat. NH4Cl (aq.) at 0°C. The aqueous layer was extracted with EtOAc (3x30 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford tert-butyl N-[(4- methoxyphenyl)methyl]-N-[(cis)-4-[(4-methylbenzenesulfonyl)oxy]cyclohexyl]carbamate (1.2 g, 30% yield) as a yellow oil.[000366] A solution of 3,3-difluoropyrrolidin-2-one (300 mg, 2.47 mmol, 1 equiv), tert- butyl N-[(4-methoxyphenyl)methyl]-N-[(cis)-4-[(4- methylbenzenesulfonyl)oxy]cyclohexyl]carbamate (1334 mg, 2.72 mmol, 1.1 equiv) and t- BuOK (556 mg, 4.95 mmol, 2 equiv) in THF (5 mL) was stirred for 16 h at 80°C. The resulting mixture was diluted with water and extracted with EtOAc, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography (method 2) to afford tert-butyl N-[(4-methoxyphenyl)methyl]-N-[(trans)-4-(3,3-difluoro-2-oxopyrrolidin-1- yl)cyclohexyl]carbamate (180 mg, 17% yield) as a yellow solid. [000367] To a solution of tert-butyl N-[(4-methoxyphenyl)methyl]-N-[(trans)-4-(3,3- difluoro-2-oxopyrrolidin-1-yl)cyclohexyl]carbamate (180 mg, 0.41 mmol, 1 equiv) in MeOH (3 mL) was added Pd / C (10%, 180 mg) under nitrogen atmosphere. The mixture was hydrogenated for 16 h at 50°C under hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad and concentrated under reduced pressure to afford tert-butyl N-[(trans)- 4-(3,3-difluoro-2-oxopyrrolidin-1-yl)cyclohexyl]carbamate (120 mg, 92% yield) as a white solid. [000368] A solution of tert-butyl N-[(trans)-4-(3,3-difluoro-2-oxopyrrolidin-1- yl)cyclohexyl]carbamate (120 mg, 0.37 mmol, 1 equiv) in HCl in 1,4-dioxane(4.0 M) (4 mL) was stirred for 1h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 3,3-difluoro-1-[(trans)-4-aminocyclohexyl]pyrrolidin-2-one (80 mg, 97% yield) as a yellow oil. [000369] A solution of 3,3-difluoro-1-[(trans)-4-aminocyclohexyl]pyrrolidin-2-one (80 mg, 0.36 mmol, 1 equiv), 2-(imidazol-1-yl)-5H,6H,7H-cyclopenta[d]pyrimidine-4-carboxylic acid (92.83 mg, 0.40 mmol, 1.1 equiv), TCFH (154.27 mg, 0.55 mmol, 1.5 equiv) and NMI (451.45 mg, 5.50 mmol, 15 equiv) in ACN (2 mL) was stirred for 1h at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC (Method 10) to afford N-((trans)-4-(3,3-difluoro-2-oxopyrrolidin-1- yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4- carboxamide (58.7 mg, 37% yield) as a white solid. LCMS (ESI) [M+H]+: 431.25.1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.79 (d, J = 8.7 Hz, 1H), 8.20 (s, 1H), 7.16 (s, 1H), 3.83 (d J = 252 Hz 2H) 346 (t J = 65 Hz 2H) 327 (t J = 75 Hz 2H) 303 (t J = 78 HzExample 90: CD38 Hydrolase Inhibition Assay [000370] The CD38 hydrolase inhibition assay measures the glycohydrolase activity of CD38, using an NAD analog as substrate and measuring formation of a fluorescent ADP ribose analog. A 4x buffer was prepared with 1M sucrose and 160 mM Tris-HCl at pH 7.4, for a final assay concentration of 250 mM sucrose and 40 mM Tris-HCl. The 4x solution was kept at 4 °C and warmed to room temperature before use. Tween20 was added to 1x buffer for a final concentration of 0.05%. Human recombinant CD38 (BPS Bioscience) was diluted to 0.4 ng / µL in 1x buffer and 12.5 µL added to each plate well. Inhibitors were added and DMSO content was normalized to the highest concentration on the plate, with an upper limit of 0.5%. Finally, ε-NAD was diluted to 200 µM in 1x buffer and 12.5 µL added to each plate well, for final well concentrations of 0.2 ng / µL CD38 and 100 µM ε-NAD. Plates were covered and incubated at room temperature for 15m, and then read on a plate reader using excitation 300nm and emission 410 nm. 200 nM 78c was included as a fully inhibited well, as well as DMSO-only wells as uninhibited. IC50s for test compounds were determined either using GraphPad Prism software v9.3, or CDD Vault. The results are shown in Table 2, wherein + <0.1 uM; ++ 0.1 uM to 1.0 uM; +++ >1.0 uM. Table 2.INCORPORATION BY REFERENCE [000371] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EQUIVALENTS AND SCOPE [000372] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or all of the group members are present in employed in or otherwise relevant to a given product or process[000373] Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the disclosure, or aspects of the disclosure, is / are referred to as comprising particular elements and / or features, certain embodiments of the disclosure or aspects of the disclosure consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub–range within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. [000374] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art. [000375] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the artwithout departing from the spirit or scope of the present disclosure, as defined in the following claims.

Claims

CLAIMS What is claimed is:

1. A compound represented by Formula I:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: X1and X2are each independently selected from N and CH; Y is -C(O)-NRa- or -S(O)2-NRa-; R1is 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl; wherein R1may optionally be substituted by one or more substituents each independently selected from R11; R11is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, -CN, -CF3-NRaRb, - C(O)-NRaRb, -NRa-C(O)-Rb, and deuterium; wherein -C1-6alkyl and -C1-6alkoxy may optionally be substituted by one or more substituents each independently selected from hydroxyl, halogen, deuterium, and -C1-3alkoxy; Ring A is a 5-6 membered ring selected from the group consisting of phenyl, 5-6 membered carbocycle, and 5-6 membered heterocyclyl; and wherein ring A may optionally be substituted by one, two or three substituents each independently selected from RA; Ring B is selected from the group consisting of a 4-12 membered monocyclic, fused bicyclic, bridged bicyclic, or spirocyclic carbocycle, and a 5-7 membered heterocyclyl; wherein ring B may optionally be substituted by one, two or three substituents each independently selected from RB; RAis independently selected for each occurrence from the group consisting ofheterocyclyl, -CN, -CF3-OC(O)-C1-6alkyl, -NRaRb, -C(O)-NRaRb, and -NRa-C(O)-Rb; wherein -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, and 5-6 membered heterocyclyl may optionally be substituted by one or more substituents each independently selected from hydroxyl, halogen, deuterium, and -C1-3alkoxy; RBis independently selected for each occurrence from the group consisting of halogen, hydroxyl, deuterium, -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, 5-6 membered heterocyclyl, -CN, -CF3, oxo, -OC(O)-C1-6alkyl, -NRaRb, -C(O)-NRaRb, and -NRa-C(O)-Rb; wherein -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, and 5-6 membered heterocyclyl may optionally be substituted by one or more substituents each independently selected from hydroxyl, halogen, oxo, deuterium, and -C1-3alkoxy; Raand Rbare each independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl, wherein C1-C6alkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1-C6alkoxy; or Raand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; p is 0, 1, or 2; and q is 01, or 2.

2. The compound of claim 1, wherein the compound is represented by Formula 1A:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein: X1and X2are each independently selected from N and CH;R1is 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl; wherein R1may optionally be substituted by one or more substituents each independently selected from R11; R11is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, -CN, -CF3-NRaRb, - C(O)-NRaRb, -NRa-C(O)-Rb, and deuterium; wherein -C1-6alkyl and -C1-6alkoxy may optionally be substituted by one or more substituents each independently selected from hydroxyl, halogen, deuterium, and -C1-3alkoxy; Ring A is a 5-6 membered ring selected from the group consisting of phenyl, 5-6 membered carbocycle, and 5-6 membered heterocyclyl; and wherein ring A may optionally be substituted by one, two or three substituents each independently selected from RA; RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, deuterium, -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, 5-6 membered heterocyclyl, -CN, -CF3-OC(O)-C1-6alkyl, -NRaRb, -C(O)-NRaRb, and -NRa-C(O)-Rb; wherein -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, and 5-6 membered heterocyclyl may optionally be substituted by one or more substituents each independently selected from hydroxyl, halogen, deuterium, and -C1-3alkoxy; R2is selected from the group consisting of halogen, hydroxyl, deuterium, -C1-6alkyl, - C1-6alkoxy, -C3-6cycloalkyl, phenyl, 5-6 membered heterocyclyl, -CN, -CF3, oxo, -OC(O)-C1-6alkyl, -NRaRb, -C(O)-NRaRb, and -NRa-C(O)-Rb; wherein -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, and 5-6 membered heterocyclyl may optionally be substituted by one or more substituents each independently selected from hydroxyl, halogen, oxo, deuterium, and - C1-3alkoxy; R3is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, - C1-6alkyl, -C1-6alkoxy, -CN, -NRaRb, -C(O)-NRaRb, and -NRa-C(O)-Rb; R4and R5are each independently selected from the group consisting of hydrogen and -C1-3alkyl optionally substituted by one or more halogens; Raand Rbare each independently selected for each occurrence from the groupwith one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and C1-C6alkoxy; or Raand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, C1-C6alkyl, and C1-C6alkoxy; m is 1 or 2; n is 1, 2, or 3; and p is 0, 1, 2, or 3.

3. The compound of claim 1 or 2, wherein m and n are each 2, or m and n are each 1.

4. The compound of any one of claims 1-3, wherein the compound is represented by:

5. The compound of any one of claims 1-4, wherein Y is -C(O)-NH-.

6. The compound of any one of claims 1-4, wherein the compound is represented by:

8. The compound of any one of claims 1-6, wherein X1is CH and X2is N.

9. The compound of any one of claims 1-6, wherein X1is N and X2is N.

10. The compound of any one of claims 1-6, wherein X1is CH and X2is CH.

11. The compound of any one of claims 1-10, wherein R1is a 5-6 membered heteroaryl containing at least one ring nitrogen, wherein R1may optionally be substituted by one or two substituents each independently selected from R11.

12. The compound of any one of claims 1-11, wherein R1is selected from the group consisting of imidazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, and pyridyl, wherein R1may optionally be substituted by one or two substituents each independently selected from the group consisting of -CH2OH, -OH and -NH2.

13. The compound of any one of claims 1-12, wherein R1is selected from the group consisting of.

14. The compound of any one of claims 1-13, wherein R1is selected from the group consisting of15. The compound of any one of claims 2-14, wherein R2is selected from the group consisting of -OH, -CN, -CD3, -CF3, -OCH3, -OCD3, -OCH2CH2OCH3, - OCH2CH2OCH2CH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OC(CH3)3, -C(CH3)2OH, -16. The compound of any one of claims 2-15, wherein R2is selected from the group consisting of -OH, -CN, -CD3, -CF3, -OCH3, -OCD3, -OCH2CH2OCH3, -C(CH3)2OH, -17. The compound of any one of claims 1-16, wherein p is 1 and RAis selected from the group consisting of -CN, -CH2OH, -OC(O)CH3, morpholino, fluoro, chloro, and bromo.

18. The compound of any one of claims 1-16, wherein p is 0.

19. The compound of any one of claims 2-18, wherein R3and R5are, for each occurrence, hydrogen.

20. The compound of any one of claims 2-19, wherein R4is selected from the group consisting of hydrogen, -CH3, and -CH2CH3.

21. A compound represented by Formula II:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X1is N and X2is CH; or X1is N and X2is N; R1is 5-6 membered heteroaryl containing at least one ring nitrogen; wherein R1may optionally be substituted by one, two or three substituents each independently selected from the group consisting of halogen, hydroxyl, deuterium, -NH2, -C1-3alkyl, -C1-3alkyl-OH, and - C1-3alkoxy; R2is selected from the group consisting of halogen, hydroxyl, deuterium, -C1-6alkyl, - C1-6alkoxy, -C3-6cycloalkyl, phenyl, 5-6 membered heterocyclyl, -CN, -CF3, oxo, -OC(O)-C1-6alkyl, -NRaRb, -C(O)-NRaRb, and -NRa-C(O)-Rb; wherein -C1-6alkyl, -C1-6alkoxy, -C3-6cycloalkyl, phenyl, and 5-6 membered heterocyclyl may optionally be substituted by one or more substituents each independently selected from hydroxyl, halogen, oxo, deuterium, and - C1-3alkoxy; R3is selected from the group consisting of hydrogen, -CH3, and -CH2CH3; RAis independently selected for each occurrence from the group consisting of halogen, hydroxyl, deuterium, -C1-6alkyl, -C1-6alkoxy, -CN, and 5-6 membered heterocyclyl, wherein -C1-6alkyl and -C1-6alkoxy may optionally be substituted by one or more substituents each independently selected from hydroxyl, deuterium, and halogen; and p is 0, 1, 2, or 3.

22. The compound of claim 18, wherein the compound is represented by:

25. The compound of any one of claims 21-24, wherein p is 1 and RAis selected from the group consisting of -CN, -CH2OH, morpholino, fluoro, chloro, and bromo.

26. The compound of any one of claims 21-24, wherein p is 0.

27. A compound selected from the group consisting of:, , ,or a pharmaceutically acceptable salt and / or a stereoisomer thereof.

28. A pharmaceutical composition comprising the compound of any one of claims 1-27, and a pharmaceutically acceptable excipient.

29. A method of treating a disease that benefits from inhibition of CD38 in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1-27, or the pharmaceutical composition of claim 28.

30. A method of treating a disease that benefits from an increase in NAD+ in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1-27, or the pharmaceutical composition of claim 28.

31. A method of treating neurodegenerative disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1-27, or th h ti l iti f l i 2832. The method of claim 31, wherein the neurodegenerative disease is Parkinson’s disease.

33. A method of treating a cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1-27, or the pharmaceutical composition of claim 28.

34. The method of claim 33, wherein the cancer is selected from the group consisting of lung cancer, breast cancer, melanoma, glioma, and colon cancer.

35. A method of treating a patient suffering from fibrosis, and in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1-27, or the pharmaceutical composition of claim 28.

36. The method of claim 35, wherein the patient suffering from fibrosis also suffers from systemic sclerosis.

37. The method of claim 35 or 36, wherein the fibrosis is selected from the group consisting of skin fibrosis, lung fibrosis, and peritoneal fibrosis.

38. A method of treating a fatty liver disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1-27, or the pharmaceutical composition of claim 28.

39. The method of claim 38, wherein the fatty liver disease is selected from the group consisting of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).

40. A method of treating an inflammatory disease in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1-27, or the pharmaceutical composition of claim 28.

41. The method of claim 40, wherein the inflammatory disease is irritable bowel syndrome or inflammatory bowel disease.

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