Condensed azines as inhibitors of cyclic ADP ribohydrolase

Abstract

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

Description

Cross-reference to related applications

[0001] This application claims the rights and priorities of USSN 63 / 506,642, filed June 7, 2023, and USSN 63 / 561,950, filed March 6, 2024, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0002] Glycoprotein CD38 (Cluster 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 act as a cyclase that converts NAD+ to cyclic ADP-ribose (cADPR). Its NAD-cyclase activity is more significant than its function as an ADP-ribosyl-cyclase, being 100 times less efficient at cyclizing NAD+ to cADPR than at hydrolyzing NAD+ to ADP-ribose. CD38 can also hydrolyze nicotinamide adenine dinucleotide phosphate (NADP) to nicotinic adenine dinucleotide phosphate (NAADP), both of which are derived from NAD+. Therefore, CD38 is considered a significant consumer of NAD+ and a regulator of NAD+ levels.

[0003] Disorders of NAD+ levels are associated with a variety of disease states. For example, disease states associated with NAD+ depletion and dysregulation of NAD+-related metabolites include, but are not limited to, obesity, diabetes, cancer, heart disease, asthma, and inflammation. Therefore, restoring NAD+ to its normal levels in disease states that deplete significant amounts of NAD+ can produce therapeutic benefits.

[0004] For example, decreased NAD+ levels are associated with aging, and this age-related dysfunction may contribute to increased neurogenesis and the onset of neurodegenerative disorders. The expression of CD38 (an enzyme responsible for NAD+ degradation) is envisioned to increase due to aging, thus providing a plausible explanation for decreased NAD+ levels due to aging. Therefore, one approach to regulating cellular NAD+ levels could be to inhibit enzymes that deplete NAD+, such as CD38.

[0005] Inhibition of CD38 enzyme activity (which in turn regulates NAD+ tissue levels) presents a potential approach for treating diseases associated with increased CD38 expression and / or decreased cellular NAD+ levels. Therefore, small molecule inhibitors of CD38 are continuously needed in the treatment of diseases or conditions that respond to regulation (e.g., inhibition) of cellular NAD+ levels. Summary of the Invention

[0006] This disclosure relates, at least in part, to compounds that regulate (e.g., inhibit) the expression and / or activity of CD38. Pharmaceutical compositions comprising at least one of the disclosed compounds and a pharmaceutically acceptable excipient are also disclosed herein.

[0007] For example, this paper discloses compounds represented by formula I: (I); Or its pharmaceutically acceptable salts and / or stereoisomers, wherein: X 1 and X 2 Each is independently selected from N and CH; Y is -C(O)-NR a -or-S(O)2-NR a -; R 1 It is a 5-6 member monocyclic heteroaryl or an 8-10 member bicyclic heteroaryl; wherein R 1 It can be optionally selected by one or more independently chosen from R 11 Substituents of the substituents; R 11 Each time it appears, it is independently selected from the following groups: halogen, hydroxyl, -C. 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, -CN, -CF3, -NR a R b -C(O)-NR a R b -NR a -C(O)-R b , and deuterium; where -C 1-6 Alkyl and -C 1-6 The alkoxy group can optionally be selected by one or more elements, each independently chosen from hydroxyl, halogen, deuterium, and -C. 1-3 Substitution of alkoxy groups; Ring A is a 5-6 membered ring selected from the group consisting of: phenyl, 5-6 membered carbon rings, and 5-6 membered heterocyclic groups; and wherein ring A may optionally be selected independently by one, two, or three groups from R. A Substituents of the substituents; Ring B is selected from the group consisting of: 4-12 member monocyclic, fused bicyclic, bridging bicyclic or spirocyclic carbon rings, and 5-7 member heterocyclic groups; wherein ring B may optionally be selected independently by one, two or three members from R B Substituents of the substituents; R A Each time it appears, it is independently selected from the following groups: halogen, hydroxyl, deuterium, -C. 1-6 Alkyl, -C1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, 5-6 membered heterocyclic groups, -CN, -CF3, -OC(O)-C 1-6 Alkyl, -NR a R b -C(O)-NR a R b , and -NR a -C(O)-R b ;where -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, and 5-6 membered heterocyclic groups may optionally be selected independently by one or more groups chosen from hydroxyl, halogen, deuterium, and -C. 1-3 Substitution of alkoxy groups; R B Each time it appears, it is independently selected from the following groups: halogen, hydroxyl, deuterium, -C. 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, 5-6 membered heterocyclic groups, -CN, -CF3, oxo groups, -OC(O)-C 1-6 Alkyl, -NR a R b -C(O)-NR a R b , and -NR a -C(O)-R b ;where -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, and 5-6 membered heterocyclic groups may optionally be selected independently by one or more groups chosen from hydroxyl, halogen, oxo, deuterium, and -C. 1-3 Substitution of alkoxy groups; R a and R b Each occurrence is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups may optionally be substituted by one or more substituents independently selected from the group consisting of halogens, deuterium, hydroxyl groups, and C1-C6 alkoxy groups; or R a and R b The nitrogen atoms attached to them can be linked together to form 4-7 membered heterocyclic groups, which may be optionally substituted by one or more substituents selected independently from the group consisting of: halogen, deuterium, hydroxyl, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy groups; p is 0, 1, or 2; and q can be 0, 1, or 2.

[0008] This article also discloses compounds represented by formula II: (II); Or its pharmaceutically acceptable salts and / or stereoisomers, wherein: A is phenyl, cyclohexyl, cyclopentyl, or dihydrofuranyl; X 1 It is N and X 2 It is CH; or X 1 It is N and X 2 It is N; R 1 It is a 5-6 membered heteroaryl group containing at least one cyclic nitrogen; wherein R 1 It may optionally be substituted by one, two, or three substituents, each independently selected from the group consisting of: halogen, hydroxyl, deuterium, -NH2, -C 1-3 Alkyl, -C 1-3 Alkyl -OH and -C 1-3 Alkoxy; R 2 Choose from the following groups: halogens, hydroxyl groups, deuterium, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, 5-6 membered heterocyclic groups, -CN, -CF3, oxo groups, -OC(O)-C 1-6 Alkyl, -NR a R b -C(O)-NR a R b , and -NR a -C(O)-R b ;where -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, and 5-6 membered heterocyclic groups may optionally be selected independently by one or more groups chosen from hydroxyl, halogen, oxo, deuterium, and -C. 1-3 Substitution of alkoxy groups; R 3 Choose from the following groups: hydrogen, -CH3, and -CH2CH3; R A Each time it appears, it is independently selected from the following groups: halogen, hydroxyl, deuterium, -C. 1-6 Alkyl, -C 1-6 Alkoxy groups, -CN groups, and 5-6 membered heterocyclic groups, wherein -C 1-6 Alkyl and -C1-6 The alkoxy group 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] This article also discloses a method for treating diseases (e.g., neurodegenerative diseases) in patients who benefit from CD38 inhibition and / or NAD+ increase, comprising administering an effective amount of the disclosed CD38 inhibitor to the patient. In some embodiments, the neurodegenerative disease is, for example, Parkinson's disease, Alzheimer's disease, or Huntington's disease. Detailed Implementation

[0010] The features and other details of this disclosure will now be described in more detail. Before further describing this disclosure, certain terms used in the specification, examples, and appended claims are collected herein. These definitions should be interpreted in accordance with the remainder of this disclosure and as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. definition

[0011] As used herein, the term "alkyl" refers to a saturated straight-chain or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight-chain or branched hydrocarbons with 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C14-C24-C3 ... 1-6 Alkyl, C 1-4 Alkyl and C 1-3 Alkyl groups. 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, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

[0012] As used herein, the term "alkenyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, straight-chain or branched groups with 2-6 or 3-4 carbon atoms, referred to herein as C1-C5 alkenyl, C2-C6 alkenyl, and C3-C4 alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

[0013] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight-chain or branched groups with 2-6 or 3-6 carbon atoms, referred to herein as C14-C2 ... 2-6alkynyl group and C 3-6 Alkyne groups. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, penynyl, hexynyl, methylpropynyl, etc.

[0014] As used herein, the term "alkoxy" refers to a straight-chain or branched alkyl group (alkyl-O-) attached to an oxygen atom. Exemplary alkoxy groups include, but are not limited to, alkoxy groups with 1-6 or 2-6 carbon atoms, referred to herein as C1-C5 alkoxy, C1-C6 alkoxy, and C2-C6 alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, etc.

[0015] The term "aryl" refers to a group ("C") in 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) that provides 6-14 ring carbon atoms and zero heteroatoms in an aromatic ring system. 6-14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”, for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”). 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen cyclic carbon atoms ("C"). 14 "Aryl"; for example, anthracene. "Aryl" also includes ring systems in which the aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the group or attachment site is on the aryl ring, and in such cases, the number of carbon atoms continues to specify the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, those derived from the following groups: acepane, acenaphthene, phenanthrene, anthracene, azulene, benzene, acetylene, fentanyl, fluoranthene, fluorene, hexaphene, hexalene, and asymmetric indole. Aryl groups include phenoxide, symmetric phenoxide, indene, indene, naphthalene, octacene, octaphene, octalene, ovalene, pentane-2,4-diene, pentaphenyl, pentalene, pentanene, perylene, phenanthracene, pleiadene, pyrene, anthracene, rubigin, benzo[a]phenanthrene, and trinaphthalene. Specifically, aryl groups include phenyl, naphthyl, indene, and tetrahydronaphthyl. Examples of representative substituted aryl groups include the following: Where R 56 and R 57 One of them could be hydrogen and R 56 and R 57At least one of them is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, 4-10 membered heterocyclic, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 NR 58 SOR 59 NR 58 SO2R 59 COO alkyl, COO aryl, CONR 58 R 59 CONR 58 OR 59 NR 58 R 59 SO2NR 58 R 59 S-alkyl, SO-alkyl, SO2-alkyl, S-aryl, SO-aryl, SO2-aryl; or R 56 and R 57 They can be linked to form cyclic rings (saturated or unsaturated) of 5 to 8 atoms, which optionally contain one or more heteroatoms selected from the group N, O, or S. R 60 and R 61 Each of these can be independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, or C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl, substituted C6-C 10 Aryl, 5-10 heteroaryl, or substituted 5-10 heteroaryl.

[0016] As used in this article, the term "carbonyl" refers to the group -C(O)-.

[0017] As used in this article, the term "cyano" refers to the group -CN.

[0018] As used herein, the terms “cycloalkyl,” “carbocyclic,” or “carbocyclic group” refer to, for example, saturated or partially unsaturated hydrocarbon groups of 3-6 or 4-6 carbons, referred to herein as C3-C4, respectively. 10 cycloalkyl, C 3-6 cycloalkyl or C 4-6 Cycloalkyl. 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- to 10-membered saturated or partially unsaturated ring structures with bridging, fused, or spirocyclic ring structures.

[0019] As used in this article, the term "halogenated" or "halogen" refers to F, Cl, Br, or I.

[0020] As used herein, the term "haloalkyl" refers to an alkyl group 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, etc. Exemplary haloalkyl groups include, but are not limited to, straight-chain or branched hydrocarbons with 1-6, 1-4, or 1-3 carbon atoms substituted with halogens (i.e., Cl, F, Br, and I), referred to herein as C14, C24, C34, C44, C54, C64, C74, C64, C74, C74, C75 ... 1-6 Haloalkyl, C 1-4 Halogenated alkyl groups and C 1-3 Halogenated alkyl groups.

[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 nitrogen, oxygen, or sulfur heteroatoms. "Hetero" can be applied to any of the hydrocarbon groups described above, such as alkyl (e.g., heteroalkyl), cycloalkyl (e.g., heterocyclic), aryl (e.g., heteroaryl), cycloalkenyl (e.g., cycloheterenyl), etc., having 1 to 5, and particularly 1 to 3, heteroatoms.

[0022] As used herein, the term "heteroaryl" or "heteroaromatic group" refers to an aromatic 5-10 membered ring system containing one or more heteroatoms (e.g., one to three heteroatoms, such as nitrogen, oxygen, and sulfur). The term can also refer to 5-7 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl. Where possible, the heteroaryl ring may be linked to an adjacent group via carbon or nitrogen. Examples of heteroaryl rings include, but are not limited to, furans, thiophenes, pyrroles, pyrrolopyridines, indoles, thiazoles, oxazoles, isothiazoles, isoxazoles, imidazoles, benzimidazoles, imidazopyridines, pyrazoles, triazoles, pyridines, or pyrimidines.

[0023] The terms “heterocyclic group,” “heterocycle,” or “heterocyclic radical” are recognized in the field and refer to saturated or partially unsaturated 4-10 membered ring structures containing one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, the heterocyclic ring can be connected to an adjacent group via carbon or nitrogen. The term can also be used to refer to 4-10 membered saturated or partially unsaturated ring structures as bridging, fused, or spirocyclic ring structures containing one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Examples of heterocyclic groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxoheterocyclic butane, azaheterocyclic butane, tetrahydrofuran, dihydrofuran, dihydropyran, tetrahydropyran, etc. In some embodiments, the heterocycle is a spiroheterocycle (e.g., 2,8-diazaspiro[4.5]decane). In some embodiments, the heterocycle is a bridging heterocycle (e.g., octahydro-1H-4,7-bridged methylene isoindole). A "spiroheterocyclic group" or "spirocyclic ring" refers to a polycyclic heterocyclic group having rings connected by a common atom (called a spiro atom), wherein these rings have one or more elements chosen from N, O, and S(O). m The heteroatoms of the group (where m is an integer from 0 to 2) are used as ring atoms.

[0024] As used in this article, the term "hydroxyl (hydroxy and hydroxyl)" refers to the -OH group.

[0025] As used in this article, the term "oxo" refers to the =O group.

[0026] "Pharmaceutical or pharmacologically acceptable" includes molecular entities and compositions that, when administered to animals or humans, do not produce adverse, allergic, or other adverse reactions, as appropriate. For human use, formulations should meet the sterility, pyrogenicity, and general safety and purity standards required by the FDA Office of Biologics standards.

[0027] As used herein, the terms "pharmaceutically acceptable carrier" or "pharmaceuticalally acceptable excipient" refer to any and all solvents, dispersion media, coatings, isotonic agents, and absorption delay agents compatible with drug administration. The use of such media and agents for the active pharmaceutical ingredient is well known in the art. The composition may also contain other active compounds that provide supplemental, additional, or enhanced therapeutic function.

[0028] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound as disclosed herein, formulated together with one or more pharmaceutically acceptable carriers.

[0029] As used herein, the term "one or more pharmaceutically acceptable salts" refers to salts that may contain acidic or basic groups in the compounds used in the compositions. Compounds that are basic in nature and included in the compositions of the present invention are capable of forming a variety of salts with various inorganic and organic acids. The pharmaceutically acceptable acids that can be used to prepare such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to malates, oxalates, chlorides, bromides, iodides, nitrates, sulfates, hydrogen sulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucuronides, glycosides, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and bis(hydroxynaphthyl)ate (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthylcarbamate)). Acidic compounds contained in the compositions of the present invention are capable of forming basic salts with a variety of 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 containing a basic or acidic moiety included in the compositions of this invention can also form pharmaceutically acceptable salts with various amino acids. The compounds disclosed herein may contain both acidic and basic groups; for example, an amino group and a carboxylic acid group. In this case, the compound may exist as an acid addition salt, a zwitterion, or a basic salt.

[0030] The compounds disclosed herein may contain one or more chiral centers and, therefore, exist as stereoisomers. When used herein, the term "stereoisomer" comprises all enantiomers or diastereomers. These compounds may be designated by the symbols "(+)", "(-)", "R", or "S", depending on the configuration of the substituents surrounding the stereocarbon atom, but those skilled in the art will recognize that the structure may implicitly represent the chiral center. This disclosure covers a wide variety of stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated in nomenclature as "(±)", but those skilled in the art will recognize that the structure may implicitly represent the chiral center.

[0031] The compounds disclosed herein may contain one or more double bonds, and therefore exist as geometric isomers resulting from the arrangement of substituents surrounding the carbon-carbon double bonds. (Symbol) The bond can be a single, double, or triple bond as described herein. Substituents surrounding the carbon-carbon double bond are designated as being in the "Z" or "E" configuration, where the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise stated, the structure describing the double bond encompasses both the "E" and "Z" isomers. Substituents surrounding the carbon-carbon double bond may alternatively be referred to as "cis" or "trans," where "cis" indicates a substituent on the same side of the double bond, and "trans" indicates a substituent on the opposite side of the double bond.

[0032] The compounds disclosed herein may contain a carbocyclic or heterocyclic ring, and thus exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around the carbocyclic or heterocyclic ring is specified as being in a “Z” or “E” configuration, wherein the terms “Z” and “E” are used according to IUPAC standards. Unless otherwise stated, the description of the carbocyclic or heterocyclic structure encompasses both “Z” and “E” isomers. Substituents around the carbocyclic or heterocyclic ring may also be referred to as “cis” or “trans”, wherein the term “cis” indicates a substituent on the same side of the ring plane, and the term “trans” indicates a substituent on the opposite side of the ring plane. Mixtures of compounds in which substituents are disposed on both the same side and the opposite side of the ring plane are specified as “cis / trans”.

[0033] Individual enantiomers and diastereomers of the disclosed compounds can be prepared synthetically from commercially available starting materials containing asymmetric or stereocenters, or by preparing racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by: (1) attaching a mixture of enantiomers to a chiral auxiliary agent, separating the resulting mixture of diastereomers by recrystallization or chromatography, and releasing an optically pure product from the auxiliary agent; (2) forming a salt using an optically active resolving agent; (3) directly separating a mixture of optically enantiomers on a chiral liquid chromatography column; 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 liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective synthesis (where a single reactant forms an unequal mixture of stereoisomers during the generation of a new stereocenter or during the transformation of a pre-existing stereocenter) is well known in the art. Stereoselective synthesis encompasses both enantioselective and diastereoselective transformations and can involve the use of chiral auxiliaries. See, for example, Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0034] The compounds disclosed herein can exist in both solvated and non-solvated forms with pharmaceutically acceptable solvents (such as water, ethanol, etc.), and are intended to cover both solvated and non-solvated forms in this disclosure. 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 yet another embodiment, the compound is crystalline.

[0035] This disclosure also covers compounds with the same isotopic labels as those listed herein, except that one or more atoms are replaced by atoms having an atomic weight or mass number different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, as follows: 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F, and 36 Cl. For example, the compounds disclosed herein may have one or more H atoms substituted with deuterium.

[0036] The disclosed compounds are labeled with certain isotopes (e.g., using...). 3 H and 14 Those labeled with C can be used in the determination of compound and / or substrate tissue distribution. Tritium (i.e., 3 H) and carbon-14 (i.e., ... 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, heavier isotopes such as deuterium (i.e., 2 Substitution of H) can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements), and is therefore preferred in some cases. The isotopically labeled compounds disclosed herein can generally be prepared by replacing non-isotopically labeled reagents with isotopically labeled reagents according to procedures similar to those disclosed in the examples herein.

[0037] The term "prodrug" refers to a compound that is converted in vivo to produce the disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound. Conversion can occur through various mechanisms, such as esterases, amidases, phosphatases, oxidative and / or reductive metabolism, at various locations (e.g., in the intestinal lumen or during transport in the intestine, blood, or liver). Prodrugs are well known in the art (e.g., see Rautio, Kumpulainen et al., Nature Reviews Drug Discovery 2008, 7, 255). For example, if the disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound contains a carboxylic acid functional group, the prodrug may comprise an ester formed by replacing the hydrogen atom of an acid group with a group such as (C 1-8 )alkyl, (C 2-12 alkylcarbonyloxymethyl, 1-(alkylcarbonyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkylcarbonyloxy)-ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonic acid lactone, γ-butyrolactone-4-yl, di-N,N-(C 1-2 )alkylamino(C 2-3 )alkyl (such as β-dimethylaminoethyl), carbamoyl-(C 1-2 )alkyl, N,N-di(C 1-2 )alkylcarbamoyl-(C 1-2 )alkyl and piperidinyl-, pyrrolidine- or morpholino (C 2-3 )alkyl.

[0038] Similarly, if the compounds disclosed herein contain an alcohol functional group, the prodrug can be formed by replacing the hydrogen atoms of the alcohol group with groups such as (C 1-6 )alkylcarbonyloxymethyl, 1-((C 1-6 )alkylcarbonyloxy)ethyl, 1-methyl-1-((C 1-6 )alkoxycarbonyloxy)ethyl, (C 1-6 )alkoxycarbonyloxymethyl, N-(C 1-6 )alkoxycarbonylaminomethyl, succinoyl, (C 1-6 )alkyl carbonyl, α-amino (C 1-4)alkyl carbonyl, arylalkyl carbonyl and α-aminoalkyl carbonyl, or α-aminoalkyl carbonyl-α-aminoalkyl carbonyl (where each α-aminoalkyl carbonyl is independently selected from naturally occurring L-amino acids), P(O)(OH)2, -P(O)(O(C 1-6 Alkyl group or glycosyl group (a group produced by removing the hydroxyl group from the hemiacetal form of a carbohydrate).

[0039] If the compounds disclosed herein incorporate an amine functional group, the prodrug can be formed, for example, by generating an amide or carbamate, an N-alkylcarbonyloxyalkyl derivative, a (oxodioxacyclopentenyl)methyl derivative, an N-Mannich base, an imine, or an enamine. Furthermore, secondary amines can be metabolically cleaved to generate a bioactive primary amine, or tertiary amines can be metabolically cleaved to generate a bioactive primary or secondary amine. See, for example, Simplício et al., Molecules [Molecules] 2008, 13, 519 and its references.

[0040] The term "treatment" or "treating" refers to the medical management of a patient aimed at improving, alleviating, stabilizing (i.e., preventing worsening), preventing, or curing a disease, pathological condition, or disorder. "Treatment" includes active treatment (treatment aimed at improving a disease, pathological condition, or disorder), etiological treatment (treatment targeting the underlying cause of the disease, pathological condition, or disorder), palliative treatment (treatment aimed at relieving symptoms), preventative treatment (treatment aimed at minimizing or partially or completely suppressing the development of the disease, pathological condition, or disorder), and supportive treatment (treatment used to complement another therapy). Treatment also includes reducing the severity of a disease or condition; preventing the spread of a disease or condition; delaying or slowing the progression of a disease or condition; alleviating or mitigating a disease or condition; and achieving remission (whether partial or complete), whether detectable or undetectable. "Alleviating" or "mitigating" a disease or condition means that the severity and / or undesirable clinical manifestations of the disease, disorder, or condition are reduced and / or the time course of progression is slowed or prolonged compared to the severity or time course without treatment. "Treatment" also includes extending survival compared to the expected survival without treatment. Those who need treatment include those who already have a condition or disability, those who are susceptible to a condition or disability, or those who need to prevent a condition or disability.

[0041] The terms “effective amount,” “therapeutic effective amount,” or “sufficient amount” refer to an amount sufficient to achieve a therapeutic effect (e.g., produce a beneficial or desired outcome) (including effects at the cellular, tissue, or clinical level) when administered to a patient (e.g., a mammal, such as a human patient). Thus, the term depends on the context in which it is applied. For example, in the context of treating the disclosed neurodegenerative disease, it is the amount of the disclosed CD38 inhibitor sufficient to achieve a response compared to the response obtained without the administration of the CD38 inhibitor. The amount of a given composition described herein that corresponds to such an amount will vary depending on various factors such as the given CD38 inhibitor, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the patient’s identity (e.g., age, sex, weight), or the host receiving treatment, but can still be routinely determined by those skilled in the art. In some embodiments, the “therapeutic effective amount” of the disclosed composition is the amount that produces a beneficial or desired outcome (e.g., compared to a control) in a patient. Therapeutic effective amounts of the disclosed compositions can be readily determined by those skilled in the art using conventional methods known in the art. Dosing regimens can be adjusted to provide an optimal therapeutic response.

[0042] The terms “individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and most preferably humans. The compounds disclosed herein can be administered to mammals such as humans, but can also be administered to other mammals such as animals requiring veterinary treatment, for example, domestic animals (e.g., dogs, cats, etc.), farm animals (e.g., cattle, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

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

[0044] This disclosure relates in part to compounds that are contemplated as regulators (e.g., inhibitors) of CD38.

[0045] For example, this paper discloses compounds represented by formula I: (I); Or its pharmaceutically acceptable salts and / or stereoisomers, wherein: X 1 and X 2 Each is independently selected from N and CH; Y is -C(O)-NR a -or-S(O)2-NR a -; R 1 It is a 5-6 member monocyclic heteroaryl or an 8-10 member bicyclic heteroaryl; wherein R 1 It can be optionally selected by one or more independently chosen from R 11 Substituents of the substituents; R 11 Each time it appears, it is independently selected from the following groups: halogen, hydroxyl, -C. 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, -CN, -CF3, -NR a R b -C(O)-NR a R b -NR a -C(O)-R b , and deuterium; where -C 1-6 Alkyl and -C 1-6 The alkoxy group can optionally be selected by one or more elements, each independently chosen from hydroxyl, halogen, deuterium, and -C. 1-3 Substitution of alkoxy groups; Ring A is a 5-6 membered ring selected from the group consisting of: phenyl, 5-6 membered carbon rings, and 5-6 membered heterocyclic groups; and wherein ring A may optionally be selected independently by one, two, or three groups from R. A Substituents of the substituents; Ring B is selected from the group consisting of: 4-12 member monocyclic, fused bicyclic, bridging bicyclic or spirocyclic carbon rings, and 5-7 member heterocyclic groups; wherein ring B may optionally be selected independently by one, two or three members from R B Substituents of the substituents; R A Each time it appears, it is independently selected from the following groups: halogen, hydroxyl, deuterium, -C. 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, 5-6 membered heterocyclic groups, -CN, -CF3, -OC(O)-C 1-6 Alkyl, -NR a R b -C(O)-NR a R b , and -NR a -C(O)-R b ;where -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6Cycloalkyl, phenyl, and 5-6 membered heterocyclic groups may optionally be selected independently by one or more groups chosen from hydroxyl, halogen, deuterium, and -C. 1-3 Substitution of alkoxy groups; R B Each time it appears, it is independently selected from the following groups: halogen, hydroxyl, deuterium, -C. 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, 5-6 membered heterocyclic groups, -CN, -CF3, oxo groups, -OC(O)-C 1-6 Alkyl, -NR a R b -C(O)-NR a R b , and -NR a -C(O)-R b ;where -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, and 5-6 membered heterocyclic groups may optionally be selected independently by one or more groups chosen from hydroxyl, halogen, oxo, deuterium, and -C. 1-3 Substitution of alkoxy groups; R a and R b Each occurrence is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups may optionally be substituted by one or more substituents independently selected from the group consisting of halogens, deuterium, hydroxyl groups, and C1-C6 alkoxy groups; or R a and R b The nitrogen atoms attached to them can be linked together to form 4-7 membered heterocyclic groups, which may be optionally substituted by one or more substituents selected independently from the group consisting of: halogen, deuterium, hydroxyl, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy groups; p is 0, 1, or 2; and q can be 0, 1, or 2.

[0046] In some embodiments, the compounds disclosed herein are represented by Formula 1A: (IA); Or its pharmaceutically acceptable salts and / or stereoisomers, wherein: X 1 and X 2 Each is independently selected from N and CH; Y is -C(O)-NR a-or-S(O)2-NR a -; R 1 It is a 5-6 member monocyclic heteroaryl or an 8-10 member bicyclic heteroaryl; wherein R 1 It can be optionally selected by one or more independently chosen from R 11 Substituents of the substituents; R 11 Each time it appears, it is independently selected from the following groups: halogen, hydroxyl, -C. 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, -CN, -CF3, -NR a R b -C(O)-NR a R b -NR a -C(O)-R b , and deuterium; where -C 1-6 Alkyl and -C 1-6 The alkoxy group can optionally be selected by one or more elements, each independently chosen from hydroxyl, halogen, deuterium, and -C. 1-3 Substitution of alkoxy groups; Ring A is a 5-6 membered ring selected from the group consisting of: phenyl, 5-6 membered carbon rings, and 5-6 membered heterocyclic groups; and wherein ring A may optionally be selected independently by one, two, or three groups from R. A Substituents of the substituents; R A Each time it appears, it is independently selected from the following groups: halogen, hydroxyl, deuterium, -C. 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, 5-6 membered heterocyclic groups, -CN, -CF3, -OC(O)-C 1-6 Alkyl, -NR a R b -C(O)-NR a R b , and -NR a -C(O)-R b ;where -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, and 5-6 membered heterocyclic groups may optionally be selected independently by one or more groups chosen from hydroxyl, halogen, deuterium, and -C. 1-3 Substitution of alkoxy groups; R 2 Choose from the following groups: halogens, hydroxyl groups, deuterium, -C 1-6 Alkyl, -C 1-6Alkoxy, -C 3-6 Cycloalkyl, phenyl, 5-6 membered heterocyclic groups, -CN, -CF3, oxo groups, -OC(O)-C 1-6 Alkyl, -NR a R b -C(O)-NR a R b , and -NR a -C(O)-R b ;where -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, and 5-6 membered heterocyclic groups may optionally be selected independently by one or more groups chosen from hydroxyl, halogen, oxo, deuterium, and -C. 1-3 Substitution of alkoxy groups; R 3 Choose from the following groups: hydrogen, deuterium, halogen, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -CN, -NR a R b -C(O)-NR a R b , and -NR a -C(O)-R b ; R 4 and R 5 Each is independently selected from the group consisting of hydrogen and -C atoms optionally substituted with one or more halogens. 1-3 alkyl; R a and R b Each occurrence is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups may optionally be substituted by one or more substituents independently selected from the group consisting of halogens, deuterium, hydroxyl groups, and C1-C6 alkoxy groups; or R a and R b The nitrogen atoms attached to them can be linked together to form 4-7 membered heterocyclic groups, which may be optionally substituted by one or more substituents selected independently from the group consisting of: halogen, deuterium, hydroxyl, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy groups; m is 1 or 2; n is 1, 2, or 3; and p 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, the compounds disclosed herein are represented, for example, by: (IB) or (IC).

[0048] In some embodiments, Y is -C(O)-NH-. In other embodiments, the compounds disclosed herein are represented by, for example, the following: (ID) (IE) (IF), or (IG).

[0049] In some embodiments, X 1 It is N and X 2 It is CH. In other embodiments, X 1 It is CH and X 2 It is N. In other embodiments, X 1 It is N and X 2 It is N. In another embodiment, X 1 It is CH and X 2 It is CH.

[0050] In some embodiments, R 1 It is a 5-6 membered heteroaryl group containing at least one cyclic nitrogen, wherein R 1 It can be optionally selected by one or two independently chosen from R 11 Substituents are substituted. In other embodiments, R 1 Choose from the group consisting of, for example, the following: imidazole, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, and pyridinyl, wherein R 1 It can optionally be substituted by one or two substituents, each independently selected from the group consisting of -CH2OH, -OH, and -NH2. For example, in some embodiments, R 1 Choose from the following groups: , , , , , , , ,and .

[0051] In another embodiment, for example, R 1 Choose from the following groups: , ,and .

[0052] In some embodiments, R 2 Choose from the following groups: -OH, -CN, -CD3, -CF3, -OCH3, -OCD3, -OCH2CH2OCH3, -OCH2CH2OCH2CH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OC(CH3)3, -C(CH3)2OH, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, -NHCH2CF3. , , , ,and For example, in some embodiments, R 2 Choose from the following groups: -OH, -CN, -CD3, -CF3, -OCH3, -OCD3, -OCH2CH2OCH3, -C(CH3)2OH, -C(O)NH(CH3), -C(O)N(CH3)2, -NHCH2CF3, , , , ,and .

[0053] In some embodiments, p is 1 and R A The following groups are selected: -CN, -CH2OH, -OC(O)CH3, morpholino, fluorine, chlorine, and bromine. In other embodiments, p is 0. In further embodiments, R 3 and R 5 It appears each time as hydrogen. In some embodiments, R 4 Choose from the following groups: hydrogen, -CH3, and -CH2CH3.

[0054] This article also discloses compounds represented by formula II: (II); Or its pharmaceutically acceptable salts and / or stereoisomers, wherein: A is phenyl, cyclohexyl, cyclopentyl, or dihydrofuranyl; X 1 It is N and X 2 It is CH; or X 1 It is N and X 2 It is N; R 1 It is a 5-6 membered heteroaryl group containing at least one cyclic nitrogen; wherein R 1It may optionally be substituted by one, two, or three substituents, each independently selected from the group consisting of: halogen, hydroxyl, deuterium, -NH2, -C 1-3 Alkyl, -C 1-3 Alkyl -OH and -C 1-3 Alkoxy; R 2 Choose from the following groups: halogens, hydroxyl groups, deuterium, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, 5-6 membered heterocyclic groups, -CN, -CF3, oxo groups, -OC(O)-C 1-6 Alkyl, -NR a R b -C(O)-NR a R b , and -NR a -C(O)-R b ;where -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, and 5-6 membered heterocyclic groups may optionally be selected independently by one or more groups chosen from hydroxyl, halogen, oxo, deuterium, and -C. 1-3 Substitution of alkoxy groups; R 3 Choose from the following groups: hydrogen, -CH3, and -CH2CH3; R A Each time it appears, it is independently selected from the following groups: halogen, hydroxyl, deuterium, -C. 1-6 Alkyl, -C 1-6 Alkoxy groups, -CN groups, and 5-6 membered heterocyclic groups, wherein -C 1-6 Alkyl and -C 1-6 The alkoxy group 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, the compounds disclosed herein are represented by the following: (IIA) (IIB), or (IIC), or (IID).

[0056] In some embodiments, R 1 Choose from groups consisting of, for example, the following: , , , , , , , ,and .

[0057] In other embodiments, R 2 Choose from the following groups: -OH, -CN, -CD3, -CF3, -OCH3, -OCD3, -OCH2CH2OCH3, -OCH2CH2OCH2CH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OC(CH3)3, -C(CH3)2OH, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, -NHCH2CF3. , , , ,and .

[0058] In another embodiment, p is 1 and R A The following groups are selected: -CN, -CH2OH, morpholino, fluorine, chlorine, and bromine. In some 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 preparing the compounds described herein are provided in the following examples. In the reactions described below, it may be necessary to protect reactive functional groups (such as hydroxyl, amino, thio, or carboxyl groups) to prevent them from undesirably participating in the reaction. Methods for incorporating such groups and for introducing and removing them are known to those skilled in the art (e.g., 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 the protecting group yields the compound as disclosed herein. The starting materials used in the following schemes may be purchased or prepared using methods known to those skilled in the art, either by means of methods described in the chemical literature or by adaptive variations thereof. The order in which these steps are performed may vary depending on the groups introduced and the reagents used, but will be apparent to those skilled in the art.

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

[0062] In cases where it is desired to obtain specific enantiomers of the disclosed compound, this can be achieved by employing any suitable conventional procedure known to those skilled in the art for resolving enantiomers from a mixture of the corresponding enantiomers. For example, diastereomeric derivatives (such as salts) can be produced by reacting a mixture of enantiomers of the disclosed compound (such as racemates) with a suitable 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 enantiomers can be recovered (e.g., by treatment with acid if the diastereomer is a salt). Alternatively, racemic mixtures of esters can be resolved by kinetic hydrolysis using a variety of biocatalysts (see, for example, Patel Stereoselective Biocatalysts, Marcel Decker; New York 2000).

[0063] In another separation method, chiral high-performance liquid chromatography (HPLC) can be used to separate the racemic mixture of the disclosed compound. Alternatively, specific enantiomers can be obtained by using a suitable chiral intermediate in one of the methods described above. In cases where it is desired to obtain an intermediate or final product that is a specific geometrical isomer of this disclosure, chromatography, recrystallization, and other conventional separation procedures may also be used.

[0064] In alternative embodiments, the disclosed compound may also contain one or more isotopic substitutions. For example, hydrogen may be... 2 H (D or deuterium) or 3 H (T or tritium); carbon can be, for example... 13 C or 14 C; oxygen can be, for example 18 O; nitrogen can be, for example 15 N, etc. In other embodiments, specific isotopes (e.g., 3 H, 13 C 14 C 18 O, or 15 N) may occupy 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 the element occupying a specific site in the compound. II. Methods

[0065] The compounds disclosed herein are conceived to inhibit the activity of CD38. For example, this document provides a method for inhibiting the activity or function of CD38 in cells or in patients who require CD38 inhibition, comprising administering to the cells or patient an effective amount of a compound disclosed herein, such as a compound having formula I or II. For example, this document also discloses a method for treating a disease in a patient who benefits from CD38 inhibition, comprising administering to the patient an effective amount of a CD38 inhibitor described herein, thereby treating the disease in the patient.

[0066] The compounds disclosed herein are conceivable to increase NAD+ levels. For example, this document provides a method for increasing NAD+ levels in a sample or in a patient in need, comprising exposing the sample to an effective amount of a compound disclosed herein, such as a compound having Formula I or Formula II, or administering an effective amount of a compound disclosed herein to a patient, wherein the increased NAD+ level is relative to the NAD+ level prior to exposure or administration. This document further discloses a method for treating a disease in a patient in need that benefits from increased NAD+, comprising administering an effective amount of a CD38 inhibitor described herein, such as a compound having Formula I or Formula II, to the patient to treat the disease in the patient.

[0067] The compounds disclosed herein can be used to treat diseases associated with aberrant expression or activity of CD38. For example, this disclosure provides a method of treating cancer in a patient in need, comprising administering to the patient an effective amount of a CD38 inhibitor described herein, such as a compound having formula I or II, thereby treating the cancer in the patient. In some embodiments, the cancer is characterized by aberrant expression or activity of CD38 compared to normal cells, such as elevated expression or activity. In other embodiments, the cancer may be selected from the group consisting of, for example, cancers 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 some 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 lymphoma 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, pilocellular lymphoma, and Burkitt's lymphoma. Examples of leukemias contemplated herein include, but are not limited to, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML). In further embodiments, cancer may be selected from, for example, the group consisting of: cancers treated with checkpoint therapy, refractory cancers treated with checkpoint therapy, adenosine-dependent tumors, Treg-invasive tumors, and MDSC-invasive tumors.

[0068] For example, cancers contemplated in this disclosure that can be treated by application 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 respiratory and digestive tract cancers), intestinal cancer, 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, clear cell renal cell carcinoma, skin cancer, gastric cancer, testicular cancer, thyroid cancer, and uterine cancer. In some embodiments, the cancers contemplated in this disclosure that can be treated by application 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 respiratory and digestive tract cancer), kidney cancer, prostate cancer, rectal cancer, gastric cancer, thyroid cancer, uterine cancer, and breast cancer.

[0069] This article also provides methods for treating conditions or disorders in patients in need, comprising administering to the patient an effective amount of the compounds disclosed herein, such as compounds having 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, cardiomegaly, 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), colon... Inflammation, gout, obesity, sarcopenic obesity, end-stage renal disease, dyslipidemia, hearing loss, liver disease, fatty degeneration, non-alcoholic steatohepatitis (NASH / NAFLD), Alzheimer's disease, multiple sclerosis, neurocognitive impairment, optic neuropathy, postmenopausal osteoporosis, bipolar disorder, schizophrenia, Huntington's disease, diabetes, Hartnap disease, hyperpigmentation, diabetic neuropathy, radiation exposure, UV skin damage, psoriasis, periodontitis, chronic lymphocytic leukemia, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, Leber's hereditary amaurosis, insulin resistance, type 1 diabetes, and type 2 diabetes.

[0070] The compounds described herein are envisioned to have therapeutic efficacy in CD38-related disorders in disease areas such as cardiology, virology, neurodegeneration, inflammation, and pain, where these diseases are characterized by CD38 overexpression or increased activity.

[0071] Another aspect of this disclosure provides methods for treating patients with neurodegenerative diseases or disorders, such as 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 cease to function or die. Neurodegenerative diseases typically worsen over time and are incurable. Such diseases can be hereditary or caused by tumors or stroke. Neurodegenerative diseases also occur in people who ingest 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), prions, spinocerebellar ataxia (SCA), vascular dementia, frontotemporal dementia (FTD), mixed dementia, and Lewy body dementia (LBD). In some embodiments, the neurodegenerative disease is a late-onset disease. In other embodiments, this disclosure provides a method for treating a patient suffering from neuroinflammatory conditions.

[0072] In some embodiments, neurodegenerative diseases affect the basal ganglia, thalamus, red nucleus, locus coeruleus, parahippocampal gyrus, or combinations thereof. In some embodiments, neurodegenerative diseases affect the basal ganglia and / or thalamus.

[0073] In some embodiments, the neurodegenerative disease is ALS, HD, PD, or SCA. In a specific embodiment, the neurodegenerative disease is PD. In some embodiments, PD is familial Parkinson's disease.

[0074] Patients who are to be treated according to the methods described herein may be patients who have been diagnosed with a neurodegenerative disease (e.g., PD) or patients who are at risk of developing such a disease. The diagnosis of a neurodegenerative disease or the risk of developing a neurodegenerative disease can be performed by a skilled medical professional using any suitable methods or techniques known in the art. Those skilled in the art will understand that patients who are to be treated according to this disclosure may have already undergone standard testing, or may not require examination of patients identified as being 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 PD or is at risk of developing PD.

[0076] For example, this disclosure provides a method for treating a neurodegenerative disease in a patient in need, comprising administering to the patient an effective amount of a CD38 inhibitor described herein, such as a compound having formula I or 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] This article also discloses a method for slowing the progression of Parkinson's disease in patients in need, comprising administering to the patient an effective amount of any compound described herein (e.g., a compound having Formula I or Formula II) or a pharmaceutical composition comprising any compound described herein and a pharmaceutically acceptable carrier or excipient.

[0078] Neurodegenerative diseases or disorders of the eye are also envisioned, which include the administration of an effective amount of the disclosed CD38 inhibitor, such as a compound having formula I or formula II. For example, this article provides a method for treating one or more of the following eye disorders: macular degeneration (e.g., age-related macular degeneration (AMD) or dry macular degeneration), diabetic macular edema (DME), diabetic retinopathy, glaucoma, cataract, retinitis pigmentosa (RP), Staghort's disease, myopic macular degeneration (MMD), submacular hemorrhage, diabetic macular edema (DME), or uveitis.

[0079] Another aspect of this disclosure provides methods for treating patients with fatty liver disease or disorders (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 disease is the accumulation of fat in the liver due to heavy alcohol consumption. Nonalcoholic fatty liver disease (NAFLD) occurs in non-heavy drinkers.

[0080] In some embodiments, fatty liver disease is NAFLD. NAFLD is a spectrum of liver diseases in which hepatic steatosis (macrovesicular accumulation of triglycerides in hepatocytes) develops in the absence of secondary causes (e.g., medications, excessive alcohol consumption, or certain heritable conditions). In some embodiments, NAFLD is simple hepatic steatosis (NAFL). In a specific embodiment, NAFLD is nonalcoholic steatohepatitis (NASH). NASH is an inflammatory subtype of NAFLD, characterized by steatosis and evidence of hepatocyte damage (ballooning degeneration) and inflammation, with or without fibrosis.

[0081] Patients to be treated according to the methods described herein may be patients already diagnosed with fatty liver disease (e.g., NAFLD) or patients at risk of developing such disease. The diagnosis of fatty liver disease or the risk of developing fatty liver disease can be determined by a skilled medical professional using any suitable methods or techniques known in the art. Those skilled in the art will understand that subjects to be treated according to this disclosure may have already undergone standard testing, or may not need to be examined as subjects identified as being 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 fatty liver disease (e.g., NAFLD, such as NASH). In some embodiments, the patient has been diagnosed with fatty liver disease (e.g., NAFLD, such as NASH). In other embodiments, the patient is at risk of developing fatty liver disease (e.g., NAFLD, such as NASH). In some embodiments, the patient has NAFLD or is at risk of developing NAFLD. In some embodiments, the patient has NASH 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, this disclosure provides a method for treating a metabolic disease in a patient in need, comprising administering to the patient an effective amount of a CD38 inhibitor described herein, such as a compound having Formula I or Formula II, thereby treating the metabolic disease in the patient. In some embodiments, the metabolic disease is selected from, for example, the group consisting of: non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and diabetes (type I or type II).

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

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

[0087] For example, this document discloses a method for treating neurodegenerative diseases in patients in need, comprising administering to the patient an effective amount of any compound described herein (e.g., a compound having Formula I or Formula II) or a pharmaceutical composition comprising any compound described herein and a pharmaceutically acceptable carrier or excipient. In some embodiments, the neurodegenerative disease is Parkinson's disease.

[0088] This article also discloses a method for treating neuroinflammation in patients in need, comprising administering to the patient an effective amount of any compound described herein (e.g., a compound having Formula I or Formula II) or a pharmaceutical composition comprising any compound described herein and a pharmaceutically acceptable carrier or excipient.

[0089] This document further discloses a method for treating fatty liver disease in patients in need, comprising administering to the patient an effective amount of any compound described herein (e.g., a compound having Formula I or Formula II) or a pharmaceutical composition comprising any compound described herein and a pharmaceutically acceptable carrier or excipient. In some embodiments, fatty liver disease is non-alcoholic fatty liver disease (NAFLD). In other embodiments, fatty liver disease is non-alcoholic steatohepatitis (NASH). In still other embodiments, fatty liver disease is simple hepatic steatosis. In some embodiments, treatment of fatty liver disease includes slowing the progression of fatty liver disease.

[0090] Furthermore, this document discloses a method for treating fibrosis in patients in need, comprising administering to the patient an effective amount of any compound described herein (e.g., a compound having Formula I or Formula II) or a pharmaceutical composition comprising any compound described herein and a pharmaceutically acceptable carrier or excipient. In some embodiments, the fibrosis is multi-organ fibrosis. In other embodiments, the fibrosis is associated with systemic sclerosis. For example, a patient with fibrosis also has systemic sclerosis. In still other embodiments, the fibrosis is selected from the group consisting of: cutaneous fibrosis, pulmonary fibrosis, and peritoneal fibrosis.

[0091] In some embodiments, the methods described herein further include administering an additional therapeutic agent to a patient that treats the disclosed disease or disorder, or treats the disclosed disease or disorder that is affected by, is associated with, or would benefit from selective regulation of (e.g., inhibition) of CD38.

[0092] The compounds described herein can be administered in combination with one or more other therapeutic agents to treat the disorders described herein. For clarity, both fixed compositions comprising the disclosed compounds and another therapeutic agent as disclosed herein, and methods of separately administering the disclosed compounds and the disclosed therapeutic agents are contemplated herein. For example, this disclosure provides a pharmaceutical composition comprising the compounds described herein, one or more other therapeutic agents, and pharmaceutically acceptable excipients. In some embodiments, the disclosed compounds and one other therapeutic agent are administered. In some embodiments, the disclosed compounds and two other therapeutic agents as defined herein are administered. In some embodiments, the disclosed compounds and three other therapeutic agents as defined herein are administered.

[0093] For example, in some embodiments, the additional agent is NAD+ or an NAD+ precursor. Examples of contemplated NAD+ precursors may include, but are not limited to, NR, NA, NaR, NAM, NMN, NaMN, TRP, vitamin B3, and NAAD. In some embodiments, the NAD+ precursor is vitamin B3. In some embodiments, the NAD+ precursor is a form of vitamin B3. In some embodiments, the NAD+ precursor is nicotinamide nucleoside (NR), also known as 1-(β-D-furanosyl)nicotinamide or N-ribosylnicotinamide. In some embodiments, the NAD+ precursor is nicotinic acid (NA), also known as niacin. In some embodiments, the NAD+ precursor is nicotinic acid nucleoside (NaR). In some embodiments, the NAD+ precursor is nicotinamide (NAM), also known as 3-pyridinecarboxamide, niacinamide, nicotinic acid amide, or nicotinicamide. In some embodiments, the NAD+ precursor is nicotinamide mononucleotide (NMN), also known as nicotinamide ribonucleoside 5'-phosphate, nicotinamide D-ribonucleotide, β-nicotinamide ribonucleophosphate, or nicotinamide nucleotide. In some embodiments, the NAD+ precursor is nicotinic acid mononucleotide (NaMN). In some embodiments, the NAD+ precursor is tryptophan (TRP), also known as (2S)-2-amino-3-(1H-indole-3-yl)propionic acid or 2-amino-3-(1H-indole-3-yl)propionic acid. In some embodiments, the NAD+ precursor is deamidated-NAD+, also known as deadenosine-NAD, deamino-NAD+, or nicotinic acid adenine dinucleotide (NAAD). In some embodiments, the NAD+ precursor is nicotinic acid nucleoside, O-ethylnicotinate nucleoside, or O-methylnicotinate nucleoside. In some embodiments, the NAD+ precursor is β-nicotinamide nucleoside. In some embodiments, the NAD+ precursor is a nicotinate nucleoside derivative. In some embodiments, the NAD+ precursor is triacetyl-O-ethylnicotinate nucleoside.

[0094] For example, this document provides a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound having Formula I or Formula II), NAD+ or a disclosed NAD+ precursor, and a pharmaceutically acceptable excipient. For example, this document provides a method of treating a disease or disorder contemplated herein in a patient in need, comprising administering to the patient a compound disclosed herein (e.g., a compound having Formula I or Formula II) and an NAD+ precursor. This document also provides a method of treating a disease or disorder contemplated herein in a patient in need, comprising administering to the patient a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound having Formula I or Formula II), NAD+ or a disclosed NAD+ precursor, and a pharmaceutically 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, the disclosed compound and additional therapeutic agents can be formulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, such as a pharmaceutical composition comprising the disclosed compound as one therapeutic agent and one or more additional therapeutic agents. For example, the disclosed compound and additional therapeutic agents can be administered in a single formulation. Combination therapy also encompasses other combinations. While the two or more agents in a combination therapy can be administered simultaneously, this is not mandatory. For example, the administration of the first agent (or combination of agents) can occur minutes, hours, days, or weeks before the administration of the second agent (or combination of agents). Therefore, these two or more medications 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, or 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, or 9 weeks of each other. In some cases, even longer intervals are possible. While in many cases it is desirable for these two or more medications used in combination therapy to be present in the patient's body simultaneously, this is not mandatory.

[0096] Combination therapy may also involve administering one or more of the drugs used in the combination two or more times using different sequences of the component drugs. For example, if drug X and drug Y are used in combination, they can be administered once or multiple times in any combined order, such as in the order of XYX, XXY, YXY, YYX, XXYY, etc.

[0097] In particular, in some embodiments, this disclosure provides a method for treating the above medical indications, comprising administering a therapeutically effective amount of the compound described herein, such as a compound having formula I or formula II, to a patient in need. III. Pharmaceutical Compositions and Kits

[0098] Another aspect of this disclosure provides pharmaceutical compositions comprising compounds as disclosed herein, formulated with a pharmaceutically acceptable carrier. Specifically, this disclosure provides pharmaceutical compositions comprising compounds as disclosed herein, formulated 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 extent and severity of the condition being treated and the nature of the specific compound used. For example, the disclosed compositions may be formulated as unit doses and / or may be formulated for oral or subcutaneous administration.

[0099] The exemplary pharmaceutical compositions disclosed herein can be used in the form of pharmaceutical formulations, such as solid, semi-solid, or liquid forms, containing one or more of the compounds disclosed herein as active ingredients, incorporated with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral application. The active ingredient can be co-formulated, for example, with a generally non-toxic, pharmaceutically acceptable carrier for use in tablets, pills, capsules, suppositories, solutions, emulsions, suspensions, and any other suitable form. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect against the progression or condition of the disease.

[0100] To prepare solid compositions (such as tablets), the main active ingredient may be mixed with a pharmaceutical carrier (e.g., a conventional tableting ingredient such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum) and other pharmaceutical diluents (e.g., water) to form a solid preformed composition containing a homogeneous mixture of the compounds disclosed herein or their non-toxic, pharmaceutically acceptable salts. When these preformed compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition, such that the composition can be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0101] In solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules, etc.) intended for oral administration, 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 starch, lactose, sucrose, glucose, mannitol, and / or silica; (2) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or farnesian gum; (3) humectants, such as glycerin; (4) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; (5) solution retarders, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds; (7) wetting agents, such as acetyl alcohol and glyceryl monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) colorants. In the case of capsules, tablets, and pills, the composition may also contain buffers. Excipients such as lactose (or milk sugar) and high molecular weight polyethylene glycol may also be used as fillers in soft-filled and hard-filled gelatin capsules.

[0102] Tablets can be prepared by compression or molding, optionally together with one or more excipients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be prepared by molding a mixture of a subject composition wetted with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms (such as sugar-coated pills, capsules, pellets, and granules) can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulation.

[0103] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject composition, liquid dosage forms may also contain inert diluents commonly used in the art (e.g., water or other solvents), solubilizers and emulsifiers (e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol), oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, fatty acid esters of tetrahydrofuranol, polyethylene glycol, and sorbitol, cyclodextrins, and mixtures thereof.

[0104] In addition to the main composition, the suspension may also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and astragalus gum, and mixtures thereof.

[0105] Preparations for rectal or vaginal application can be presented as suppositories, which can be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers (including, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylates), and are solid at room temperature but liquid at body temperature, and thus will melt in the body cavity and release the active agent.

[0106] Dosage forms for transdermal application of the subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active ingredient can be mixed under aseptic conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0107] In addition to the main composition, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin waxes, starches, astragalus gums, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0108] In addition to the main composition, powders and aerosols may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. Aerosols may also contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0109] The compositions and compounds disclosed herein can alternatively be administered via aerosols. This is achieved by preparing aqueous aerosols, liposome formulations, or solid particles containing said compounds. Non-aqueous suspensions (e.g., fluorocarbon propellants) can be used. Sonic atomizers can be used because they minimize the reagent's exposure to shear, which could lead to degradation of the compounds contained in the subject composition. Typically, aqueous aerosols are prepared by formulating the subject composition together with an aqueous solution or suspension of a conventionally pharmaceutically acceptable carrier and stabilizer. The carrier and stabilizer vary depending on the requirements of the specific subject composition but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), harmless proteins (like serum albumin), sorbitol esters, oleic acid, lecithin, amino acids (such as glycine), buffers, salts, sugars, or sugar alcohols. Aerosols are typically prepared from isotonic solutions.

[0110] The pharmaceutical compositions disclosed herein 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 that can be reconstituted into sterile injectable solutions or dispersions prior to use, and may contain antioxidants, buffers, antibacterial agents, solutes or suspending agents or thickeners that make the formulation isotonic with the blood of the intended recipient.

[0111] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions disclosed herein include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate) and cyclodextrins. For example, by using coating materials (such as lecithin), the desired particle size can be maintained in the case of dispersions, and by using surfactants, appropriate flowability can be maintained.

[0112] On the other hand, this disclosure provides enteric pharmaceutical formulations comprising the disclosed compounds and enteric-coated materials, as well as pharmaceutically acceptable carriers or excipients thereof. Enteric-coated materials are polymers that are substantially insoluble in the acidic environment of the stomach and are primarily soluble in intestinal fluid at a specific pH. The small intestine is the gastrointestinal tract (digestive tract) portion between the stomach and large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is approximately 5.5, the pH of the jejunum is approximately 6.5, and the pH of the terminal ileum is approximately 7.5. Therefore, enteric-coated materials are insoluble up to, for example, pH values ​​up to approximately 5.0, approximately 5.2, approximately 5.4, approximately 5.6, approximately 5.8, approximately 6.0, approximately 6.2, approximately 6.4, approximately 6.6, approximately 6.8, approximately 7.0, approximately 7.2, approximately 7.4, approximately 7.6, approximately 7.8, approximately 8.0, approximately 8.2, approximately 8.4, approximately 8.6, approximately 8.8, approximately 9.0, approximately 9.2, approximately 9.4, approximately 9.6, approximately 9.8, or approximately 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methyl phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), cellulose trimellitate, hydroxypropyl methyl succinate, cellulose acetate succinate, cellulose hexahydrophthalate, cellulose propionate, cellulose maleate, cellulose butyrate, cellulose propionate, copolymers of methyl methacrylate and methyl methacrylate, copolymers of methyl acrylate, methyl methacrylate and methacrylate, copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methacrylate-methyl methacrylate-trimethylammonium chloride ethyl acrylate copolymers, natural resins (such as corn gluten, 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 known or readily measurable in vitro. The foregoing is a list of possible materials, but those skilled in the art who benefit from this disclosure will recognize that it is not exhaustive and that other enteric-coated materials exist that would satisfy the purposes of this disclosure.

[0113] Advantageously, this disclosure also provides kits for use by consumers, for example, those requiring treatment for the diseases or disorders described herein. Such kits include a suitable dosage form (as described above) and instructions for use describing methods of mediating, reducing, or preventing inflammation using such a dosage form. The instructions will instruct the consumer or healthcare professional to administer the dosage form according to administration methods known to those skilled in the art. Such kits can advantageously be packaged and marketed as single or multiple kit units. An example of such kits is the so-called blister pack. Blister packs are well-known in the packaging industry and are widely used for packaging unit dosage forms of pharmaceuticals (tablets, capsules, etc.). Blister packs typically consist of a sheet of relatively rigid material covered with a foil, preferably a transparent plastic material. During the packaging process, grooves are formed in the plastic foil. The grooves have the size and shape of the tablets or capsules to be packaged. The tablets or capsules are then placed in the grooves, and the sheet of relatively rigid material is sealed against the plastic foil, the seal being on the front side of the foil, i.e., opposite to the direction in which the grooves are formed. Thus, the tablets or capsules are sealed in the grooves between the plastic foil and the sheet. Preferably, the sheet is strong enough that tablets or capsules can be removed from the blister pack by manually applying pressure to the groove, thereby creating an opening in the sheet at the location of the groove. The tablet or capsule can then be removed through said opening.

[0114] It may be desirable to provide memory aids on the kit, for example, in the form of numbers next to the tablets or capsules, with these numbers corresponding to the number of days of the regimen in which the specified tablets or capsules should be taken. Another example of such a memory aid is a calendar printed on a card, for example, "Week 1, Monday, Tuesday, ... etc., Week 2, Monday, Tuesday, ... etc." Other variations of the memory aid will be readily apparent. The "daily dose" can be a single tablet or capsule to be taken on a given day, or several tablets or capsules. Furthermore, the daily dose of the first compound may consist of one tablet or capsule, while the daily dose of the second compound may consist of several tablets or capsules, and vice versa. The memory aid should reflect this. Example

[0115] The compounds described herein can be prepared in a variety 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 should be understood that, unless otherwise stated, all proposed reaction conditions (including the choice of solvent, reaction atmosphere, reaction temperature, duration of experiment, and post-treatment procedure) can be selected as standard conditions for the reactions. Those skilled in the art of organic synthesis will understand that functional groups present on various parts of the molecule should be compatible with the proposed reagents and reactions. Substituents incompatible with the reaction conditions will be apparent to those skilled in the art and thus indicate alternative methods. The starting materials of the examples are commercially available or readily prepared from known materials by standard methods. At least some of the compounds used as intermediates are contemplated as compounds disclosed herein. General Method Reversed-phase rapid chromatography: Method 1: C18 silica column; mobile phase, MeCN in water (0.1% formic acid); detector, UV 254 nm. Method 2: C18 silica column; mobile phase, MeCN in water (10 mmol / L NH4HCO3); detector, UV 254 nm. Preparative HPLC: Method 3: XBridge Prep C18 OBD column, 19 150 mm, 5 µm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: MeOH--HPLC; Flow rate: 25 mL / min; Wavelength: 254 / 220 nm. Method 4: XBridge Prep OBD C18 column, 30 150 mm, 5 µm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: MeOH--HPLC; Flow rate: 60 mL / min; Wavelength: 254 / 220 nm. Method 5: YMC-Actus Triart C18 ExRS, 30 150 mm, 5 µm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Wavelength: 254 / 220 nm. Method 6: Sunfire Prep C18 OBD column, 30 100 mm, 5 µm; Mobile phase A: water (0.1% formic acid), mobile phase B: ACN; Flow rate: 60 mL / min; Wavelength: 254 / 220 nm. Method 7: XSelect CSH Prep C18 OBD column, 30 150 mm, 5 µm; Mobile phase A: water (0.1% formic acid), mobile phase B: ACN; Flow rate: 60 mL / min; Wavelength: 254 nm / 220 nm. Method 8: XBridge Shield RP18 OBD column 30 150 mm, 5 µm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Wavelength: 254 nm / 220 nm. Method 9: XBridge PrepPhenyl OBD column 19 250 mm, 5 µm; Mobile phase A: water (0.1% formic acid), mobile phase B: ACN; Flow rate: 60 mL / min; Wavelength: 254 nm / 220 nm. Method 10: XBridge Prep Phenyl OBD column 19 250 mm, 5 µm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min. Example 1: Synthesis of 2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (compound 121)

[0116] At 0°C and in air, DIEA (1.56 g, 12.040 mmol, 1 equivalent) and HATU (1.83 g, 4.816 mmol, 2 equivalent) were added partically to a mixture of 2-chloroquinoline-4-carboxylic acid (500 mg, 2.408 mmol, 1 equivalent) and trans-4-methoxycyclohexyl-1-amine (934 mg, 7.224 mmol, 3 equivalent) in DMF (50 mL). The mixture was stirred at room temperature for 1 h and then diluted with water (500 mL). The resulting mixture was extracted with EtOAc (3 × 200 mL), and the organic phase was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give the desired product, 2-chloro-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (520 mg, 67.73%), as a white solid.

[0117] A mixture of 2-chloro-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (250 mg, 0.784 mmol, 1.00 equivalent), imidazole (267 mg, 3.920 mmol, 5 equivalent), CuI (299 mg, 1.568 mmol, 2 equivalent), and K₂CO₃ (325 mg, 2.352 mmol, 3 equivalent) in DMF (5 mL) was stirred at 120°C under nitrogen atmosphere for 2 days. The mixture was washed with 3 × 10 mL MeOH and the resulting solution was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 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. 1 H 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-thiazolyl-5-yl)quinoline-4-carboxamide (compound 120)

[0118] At 0°C and in air, DIEA (1.56 g, 12.040 mmol, 1 equivalent) and HATU (1.83 g, 4.816 mmol, 2 equivalent) were added partically to a mixture of 2-chloroquinoline-4-carboxylic acid (500 mg, 2.408 mmol, 1 equivalent) and trans-4-methoxycyclohexyl-1-amine (934 mg, 7.224 mmol, 3 equivalent) in DMF (10 mL). The mixture was stirred at room temperature for 1 h and then diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 × 200 mL), and the organic phase was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 2-chloro-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (520 mg, 67.73%) as a white solid.

[0119] A mixture of 2-chloro-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (250 mg, 0.784 mmol, 1 equivalent), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3-thiazole (166 mg, 0.784 mmol, 1 equivalent), Pd(dppf)Cl2 (57 mg, 0.078 mmol, 0.1 equivalent), and K2CO3 (325 mg, 2.352 mmol, 3 equivalent) in dioxane (5 mL) and H2O (1.25 mL) was stirred at 90°C under a nitrogen atmosphere for 1 h. The resulting mixture was filtered; the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (Method 1) to give N-[(trans)-4-methoxycyclohexyl]-2-(1,3-thiazolyl-5-yl)quinoline-4-carboxamide (40.3 mg, 13.98%) as a white solid. LCMS (ESI) [M+H] + 368.15. 1H NMR (400MHz, 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-thiazolyl-5-yl)quinoline-4-carboxamide (compound 116)

[0120] At room temperature, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexane-2-yl)-1,3-thiazole (190 mg, 0.902 mmol, 1.2 equivalents), Pd(dppf)Cl2 (55 mg, 0.075 mmol, 0.1 equivalents), and K2CO3 (311 mg, 2.256 mmol, 3 equivalents) were added partically to a stirred solution of methyl 2-bromoquinoline-4-carboxylate (200 mg, 0.752 mmol, 1 equivalent) in a mixture of 1,4-dioxane (10 mL) and H2O (2 mL). The mixture was stirred at 80°C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:1) elution to give methyl 2-(1,3-thiazolyl-5-yl)quinoline-4-carboxylate (120 mg, 59.06%) as a brown solid.

[0121] A mixture of LiOH (44 mg, 1.850 mmol, 5 equivalents) and methyl 2-(1,3-thiazolyl-5-yl)quinoline-4-carboxylic acid (100 mg, 0.370 mmol, 1 equivalent) in THF (2 mL) and H₂O (2 mL) was stirred at room temperature for 2 h. The mixture was acidified to pH 5 with HCl (1 M). The resulting mixture was concentrated under reduced pressure to give 2-(1,3-thiazolyl-5-yl)quinoline-4-carboxylic acid (70 mg, 73.83%) as a white solid.

[0122] At room temperature, (1r,4r)-4-(2-methoxyethoxy)cyclohexyl-1-amine (49 mg, 0.281 mmol, 1 equivalent), TCFH (98 mg, 0.351 mmol, 1.5 equivalent), and NMI (58 mg, 0.702 mmol, 3 equivalent) were added to a stirred mixture of 2-(1,3-thiazol-5-yl)quinoline-4-carboxamide (23.4 mg, 24.04%) in ACN (3.00 mL). The mixture was then stirred at room temperature for 4 h and then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 2) to give 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. 1 H 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]quinoline-4-carboxamide (compound 113)

[0123] Trimethylaluminum (0.75 mL, 1.504 mmol, 2 equivalents) was added partically to a mixture of methyl 2-bromoquinoline-4-carboxylate (200 mg, 0.752 mmol, 1 equivalent) and trans-4-(2-methoxyethoxy)cyclohexyl-1-amine (156 mg, 0.902 mmol, 1.2 equivalents) in toluene (5 mL). The resulting mixture was stirred at 100°C for another 1 h. The resulting mixture was extracted with EtOAc (3 × 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 reversed-phase rapid chromatography (Method 1) to give 2-bromo-N-[(trans)-4-(2-methoxyethoxy)cyclohexyl]quinoline-4-carboxamide (200 mg, 65.33%) as a yellow oil.

[0124] At room temperature, under a nitrogen atmosphere, K₂CO₃ (102 mg, 0.738 mmol, 3 equivalents) and CuI (94 mg, 0.492 mmol, 2 equivalents) were added partically to a mixture of 2-bromo-N-[(trans)-4-(2-methoxyethoxy)cyclohexyl]quinoline-4-carboxamide (100 mg, 0.246 mmol, 1 equivalent) and imidazole (84 mg, 1.230 mmol, 5 equivalents) in DMF (5 mL). The resulting mixture was stirred at 120°C for 3 h. The resulting mixture was filtered; the filter cake was washed with MeOH (3 × 30 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (Method 1) to give 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. 1 H 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-methoxycyclohexyl)quinoline-4-carboxamide (compound 110)

[0125] At room temperature, HATU (260 mg, 0.70 mmol, 2 equivalents) and DIEA (130 mg, 1.005 mmol, 3 equivalents) were added to a stirred mixture of 1-(8-bromo-2-chloroquinoline-4-yl) ethyl ketone (100 mg, 0.35 mmol, 1 equivalent) and trans-4-methoxycyclohexyl-1-amine (90 mg, 0.70 mmol, 2 equivalents) in DMF (3 mL). The resulting mixture was stirred at room temperature for 1 h. The mixture was purified by reversed-phase rapid chromatography (Method 1) to give 8-bromo-2-chloro-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (70 mg, 50.08% yield) as a yellow solid.

[0126] A mixture of 8-bromo-2-chloro-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (80 mg, 0.201 mmol, 1 equivalent), imidazole (16 mg, 0.241 mmol, 1.2 equivalent), t-BuBrettPhos (19 mg, 0.040 mmol, 0.2 equivalent), t-BuBrettPhos Pd G3 (17 mg, 0.020 mmol, 0.1 equivalent), and Cs2CO3 (196 mg, 0.603 mmol, 3 equivalent) in dioxane (8 mL) was stirred at 100°C under a nitrogen atmosphere for 1 h. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (Method 2) to give 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) δ8.81 (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]quinoline-4-carboxamide (compound 109)

[0127] TCFH (391 mg, 1.39 mmol, 2 equivalents) was added to a stirred mixture of 6-bromo-2-chloroquinoline-4-carboxylic acid (200 mg, 0.69 mmol, 1 equivalent), NMI (286 mg, 3.49 mmol, 5 equivalents), and trans-4-methoxycyclohexyl-1-amine (108 mg, 0.83 mmol, 1.2 equivalents) in DMF (4 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred for 1 h at room temperature under a nitrogen atmosphere. The resulting mixture was diluted with water and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:1) elution to give 6-bromo-2-chloro-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (263 mg, 94.73% yield) as a white solid.

[0128] At room temperature, 6-bromo-2-chloro-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (100 mg, 0.25 mmol, 1 equivalent), Cs₂CO₃ (246 mg, 0.75 mmol, 3 equivalents), and imidazole (17 mg, 0.25 mmol, 1 equivalent) were stirred in DMF (2 mL). The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure, and the crude product (100 mg) was purified by preparative HPLC (Method 3) to give 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. 1 H 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-methoxycyclohexyl]quinoline-4-carboxamide (compound 106)

[0129] A mixture of 8-bromo-2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (20 mg, 0.047 mmol, 1 equivalent), (tributylmethanesulfonyl)methanol (30 mg, 0.094 mmol, 2 equivalents), and Pd(PPh3)2Cl2 (3 mg, 0.005 mmol, 0.1 equivalents) in DMF (6 mL) was stirred at 80°C under a nitrogen atmosphere for 1 h. The reaction was quenched with KF (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL), and the combined organic phases were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Method 9) to give 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. 1 H 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 = 9.8Hz, 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-methoxycyclohexyl]quinoline-4-carboxamide (compound 105)

[0130] A mixture of 8-bromo-2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (90 mg, 0.210 mmol, 1 equivalent), morpholine (27 mg, 0.315 mmol, 1.5 equivalent), Pd2(dba)3 (19 mg, 0.021 mmol, 0.1 equivalent), BINAP (26 mg, 0.042 mmol, 0.2 equivalent), and Cs2CO3 (205 mg, 0.630 mmol, 3 equivalent) in dioxane (6 mL) was stirred at 100°C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product (45 mg) was purified by preparative HPLC (Method 4) to give 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. 1 H 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-(thiazolyl-5-yl)quinoline-4-carboxamide (compound 103)

[0131] At 0°C under a nitrogen atmosphere, DIEA (151 mg, 1.170 mmol, 3 equivalents) and HATU (223 mg, 0.585 mmol, 1.5 equivalents) were added partically to a mixture of 2-(1,3-thiazol-5-yl)quinoline-4-carboxylic acid (100 mg, 0.390 mmol, 1 equivalent) and (trans)-4-amino-N-methylcyclohexane-1-carboxamide (91 mg, 0.585 mmol, 1.5 equivalents) in DMF (2 mL). The resulting mixture was stirred at 0°C for 1 h. The resulting mixture was concentrated under reduced pressure, and the crude product (80 mg) was purified by preparative HPLC (Method 5) to give 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. 1 H 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-methoxycyclohexyl]quinoline-4-carboxamide (compound 102)

[0132] At 0°C, NaOH (752 mg, 18.790 mmol, 10 equivalents) in H₂O (1 mL) was added dropwise to a stirred solution of methyl 2-bromoquinoline-4-carboxylate (500 mg, 1.879 mmol, 1 equivalent) in THF (4 mL). The mixture was stirred at room temperature for 1 h and then acidified to pH 6 with 1 M HCl (aqueous solution). The resulting mixture was concentrated under reduced pressure, and the crude product (400 mg) was used directly in the next step without further purification.

[0133] At 0°C under a nitrogen atmosphere, DIEA (615 mg, 4.761 mmol, 1 equivalent) and HATU (905 mg, 2.381 mmol, 1.5 equivalent) were added partically to a stirred mixture of 2-bromoquinoline-4-carboxylic acid (400 mg, 1.561 mmol, 1 equivalent) and (trans)-4-methoxycyclohexyl-1-amine (410 mg, 3.174 mmol, 2 equivalent) in 10 mL of DMF. The mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction mixture was diluted with water (100 mL) and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 2-bromo-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (250 mg, 43.37% yield) as a pale yellow solid.

[0134] A mixture of 2-bromo-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (150 mg, 0.413 mmol, 1 equivalent), 3H-imidazol-4-ylmethanol (81 mg, 0.826 mmol, 2 equivalents), CuI (157 mg, 0.826 mmol, 2 equivalents), and K₂CO₃ (171 mg, 1.239 mmol, 3 equivalents) in DMF (5 mL) was stirred at 100°C under a nitrogen atmosphere for 2 h. The resulting mixture was filtered, the filter cake was washed with MeOH (3 × 20 mL), and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 6) to give 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. 1 H 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-methoxycyclohexyl]quinoline-4-carboxamide (compound 101)

[0135] A mixture of 2-bromo-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (150 mg, 0.413 mmol, 1 equivalent), 3H-imidazol-4-ylmethanol (81 mg, 0.826 mmol, 2.00 equivalent), CuI (157 mg, 0.826 mmol, 2 equivalent), and K₂CO₃ (171 mg, 1.239 mmol, 3 equivalent) in DMF (5 mL) was stirred at 100°C under nitrogen atmosphere for 2 h. The resulting mixture was filtered, the filter cake was washed with MeOH (3 × 20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Method 6) to give 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. 1 H 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)

[0136] A mixture of 7-bromo-1H-indole-2,3-dione (5 g, 22.121 mmol, 1 equivalent) and malonic acid (4.60 g, 44.242 mmol, 2 equivalents) in AcOH (100 mL) was stirred at 90°C under a nitrogen atmosphere for 20 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (Method 1) to give 8-bromo-2-hydroxyquinoline-4-carboxylic acid (1.5 g, 25.30% yield) as a brown oil.

[0137] A solution of 8-bromo-2-hydroxyquinoline-4-carboxylic acid (1.4 g, 5.223 mmol, 1 equivalent) in POCl3 (100 mL) was stirred at 80°C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure, and the residue was quenched with water at 0°C. The resulting mixture was extracted with EtOAc (3 × 200 mL), and the combined organic phases were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase (Method 1) to give 8-bromo-2-chloroquinoline-4-carboxylic acid (800 mg, 53.46% yield) as a brown solid.

[0138] A mixture of 8-bromo-2-chloroquinoline-4-carboxylic acid (790 mg, 2.757 mmol, 1 equivalent), (trans)-4-methoxycyclohexyl-1-amine (534 mg, 4.136 mmol, 1.5 equivalent), TCFH (1.54 g, 5.514 mmol, 2 equivalent), and NMI (452 ​​mg, 5.514 mmol, 2 equivalent) in ACN (10 mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (Method 1) to give 8-bromo-2-chloro-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (610 mg, 55.63% yield) as a white solid.

[0139] A mixture of 8-bromo-2-chloro-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (600 mg, 1.509 mmol, 1 equivalent), imidazole (205 mg, 3.018 mmol, 2 equivalents), and K₂CO₃ (625 mg, 4.527 mmol, 3 equivalents) in DMF (8 mL) was stirred at 100°C under a nitrogen atmosphere for 2 h. The resulting mixture was filtered, and the filter cake was washed with DMF (3 × 2 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (Method 1) to give 8-bromo-2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (430 mg, 66.39% yield) as a yellow solid.

[0140] A mixture of 8-bromo-2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (150 mg, 0.349 mmol, 1 equivalent) and CuCN (63 mg, 0.699 mmol, 2.00 equivalent) in DMSO (4 mL) was stirred at 150°C under nitrogen atmosphere for 16 h. The mixture was purified by preparative HPLC (Method 7) to give 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. 1 H 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)

[0141] A solution of 8-bromo-2-chloroquinoline-4-carboxylic acid (290 mg, 1.012 mmol, 1 equivalent), (trans)-4-methoxycyclohexyl-1-amine (156 mg, 1.214 mmol, 1.2 equivalent), TCFH (851 mg, 3.036 mmol, 3 equivalent), and NMI (498 mg, 6.072 mmol, 6 equivalent) in ACN (10 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (Method 1) to give 8-bromo-2-chloro-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (200 mg, 49.68% yield) as a white solid.

[0142] A solution of 8-bromo-2-chloro-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (78 mg, 0.196 mmol, 1 equivalent), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)imidazolium (48 mg, 0.235 mmol, 1.2 equivalent), Pd(dppf)Cl2 (28 mg, 0.039 mmol, 0.2 equivalent), and K2CO3 (81 mg, 0.588 mmol, 3 equivalent) in dioxane (5 mL) and H2O (1 mL) was stirred at 90°C under a nitrogen atmosphere for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (Method 1) to give 8-bromo-2-(3-methylimidazol-4-yl)-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (80 mg, 92.3% yield) as a pale yellow solid.

[0143] A mixture of 8-bromo-2-(3-methylimidazol-4-yl)-N-[(trans)-4-methoxycyclohexyl]quinoline-4-carboxamide (80 mg, 0.180 mmol, 1 equivalent) and CuCN (32 mg, 0.360 mmol, 2 equivalents) in DMSO (3 mL) was stirred at 150°C under a nitrogen atmosphere for 16 h. The residue was purified by preparative HPLC (Method 4) to give 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. 1 H 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]quinazolin-4-carboxamide (compound 134)

[0144] At 0°C, LiOH (198 mg, 8.290 mmol, 10 equivalents) in water (2 mL) was added dropwise to a stirred solution of methyl 8-bromo-2-chloroquinazoline-4-carboxylic acid (250 mg, 0.829 mmol, 1 equivalent) in THF (10 mL). The mixture was stirred at room temperature for 2 h and then acidified to pH 5 with 1 M HCl (aqueous solution). The resulting mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (Method 1) to give 8-bromo-2-chloroquinazoline-4-carboxylic acid (200 mg, 83.90% yield) as a yellow solid.

[0145] At 0°C, DIEA (256 mg, 1.983 mmol, 1 equivalent) and HATU (502 mg, 1.322 mmol, 2 equivalent) were added partically to a stirred mixture of 8-bromo-2-chloroquinazoline-4-carboxylic acid (190 mg, 0.661 mmol, 1 equivalent) and (trans)-4-methoxycyclohexyl-1-amine (171 mg, 1.322 mmol, 2 equivalent) in DMF (5 mL). The mixture was stirred at room temperature for 1 h and diluted with water. The resulting mixture was extracted with EtOAc (3 × 100 mL), and the combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 8-bromo-2-chloro-N-[(trans)-4-methoxycyclohexyl]quinazolin-4-carboxamide (120 mg, 45.54% yield) as a pale yellow solid.

[0146] A mixture of 8-bromo-2-chloro-N-[(trans)-4-methoxycyclohexyl]quinazoline-4-carboxamide (120 mg, 0.301 mmol, 1 equivalent), imidazole (41 mg, 0.602 mmol, 2 equivalents), and K₂CO₃ (125 mg, 0.903 mmol, 3 equivalents) in DMF (5 mL) was stirred at 100°C under nitrogen atmosphere for 2 h. The reaction mixture was diluted with water and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 8-bromo-2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]quinazoline-4-carboxamide (75 mg, 57.91% yield) as a light brown solid.

[0147] A mixture of 8-bromo-2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]quinazolin-4-carboxamide (70 mg, 0.163 mmol, 1 equivalent), CuCN (29 mg, 0.326 mmol, 2 equivalents), and Pd(PPh3)2Cl2 (11 mg, 0.016 mmol, 0.1 equivalents) in DMSO (5 mL) was stirred at 140°C under nitrogen atmosphere for 4 h. The mixture was diluted with water and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (70 mg) was purified by preparative HPLC (Method 7) to give 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. 1 H NMR (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-thiazolyl-5-yl)quinazolin-4-carboxamide (compound 140)

[0148] A mixture of ethyl 2-chloroquinazoline-4-carboxylate (200 mg, 0.845 mmol, 1.00 equivalent), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,3-thiazole (267 mg, 1.268 mmol, 1.5 equivalent), Pd(dppf)Cl2 (69 mg, 0.085 mmol, 0.10 equivalent), and K2CO3 (350 mg, 2.535 mmol, 3 equivalent) in dioxane (4 mL) and H2O (1 mL) was stirred at 100°C under a nitrogen atmosphere for 1 h. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 2-(1,3-thiazolyl-5-yl)quinazolin-4-carboxylic acid (120 mg, 55.19% yield) as a brown solid.

[0149] At 0°C under a nitrogen atmosphere, TCFH (109 mg, 0.388 mmol, 2 equivalents) and NMI (48 mg, 0.582 mmol, 3 equivalents) were added partically to a stirred mixture of 2-(1,3-thiazolyl-5-yl)quinazolin-4-carboxylic acid (50 mg, 0.194 mmol, 1 equivalent) and (trans)-4-methoxycyclohexyl-1-amine (37 mg, 0.291 mmol, 1.5 equivalents) in acetonitrile (4 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 1 h and then concentrated under reduced pressure. The crude product (50 mg) was purified by preparative HPLC (Method 5) to give N-[(trans)-4-methoxycyclohexyl]-2-(1,3-thiazolyl-5-yl)quinazolin-4-carboxamide (23.9 mg, 32.71% yield) as a white solid. LCMS (ESI) [M+H] + 369.00. 1 H 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)quinazolin-4-carboxamide (compound 141)

[0150] At room temperature, under a nitrogen atmosphere, K₂CO₃ (525 mg, 3.804 mmol, 3 equivalents) was added to a mixture of ethyl 2-chloroquinazoline-4-carboxylate (300 mg, 1.268 mmol, 1 equivalent) and imidazole (172 mg, 2.536 mmol, 2 equivalents) in DMF (10 mL). The mixture was stirred at 100°C under a nitrogen atmosphere for 1 h and then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 2-(imidazol-1-yl)quinazoline-4-carboxylic acid (140 mg, 45.97% yield) as a white solid.

[0151] At 0°C under a nitrogen atmosphere, TCFH (163 mg, 0.582 mmol, 1 equivalent) and NMI (119 mg, 1.455 mmol, 5 equivalent) were added partically to a stirred mixture of 2-(imidazol-1-yl)quinazolin-4-carboxylic acid (70 mg, 0.291 mmol, 1 equivalent) and (trans)-4-methoxycyclohexyl]quinazolin-4-carboxamide (27.9 mg, 27.25% yield) in ACN (8 mL). The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The crude product (40 mg) was purified by preparative HPLC (Method 6) to give 2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]quinazolin-4-carboxamide as a pale yellow solid. LCMS (ESI) [M+H] + : 352.20. 1 H 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]quinazolin-4-carboxamide (compound 145)

[0152] A mixture of 8-bromo-2-chloroquinazoline-4-carboxylic acid (290 mg, 1.009 mmol, 1 equivalent), (trans)-4-methoxycyclohexyl-1-amine (156 mg, 1.211 mmol, 1.2 equivalent), TCFH (849 mg, 3.027 mmol, 3 equivalent), and NMI (496 mg, 6.054 mmol, 6 equivalent) in DMF (10 mL) was stirred at room temperature under nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (Method 1) to give 8-bromo-2-chloro-N-[(trans)-4-methoxycyclohexyl]quinazoline-4-carboxamide (210 mg, 52.22% yield) as a white solid.

[0153] A mixture of 8-bromo-2-chloro-N-[(trans)-4-methoxycyclohexyl]quinazolin-4-carboxamide (200 mg, 0.502 mmol, 1 equivalent), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)imidazolium (125 mg, 0.602 mmol, 1.2 equivalent), Pd(dppf)Cl2 (73 mg, 0.100 mmol, 0.2 equivalent), and K2CO3 (208 mg, 1.506 mmol, 3 equivalent) in dioxane (10 mL) and H2O (2 mL) was stirred at 90°C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (Method 1) to give 8-bromo-2-(3-methylimidazol-4-yl)-N-[(trans)-4-methoxycyclohexyl]quinazolin-4-carboxamide (130 mg, 58.32% yield) as a white solid.

[0154] A solution of 8-bromo-2-(3-methylimidazol-4-yl)-N-[(trans)-4-methoxycyclohexyl]quinazolin-4-carboxamide (120 mg, 0.270 mmol, 1 equivalent), Pd(PPh3)2Cl2 (38 mg, 0.054 mmol, 0.2 equivalent), and CuCN (48 mg, 0.540 mmol, 2 equivalent) in DMSO (15 mL) was stirred at 150°C under a nitrogen atmosphere for 16 h. The mixture was diluted with water. The resulting mixture was extracted with EtOAc (3 × 50 mL), and the combined organic phases were dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reversed-phase rapid chromatography (Method 4) to give 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. 1 H 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-hydroxypropyl-2-yl)cyclohexyl]quinazolin-4-carboxamide (compound 143)

[0155] A mixture of methyl 2-chloroquinazoline-4-carboxylate (250 mg, 1.123 mmol, 1 equivalent), K₂CO₃ (465 mg, 3.369 mmol, 3 equivalents), and imidazole (153 mg, 2.246 mmol, 2 equivalents) in DMF (5 mL) was stirred at 90°C under a nitrogen atmosphere for 6 h. The mixture was diluted with water. The resulting mixture was extracted with EtOAc (3 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 2-(imidazol-1-yl)quinazoline-4-carboxylic acid (150 mg, 55.65% yield) as a yellow solid.

[0156] At room temperature, TCFH (263 mg, 0.936 mmol, 1 equivalent) and NMI (102 mg, 1.248 mmol, 2 equivalent) were added partically to a stirred mixture of 2-(imidazol-1-yl)quinazolin-4-carboxylic acid (150 mg, 0.624 mmol, 1 equivalent) and 2-[(trans)-4-aminocyclohexyl]prop-2-ol (147 mg, 0.936 mmol, 1.5 equivalent) in ACN (2 mL). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 8) to give 2-(imidazol-1-yl)-N-[(trans)-4-(2-hydroxypropyl-2-yl)cyclohexyl]quinazolin-4-carboxamide (40.1 mg, 16.70% yield) as a pale yellow solid. LCMS (ESI) [M+H] + : 380.10. 1 H NMR (400MHz, 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)

[0157] To a mixture of methyl 3-bromonaphthalene-1-carboxylate (100 mg, 0.38 mmol, 1.0 equivalent) in MeOH (2 mL), NaOH (151 mg, 3.78 mmol, 10.0 equivalent) and H₂O (0.5 mL) were added. The resulting mixture was stirred at 50°C under a nitrogen atmosphere for 1 h. The mixture was allowed to cool to room temperature and neutralized to pH 6 with HCl (aqueous solution). The resulting mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (Method 1) to give 3-bromonaphthalene-1-carboxylic acid (90 mg, 95.03%) as a yellow solid.

[0158] At room temperature and under a nitrogen atmosphere, trans-4-methoxycyclohexyl-1-amine (77 mg, 0.60 mmol, 1.5 equivalent), DIEA (154 mg, 1.20 mmol, 3.0 equivalent), and HATU (454 mg, 1.20 mmol, 3.0 equivalent) were added to a mixture of 3-bromonaphthalene-1-carboxylic acid (100 mg, 0.40 mmol, 1.0 equivalent) in DMF (10 mL). The mixture was stirred for 1 hour and diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL) and the combined organic phases were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 3-bromo-N-[(trans)-4-methoxycyclohexyl]naphthalene-1-carboxamide (90 mg, 62.38%) as a yellow solid.

[0159] Imidazole (34 mg, 0.50 mmol, 2.0 equivalent), CuI (142 mg, 0.74 mmol, 3.0 equivalent), and K₂CO₃ (103 mg, 0.74 mmol, 3.0 equivalent) were added to a mixture of 3-bromo-N-[(trans)-4-methoxycyclohexyl]naphthalene-1-carboxamide (90 mg, 0.250 mmol, 1.0 equivalent) in DMF (5 mL). The mixture was stirred overnight at 120°C under a nitrogen atmosphere and then allowed to cool to room temperature. The reaction was quenched with saturated NH₄Cl (aqueous solution) at room temperature, and the resulting mixture was extracted with EtOAc (10 × 3 mL). The combined organic phases were washed with brine (3 × 10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product (90 mg) was purified by preparative HPLC (Method 5) to give 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. 1 H 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-thiazolyl-5-yl)naphthalene-1-carboxamide (compound 117)

[0160] Add 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexane-2-yl)-1,3-thiazole (120 mg, 0.57 mmol, 1.5 equivalent), K₂CO₃ (156 mg, 1.13 mmol, 3.0 equivalent), Pd(dppf)Cl₂ (28 mg, 0.04 mmol, 0.1 equivalent), and H₂O (2 mL) to a mixture of methyl 3-bromonaphthalene-1-carboxylate (100 mg, 0.38 mmol, 1.0 equivalent) in dioxane (10 mL). Stir the resulting mixture overnight at 90°C under a nitrogen atmosphere. Allow the mixture to cool to room temperature. Filter the resulting mixture, and wash the filter cake with MeOH (3 × 10 mL). Concentrate the filtrate under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give methyl 3-(1,3-thiazolyl-5-yl)naphthyl-1-carboxylate (77 mg, 75.80%) as a yellow solid.

[0161] To a mixture of methyl 3-(1,3-thiazolyl-5-yl)naphth-1-carboxylate (67 mg, 0.25 mmol, 1.0 equivalent) in MeOH (5 mL), NaOH (100 mg, 2.49 mmol, 10.0 equivalent) and H₂O (1 mL) were added. The resulting mixture was stirred at 50°C under a nitrogen atmosphere for 1 h and allowed to cool to room temperature. The mixture was neutralized to pH 6 with HCl (aqueous solution) and the resulting mixture was concentrated under reduced pressure to give 3-(1,3-thiazolyl-5-yl)naphth-1-carboxylic acid (60 mg, 94.47%) as a yellow solid. The crude product was used directly in the next step without further purification.

[0162] To a mixture of 3-(1,3-thiazolyl-5-yl)naphthyl-1-carboxylic acid (60 mg, 0.24 mmol, 1.0 equivalent) in DMF (2 mL), trans-4-methoxycyclohexyl-1-amine (61 mg, 0.47 mmol, 2.0 equivalent), DIEA (91 mg, 0.70 mmol, 3.0 equivalent), and HATU (179 mg, 0.47 mmol, 2.0 equivalent) were added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The crude product (50 mg) was purified by preparative HPLC (Method 7) to give N-[(trans)-4-methoxycyclohexyl]-3-(1,3-thiazolyl-5-yl)naphthyl-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-thiazolyl-5-yl)-5,6,7,8-tetrahydroquinazoline-4-carboxamide (compound 119)

[0163] A solution of 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (1 g, 4.92 mmol, 1 equivalent), oxalic acid (4.4 g, 49.24 mmol, 10 equivalents), Ac₂O (1.507 g, 14.76 mmol, 3 equivalents), Pd(OAc)₂ (440 mg, 1.97 mmol, 0.4 equivalents), Xantphos (570 mg, 0.99 mmol, 0.2 equivalents), and DIEA (3.2 g, 24.62 mmol, 5 equivalents) in DMF (20 mL) was stirred at 100°C under a nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 2-chloro-5,6,7,8-tetrahydroquinazoline-4-carboxylic acid (340 mg, 32.47%) as a white solid.

[0164] A solution of 2-chloro-5,6,7,8-tetrahydroquinazoline-4-carboxylic acid (100 mg, 0.47 mmol, 1.0 equivalent), trans-4-(2-methoxyethoxy)cyclohexyl-1-amine (81 mg, 0.470 mmol, 1 equivalent), TCFH (198 mg, 0.71 mmol, 1.5 equivalent), and NMI (116 mg, 1.41 mmol, 3 equivalent) in ACN (3 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (Method 1) to give 2-chloro-N-[(trans)-4-(2-methoxyethoxy)cyclohexyl]-5,6,7,8-tetrahydroquinazoline-4-carboxamide (105 mg, 60.69%) as a white solid.

[0165] A solution of 2-chloro-N-[(trans)-4-(2-methoxyethoxy)cyclohexyl]-5,6,7,8-tetrahydroquinazolin-4-carboxamide (100 mg, 0.27 mmol, 1 equivalent), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3-thiazole (86 mg, 0.41 mmol, 1.5 equivalent), K₂CO₃ (113 mg, 0.82 mmol, 3 equivalent), and Pd(dppf)Cl₂ (20 mg, 0.03 mmol, 0.1 equivalent) in dioxane (2 mL) and H₂O (0.2 mL) was stirred at 80°C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 8 mL). The resulting solution was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give N-[(trans)-4-(2-methoxyethoxy)cyclohexyl]-2-(1,3-thiazolyl-5-yl)-5,6,7,8-tetrahydroquinazoline-4-carboxamide (15.4 mg, 13.39%) as a pale yellow solid. LCMS (ESI) [M+H] + :417.15. 1 H 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-thiazolyl-5-yl)-5,6,7,8-tetrahydroquinazoline-4-carboxamide (compound 118)

[0166] A solution of 2-chloro-5,6,7,8-tetrahydroquinazoline-4-carboxylic acid (100 mg, 0.47 mmol, 1 equivalent), trans-4-methoxycyclohexyl-1-amine (73 mg, 0.56 mmol, 1.2 equivalent), TCFH (198 mg, 0.71 mmol, 1.5 equivalent), and NMI (116 mg, 1.41 mmol, 3 equivalent) in ACN (2 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 2-chloro-N-[(trans)-4-methoxycyclohexyl]-5,6,7,8-tetrahydroquinazoline-4-carboxamide (60 mg, 39.40%) as a white solid.

[0167] A solution of 2-chloro-N-[(trans)-4-methoxycyclohexyl]-5,6,7,8-tetrahydroquinazoline-4-carboxamide (50 mg, 0.154 mmol, 1 equivalent), 5-(tributyltinyl)-1,3-thiazole (87 mg, 0.23 mmol, 1.5 equivalent), and Pd(PPh3)4 (18 mg, 0.02 mmol, 0.1 equivalent) in a DCE (3 mL) was stirred at 80°C under a nitrogen atmosphere for 4 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (Method 1) to give N-[(trans)-4-methoxycyclohexyl]-2-(1,3-thiazolyl-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-tetrahydroquinazolin-4-carboxamide (compound 112)

[0168] A solution of 2-chloro-N-[(trans)-4-methoxycyclohexyl]-5,6,7,8-tetrahydroquinazoline-4-carboxamide (50 mg, 0.154 mmol, 1.00 equivalent), imidazole (13 mg, 0.19 mmol, 1.2 equivalent), t-Buxphos (13 mg, 0.03 mmol, 0.2 equivalent), Pd2(dba)3 (14 mg, 0.02 mmol, 0.1 equivalent), and K3PO4 (98 mg, 0.462 mmol, 3 equivalent) in toluene (2 mL) was stirred at 110°C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The crude product (30 mg) was purified by preparative HPLC (Method 7) to give 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-tetrahydroquinazolin-4-carboxamide (compound 111)

[0169] A solution of 2-chloro-5,6,7,8-tetrahydroquinazoline-4-carboxylic acid (100 mg, 0.47 mmol, 1.0 equivalent), trans-4-(2-methoxyethoxy)cyclohexyl-1-amine (81 mg, 0.470 mmol, 1 equivalent), TCFH (198 mg, 0.71 mmol, 1.5 equivalent), and NMI (116 mg, 1.41 mmol, 3 equivalent) in ACN (3 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 2-chloro-N-[(trans)-4-(2-methoxyethoxy)cyclohexyl]-5,6,7,8-tetrahydroquinazoline-4-carboxamide (60 mg, 30.69%) as a white solid.

[0170] A solution of 2-chloro-N-[(trans)-4-(2-methoxyethoxy)cyclohexyl]-5,6,7,8-tetrahydroquinazoline-4-carboxamide (60 mg, 0.16 mmol, 1 equivalent), imidazole (13 mg, 0.20 mmol, 1.2 equivalent), t-Buxphos (14 mg, 0.03 mmol, 0.2 equivalent), Pd2(dba)3 (15 mg, 0.02 mmol, 0.1 equivalent), and K3PO4 (104 mg, 0.49 mmol, 3 equivalent) in toluene (2 mL) was stirred at 110°C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reversed-phase rapid chromatography (Method 1) to obtain 2-(imidazol-1-yl)-N-[(trans)-4-(2-methoxyethoxy)cyclohexyl]-5,6,7,8-tetrahydroquinazoline-4-carboxamide (25.3 mg, 37.94%) as a pale yellow solid. LCMS (ESI) [M+H] + :400.20. 1 H 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-tetrahydroquinazolin-4-carboxamide (compound 104)

[0171] A solution of 2-chloro-5,6,7,8-tetrahydroquinazoline-4-carboxylic acid (150 mg, 0.71 mmol, 1 equivalent), (trans)-4-amino-N-methylcyclohexane-1-carboxamide (165 mg, 1.06 mmol, 1.5 equivalent), HATU (402 mg, 1.06 mmol, 1.5 equivalent), and DIEA (274 mg, 2.12 mmol, 3 equivalent) in DMF (5 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reversed-phase rapid chromatography (Method 1) to give 2-chloro-N-[(trans)-4-(methylcarbamoyl)cyclohexyl]-5,6,7,8-tetrahydroquinazoline-4-carboxamide (90 mg, 36.36% yield) as a white solid.

[0172] A solution of 2-chloro-N-[(trans)-4-(methylcarbamoyl)cyclohexyl]-5,6,7,8-tetrahydroquinazoline-4-carboxamide (80 mg, 0.23 mmol, 1 equivalent), imidazole (23 mg, 0.34 mmol, 1.5 equivalent), t-BuBrettphos (22 mg, 0.05 mmol, 0.2 equivalent), t-BuBrettPhos Pd G3 (19 mg, 0.02 mmol, 0.1 equivalent), and Cs₂CO₃ (223 mg, 0.68 mmol, 3 equivalent) in dioxane (10 mL) was stirred at 120°C under nitrogen atmosphere for 1 h. The mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The crude product (48 mg) was purified by preparative HPLC (Method 6) to give 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. 1 H 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-thiazolyl-5-yl)-5H,6H,7H-cyclopentadien[d]pyrimidine-4-carboxamide (compound 115)

[0173] At room temperature, Pd(OAc)₂ (356 mg, 1.58 mmol, 1 equivalent), XantPhos (459 mg, 0.79 mmol, 0.5 equivalent), Ac₂O (324 mg, 3.17 mmol, 2 equivalent), and DIEA (1.03 g, 7.93 mmol, 5 equivalent) were added dropwise to a stirred solution of 2,4-dichloro-5H,6H,7H-cyclopentadieno[d]pyrimidine (300 mg, 1.58 mmol, 1 equivalent) and oxalic acid (1.43 g, 15.87 mmol, 10 equivalent) in DMF. The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 3 h. The mixture was allowed to cool to room temperature. The crude product was purified by reversed-phase rapid chromatography (Method 2) to obtain 2-chloro-5H,6H,7H-cyclopentadien[d]pyrimidine-4-carboxylic acid (90 mg, 28.55%), which was a light yellow oil.

[0174] At room temperature and under an air atmosphere, TCFH (254 mg, 0.90 mmol, 1 equivalent) and NMI (185 mg, 2.26 mmol, 5 equivalent) were added dropwise to a stirred solution of 2-chloro-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylic acid (90 mg, 0.45 mmol, 1 equivalent) and trans-4-(2-methoxyethoxy)cyclohexyl-1-amine (117 mg, 0.67 mmol, 1.5 equivalent) in MeCN (1 mL). The resulting mixture was stirred at room temperature for 1 h. The mixture was allowed to cool to room temperature. The crude product was purified by reversed-phase rapid chromatography (Method 2) to obtain 2-chloro-N-[(trans)-4-(2-methoxyethoxy)cyclohexyl]-5H,6H,7H-cyclopentadien[d]pyrimidine-4-carboxamide (100 mg, 62.36%), which was a light yellow oil.

[0175] At room temperature, under a nitrogen atmosphere, Pd(dppf)Cl2 (23 mg, 0.03 mmol, 0.15 equivalent) and K2CO3 (73 mg, 0.530 mmol, 2.5 equivalent) were added dropwise to a stirred mixture of 2-chloro-N-[(trans)-4-(2-methoxyethoxy)cyclohexyl]-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxamide (75 mg, 0.21 mmol, 1 equivalent) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3-thiazole (67 mg, 0.31 mmol, 1.5 equivalent) in 1,4-dioxane (1 mL). The resulting mixture was stirred at 90°C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The crude product was purified by reversed-phase rapid chromatography (Method 2) to give N-[(trans)-4-(2-methoxyethoxy)cyclohexyl]-2-(1,3-thiazolyl-5-yl)-5H,6H,7H-cyclopentadien[d]pyrimidine-4-carboxamide (12.5 mg, 14.60%) as a white solid. LCMS (ESI) [M+H] + : 403.00. 1 H 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 = 1.27 (t, J = 12.7 Hz, 2H). Example 27: Synthesis of 2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]-5H,6H,7H-cyclopentadien[d]pyrimidine-4-carboxamide (compound 108)

[0176] At room temperature and under a nitrogen atmosphere, LiOH (158 mg, 6.62 mmol, 5 equivalents) was added partically to a stirred solution of ethyl 2-chloro-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylate (300 mg, 1.32 mmol, 1 equivalent) in THF (2 mL) and H₂O (2 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 1 h and then acidified to pH 6 with 1 M HCl (aqueous solution). The resulting mixture was filtered, and the filter cake was washed with THF (3 × 5 mL). The filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0177] At room temperature and under a nitrogen atmosphere, TCFH (282 mg, 1.00 mmol, 1 equivalent) and NMI (206 mg, 2.51 mmol, 5 equivalent) were added partically to a stirred solution of 2-chloro-5H,6H,7H-cyclopentadieno[d]pyrimidine-4-carboxylic acid (100 mg, 0.50 mmol, 1 equivalent) and trans-4-methoxycyclohexyl-1-amine (65 mg, 0.50 mmol, 1 equivalent) in 2.5 mL of DMF. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The crude product was purified by reversed-phase rapid chromatography (Method 2) to give 2-chloro-N-[(trans)-4-methoxycyclohexyl]-5H,6H,7H-cyclopentadieno[d]pyrimidine-4-carboxamide (117 mg, 75.01% yield) as a pale yellow oil.

[0178] At room temperature, under a nitrogen atmosphere, CuI (30 mg, 0.16 mmol, 1 equivalent) and K₂CO₃ (66 mg, 0.48 mmol, 3.00 equivalent) were added partically to a stirred solution of 2-chloro-N-[(trans)-4-methoxycyclohexyl]-5H,6H,7H-cyclopentadieno[d]pyrimidine-4-carboxamide (50 mg, 0.16 mmol, 1 equivalent) and imidazole (32 mg, 0.48 mmol, 3 equivalent) in 1 mL of DMF. The mixture was stirred at 120°C under a nitrogen atmosphere for 1 h. The resulting mixture was filtered, and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The crude product (50 mg) was purified by reversed-phase rapid chromatography (Method 2) to give 2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]-5H,6H,7H-cyclopentadien[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]-5H,6H,7H-cyclopentadien[d]pyrimidine-4-carboxamide (compound 142)

[0179] At room temperature and under a nitrogen atmosphere, (trans)-4-(2-methoxyethoxy)cyclohexyl-1-amine (56 mg, 0.32 mmol, 1.5 equivalent) was added to a stirred mixture of 2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylic acid (50 mg, 0.21 mmol, 1 equivalent), NMI (89 mg, 1.08 mmol, 5 equivalent), and TCFH (121 mg, 0.43 mmol, 2 equivalent) in MeCN (0.5 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 15 min. The resulting mixture was filtered, and the filter cake was washed with MeCN (3 × 1 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 5) to obtain 2-(imidazol-1-yl)-N-[(trans)-4-(2-methoxyethoxy)cyclohexyl]-5H,6H,7H-cyclopentadien[d]pyrimidine-4-carboxamide (20.1 mg, 24.01% yield) as a creamy 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)-oxacyclopentan-3-yl]-5H,6H,7H-cyclopentadien[d]pyrimidine-4-carboxamide (compound 139)

[0180] At room temperature, (3S)-oxacyclopentane-3-amine (62 mg, 0.72 mmol, 1.5 equivalent), DIEA (93 mg, 0.72 mmol, 1.5 equivalent), and HATU (545 mg, 1.43 mmol, 3.0 equivalent) were added to a mixture of 2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylic acid (110 mg, 0.478 mmol, 1 equivalent) in DMF (3 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction mixture was diluted with water and the resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC (Method 4) to give 2-(imidazol-1-yl)-N-[(3S)-oxacyclopentan-3-yl]-5H,6H,7H-cyclopentadien[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 = 7.4Hz, 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-cyclopentadien[d]pyrimidine-4-carboxamide (compound 137)

[0181] A solution of (trans)-4-aminocyclohexane-1-ol (500 mg, 4.341 mmol, 1 equivalent), Cs₂CO₃ (4.24 g, 13.023 mmol, 3 equivalents), and BnBr (1.86 g, 10.853 mmol, 2.5 equivalents) in acetonitrile (100 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with EtOAc (3 × 100 mL). The combined organic phases were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give (trans)-4-(dibenzylamino)cyclohexane-1-ol (660 mg, 51.46% yield) as a white solid.

[0182] At 0°C under a nitrogen atmosphere, NaH (173 mg, 4.332 mmol, 2 equivalents) was added partically to a stirred solution of (trans)-4-(dibenzylamino)cyclohexane-1-ol (640 mg, 2.166 mmol, 1 equivalent) in 10 mL of THF. The mixture was stirred at 0°C under a nitrogen atmosphere for 20 min. Iodomethane-d3 (628 mg, 4.332 mmol, 2 equivalents) was added dropwise to the above mixture at 0°C under a nitrogen atmosphere. The mixture was stirred at 25°C for 30 min. The reaction was quenched with water at 0°C. The resulting mixture was extracted with EtOAc (3 × 100 mL), and the combined organic phases were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (10:1) elution to give (trans)-N,N-dibenzyl-4-(methoxy-d3)cyclohexyl-1-amine (350 mg, 51.70% yield), which was a pale yellow oil.

[0183] At room temperature, Pd(OH)₂ / C (66 mg, 0.095 mmol, 0.09 equivalent, 20%) was added partically to a stirred solution of (trans)-N,N-dibenzyl-4-(methoxy-d3)cyclohexyl-1-amine (330 mg, 1.056 mmol, 1 equivalent) in MeOH (5 mL). The mixture was stirred at 25°C under a hydrogen atmosphere for 16 h. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure to give (trans)-4-(methoxy-d3)cyclohexyl-1-amine (130 mg, 93.10% yield) as a pale yellow solid.

[0184] At room temperature, HATU (150 mg, 0.394 mmol, 1.30 equivalent) was added partically to a stirred solution of (trans)-4-(methoxy-d3)cyclohexyl-1-amine (40 mg, 0.303 mmol, 1 equivalent), DIEA (100 mg, 0.774 mmol, 2.56 equivalent), and 2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylic acid (60 mg, 0.261 mmol, 0.86 equivalent) in DMF (10 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with EtOAc (3 × 50 mL), and the combined organic phases were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (55 mg) was purified by preparative HPLC (Method 9) to give 2-(1H-imidazol-1-yl)-N-((trans)-4-(methoxy-d3)cyclohexyl)-6,7-dihydro-5H-cyclopentadien[d]pyrimidine-4-carboxamide (23.9 mg, 22.75% yield) as a white solid. LCMS (ESI) [M+H] + 345.25. 1 H 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 = 1.4Hz,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-cyclopentadien[d]pyrimidine-4-carboxamide (compound 136)

[0185] At room temperature, NMI (106 mg, 1.302 mmol, 1 equivalent) and TCFH (365 mg, 1.302 mmol, 3 equivalent) were added partically to a stirred solution of 2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylic acid (100 mg, 0.434 mmol, 1 equivalent) and (5R)-5-amino-1-methylpiperidin-2-one (83 mg, 0.651 mmol, 1.5 equivalent) in MeCN (3 mL). The reaction was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, and the crude product (57 mg) was purified by preparative HPLC (Method 9) to give 2-(imidazol-1-yl)-N-[(3R)-1-methyl-6-oxopiperidin-3-yl]-5H,6H,7H-cyclopentadien[d]pyrimidine-4-carboxamide (33 mg, 22.46% yield) as a white solid. LCMS (ESI)[M+H] + : 341.20. 1 H 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-oxopyrrolidone-3-yl]-5H,6H,7H-cyclopentadien[d]pyrimidine-4-carboxamide (compound 135)

[0186] At room temperature, (4S)-4-aminopyrrolidone-2-one (52 mg, 0.521 mmol, 1.2 equivalents), TCFH (244 mg, 0.87 mmol, 2.0 equivalents), and NMI (107 mg, 1.30 mmol, 3.0 equivalents) were added partically to a stirred mixture of 2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylic acid (100 mg, 0.43 mmol, 1.0 equivalents) in DMF (4 mL). The resulting mixture was stirred at room temperature for 1 h. The crude product was purified by preparative HPLC (Method 8) to give 2-(imidazol-1-yl)-N-[(3S)-5-oxopyrrolidine-3-yl]-5H,6H,7H-cyclopentadien[d]pyrimidine-4-carboxamide (24.8 mg, 18.10% yield) as a white solid. LCMS (ESI) [M+H] + : 313.20. 1 H NMR (400MHz, 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-cyclopentadien[d]pyrimidine-4-carboxamide (compound 133)

[0187] A solution of 2-chloro-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylic acid (150 mg, 0.76 mmol, 1.0 equivalent), (trans)-4-aminocyclohexane-1-carboxylonitrile (188 mg, 1.51 mmol, 2.0 equivalent), TCFH (424 mg, 1.51 mmol, 2.0 equivalent), and NMI (124 mg, 1.51 mmol, 2.0 equivalent) in ACN (5 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The crude product was purified by reversed-phase rapid chromatography (Method 1) to give 2-chloro-N-[(trans)-4-cyanocyclohexyl]-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxamide (160 mg, 69.51% yield) as a pale yellow solid.

[0188] A solution of 2-chloro-N-[(trans)-4-cyanocyclohexyl]-5H,6H,7H-cyclopentadieno[d]pyrimidine-4-carboxamide (70 mg, 0.23 mmol, 1.0 equivalent), imidazole (156 mg, 2.30 mmol, 10.0 equivalent), and K₂CO₃ (95 mg, 0.69 mmol, 3.0 equivalent) in DMF (4 mL) was stirred at 90°C under nitrogen atmosphere for 1 h. The mixture was purified by preparative HPLC (Method 6) to give 2-(imidazol-1-yl)-N-[(trans)-4-cyanocyclohexyl]-5H,6H,7H-cyclopentadieno[d]pyrimidine-4-carboxamide (22 mg, 28.19% yield) as a white solid. LCMS (ESI) [M+H] + 337.25. 1 H 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-cyclopentadien[d]pyrimidine-4-carboxamide (compound 132)

[0189] At room temperature, (trans)-4-aminocyclohexane-1-carboxylonitrile (125 mg, 1.00 mmol, 2.0 equivalent), TCFH (283 mg, 1.00 mmol, 2.0 equivalent), and NMI (124 mg, 1.51 mmol, 3.0 equivalent) were added partically to a mixture of 2-chloro-5H,6H,7H-cyclopentadieno[d]pyrimidine-4-carboxylic acid (100 mg, 0.50 mmol, 1.0 equivalent) in ACN (5 mL). The reaction was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (Method 1) to give 2-chloro-N-[(trans)-4-cyanocyclohexyl]-5H,6H,7H-cyclopentadieno[d]pyrimidine-4-carboxamide (80 mg, 52.13% yield) as a yellow solid.

[0190] At room temperature, imidazole (147 mg, 2.16 mmol, 10.0 equivalent) and K₂CO₃ (89 mg, 0.65 mmol, 3.0 equivalent) were added partically to a mixture of 2-chloro-N-[(trans)-4-(trifluoromethyl)cyclohexyl]-5H,6H,7H-cyclopentadieno[d]pyrimidine-4-carboxamide (75 mg, 0.22 mmol, 1.0 equivalent) in DMF (3 mL). The mixture was stirred at 90°C under a nitrogen atmosphere for 1 h. The mixture was allowed to cool to room temperature. The residue was purified by preparative HPLC (Method 6) to give 2-(imidazol-1-yl)-N-[(trans)-4-(trifluoromethyl)cyclohexyl]-5H,6H,7H-cyclopentadieno[d]pyrimidine-4-carboxamide (21.3 mg, 25.80% yield) as a white solid. LCMS (ESI) [M+H] + 380.10. 1 H 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-cyclopentadien[d]pyrimidine-4-carboxamide (compound 131)

[0191] NMI (372 mg, 4.530 mmol, 3.0 equivalent) and TCFH (1271 mg, 4.530 mmol, 3.0 equivalent) were added to a stirred solution of 2-chloro-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylic acid (300 mg, 1.510 mmol, 1.0 equivalent) and (trans)-3-aminocyclobutane-1-carboxylic acid methyl ester (292 mg, 2.265 mmol, 1.5 equivalent) in MeCN (10 mL). The reaction was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with PE / EA (1:1) elution to give methyl (trans)-3-{2-chloro-5H,6H,7H-cyclopentadien[d]pyrimidine-4-amido}cyclobutane-1-carboxylate (200 mg, 42.75% yield) as a colorless oil.

[0192] A solution of methyl (trans)-3-{2-chloro-5H,6H,7H-cyclopentadien[d]pyrimidin-4-amido}cyclobutane-1-carboxylate (200 mg, 0.646 mmol, 1.0 equivalent), imidazole (87 mg, 1.292 mmol, 2.0 equivalent), and K₂CO₃ (267 mg, 1.938 mmol, 3.0 equivalent) in DMF (10 mL) was stirred at 100°C under nitrogen atmosphere for 3 h. The reaction mixture was diluted with water and extracted with EtOAc (3 × 50 mL). The combined organic phases were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give (trans)-3-[2-(imidazol-1-yl)-5H,6H,7H-cyclopentadienyl[d]pyrimidin-4-amido]cyclobutane-1-carboxylic acid (150 mg, 61.51% yield) as a light green solid.

[0193] At room temperature, TCFH (372 mg, 1.329 mmol, 3.0 equivalent) and NMI (109 mg, 1.329 mmol, 3.0 equivalent) were added to a stirred solution of (trans)-3-[2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-amido]cyclobutane-1-carboxylic acid (145 mg, 0.443 mmol, 1.0 equivalent) and methylamine hydrochloride (134 mg, 0.886 mmol, 2.0 equivalent) in MeCN (10 mL). The reaction was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, and the crude product (200 mg) was purified by preparative HPLC (Method 8) to give 2-(1H-imidazol-1-yl)-N-((trans)-3-(methylcarbamoyl)cyclobutyl)-6,7-dihydro-5H-cyclopentadien[d]pyrimidine-4-carboxamide (21.8 mg, 14.26% yield) as a pale yellow solid. LCMS (ESI) [M+H] + : 341.15. 1 H 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-cyclopentadieno[d]pyrimidine-4-carboxamide and 2-(imidazol-1-yl)-N-[(cis)-4-(methylcarbamoyl)cyclohexyl]-5H,6H,7H-cyclopentadieno[d]pyrimidine-4-carboxamide (compounds 129 and 130)

[0194] At room temperature, under a nitrogen atmosphere, methyl (trans)-4-aminocyclohexane-1-carboxylate (356 mg, 2.27 mmol, 1.5 equivalent), NMI (248 mg, 3.02 mmol, 2.0 equivalent), and TCFH (1271 mg, 4.53 mmol, 3.0 equivalent) were added in portions to a mixture of 2-chloro-5H,6H,7H-cyclopentadienyl[d]pyrimidin-4-carboxylic acid (300 mg, 1.51 mmol, 1.0 equivalent) in ACN (5 mL), and the mixture was stirred for 1 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with PE / EA (3:1) elution to give methyl (trans)-4-{2-chloro-5H,6H,7H-cyclopentadienyl[d]pyrimidine-4-amido}cyclohexane-1-carboxylate (280 mg, 54.88% yield) as a yellow solid.

[0195] At room temperature, under a nitrogen atmosphere, imidazole (544 mg, 7.99 mmol, 10.0 equivalent) and K₂CO₃ (331 mg, 2.40 mmol, 3.0 equivalent) were added partically to a mixture of (trans)-4-{2-chloro-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-amido}cyclohexane-1-carboxylate (270 mg, 0.80 mmol, 1.0 equivalent) in DMF (5 mL). The mixture was stirred at 90°C under a nitrogen atmosphere for 12 h and then allowed to cool to room temperature. The residue was purified by reversed-phase rapid chromatography (Method 1) to give methyl (trans)-4-[2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-amido]cyclohexane-1-carboxylate and methyl (cis)-4-[2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-amido]cyclohexane-1-carboxylate (mixture) as brown solids (160 mg, 54.19% yield).

[0196] At room temperature, methyl (trans)-4-[2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-amido]cyclohexane-1-carboxylate and (cis)-4-[2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-amido]cyclohexane-1-carboxylate (mixture) (110 mg, 0.31 mmol, 1.0 equivalent) in ACN (4 mL) were partially added to THF with 2 M methylamine (0.75 mL, 0.465 mmol, 1.5 equivalent), TCFH (174 mg, 0.62 mmol, 2.0 equivalent), and NMI (76 mg, 0.93 mmol, 3.0 equivalent). The mixture was stirred at room temperature under a nitrogen atmosphere for 1 h and then concentrated under reduced pressure. The crude product (110 mg) was purified by preparative HPLC (Method 6) to give 2-(imidazol-1-yl)-N-[(trans)-4-(methylcarbamoyl)cyclohexyl]-5H,6H,7H-cyclopentadieno[d]pyrimidine-4-carboxamide (27.6 mg, 24.17%) and 2-(imidazol-1-yl)-N-[(cis)-4-(methylcarbamoyl)cyclohexyl]-5H,6H,7H-cyclopentadieno[d]pyrimidine-4-carboxamide (17.0 mg, 14.96%) as white solids. Compound 130: LCMS (ESI) [M+H] + 369.25. 1 H 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-cyclopentadieno[d]pyrimidine-4-carboxamide and acetic acid 2-(imidazol-1-yl)-4-{[(trans)-4-methoxycyclohexyl]carbamoyl}-5H,6H,7H-cyclopentadieno[d]pyrimidine-7-yl esters (compounds 124 and 144)

[0197] A solution of 2,4-dichloro-5H,6H,7H-cyclopentadieno[d]pyrimidine (2 g, 10.580 mmol, 1.0 equivalent) and Pb(OAc)4 (9.38 g, 21.160 mmol, 2.0 equivalent) in AcOH (40 mL) was stirred at 120°C under nitrogen atmosphere for 28 h. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by reversed-phase rapid chromatography (Method 1) to give 2,4-dihydroxy-5H,6H,7H-cyclopentadieno[d]pyrimidine-7-yl acetate (700 mg, 31.48% yield) as a pale yellow solid.

[0198] POCl3 (1.27 g, 8.27 mmol, 3.0 equivalent) was added dropwise to a stirred mixture of 2,4-dihydroxy-5H,6H,7H-cyclopentadieno[d]pyrimidin-7-yl acetate (580 mg, 2.76 mmol, 1.0 equivalent) in ACN (5 mL) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 80°C under a nitrogen atmosphere for 1 h and then allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography with PE / EA (3:1) elution to give 2,4-dichloro-5H,6H,7H-cyclopentadieno[d]pyrimidin-7-yl acetate (280 mg, 41.07% yield) as a pale yellow oil.

[0199] A solution of 2,4-dichloro-5H,6H,7H-cyclopentadien[d]pyrimidin-7-yl ester of acetate (270 mg, 1.09 mmol, 1.0 equivalent), tributyl(1-ethoxyvinyl)stanane (395 mg, 1.09 mmol, 1.0 equivalent), and Pd(PPh3)2Cl2 (77 mg, 0.11 mmol, 0.1 equivalent) in DMF (20 mL) was stirred at 65°C under a nitrogen atmosphere for 1 h. The mixture was allowed to cool to room temperature. The reaction was quenched with KF (aqueous solution). The mixture was then diluted with water. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (2:1) elution to give 2-chloro-4-(1-ethoxyvinyl)-5H,6H,7H-cyclopentadien[d]pyrimidine-7-yl ester (200 mg, 64.74% yield), which was a pale yellow oil.

[0200] At 0°C, NaIO4 (287 mg, 1.34 mmol, 2.0 equivalent) and KMnO4 (53 mg, 0.34 mmol, 0.5 equivalent) were added partically to a stirred mixture of 2-chloro-4-(1-ethoxyvinyl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-7-yl ester (190 mg, 0.67 mmol, 1.0 equivalent) in dioxane (5 mL) and H2O (5 mL). The resulting mixture was stirred overnight at room temperature. The reaction was quenched at 0°C with Na2S2O3 (aqueous solution) and NaHCO3 (aqueous solution). The mixture was diluted with water, and the resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:1) elution to give 7-(acetoxy)-2-chloro-5H,6H,7H-cyclopentadien[d]pyrimidine-4-carboxylic acid (100 mg, 57.98% yield), which was a pale yellow oil.

[0201] At room temperature, (trans)-4-methoxycyclohexyl-1-amine (506 mg, 3.92 mmol, 1.5 equivalent), TCFH (1.10 g, 3.92 mmol, 1.5 equivalent), and NMI (643 mg, 7.83 mmol, 3.0 equivalent) were added partically to a mixture of 7-(acetoxy)-2-chloro-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylic acid (670 mg, 2.61 mmol, 1.0 equivalent) in 10 mL of ACN. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The mixture was then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 2-chloro-4-{[(trans)-4-methoxycyclohexyl]carbamoyl}-5H,6H,7H-cyclopentadienyl[d]pyrimidin-7-yl ester as a pale yellow solid (580 mg, 60.40% yield).

[0202] A mixture of 2-chloro-4-{[(trans)-4-methoxycyclohexyl]carbamoyl}-5H,6H,7H-cyclopentadieno[d]pyrimidin-7-yl ester (570 mg, 1.55 mmol, 1.0 equivalent) and imidazole (316 mg, 4.65 mmol, 3.0 equivalent) in DMF (8 mL) was stirred overnight at 80°C under a nitrogen atmosphere. The mixture was allowed to cool to room temperature, and the crude product was purified by reversed-phase rapid chromatography (Method 1) to give 2-(imidazol-1-yl)-4-{[(trans)-4-methoxycyclohexyl]carbamoyl}-5H,6H,7H-cyclopentadieno[d]pyrimidin-7-yl ester (380 mg, 61.39% yield) as a pale yellow solid. LCMS (ESI) [M+H] + :400.20. 1 H 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).

[0203] At 0°C, LiOH (222 mg, 9.26 mmol, 10.0 equivalent) was added partically to a mixture of 2-(imidazol-1-yl)-4-{[(trans)-4-methoxycyclohexyl]carbamoyl}-5H,6H,7H-cyclopentadien[d]pyrimidin-7-yl ester (370 mg, 0.93 mmol, 1.0 equivalent) in MeOH (4 mL) and H₂O (1 mL). The mixture was stirred at room temperature for 1 h and then acidified to pH 5 with 1 M HCl (aqueous solution). The resulting mixture was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (Method 8) to give 7-hydroxy-2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]-5H,6H,7H-cyclopentadieno[d]pyrimidine-4-carboxamide (17.1 mg, 5.05% yield) as a white solid. LCMS (ESI)[M+H] + 358.15. 1 H 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 = 6.9Hz, 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-cyclopentadien[d]pyrimidine-4-carboxamide (compound 127)

[0204] A solution of methyl 2-chloro-5H,6H,7H-cyclopentadien[d]pyrimidin-4-carboxylate (500 mg, 2.352 mmol, 1.0 equivalent), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)imidazolium (733 mg, 3.528 mmol, 1.5 equivalent), Pd(dppf)Cl2 (172 mg, 0.235 mmol, 0.1 equivalent), and K2CO3 (974 mg, 7.056 mmol, 3.0 equivalent) in dioxane (10 mL) and H2O (2 mL) was stirred at 90°C under a nitrogen atmosphere for 1 h. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (Method 1) to give methyl 2-(3-methylimidazol-4-yl)-5H,6H,7H-cyclopentadienyl[d]pyrimidine-4-carboxylate (350 mg, 57.63% yield) as a yellow solid.

[0205] A solution of methyl 2-(3-methylimidazol-4-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylic acid (340 mg, 1.316 mmol, 1.0 equivalent) and LiOH (315 mg, 13.160 mmol, 10 equivalent) in THF (10 mL) and H₂O (2.5 mL) was stirred at room temperature for 1 h. The mixture was acidified to pH 6 with 1 M HCl (aqueous solution) and then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 2-(3-methylimidazol-4-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylic acid (280 mg, 87.08% yield) as a pale yellow solid.

[0206] A solution of 2-(3-methylimidazol-4-yl)-5H,6H,7H-cyclopentadien[d]pyrimidin-4-carboxylic acid (80 mg, 0.328 mmol, 1 equivalent), (trans)-4-methoxycyclohexyl-1-amine (63 mg, 0.492 mmol, 1.5 equivalent), TCFH (275 mg, 0.984 mmol, 3 equivalent), and NMI (80 mg, 0.984 mmol, 3 equivalent) in ACN (5 mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, and the crude product (80 mg) was purified by preparative HPLC (Method 8) to give N-((trans)-4-methoxycyclohexyl)-2-(1-methyl-1H-imidazol-5-yl)-6,7-dihydro-5H-cyclopentadien[d]pyrimidine-4-carboxamide (25.8 mg, 22.14% yield) as a white solid. LCMS (ESI) [M+H] + 356.15.1 H 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-cyclopentadien[d]pyrimidine-4-carboxamide (compound 126)

[0207] A solution of 2-(3-methylimidazol-4-yl)-5H,6H,7H-cyclopentadien[d]pyrimidin-4-carboxylic acid (80 mg, 0.328 mmol, 1.0 equivalent), (trans)-4-aminocyclohexyl-1-ol (56 mg, 0.492 mmol, 1.5 equivalent), TCFH (275 mg, 0.984 mmol, 3.0 equivalent), and NMI (80 mg, 0.984 mmol, 3 equivalent) in ACN (5 mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, and the crude product (60 mg) was purified by preparative HPLC (Method 6) to give N-((trans)-4-hydroxycyclohexyl)-2-(1-methyl-1H-imidazol-5-yl)-6,7-dihydro-5H-cyclopentadien[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-cyclopentadien[d]pyrimidine-4-carboxamide (compound 125) A solution of methyl 2-chloro-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylic acid (150 mg, 0.705 mmol, 1 equivalent), 1H-imidazolium-d4 (76 mg, 1.057 mmol, 1.5 equivalent), and K2CO3 (292 mg, 2.115 mmol, 3 equivalent) in DMF (10 mL) was stirred at 90°C for 2 h. The crude product was purified by reversed-phase rapid chromatography (Method 1) to give 2-(1H-imidazolium-1-yl-d3)-6,7-dihydro-5H-cyclopentadieno[d]pyrimidin-4-carboxylic acid (90 mg, 54.70% yield) as a pale yellow solid.

[0208] A solution of 2-(1H-imidazol-1-yl-d3)-6,7-dihydro-5H-cyclopentadien[d]pyrimidine-4-carboxylic acid (80 mg, 0.343 mmol, 1.0 equivalent), (trans)-4-methoxycyclohexyl-1-amine (66 mg, 0.515 mmol, 1.5 equivalent), TCFH (288 mg, 1.029 mmol, 3 equivalent), and NMI (84 mg, 1.029 mmol, 3 equivalent) in ACN (5 mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, and the crude product (60 mg) was purified by preparative HPLC (Method 5) to give 2-(1H-imidazol-1-yl-d3)-N-((trans)-4-methoxycyclohexyl)-6,7-dihydro-5H-cyclopentadien[d]pyrimidine-4-carboxamide (32.3 mg, 27.34% yield) as a white solid. LCMS (ESI) [M+H] + 345.40.1 HNMR (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-cyclopentadien[d]pyrimidine-4-carboxamide (compound 123)

[0209] A solution of 2-(imidazol-1-yl)-5H,6H,7H-cyclopentadien[d]pyrimidin-4-carboxylic acid (100 mg, 0.434 mmol, 1.0 equivalent), (trans)-4-aminocyclohexyl-1-ol (75 mg, 0.651 mmol, 1.5 equivalent), TCFH (365 mg, 1.302 mmol, 3 equivalent), and NMI (106 mg, 1.302 mmol, 3.0 equivalent) in ACN (5 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure, and the crude product (80 mg) was purified by preparative HPLC (Method 6) to give N-((trans)-4-hydroxycyclohexyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopentadien[d]pyrimidine-4-carboxamide (21.2 mg, 14.58% yield) as a creamy white solid. LCMS (ESI) [M+H] + 328.15. 1H NMR (400MHz, 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-hydroxypropyl-2-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopentadien[d]pyrimidine-4-carboxamide (compound 122)

[0210] A solution of 2-(imidazol-1-yl)-5H,6H,7H-cyclopentadien[d]pyrimidin-4-carboxylic acid (100 mg, 0.434 mmol, 1 equivalent), 2-[(trans)-4-aminocyclohexyl]prop-2-ol (102 mg, 0.651 mmol, 1.5 equivalent), TCFH (365 mg, 1.302 mmol, 3 equivalent), and NMI (106 mg, 1.302 mmol, 3 equivalent) in ACN (1 mL) was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, and the crude product (80 mg) was purified by preparative HPLC (Method 8) to give N-((trans)-4-(2-hydroxypropyl-2-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopentadien[d]pyrimidine-4-carboxamide (24.1 mg, 14.64% yield) as a creamy white solid. LCMS (ESI) [M+H] + 370.20. 1HNMR (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-thiazolyl-5-yl)-5H,6H,7H-cyclopentadieno[b]pyridine-4-carboxamide (compound 107)

[0211] At room temperature and under a nitrogen atmosphere, TCFH (136 mg, 0.48 mmol, 1.5 equivalent) and NMI (80 mg, 0.97 mmol, 3 equivalent) were added to a stirred solution of 2-(1,3-thiazolyl-5-yl)-5H,6H,7H-cyclopentadieno[b]pyridine-4-carboxylic acid (80 mg, 0.32 mmol, 1 equivalent) and trans-4-methoxycyclohexyl-1-amine (83 mg, 0.65 mmol, 2 equivalent) in DMF (2.5 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 5 mL). The filtrate was concentrated under reduced pressure. The crude product (80 mg) was purified by preparative HPLC (Method 8) to give N-[(trans)-4-methoxycyclohexyl]-2-(1,3-thiazolyl-5-yl)-5H,6H,7H-cyclopentadieno[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-cyclopentadieno[b]pyridine-4-carboxamide (compound 138)

[0212] At 0°C, NaOH (19 mg, 0.47 mmol, 0.5 equivalent) was added partically to a stirred mixture of methyl 2-chloro-5H,6H,7H-cyclopentadieno[b]pyridine-4-carboxylic acid (200 mg, 0.95 mmol, 1.0 equivalent) in THF (5 mL) and H₂O (2 mL). The resulting mixture was stirred at room temperature for another 1 h. The reaction was acidified to pH 6 with 1 M HCl (aqueous solution). The resulting mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography (Method 1) to give 2-chloro-5H,6H,7H-cyclopentadieno[b]pyridine-4-carboxylic acid (140 mg, 74.97% yield) as a yellow solid.

[0213] At room temperature, (trans)-4-methoxycyclohexyl-1-amine (127 mg, 0.99 mmol, 1.5 equivalent), HATU (375 mg, 0.99 mmol, 1.5 equivalent), and DIEA (255 mg, 1.97 mmol, 3.0 equivalent) were added partically to a stirred mixture of 2-chloro-5H,6H,7H-cyclopentadieno[b]pyridine-4-carboxylic acid (130 mg, 0.66 mmol, 1.0 equivalent) in DMF (3 mL). The reaction was stirred at room temperature under a nitrogen atmosphere for 1 h. The mixture was diluted with water, and the resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 2-chloro-N-((trans)-4-methoxycyclohexyl)-6,7-dihydro-5H-cyclopentadien[b]pyridine-4-carboxamide (80 mg, 33.05% yield) as a yellow solid.

[0214] A mixture of 2-chloro-N-((trans)-4-methoxycyclohexyl)-6,7-dihydro-5H-cyclopentadieno[b]pyridine-4-carboxamide (80 mg, 0.26 mmol, 1.0 equivalent), imidazole (353 mg, 5.18 mmol, 20.0 equivalent), t-BuBrettphos (25 mg, 0.05 mmol, 0.2 equivalent), t-BuBrettPhos Pd G3 (22 mg, 0.03 mmol, 0.1 equivalent), and Cs2CO3 (253 mg, 0.78 mmol, 3.0 equivalent) in dioxane (4 mL) was stirred at 120°C under a nitrogen atmosphere for 1 h. The mixture was allowed to cool to room temperature. After filtration, the filtrate was concentrated under reduced pressure. The crude product (35 mg) was purified by preparative HPLC (Method 8) to give 2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]-5H,6H,7H-cyclopentadieno[b]pyridine-4-carboxamide (20.3 mg, 23.00% yield) as a white solid. LCMS (ESI) [M+H] + : 341.20. 1HNMR (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-cyclopentadien[d]pyrimidine-4-carboxamide (compound 176)

[0215] A mixture of 2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylic acid (90 mg, 0.391 mmol, 1 equivalent), (trans)-4-amino-1-(trifluoromethyl)cyclohexyl-1-ol (107 mg, 0.587 mmol, 1.5 equivalent), TCFH (329 mg, 1.173 mmol, 3 equivalent), and NMI (96 mg, 1.173 mmol, 3 equivalent) in ACN (5 mL) was stirred at room temperature under a nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 6) to give N-((trans)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopentadien[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-cyclopentadien[d]pyrimidine-4-carboxamide (compound 189)

[0216] A solution of 2,4-dichloro-5H,6H,7H-cyclopentadien[d]pyrimidine (10 g, 52.899 mmol, 1 equivalent), tributyl(1-ethoxyvinyl)stanane (19.10 g, 52.899 mmol, 1 equivalent), and Pd(PPh3)2Cl2 (3.71 g, 5.290 mmol, 0.1 equivalent) in DMF (40 mL) was stirred at 65°C under a nitrogen atmosphere for 12 h. The reaction was quenched with KF (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (5:1) elution to give 2-chloro-4-(1-ethoxyvinyl)-5H,6H,7H-cyclopentadien[d]pyrimidine (6 g, 51% yield) as a brown solid.

[0217] At 0°C, NaIO4 (11.42 g, 53.406 mmol, 2.00 equivalent) and KMnO4 (2.11 g, 13.351 mmol, 0.5 equivalent) were added partically to a stirred solution of 2-chloro-4-(1-ethoxyvinyl)-5H,6H,7H-cyclopentadieno[d]pyrimidine (6 g, 26.703 mmol, 1 equivalent) in dioxane (50 mL) and water (20 mL). The mixture was stirred at room temperature for 12 h. The reaction was quenched at 0°C with Na2S2O3 (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This produces ethyl 2-chloro-5H,6H,7H-cyclopentadienyl[d]pyrimidine-4-carboxylate as a brown solid (3.2 g, 53% yield).

[0218] A mixture of ethyl 2-chloro-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylic acid (1.5 g, 6.618 mmol, 1 equivalent), imidazole (0.90 g, 13.236 mmol, 2 equivalents), and K₂CO₃ (2.74 g, 19.854 mmol, 3 equivalents) in DMF (10 mL) was stirred at 100°C under a nitrogen atmosphere for 4 h. The residue was purified by reversed-phase rapid chromatography (Method 1). This yielded 2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylic acid (800 mg, 53% yield) as an off-white solid.

[0219] A solution of 2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylic acid (70 mg, 0.304 mmol, 1 equivalent), (trans)-4-amino-1-methylcyclohexyl-1-ol (58 mg, 0.456 mmol, 1.5 equivalent), TCFH (255 mg, 0.912 mmol, 3 equivalent), and NMI (74 mg, 0.912 mmol, 3 equivalent) in ACN (5 mL) was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 7) to give 2-(imidazol-1-yl)-N-[(trans)-4-hydroxy-4-methylcyclohexyl]-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxamide (36.4 mg, 34% yield) as a white solid. LCMS (ESI) [M+H] + 342.15. 1H NMR (400 MHz, DMSO-d6) δ8.88 (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-cyclopentadien[d]pyrimidine-4-carboxamide (compound 188)

[0220] A mixture of 2-(imidazol-1-yl)-5H,6H,7H-cyclopentadien[d]pyrimidin-4-carboxylic acid (50 mg, 0.217 mmol, 1 equivalent), (cis)-4-amino-1-methylcyclohexyl-1-ol (42 mg, 0.326 mmol, 1.5 equivalent), TCFH (182 mg, 0.651 mmol, 3 equivalent), and NMI (53 mg, 0.651 mmol, 3 equivalent) in ACN (5 mL) was stirred at room temperature under a nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 6) to give N-((cis)-4-hydroxy-4-methylcyclohexyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopentadien[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]oct-1-yl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopentadien[d]pyrimidine-4-carboxamide (compound 187)

[0221] A solution of 2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylic acid (60 mg, 0.261 mmol, 1 equivalent), 4-aminobicyclo[2.2.2]oct-1-ol hydrochloride (69 mg, 0.392 mmol, 1.5 equivalent), TCFH (219 mg, 0.783 mmol, 3 equivalent), and NMI (64 mg, 0.783 mmol, 3 equivalent) in ACN (5 mL) was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 8) to give N-{4-hydroxybicyclo[2.2.2]oct-1-yl}-2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxamide (15.1 mg, 16% yield) as a white solid. LCMS (ESI) [M+H] + :354.10. 1 H 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-cyclopentadien[d]pyrimidine-4-carboxamide (compound 185)

[0222] Triethylaluminum (17 mL, 17 mmol, 5 equivalents, 1 M) was added dropwise to a stirred solution of 4-(dibenzylamino)cyclohexane-1-one (1 g, 3.408 mmol, 1 equivalent) in toluene (20 mL) at 0°C under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 h. The reaction was quenched with 1 M NaOH (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give (trans)-4-(dibenzylamino)-1-ethylcyclohexane-1-ol (assumed) (120 mg, 11% yield) and (cis)-4-(dibenzylamino)-1-ethylcyclohexane-1-ol (assumed) (75 mg, 6.8% yield) as white solids.

[0223] A solution of (trans)-4-(dibenzylamino)-1-ethylcyclohexane-1-ol (hypothetically) (110 mg, 0.340 mmol, 1 equivalent) and Pd / C (36 mg, 0.034 mmol, 0.1 equivalent, 10% purity) in MeOH (2 mL) was stirred for 5 h at room temperature under a hydrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give (trans)-4-amino-1-ethylcyclohexane-1-ol (hypothetically) (50 mg, 82% yield) as a white solid.

[0224] A mixture of (trans)-4-amino-1-ethylcyclohexyl-1-ol (hypothetically) (50 mg, 0.349 mmol, 1.5 equivalents), 2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylic acid (53 mg, 0.233 mmol, 1.00 equivalents), TCFH (195 mg, 0.698 mmol, 3 equivalents), and NMI (57 mg, 0.698 mmol, 3 equivalents) in ACN (5 mL) was stirred at room temperature for 1 h. The mixture was then concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 6) to give N-((trans)-4-ethyl-4-hydroxycyclohexyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopentadien[d]pyrimidine-4-carboxamide (hypothetically) as a white solid (14.1 mg, 16.5% yield). LCMS (ESI) [M+H] + 356.20. 1 H 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-cyclopentadien[d]pyrimidine-4-carboxamide (compound 184)

[0225] A mixture of (cis)-4-(dibenzylamino)-1-ethylcyclohexane-1-ol (hypothetically) (76 mg, 0.235 mmol, 1 equivalent) and Pd / C (24 mg, 0.023 mmol, 0.1 equivalent, 10% purity) in MeOH (5 mL) was stirred at room temperature under a hydrogen atmosphere for 5 h. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give (cis)-4-amino-1-ethylcyclohexane-1-ol (hypothetically) (45 mg, 94% yield) as a white solid.

[0226] A solution of (cis)-4-amino-1-ethylcyclohexyl-1-ol (hypothetically) (45 mg, 0.314 mmol, 1 equivalent), 2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylic acid (144 mg, 0.628 mmol, 2 equivalents), TCFH (264 mg, 0.942 mmol, 3 equivalents), and NMI (77 mg, 0.942 mmol, 3 equivalents) in ACN (5 mL) was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 6) to give N-((cis)-4-ethyl-4-hydroxycyclohexyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopentadieno[d]pyrimidin-4-carboxamide (hypothetically) (13.0 mg, 12% yield) as a white solid. LCMS (ESI) [M+H] + 356.15. 1 H 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-cyclopentadien[d]pyrimidine-4-carboxamide (compound 167)

[0227] At room temperature and under a nitrogen atmosphere, TCFH (200 mg, 0.434 mmol, 1 equivalent) and NMI (300 mg, 3.654 mmol, 8.41 equivalent) were added participle to a stirred solution of 2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylic acid (100 mg, 0.434 mmol, 1 equivalent) and (trans)-3-methoxycyclobutan-1-amine hydrochloride (68 mg, 0.494 mmol, 1.14 equivalent) in ACN (3 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 min. The resulting mixture was then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 2) to give 2-(imidazol-1-yl)-N-[(trans)-3-methoxycyclobutyl]-5H,6H,7H-cyclopentadieno[d]pyrimidine-4-carboxamide (52.4 mg, 38% yield) as a white solid. LCMS (ESI) [M+H] + :314.10. 1 H 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-cyclopentadien[d]pyrimidine-4-carboxamide (compound 183)

[0228] A mixture of 2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylic acid (200 mg, 0.869 mmol, 1 equivalent), methyl (trans)-4-aminocyclohexane-1-carboxylate (205 mg, 1.304 mmol, 1.5 equivalent), TCFH (732 mg, 2.607 mmol, 3 equivalent), and NMI (214 mg, 2.607 mmol, 3 equivalent) in ACN (5 mL) was stirred at room temperature under a nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (3:1) elution to give methyl (trans)-4-[2-(imidazol-1-yl)-5H,6H,7H-cyclopentadien[d]pyrimidin-4-amido]cyclohexane-1-carboxylate (130 mg, 41% yield) as a yellow solid.

[0229] A mixture of (trans)-4-[2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-amido]cyclohexane-1-carboxylate (120 mg, 0.541 mmol, 1 equivalent), dimethylamine (0.8 mL, 1.6 mmol, 3 equivalent, 2 M) and 1H,2H,3H,4H,6H,7H,8H-[1,3]diazido[1,2-a]pyrimidin (150 mg, 1.082 mmol, 2 equivalent) in THF (10 mL) was stirred at 110°C for 12 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 7) to give N-((trans)-4-(dimethylcarbamoyl)cyclohexyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopentadien[d]pyrimidine-4-carboxamide (44.1 mg, 21% yield), a pale 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-cyclopentadien[d]pyrimidine-4-carboxamide (compound 165)

[0230] A solution of 2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylic acid (130 mg, 0.565 mmol, 1 equivalent), N-[(trans)-4-aminocyclohexyl]carbamate tert-butyl ester (181 mg, 0.847 mmol, 1.5 equivalent), TCFH (317 mg, 1.130 mmol, 2.0 equivalent), and NMI (232 mg, 2.825 mmol, 5.0 equivalent) in MeCN (8 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give N-[(trans)-4-[2-(imidazol-1-yl)-5H,6H,7H-cyclopentadien[d]pyrimidin-4-amido]cyclohexyl] tert-butyl carbamate (120 mg, 50% yield) as a grayish-white solid.

[0231] A solution of N-[(trans)-4-[2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-amido]cyclohexyl]tert-butyl carbamate (106 mg, 0.249 mmol, 1 equivalent) in 4 M HCl / dioxane (5 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. This yielded 2-(imidazol-1-yl)-N-[(trans)-4-aminocyclohexyl]-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxamide (132 mg, crude) as a brown solid.

[0232] A solution of 2-(imidazol-1-yl)-N-[(trans)-4-aminocyclohexyl]-5H,6H,7H-cyclopentadieno[d]pyrimidine-4-carboxamide (120 mg, 0.368 mmol, 1 equivalent), 2,2,2-trifluoroethyl trifluoromethanesulfonate (127 mg, 0.552 mmol, 1.5 equivalent), and TEA (186 mg, 1.840 mmol, 5 equivalent) in ACN (3 mL) was stirred at 70°C under a nitrogen atmosphere for 16 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 5) to give 2-(imidazol-1-yl)-N-[(trans)-4-[(2,2,2-trifluoroethyl)amino]cyclohexyl]-5H,6H,7H-cyclopentadieno[d]pyrimidine-4-carboxamide (24.4 mg, 16% yield) as a white solid. LCMS (ESI) [M+H + :409.20. 1 H NMR (400MHz, 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-difluoropyrrolidone-1-yl)cyclohexyl]-5H,6H,7H-cyclopentadien[d]pyrimidine-4-carboxamide (compound 162)

[0233] A solution of 4-(dibenzylamino)cyclohexane-1-one (1 g, 3.408 mmol, 1 equivalent), AcOH (200 mg, 3.408 mmol, 1 equivalent), and 3,3-difluoropyrrolidine hydrochloride (540 mg, 3.749 mmol, 1.1 equivalent) in DCM (50 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. NaBH3CN (430 mg, 6.816 mmol, 2 equivalent) was added partically to the mixture at 0°C. The resulting mixture was stirred at room temperature under air atmosphere for 3 h. The reaction was quenched at 0°C with 1 M NaOH (aqueous solution). MeOH was concentrated under reduced pressure. The aqueous layer was extracted with CH2Cl2 (3 × 150 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give (trans)-N,N-dibenzyl-4-(3,3-difluoropyrrolidone-1-yl)cyclohexyl-1-amine (430 mg, 33% yield) as a white solid.

[0234] A solution of (trans)-N,N-dibenzyl-4-(3,3-difluoropyrrolidone-1-yl)cyclohexyl-1-amine (420 mg, 1.092 mmol, 1 equivalent) and Pd(OH)₂ / C (153 mg, 0.109 mmol, 0.1 equivalent, 10% purity) in methanol (10 mL) was stirred for 3 h at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. This yielded (trans)-4-(3,3-difluoropyrrolidone-1-yl)cyclohexyl-1-amine (200 mg, 90% yield) as a creamy white solid.

[0235] A solution of (trans)-4-(3,3-difluoropyrrolidone-1-yl)cyclohexyl-1-amine (80 mg, 0.392 mmol, 1 equivalent), 2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidine-4-carboxylic acid (99 mg, 0.431 mmol, 1.1 equivalent), TCFH (219 mg, 0.784 mmol, 2 equivalent), and NMI (160 mg, 1.960 mmol, 5 equivalent) in ACN (2 mL) was stirred at room temperature under air for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 10) to give 2-(imidazol-1-yl)-N-[(trans)-4-(3,3-difluoropyrrolidone-1-yl)cyclohexyl]-5H,6H,7H-cyclopentadien[d]pyrimidine-4-carboxamide (14.6 mg, 9% yield) as a white solid. LCMS (ESI) [M+H]+ :417.20. 1 H 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-cyclopentadien[d]pyrimidine-4-carboxamide (compound 159)

[0236] At room temperature, t-BuBrettphos Pd G3 (321 mg, 0.376 mmol, 0.10 equivalent), t-BuBrettphos (360 mg, 0.743 mmol, 0.20 equivalent), and Cs2CO3 (3.7 g, 11.356 mmol, 3.02 equivalent) were added in portions to a stirred mixture of 2-chloro-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylic acid methyl ester (800 mg, 3.762 mmol, 1 equivalent) and imidazole (500 mg, 7.344 mmol, 1.95 equivalent) in 1,4-dioxane. The resulting mixture was stirred at 120°C under a nitrogen atmosphere for 1 h. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution of CH2Cl2 / MeOH (12:1) to give methyl 2-(imidazol-1-yl)-5H,6H,7H-cyclopentadien[d]pyrimidine-4-carboxylate (550 mg, 60% yield) as a yellow solid.

[0237] At room temperature, HATU (1.3 g, 3.419 mmol, 1.67 equivalent) and 2,4,6-trimethylpyridine (750 mg, 6.189 mmol, 3.02 equivalent) were added partically to a stirred mixture of methyl 2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxylate (500 mg, 2.047 mmol, 1 equivalent) and N-[(trans)-3-aminocyclobutyl]carboxylate tert-butyl ester (600 mg, 3.221 mmol, 1.57 equivalent) in DMF (10 mL). The resulting mixture was stirred at room temperature for 1 h. The mixture was diluted with water. The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:1) elution to give N-[(trans)-3-[2-(imidazol-1-yl)-5H,6H,7H-cyclopentadien[d]pyrimidin-4-amido]cyclobutyl]carbamate (420 mg, 52% yield) as a yellow solid.

[0238] At room temperature, 4 M HCl (gas) / 1,4-dioxane (2 mL) was added dropwise to a stirred mixture of N-[(trans)-3-[2-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-amido]cyclobutyl]carbamate (220 mg, 0.552 mmol, 1 equivalent) in dioxane (2 mL). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. This yielded 2-(imidazol-1-yl)-N-[(trans)-3-aminocyclobutyl]-5H,6H,7H-cyclopentadieno[d]pyrimidin-4-carboxamide (150 mg, 91% yield) as a yellow solid.

[0239] TEA (170 mg, 1.680 mmol, 5.01 equivalents) was added dropwise to a stirred solution of 2-(imidazol-1-yl)-N-[(trans)-3-aminocyclobutyl]-5H,6H,7H-cyclopentadieno[d]pyrimidine-4-carboxamide (100 mg, 0.335 mmol, 1 equivalent) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (120 mg, 0.517 mmol, 1.54 equivalents) in ACN (3 mL). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Method 5) to give 2-(imidazol-1-yl)-N-[(trans)-3-[(2,2,2-trifluoroethyl)amino]cyclobutyl]-5H,6H,7H-cyclopentadieno[d]pyrimidine-4-carboxamide (42.4 mg, 33% yield) as a white solid. LCMS (ESI) [M+H + : 381.20. 1 H 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 = 1.2Hz, 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-difluoropyrrolidone-1-yl)cyclobutyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopentadien[d]pyrimidine-4-carboxamide (Compound 150) and N-((cis)-3-(3,3-difluoropyrrolidone-1-yl)cyclobutyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopentadien[d]pyrimidine-4-carboxamide (Compound 149)

[0240] A mixture of N-(3-oxocyclobutyl)carbamate (300 mg, 1.368 mmol, 1 equivalent), 3,3-difluoropyrrolidine (175.87 mg, 1.642 mmol, 1.2 equivalent), NaBH3CN (128.98 mg, 2.052 mmol, 1.5 equivalent), and AcOH (98.61 mg, 1.642 mmol, 1.2 equivalent) in DCM (3 mL) was stirred at room temperature for 3 h. The reaction was quenched at 0°C with saturated NH4Cl (aqueous solution). The aqueous layer was extracted with EtOAc. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give (3-(3,3-difluoropyrrolidine-1-yl)cyclobutyl)carbamate (300 mg, 71% yield) as a colorless oil.

[0241] At room temperature, in a pressure vessel, Pd / C (47.7 mg, 0.045 mmol, 0.1 equivalent, 10% purity) was added to a solution of (3-(3,3-difluoropyrrolidone-1-yl)cyclobutyl)carbamate (135 mg, 0.435 mmol, 1 equivalent) in MeOH (10 mL). The resulting mixture was stirred at 50°C under 30 psi hydrogen pressure for 16 h. The resulting mixture was filtered, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. This yielded 3-(3,3-difluoropyrrolidone-1-yl)cyclobut-1-amine (70 mg, 92% yield) as a white solid.

[0242] A mixture of 3-(3,3-difluoropyrrolidone-1-yl)cyclobut-1-amine (60 mg, 0.341 mmol, 1 equivalent), 2-(imidazol-1-yl)-5H,6H,7H-cyclopentadien[d]pyrimidine-4-carboxylic acid (78.39 mg, 0.341 mmol, 1 equivalent), NMI (83.87 mg, 1.023 mmol, 3 equivalents) and TCFH (191.08 mg, 0.682 mmol, 2 equivalents) in DMF (2.5 mL) was stirred at room temperature for 2 h. The residue was purified by reverse-phase (Method 7) to give N-((trans)-3-(3,3-difluoropyrrolidone-1-yl)cyclobutyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopentadien[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) δ9.22 - 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-difluoropyrrolidone-1-yl)cyclobutyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopentadien[d]pyrimidine-4-carboxamide (9.1 mg, 7% yield), which is a white solid. 1 H 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-furano[3,4-d]pyrimidine-4-carboxamide (compound 157)

[0243] A solution of malononitrile (1 g, 15.137 mmol, 1.45 equivalents) in THF (10 mL) was treated with NaH (750 mg, 60% purity) for 10 min at 0°C under a nitrogen atmosphere. 2,4-Dichloro-5H,7H-furano[3,4-d]pyrimidine (2 g, 10.471 mmol, 1 equivalent) was added partically to the mixture at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched at 0°C with NH4Cl (aqueous solution) (10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution of CH2Cl2 / MeOH (7:1) to give 2-{2-chloro-5H,7H-furano[3,4-d]pyrimidin-4-yl}malononitrile (1.8 g, 74% yield) as a yellow solid.

[0244] At room temperature, m-CPBA (3.53 g, 17.385 mmol, 2.13 equivalents, 85% purity) was added partically to a stirred solution of 2-{2-chloro-5H,7H-furano[3,4-d]pyrimidin-4-yl}malononitrile (1.8 g, 8.159 mmol, 1 equivalent) in MeOH (40 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched at room temperature by adding saturated Na₂S₂O₃ (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (5:1) elution to give methyl 2-chloro-5H,7H-furano[3,4-d]pyrimidine-4-carboxylate (1.2 g, 68% yield) as a yellow solid.

[0245] At room temperature, Cs₂CO₃ (5.47 g, 16.776 mmol, 3 equivalents) and t-BuBrettphos Pd G₃ (0.48 g, 0.559 mmol, 0.1 equivalents) and t-BuBrettphos (0.54 g, 1.118 mmol, 0.2 equivalents) were added in portions to a stirred solution of methyl 2-chloro-5H,7H-furano[3,4-d]pyrimidin-4-carboxylate (1.2 g, 5.592 mmol, 1 equivalent) and imidazole (0.76 g, 11.184 mmol, 2 equivalents) in dioxane (40 mL). The resulting mixture was stirred at 120°C under a nitrogen atmosphere for 2 h. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution of CH2Cl2 / MeOH (12:1) to give methyl 2-(imidazol-1-yl)-5H,7H-furano[3,4-d]pyrimidine-4-carboxylate (500 mg, 36% yield) as a yellow solid.

[0246] At room temperature, TBD (60 mg, 0.431 mmol, 2.12 equivalents) was added participle to a stirred solution of methyl 2-(imidazol-1-yl)-5H,7H-furano[3,4-d]pyrimidin-4-carboxylate (50 mg, 0.203 mmol, 1 equivalent) and (trans)-4-methoxycyclohexyl-1-amine (40 mg, 0.310 mmol, 1.52 equivalents) in 2 mL of THF. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Method 10) to give 2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]-5H,7H-furano[3,4-d]pyrimidin-4-carboxamide (22.3 mg, 32% yield) as a white solid. LCMS (ESI) [M+H] + 344.05. 1 H 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-dihydrofurano[3,4-d]pyrimidine-4-carboxamide (compound 153)

[0247] At room temperature, LiOH (160 mg, 6.681 mmol, 4.11 equivalents) was added to a stirred mixture of methyl 2-(imidazol-1-yl)-5H,7H-furano[3,4-d]pyrimidin-4-carboxylic acid (400 mg, 1.625 mmol, 1 equivalent) in THF (3 mL) and H2O (3 mL). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 2-(imidazol-1-yl)-5H,7H-furano[3,4-d]pyrimidin-4-carboxylic acid (300 mg, 80% yield) as a white solid.

[0248] At room temperature, NMI (55 mg, 0.215 mmol, 1 equivalent) and TCFH (120 mg, 0.430 mmol, 2.00 equivalent) were added partically to a stirred solution of 2-(imidazol-1-yl)-5H,7H-furano[3,4-d]pyrimidin-4-carboxylic acid (50 mg, 0.300 mmol, 1.40 equivalent) in ACN (3 mL). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 10) to give 2-(1H-imidazol-1-yl)-N-(trans-4-(trifluoromethyl)cyclohexyl)-5,7-dihydrofurano[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 = 1.4Hz, 1H), 7.18 (d, J = 1.2 Hz, 1H), 5.34 (d, J = 1.7 Hz, 2H), 5.04 (d, J = 1.5Hz, 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-difluoropyrrolidone-1-yl)cyclohexyl]-5H,7H-furano[3,4-d]pyrimidine-4-carboxamide (compound 156)

[0249] At room temperature, TBD (60 mg, 0.203 mmol, 1 equivalent) was added partically to a stirred mixture of methyl 2-(imidazol-1-yl)-5H,7H-furano[3,4-d]pyrimidin-4-carboxylate (50 mg, 0.203 mmol, 1 equivalent) and (trans)-4-(3,3-difluoropyrrolidone-1-yl)cyclohexyl-1-amine (80 mg, 0.392 mmol, 1.93 equivalent) in THF (3 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h.

[0250] The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Method 10) to give 2-(imidazol-1-yl)-N-[(trans)-4-(3,3-difluoropyrrolidone-1-yl)cyclohexyl]-5H,7H-furano[3,4-d]pyrimidine-4-carboxamide (16.6 mg, 19% yield) as a white solid. LCMS (ESI) [M+H] + :419.10. 1H NMR (400MHz, 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-difluoropyrrolidone-1-yl)cyclohexyl]-2-(1,3-thiazolyl-5-yl)-5H,7H-furano[3,4-d]pyrimidine-4-carboxamide (compound 155)

[0251] A mixture of methyl 2-chloro-5H,7H-furano[3,4-d]pyrimidin-4-carboxylate (300 mg, 1.398 mmol, 1 equivalent), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3-thiazole (295 mg, 1.398 mmol, 1 equivalent), Pd(dppf)Cl2 (102 mg, 0.140 mmol, 0.1 equivalent), and K2CO3 (580 mg, 4.194 mmol, 3 equivalent) in dioxane (10 mL) and H2O (2 mL) was stirred at 90°C under a nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 2) to give 2-(1,3-thiazolyl-5-yl)-5H,7H-furano[3,4-d]pyrimidine-4-carboxylic acid (100 mg, 28% yield) as a white solid.

[0252] A mixture of 2-(1,3-thiazolyl-5-yl)-5H,7H-furano[3,4-d]pyrimidin-4-carboxylic acid (40 mg, 0.160 mmol, 1 equivalent), (1r,4r)-4-(3,3-difluoropyrrolidine-1-yl)cyclohexyl-1-amine (32.78 mg, 0.160 mmol, 1 equivalent), TCFH (90.06 mg, 0.320 mmol, 2 equivalents) and NMI (39.53 mg, 0.480 mmol, 3 equivalents) in DMF (1.5 mL) was stirred at room temperature for 1 h. The solution was purified by preparative HPLC (Method 5) to give N-[(1r,4r)-4-(3,3-difluoropyrrolidone-1-yl)cyclohexyl]-2-(1,3-thiazolyl-5-yl)-5H,7H-furano[3,4-d]pyrimidine-4-carboxamide (24.3 mg, 34% yield) as a white solid. LCMS (ESI) [M+H] + : 436.05. 1 H 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-(thiazolyl-5-yl)-5,7-dihydrofurano[3,4-d]pyrimidine-4-carboxamide (compound 154)

[0253] A mixture of 2-(1,3-thiazolyl-5-yl)-5H,7H-furano[3,4-d]pyrimidine-4-carboxylic acid (40 mg, 0.160 mmol, 1 equivalent), (1r,4r)-4-methoxycyclohexyl-1-amine (21 mg, 0.160 mmol, 1 equivalent), TCFH (68 mg, 0.240 mmol, 1.5 equivalent), and NMI (66 mg, 0.800 mmol, 5 equivalent) in ACN (1 mL) was stirred at room temperature for 1 h. The mixture was purified by preparative HPLC (Method 5) to give N-((1r,4r)-4-methoxycyclohexyl)-2-(thiazolyl-5-yl)-5,7-dihydrofurano[3,4-d]pyrimidine-4-carboxamide (20.5 mg, 35% yield) as a white solid. LCMS(ESI) [M+H] + 361.05. 1 H 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-cyclopentadien[c]pyridine-3-carboxamide (compound 182)

[0254] At room temperature, trichloro-1,2,4-triazine (3 g, 16.269 mmol, 1 equivalent) and cyclopentene (1.11 g, 16.269 mmol, 1 equivalent) were added to a 30 mL sealed tube. The final reaction mixture was stirred at 70°C for 12 h. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 1,3-dichloro-5H,6H,7H-cyclopentadieno[c]pyridine (610 mg, 20% yield) as a brown oil.

[0255] A solution of 1,3-dichloro-5H,6H,7H-cyclopentadieno[c]pyridine (600 mg, 3.191 mmol, 1 equivalent), imidazole (434 mg, 6.382 mmol, 2 equivalents), and K₂CO₃ (1.32 g, 9.573 mmol, 3 equivalents) in DMF (10 mL) was stirred at 100°C under a nitrogen atmosphere for 24 h. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 1-{3-chloro-5H,6H,7H-cyclopentadieno[c]pyridine-1-yl}imidazolium (300 mg, 43% yield) as a light brown oil.

[0256] A mixture of 1-{3-chloro-5H,6H,7H-cyclopentadieno[c]pyridin-1-yl}imidazolium (290 mg, 1.320 mmol, 1 equivalent), zinc cyanide (310 mg, 2.640 mmol, 2 equivalents), and Pd(PPh3)4 (152 mg, 0.132 mmol, 0.1 equivalents) in DMF (5 mL) was stirred at 120°C under a nitrogen atmosphere for 16 h. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 1-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[c]pyridin-3-carboxynitrile (150 mg, 54% yield) as a brown oil.

[0257] A solution of 1-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[c]pyridine-3-carboxylonitrile (140 mg, 0.571 mmol, 1 equivalent) in 6 M HCl (aqueous solution) (1 mL) was stirred at 90°C under nitrogen atmosphere for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 1-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[c]pyridine-3-carboxylic acid (80 mg, 21% yield) as a yellow oil.

[0258] A solution of 1-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[c]pyridine-3-carboxylic acid (70 mg, 0.305 mmol, 1 equivalent), (trans)-4-methoxycyclohexyl-1-amine (78 mg, 0.610 mmol, 2 equivalents), TCFH (257 mg, 0.915 mmol, 3 equivalents), and NMI (75 mg, 0.915 mmol, 3 equivalents) in ACN (1 mL) was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 7) to give 1-(1H-imidazol-1-yl)-N-((trans)-4-methoxycyclohexyl)-6,7-dihydro-5H-cyclopentadieno[c]pyridine-3-carboxamide (16.5 mg, 16% yield) as a white solid. LCMS (ESI) [M+H] + : 341.20. 1 H 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-cyclopentadien[c]pyridine-1-carboxamide (compound 179)

[0259] A mixture of ethyl 1,2,4-triazine-3-carboxylate (1 g, 6.53 mmol, 1.0 equivalent), pyrrolidine (930 mg, 13.06 mmol, 2.0 equivalent), and cyclopentanone (1 g, 13.06 mmol, 2.0 equivalent) in toluene (20 mL) was stirred at 160°C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:1) elution to give ethyl 5H,6H,7H-cyclopentadien[c]pyridine-1-carboxylate (500 mg, 40% yield) as a yellow oil.

[0260] At room temperature, m-CPBA (722 mg, 4.18 mmol, 2.0 equivalent) was added participle to a mixture of ethyl 5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxylate (400 mg, 2.09 mmol, 1.0 equivalent) in DCM (5 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was quenched at 0°C by the addition of Na₂S₂O₃ (aqueous solution) and NaHCO₃ (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:1) elution to give 1-(ethoxycarbonyl)-5H,6H,7H-cyclopentadienyl[c]pyridine-2-onthium-2-ol salt (390 mg, 90% yield) as a pale yellow solid.

[0261] At 0°C, POCl3 (5 mL) was added dropwise to a mixture of 1-(ethoxycarbonyl)-5H,6H,7H-cyclopentadieno[c]pyridine-2-onthium-2-ol (310 mg, 1.50 mmol, 1.0 equivalent) in ACN (5 mL). The reaction was stirred at 80°C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (5:1) elution to give ethyl 3-chloro-5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxylate (200 mg, 59% yield) as a yellow solid.

[0262] At room temperature, imidazole (287 mg, 4.21 mmol, 5.0 equivalent) and K₂CO₃ (349 mg, 2.53 mmol, 3.0 equivalent) were added partically to a mixture of ethyl 3-chloro-5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxylate (190 mg, 0.84 mmol, 1.0 equivalent) in DMF (5 mL). The mixture was stirred at 120°C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The residue was purified by reversed-phase rapid chromatography (Method 1) to give ethyl 3-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxylate (120 mg, 55% yield) as a yellow solid.

[0263] At 0°C, LiOH (102 mg, 4.28 mmol, 10.0 equivalent) was added partically to a mixture of ethyl 3-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxylic acid (110 mg, 0.43 mmol, 1.0 equivalent) in THF (1.6 mL) and H₂O (0.4 mL). The mixture was stirred at room temperature for 1 h. The mixture was neutralized to pH 6 with 1 M HCl (aqueous solution). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 3-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxylic acid (80 mg, 82% yield) as a yellow solid.

[0264] A mixture of 3-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxylic acid (30 mg, 0.13 mmol, 1.0 equivalent), (trans)-4-amino-1-methylcyclohexyl-1-ol (25 mg, 0.20 mmol, 1.5 equivalent), TCFH (55 mg, 0.2 mmol, 1.5 equivalent), and NMI (32 mg, 0.39 mmol, 3.0 equivalent) in ACN (1 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 10) to give 3-(imidazol-1-yl)-N-[(trans)-4-hydroxy-4-methylcyclohexyl]-5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxamide (8.6 mg, 19% yield) as a pale yellow solid. LCMS (ESI) [M+H] + : 341.15. 1 H NMR (400MHz, 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-cyclopentadieno[c]pyridine-1-carboxamide (compound 181)

[0265] At room temperature, trichloro-1,2,4-triazine (5 g, 27.115 mmol, 1 equivalent) and cyclopentene (1.85 g, 27.115 mmol, 1 equivalent) were added to a 30 mL sealed tube. The final reaction mixture was stirred at 70°C for 12 h. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 1,3-dichloro-5H,6H,7H-cyclopentadieno[c]pyridine (1.8 g, 35% yield) as a brown oil.

[0266] A solution of 1,3-dichloro-5H,6H,7H-cyclopentadieno[c]pyridine (1.7 g, 9.040 mmol, 1 equivalent) and TBACN (3.64 g, 13.560 mmol, 1.5 equivalent) in DMF (50 mL) was stirred at 120°C for 12 h. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 3-chloro-5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxynitrile (200 mg, 12% yield) as a brown oil.

[0267] A solution of 3-chloro-5H,6H,7H-cyclopentadieno[c]pyridin-1-carboxylonitrile (120 mg, 0.672 mmol, 1 equivalent), imidazole (91 mg, 1.344 mmol, 2 equivalents), and K₂CO₃ (278 mg, 2.016 mmol, 3 equivalents) in DMF (1 mL) was stirred at 100°C under a nitrogen atmosphere for 4 h. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 3-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[c]pyridin-1-carboxylonitrile (50 mg, 35% yield) as a white solid.

[0268] A solution of 3-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[c]pyridin-1-carboxylonitrile (40 mg, 0.190 mmol, 1 equivalent) in HCl (aqueous solution) (1 mL, 6 N) was stirred at 90°C under a nitrogen atmosphere for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 3-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[c]pyridin-1-carboxylic acid (23 mg, 53% yield) as a white solid.

[0269] At room temperature, TCFH (56 mg, 0.198 mmol, 2 equivalents) and NMI (16 mg, 0.199 mmol, 2.00 equivalents) were added partically to a stirred mixture of [3-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[c]pyridin-1-yl]methyl glycol (23 mg, 0.099 mmol, 1 equivalent) and (trans)-4-methoxycyclohexyl-1-amine (19 mg, 0.149 mmol, 1.5 equivalents) in ACN (4 mL). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 8) to give 3-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]-5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxamide (3.5 mg, 10% yield) as a colorless oil. LCMS (ESI) [M+H] + : 341.19. 1 H 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-cyclopentadien[c]pyridine-1-carboxamide (compound 178)

[0270] At room temperature, (cis)-4-amino-1-methylcyclohexane-1-ol (68 mg, 0.52 mmol, 1.5 equivalent), TCFH (147 mg, 0.52 mmol, 1.5 equivalent), and NMI (86 mg, 1.05 mmol, 3.0 equivalent) were added partically to a stirred mixture of 3-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxylic acid (80 mg, 0.35 mmol, 1.0 equivalent) in 2 mL of ACN. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The resulting mixture was then concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 6) to give 3-(imidazol-1-yl)-N-[(cis)-4-hydroxy-4-methylcyclohexyl]-5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxamide (12.2 mg, 10% yield) as a white solid. LCMS (ESI) [M+H] + :341.10. 1 H 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-cyclopentadien[c]pyridine-1-carboxamide (compound 174)

[0271] At room temperature, cyclopentanone (0.82 g, 9.79 mmol, 1.5 equivalent) and pyrrolidine (0.70 g, 9.79 mmol, 1.5 equivalent) were added partically to a mixture of ethyl 1,2,4-triazine-3-carboxylate (1 g, 6.53 mmol, 1.0 equivalent) in toluene (25 mL). The resulting mixture was stirred at 160°C under a nitrogen atmosphere for 16 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (5:1) elution to give ethyl 5H,6H,7H-cyclopentadien[c]pyridine-1-carboxylate (600 mg, 48% yield) as a black oil.

[0272] At 0°C under a nitrogen atmosphere, m-CPBA (1.08 g, 6.28 mmol, 2.0 equivalent) was added partically to a mixture of 5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxylate (600 mg, 3.14 mmol, 1.0 equivalent) in DCM (5 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction was quenched at 0°C with saturated sodium thiosulfate (aqueous solution). The aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution of CH2Cl2 / MeOH (5:1) to give a yellow oil (160 mg, 74% yield).

[0273] At 0°C under a nitrogen atmosphere, POCl3 (4 mL) was added dropwise to a mixture of ethyl 2-hydroxy-5H,6H,7H-2λ4-cyclopentadieno[c]pyridine-1-carboxylate (350 mg, 1.68 mmol, 1.0 equivalent) in ACN (2 mL). The reaction was stirred at 80°C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool 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 × 100 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution of CH2Cl2 / MeOH (5:1) to give ethyl 3-chloro-5H,6H,7H-cyclopentadienyl[c]pyridine-1-carboxylate (230 mg, 61% yield) as a yellow solid.

[0274] A solution of ethyl 3-chloro-5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxylate (130 mg, 0.58 mmol, 1.0 equivalent), imidazole (78 mg, 1.15 mmol, 2.0 equivalent), and K₂CO₃ (398 mg, 2.88 mmol, 5.0 equivalent) in DMF (5 mL) was stirred at 120°C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The residue was purified by reversed-phase rapid chromatography (Method 1) to give ethyl 3-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxylate (85 mg, 57% yield) as a yellow solid.

[0275] At room temperature, LiOH (79 mg, 3.30 mmol, 10.0 equivalent) was added partically to a mixture of ethyl 3-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxylic acid (85 mg, 0.33 mmol, 1.0 equivalent) in THF (2 mL) and H₂O (2 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The mixture was neutralized to pH 6 with 1 M HCl (aqueous solution). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 3-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxylic acid (80 mg, 96% yield) as a pale yellow solid.

[0276] At room temperature, (trans)-4-amino-1-ethylcyclohexane-1-ol (presumably) (75 mg, 0.52 mmol, 1.5 equivalent), TCFH (147 mg, 0.523 mmol, 1.5 equivalent), and NMI (86 mg, 1.05 mmol, 3.0 equivalent) were added in portions to a mixture of 3-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxylic acid (80 mg, 0.35 mmol, 1.0 equivalent) in ACN (5 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The mixture was then concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 7) to give 3-(imidazol-1-yl)-N-[(trans)-4-ethyl-4-hydroxycyclohexyl]-5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxamide (34.4 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-cyclopentadien[c]pyridine-1-carboxamide (compound 172)

[0277] At 0°C under a nitrogen atmosphere, BnBr (11.28 g, 65.950 mmol, 2 equivalents) was added dropwise to a stirred solution of (trans)-4-aminocyclohexane-1-ol hydrochloride (5 g, 32.975 mmol, 1 equivalent) and Cs₂CO₃ (32.23 g, 98.925 mmol, 3 equivalents) in 50 mL of ACN. The mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The desired product was detectable by LC-MS. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give (trans)-4-(dibenzylamino)cyclohexane-1-ol (8 g, 82% yield) as a white solid.

[0278] A solution of (trans)-4-(dibenzylamino)cyclohexyl-1-ol (5 g, 16.925 mmol, 1 equivalent) in THF (100 mL) was treated with NaH (1.35 g, 33.850 mmol, 2 equivalent, 60% purity) for 20 min at 0°C under a nitrogen atmosphere. CD3I (4.91 g, 33.850 mmol, 2 equivalent) was added dropwise to the above mixture at 0°C under a nitrogen atmosphere. The mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The desired product was detected by LCMS. The reaction was quenched at 0°C with saturated NH4Cl (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:1) elution to give (trans)-N,N-dibenzyl-4-(methoxy-d3)cyclohexyl-1-amine (3.3 g, 62% yield) as a white solid.

[0279] A mixture of (trans)-N,N-dibenzyl-4-(methoxy-d3)cyclohexyl-1-amine (1.5 g, 4.800 mmol, 1 equivalent) and Pd(OH)2 / C (336 mg, 0.480 mmol, 0.1 equivalent, 20% purity) in MeOH (40 mL) was stirred at room temperature under a hydrogen atmosphere for 5 h. The desired product was detectable by LC-MS. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:1) elution to give (trans)-4-(methoxy-d3)cyclohexyl-1-amine (400 mg, 63% yield) as a white oil.

[0280] A mixture of (trans)-4-(methoxy-d3)cyclohexyl-1-amine (70 mg, 0.529 mmol, 1 equivalent), 3-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxylic acid (121 mg, 0.529 mmol, 1 equivalent), TCFH (445 mg, 1.587 mmol, 3 equivalent), and NMI (260 mg, 3.174 mmol, 6.00 equivalent) in ACN (2 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The desired product could be detected by LCMS. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Method 5) to give 3-(1H-imidazol-1-yl)-N-((trans)-4-(methoxy-d3)cyclohexyl)-6,7-dihydro-5H-cyclopentadieno[c]pyridine-1-carboxamide (38.4 mg, 21% yield) as a white solid. LCMS (ESI) [M+H] + : 344.20. 1 H 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-cyclopentadien[c]pyridine-1-carboxamide (compound 170)

[0281] A mixture of (trans)-4-methoxy-4-methylcyclohexyl-1-amine (75 mg, 0.524 mmol, 1 equivalent), 3-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxylic acid (180 mg, 0.786 mmol, 1.5 equivalent), TCFH (440 mg, 1.572 mmol, 3 equivalent), and NMI (129 mg, 1.572 mmol, 3 equivalent) in ACN (5 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was subjected to preparative HPLC (column: Kinetex EVO C18 column, 30 mL). Purification was performed using mobile phases A (10 mmol / L NH4HCO3) and B (ACN); flow rate: 60 mL / min; wavelength: 254 nm / 220 nm) to obtain 3-(1H-imidazol-1-yl)-N-((trans)-4-methoxy-4-methylcyclohexyl)-6,7-dihydro-5H-cyclopentadieno[c]pyridine-1-carboxamide (25.8 mg, 14% yield) as a pale yellow solid. LCMS (ESI) [M+H] + 355.20. 1 H 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-difluoropyrrolidone-1-yl)cyclohexyl)-3-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopentadien[c]pyridine-1-carboxamide (compound 161)

[0282] At room temperature, cyclopentanone (0.82 g, 9.795 mmol, 1.5 equivalent) and pyrrolidine (0.70 g, 9.795 mmol, 1.5 equivalent) were added to a mixture of ethyl 1,2,4-triazine-3-carboxylate (1 g, 6.530 mmol, 1 equivalent) in toluene (25 mL). The resulting mixture was stirred at 150°C for 16 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (5:1) elution to give ethyl 5H,6H,7H-cyclopentadienyl[c]pyridine-1-carboxylate (600 mg, 48% yield) as a black oil.

[0283] At room temperature, m-CPBA (1.06 g, 5.216 mmol, 1.99 equivalent, 85% purity) was added to a stirred solution of 5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxylic acid ethyl ester (500 mg, 2.615 mmol, 1 equivalent) in DCM (15 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched at room temperature with saturated NaHCO3 (aqueous solution) (15 mL) and Na2S2O3 (aqueous solution) (15 mL). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with NaHCO3 and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:1) elution to give 1-(ethoxycarbonyl)-5H,6H,7H-2λ4-cyclopentadienyl[c]pyridine-2-ol salt as a white solid (360 mg, 66% yield).

[0284] POCl3 (520 mg, 3.392 mmol, 2.01 equivalents) was added to a stirred solution of 1-(ethoxycarbonyl)-5H,6H,7H-2λ4-cyclopentadieno[c]pyridine-2-ol (350 mg, 1.689 mmol, 1 equivalent) in DCM (10 mL) under a nitrogen atmosphere. The resulting mixture was stirred at 80°C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography with PE / EA (1:2) elution to give ethyl 3-chloro-5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxylate (230 mg, 60% yield) as a yellow solid.

[0285] At room temperature, t-BuBrettphos Pd G3 (80 mg, 0.094 mmol, 0.10 equivalent), t-BuBrettphos (90 mg, 0.186 mmol, 0.20 equivalent), and Cs2CO3 (910 mg, 2.793 mmol, 3.00 equivalent) were added partically to a stirred solution of 3-chloro-5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxylic acid ethyl ester (210 mg, 0.931 mmol, 1 equivalent) and imidazole (130 mg, 1.910 mmol, 2.05 equivalent) in dioxane (10 mL). The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 1 h. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:10) elution to give ethyl 3-(imidazol-1-yl)-5H,6H,7H-cyclopentadienyl[c]pyridine-1-carboxylate (200 mg, 83% yield) as a brown solid.

[0286] At room temperature, LiOH (28 mg, 1.169 mmol, 3.01 equivalents) was added to a stirred solution of ethyl 3-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxylic acid (100 mg, 0.389 mmol, 1 equivalent) in THF (1 mL) and H2O (1 mL). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 3-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxylic acid (60 mg, 67% yield) as a white solid.

[0287] At room temperature, TCFH (140 mg, 0.499 mmol, 1 equivalent) and NMI (65 mg, 0.792 mmol, 3.02 equivalent) were added partically to a stirred solution of 3-(imidazol-1-yl)-5H,6H,7H-cyclopentadieno[c]pyridine-1-carboxylic acid (60 mg, 0.262 mmol, 1 equivalent) and (trans)-4-(3,3-difluoropyrrolidone-1-yl)cyclohexyl-1-amine (80 mg, 0.392 mmol, 1.50 equivalent) in ACN (5 mL). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 8) to give N-((trans)-4-(3,3-difluoropyrrolidone-1-yl)cyclohexyl)-3-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopentadien[c]pyridine-1-carboxamide (45.6 mg, 41% yield) as a white solid. LCMS (ESI) [M+H]+ : 416.20. 1 H NMR (400 MHz, DMSO-d6) δ8.84 (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)quinazolin-4-carboxamide (compound 186)

[0288] A solution of malononitrile (1.78 g, 26.985 mmol, 1.5 equivalents) in THF (100 mL) was treated with NaH (1.22 g, 30.583 mmol, 1.7 equivalents, 60% purity) at 0°C under a nitrogen atmosphere for 30 min. 8-Bromo-2,4-dichloroquinazoline (5 g, 17.990 mmol, 1 equivalent) was added partically to the mixture at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction was quenched with NH4Cl (aqueous solution) at 0°C. The resulting mixture was extracted with EtOAc (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:1) elution to give 2-(8-bromo-2-chloroquinazoline-4-yl)malononitrile (3.8 g, 69% yield) as a yellow solid.

[0289] At 0°C under a nitrogen atmosphere, m-CPBA (4.26 g, 24.712 mmol, 2 equivalents) was added partically to a stirred solution of 2-(8-bromo-2-chloroquinazoline-4-yl)malononitrile (3.8 g, 12.356 mmol, 1 equivalent) in MeOH (100 mL). The resulting mixture was stirred at 0°C under a nitrogen atmosphere for 1 h. The reaction was quenched at 0°C with saturated Na₂S₂O₃ (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:1) elution to give methyl 8-bromo-2-chloroquinazoline-4-carboxylate (2.5 g, 67% yield) as a white solid.

[0290] A mixture of methyl 8-bromo-2-chloroquinazoline-4-carboxylate (1 g, 3.317 mmol, 1 equivalent), K₂CO₃ (1.38 g, 9.951 mmol, 3 equivalents), and imidazole (450 mg, 6.634 mmol, 2 equivalents) in DMF (20 mL) was stirred at 100°C under a nitrogen atmosphere for 6 h. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 8-bromo-2-(imidazol-1-yl)quinazoline-4-carboxylic acid (720 mg, 68% yield) as a brown solid.

[0291] At 0°C, DIEA (425 mg, 3.291 mmol, 1 equivalent) and HATU (834 mg, 2.194 mmol, 2 equivalent) were added partically to a stirred mixture of 8-bromo-2-(imidazol-1-yl)quinazolin-4-carboxylic acid (350 mg, 1.097 mmol, 1 equivalent) and (trans)-4-methoxycyclohexyl-1-amine (283 mg, 2.194 mmol, 2 equivalent) in 10 mL of DMF. The resulting mixture was stirred at room temperature for 1 h. The mixture was diluted with water. The resulting mixture was extracted with EtOAc (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 8-bromo-2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]quinazolin-4-carboxamide (200 mg, 42% yield) as a brown solid.

[0292] A mixture of 8-bromo-2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]quinazolin-4-carboxamide (190 mg, 0.442 mmol, 1 equivalent), tert-butyl carbamate (103 mg, 0.884 mmol, 2 equivalents), Xantphos (51 mg, 0.088 mmol, 0.2 equivalents), Pd2(dba)3 (40 mg, 0.044 mmol, 0.1 equivalents), and K2CO3 (183 mg, 1.326 mmol, 3 equivalents) in dioxane (2 mL) was stirred at 120°C under a nitrogen atmosphere for 1 h. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give N-[2-(imidazol-1-yl)-4-{[(trans)-4-methoxycyclohexyl]carbamoyl}quinazolin-8-yl] tert-butyl carbamate (150 mg, 73% yield) as a yellow solid.

[0293] A solution of N-[2-(imidazol-1-yl)-4-{[(trans)-4-methoxycyclohexyl]carbamoyl}quinazolin-8-yl]tert-butyl carbamate (140 mg, 0.300 mmol, 1 equivalent) in HCl / 1,4-dioxane (10 mL, 4 M) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 6) to give 8-amino-2-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]quinazolin-4-carboxamide (13.6 mg, 12% yield) as an orange solid. LCMS (ESI) [M+H] + 367.15. 1 H 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-hydroxypropyl-2-yl)cyclohexyl]quinazolin-4-carboxamide (compound 190)

[0294] A mixture of 8-bromo-2-(imidazol-1-yl)quinazolin-4-carboxylic acid (300 mg, 0.940 mmol, 1 equivalent), 2-[(trans)-4-aminocyclohexyl]prop-2-ol (177 mg, 1.128 mmol, 1.2 equivalent), TCFH (791 mg, 2.820 mmol, 3 equivalent), and NMI (463 mg, 5.640 mmol, 6 equivalent) in ACN (10 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The desired product was detectable by LCMS. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 8-bromo-2-(imidazol-1-yl)-N-[(trans)-4-(2-hydroxypropyl-2-yl)cyclohexyl]quinazolin-4-carboxamide (240 mg, 56% yield) as a white solid.

[0295] A mixture of 8-bromo-2-(imidazol-1-yl)-N-[(trans)-4-(2-hydroxypropyl-2-yl)cyclohexyl]quinazoline-4-carboxamide (200 mg, 0.436 mmol, 1 equivalent), cuprous cyanide (78 mg, 0.872 mmol, 2 equivalents), and Pd(PPh3)2Cl2 (61 mg, 0.087 mmol, 0.2 equivalents) in DMSO (10 mL) was stirred at 140°C under a nitrogen atmosphere for 10 h. The desired product was detectable by LCMS. The residue was purified by preparative HPLC (Method 6) to give 8-cyano-2-(imidazol-1-yl)-N-[(trans)-4-(2-hydroxypropyl-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)

[0296] A solution of malononitrile (4.77 g, 72.218 mmol, 2 equivalents) in THF (150 mL) was treated with NaH (2.88 g, 72.218 mmol, 2 equivalents, 60% purity) at 0°C under a nitrogen atmosphere for 30 min. 5-Bromo-1,3-dichloroisoquinoline (10 g, 36.109 mmol, 1 equivalent) was added partically to the mixture at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The desired product was detected by LCMS. The reaction was quenched at 0°C with saturated NH4Cl (aqueous solution). The aqueous layer was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:1) elution to give 2-(5-bromo-3-chloroisoquinoline-1-yl)malononitrile (11 g, 99% yield) as a yellow solid.

[0297] A solution of 2-(5-bromo-3-chloroisoquinoline-1-yl)malononitrile (11 g, 35.883 mmol, 1 equivalent) in MeOH (150 mL) was treated with m-CPBA (12.38 g, 71.766 mmol, 2 equivalents) at 0°C under a nitrogen atmosphere for 1 h. The desired product was detectable by LC-MS. The reaction was quenched at 0°C with saturated Na₂S₂O₃ (aqueous solution). The aqueous layer was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:1) elution to give methyl 5-bromo-3-chloroisoquinoline-1-carboxylate (9 g, 83% yield) as a white solid.

[0298] A solution of methyl 5-bromo-3-chloroisoquinoline-1-carboxylate (5 g, 16.637 mmol, 1 equivalent) and CuCN (2.98 g, 33.274 mmol, 2 equivalents) in DMSO (60 mL) was stirred at 150°C under a nitrogen atmosphere for 16 h. The desired product was detectable by LCMS. The residue was purified by reversed-phase rapid chromatography (Method 1) to give methyl 3-chloro-5-cyanoisoquinoline-1-carboxylate (2 g, 49% yield) as a yellow solid.

[0299] At 0°C, LiOH (800 mg, 33.275 mmol, 5 equivalents) was added partically to a stirred solution of methyl 5-bromo-3-chloroisoquinoline-1-carboxylate (2 g, 6.655 mmol, 1 equivalent) in THF (10 mL) and H₂O (10 mL). The reaction was stirred at room temperature for 1 h. The desired product was detected by LCMS. The mixture was neutralized to pH 6 with 1 M HCl (aqueous solution). The resulting mixture was concentrated under reduced pressure. This yielded 3-chloro-5-cyanoisoquinoline-1-carboxylic acid (1.5 g, 97% yield) as a white solid.

[0300] At room temperature, DIEA (2.08 g, 16.120 mmol, 5 equivalents) and HATU (1.84 g, 4.836 mmol, 1.5 equivalents) were added participle to a stirred solution of bis(3-chloro-5-cyanoisoquinoline-1-carboxylic acid) (1.5 g, 3.224 mmol, 1 equivalent) and (trans)-4-methoxycyclohexyl-1-amine (500 mg, 3.869 mmol, 1.2 equivalents) in DMF (20 mL). The reaction was stirred at room temperature under a nitrogen atmosphere for 1 h. The desired product was detected by LCMS. The residue was purified by reversed-phase rapid chromatography (Method 1) to give bis(3-chloro-5-cyano-N-[(trans)-4-methoxycyclohexyl]isoquinoline-1-carboxamide) (700 mg, 32% yield) as a white solid.

[0301] A solution of 3-chloro-5-cyano-N-[(trans)-4-methoxycyclohexyl]isoquinoline-1-carboxamide (700 mg, 2.036 mmol, 1 equivalent), imidazole (693 mg, 10.180 mmol, 5 equivalent), t-BuBrettphos (197 mg, 0.407 mmol, 0.2 equivalent), Cs₂CO₃ (2 g, 6.138 mmol, 3.01 equivalent), and t-BuBrettPhos Pd G₃ (173 mg, 0.204 mmol, 0.1 equivalent) in dioxane (15 mL) was stirred at 120°C under a nitrogen atmosphere for 1 h. The desired product was detected by LC-MS. The residue was purified by preparative HPLC (Method 9) to give 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. 1 H 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)

[0302] A mixture of methyl 3-chloro-5-cyanoisoquinoline-1-carboxylate (115 mg, 0.466 mmol, 1 equivalent), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)imidazolium (116 mg, 0.559 mmol, 1.2 equivalent), K₂CO₃ (193 mg, 1.398 mmol, 3 equivalent), and Pd(dppf)Cl₂ (68 mg, 0.093 mmol, 0.2 equivalent) in dioxane (6 mL) and H₂O (2 mL) was stirred at 90°C under a nitrogen atmosphere for 2 h. The desired product was detected by LCMS. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 5-cyano-3-(3-methylimidazol-4-yl)isoquinoline-1-carboxylic acid (90 mg, 69% yield) as a brown solid.

[0303] A mixture of 5-cyano-3-(3-methylimidazol-4-yl)isoquinoline-1-carboxylic acid (115 mg, 0.413 mmol, 1 equivalent), (trans)-4-methoxycyclohexyl-1-amine (64 mg, 0.496 mmol, 1.2 equivalent), TCFH (347 mg, 1.239 mmol, 3 equivalent), and NMI (203 mg, 2.478 mmol, 6 equivalent) in ACN (10 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The desired product was detectable by LCMS. The residue was purified by preparative HPLC (Method 7) to give 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)

[0304] A solution of methyl isoquinoline-1-carboxylate (2 g, 10.684 mmol, 1 equivalent) and mCPBA (2.7 g, 16.026 mmol, 1.5 equivalent) in DCM (20 mL) was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was quenched with Na₂S₂O₃ (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:2) elution to give 1-(methoxycarbonyl)isoquinoline-2-onthium-2-ol (1.8 g, 83% yield) as a yellow oil.

[0305] A mixture of 1-(methoxycarbonyl)isoquinoline-2-onthium-2-ol (1.8 g, 8.858 mmol, 1 equivalent) in POCl3 (10 mL) was stirred at 80°C under nitrogen atmosphere for 2 h. 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 × 200 mL). The residue was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:1) elution to give methyl 3-chloroisoquinoline-1-carboxylate (1.5 g, 76% yield) as a yellow solid.

[0306] A mixture of methyl 3-chloroisoquinoline-1-carboxylate (1.5 g, 6.768 mmol, 1 equivalent), K₂CO₃ (2.8 g, 20.304 mmol, 3 equivalents), CuI (2.6 g, 13.536 mmol, 2 equivalents), and imidazole (0.7 g, 10.152 mmol, 1.5 equivalents) in DMF (5 mL) was stirred at 100°C under a nitrogen atmosphere for 2 h. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 3-(imidazol-1-yl)isoquinoline-1-carboxylic acid (950 mg, 59% yield) as a yellow solid.

[0307] A solution of 3-(imidazol-1-yl)isoquinoline-1-carboxylic acid (160 mg, 0.669 mmol, 1 equivalent), (trans)-4-methoxycyclohexyl-1-amine (130 mg, 1.004 mmol, 1.5 equivalent), TCFH (563 mg, 2.007 mmol, 3 equivalent), and NMI (83 mg, 2.007 mmol, 3 equivalent) in ACN (2 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 7) to give 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. 1 H 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)

[0308] A solution of (trans)-4-amino-1-methylcyclohexane-1-ol (500 mg, 3.870 mmol, 1 equivalent), benzyl bromide (1.38 g, 8.127 mmol, 2.1 equivalent), and K₂CO₃ (1.6 g, 11.610 mmol, 3 equivalent) in DMF (15 mL) was stirred at 70°C under nitrogen atmosphere for 1 h. The mixture was diluted with water. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (3:1) elution to give (trans)-4-(dibenzylamino)-1-methylcyclohexane-1-ol (750 mg, 63% yield) as a yellow solid.

[0309] At 0°C under a nitrogen atmosphere, NaH (291 mg, 7.272 mmol, 3 equivalents, 60% purity) was added partically to a stirred mixture of (trans)-4-(dibenzylamino)-1-methylcyclohexane-1-ol (750 mg, 2.424 mmol, 1 equivalent) in THF (10 mL). The mixture was stirred at 0°C under a nitrogen atmosphere for 30 min. At 0°C under a nitrogen atmosphere, CH3I (688 mg, 4.848 mmol, 2 equivalents) was added dropwise to the above mixture. The resulting mixture was stirred at room temperature for another 2 h. The reaction was quenched at 0°C with saturated NH4Cl (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:1) elution to give (trans)-N,N-dibenzyl-4-methoxy-4-methylcyclohexyl-1-amine (650 mg, 83% yield) as a white solid.

[0310] A solution of (trans)-N,N-dibenzyl-4-methoxy-4-methylcyclohexyl-1-amine (650 mg, 2.009 mmol, 1 equivalent) and Pd(OH)₂ / C (28 mg, 0.020 mmol, 0.01 equivalent, 10% purity) in MeOH (10 mL) was stirred for 12 h at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. This yielded (trans)-4-methoxy-4-methylcyclohexyl-1-amine (200 mg, 70% yield) as a dark oil.

[0311] A solution of (trans)-4-methoxy-4-methylcyclohexyl-1-amine (200 mg, 1.396 mmol, 1 equivalent), 3-chloro-5-cyanoisoquinoline-1-carboxylic acid (487 mg, 2.094 mmol, 1.5 equivalent), DIEA (541 mg, 4.188 mmol, 3 equivalent), and HATU (1.6 g, 4.188 mmol, 3 equivalent) in DMF (5 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 3-chloro-5-cyano-N-[(trans)-4-methoxy-4-methylcyclohexyl]isoquinoline-1-carboxamide (270 mg, 54% yield) as a white solid.

[0312] A solution of 3-chloro-5-cyano-N-[(trans)-4-methoxy-4-methylcyclohexyl]isoquinoline-1-carboxamide (270 mg, 0.755 mmol, 1 equivalent), imidazole (102 mg, 1.510 mmol, 2 equivalents), t-BuBrettPhos (73 mg, 0.151 mmol, 0.2 equivalents), t-BuBrettPhos Pd G3 (64 mg, 0.076 mmol, 0.1 equivalents), and Cs₂CO₃ (738 mg, 2.265 mmol, 3 equivalents) in dioxane (10 mL) was stirred at 120°C under a nitrogen atmosphere for 1 h. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 7) to give 5-cyano-3-(1H-imidazol-1-yl)-N-((trans)-4-methoxy-4-methylcyclohexyl)isoquinoline-1-carboxamide (139 mg, 46% yield) as a pale yellow solid. LCMS (ESI) [M+H + : 390.10. 1 H 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)

[0313] A solution of 3-(imidazol-1-yl)isoquinoline-1-carboxylic acid (200 mg, 0.836 mmol, 1 equivalent), (trans)-4-amino-1-ethylcyclohexyl-1-ol (hypothetically) (179 mg, 1.254 mmol, 1.5 equivalent), TCFH (703 mg, 2.508 mmol, 3 equivalent), and NMI (205 mg, 2.508 mmol, 3 equivalent) in ACN (10 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 6) to give 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. 1 H 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]hept-2-yl}isoquinoline-1-carboxamide (compound 169)

[0314] At 0°C under a nitrogen atmosphere, BnBr (789 mg, 4.61 mmol, 1.5 equivalent) was added dropwise to a mixture of {6-hydroxyspiro[3.3]hepta-2-yl}amine hydrochloride (500 mg, 3.07 mmol, 1.0 equivalent) and Cs₂CO₃ (3 g, 9.22 mmol, 3.0 equivalent) in 20 mL of ACN. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (10:1) elution to give 6-(dibenzylamino)spiro[3.3]hepta-2-ol (680 mg, 72% yield) as a colorless oil.

[0315] At 0°C under a nitrogen atmosphere, NaH (129 mg, 3.225 mmol, 1.5 equivalent, 60% purity) was added partically to a mixture of 6-(dibenzylamino)spiro[3.3]hepta-2-ol (660 mg, 2.15 mmol, 1.0 equivalent) in THF (20 mL). The mixture was stirred at 0°C under a nitrogen atmosphere for 30 min. Iodomethane (914 mg, 6.44 mmol, 3.0 equivalent) was added dropwise to the above mixture at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 0°C under a nitrogen atmosphere for 2 h. The reaction was quenched at 0°C with NH4Cl (aqueous solution). The aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:1) elution to obtain N,N-dibenzyl-6-methoxyspiro[3.3]hept-2-amine (610 mg, 88% yield) as a colorless oil.

[0316] At room temperature, Pd(OH)₂ / C (198 mg, 0.187 mmol, 0.1 equivalent, 10% purity) was added partically to a mixture of N,N-dibenzyl-6-methoxyspiro[3.3]hepta-2-amine (600 mg, 1.87 mmol, 1.0 equivalent) in MeOH (10 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 12 h. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. This yielded 6-methoxyspiro[3.3]hepta-2-amine (160 mg, 61% yield) as a pale yellow oil.

[0317] At room temperature, 6-methoxyspiro[3.3]hept-2-amine (118 mg, 0.84 mmol, 1.5 equivalent), TCFH (235 mg, 0.84 mmol, 1.5 equivalent), and NMI (138 mg, 1.68 mmol, 3.0 equivalent) were added partically to a mixture of 3-chloro-5-cyanoisoquinoline-1-carboxylic acid (150 mg, 0.56 mmol, 1.0 equivalent) in ACN (5 mL). The resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 3-chloro-5-cyano-N-{6-methoxyspiro[3.3]hept-2-yl}isoquinoline-1-carboxamide (120 mg, 60% yield) as a yellow solid.

[0318] A solution of 3-chloro-5-cyano-N-{6-methoxyspiro[3.3]hept-2-yl}isoquinoline-1-carboxamide (110 mg, 0.31 mmol, 1.0 equivalent), imidazole (32 mg, 0.46 mmol, 1.5 equivalent), t-BuBrettphos (30 mg, 0.06 mmol, 0.2 equivalent), t-BuBrettPhos Pd G3 (26 mg, 0.03 mmol, 0.1 equivalent), and Cs2CO3 (302 mg, 0.93 mmol, 3.0 equivalent) in dioxane (4 mL) was stirred at 120°C under a nitrogen atmosphere for 1 h. The mixture was allowed to cool to room temperature. The mixture was then concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 9) to give 5-cyano-3-(imidazol-1-yl)-N-{6-methoxyspiro[3.3]hept-2-yl}isoquinoline-1-carboxamide (40.8 mg, 34% yield) as a white solid. LCMS (ESI) [M+H + 388.15. 1 H 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)

[0319] A mixture of methyl 5-bromo-3-chloroisoquinoline-1-carboxylate (700 mg, 2.329 mmol, 1 equivalent), B(OH)₂ (1.49 g, 11.645 mmol, 5 equivalents), Pd(OAc)₂ (261 mg, 1.165 mmol, 0.5 equivalents), t-BuBrettPhos (225 mg, 0.466 mmol, 0.2 equivalents), and Cs₂CO₃ (2.28 g, 6.987 mmol, 3 equivalents) in NMP (10 mL) was stirred at 80°C under a nitrogen atmosphere for 16 h. The mixture was diluted with water. The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give methyl 3-chloro-5-hydroxyisoquinoline-1-carboxylate (280 mg, 51% yield) as a brown solid.

[0320] At 0°C under a nitrogen atmosphere, NaH (91 mg, 2.272 mmol, 2 equivalents, 60% purity) was added partically to a stirred solution of methyl 3-chloro-5-hydroxyisoquinoline-1-carboxylate (270 mg, 1.136 mmol, 1 equivalent) in THF (10 mL). The mixture was stirred at 0°C under a nitrogen atmosphere for 30 min. At 0°C under a nitrogen atmosphere, CH3I (322 mg, 2.272 mmol, 2 equivalents) was added dropwise to the above mixture. The resulting mixture was stirred at room temperature for another 1 h. The reaction was quenched at 0°C with saturated NH4Cl (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (2:1) elution to give methyl 3-chloro-5-methoxyisoquinoline-1-carboxylate (150 mg, 52% yield) as a yellow oil.

[0321] At 0°C, LiOH (40 mg, 1.668 mmol, 3 equivalents) was added dropwise to a stirred solution of methyl 3-chloro-5-methoxyisoquinoline-1-carboxylic acid (140 mg, 0.556 mmol, 1 equivalent) in THF (3 mL) in H₂O (3 mL). The mixture was stirred at room temperature for 1 h. The mixture was acidified to pH 5 with 1 M HCl (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give 3-chloro-5-methoxyisoquinoline-1-carboxylic acid (100 mg, 76% yield) as a yellow solid.

[0322] A solution of 3-chloro-5-methoxyisoquinoline-1-carboxylic acid (90 mg, 0.379 mmol, 1 equivalent), (trans)-4-methoxycyclohexyl-1-amine (73 mg, 0.569 mmol, 1.5 equivalent), DIEA (147 mg, 1.137 mmol, 3 equivalent), and HATU (432 mg, 1.137 mmol, 3 equivalent) in DMF (3 mL) was stirred at room temperature under a nitrogen atmosphere for 1 h. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 3-chloro-5-methoxy-N-[(trans)-4-methoxycyclohexyl]isoquinoline-1-carboxamide (60 mg, 45% yield) as a brown solid.

[0323] A solution of 3-chloro-5-methoxy-N-[(trans)-4-methoxycyclohexyl]isoquinoline-1-carboxamide (50 mg, 0.143 mmol, 1 equivalent), imidazole (20 mg, 0.286 mmol, 2 equivalents), t-BuBrettPhos (14 mg, 0.029 mmol, 0.2 equivalents), t-BuBrettPhos Pd G3 (12 mg, 0.014 mmol, 0.1 equivalents), and Cs₂CO₃ (140 mg, 0.429 mmol, 3 equivalents) in dioxane (5 mL) was stirred at 120°C under a nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 7) to give 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)

[0324] At room temperature, TCFH (220 mg, 0.430 mmol, 1 equivalent) and NMI (150 mg, 1.82 mmol, 4.25 equivalent) were added participle to a stirred solution of 3-chloro-5-cyanoisoquinoline-1-carboxylic acid (200 mg, 0.430 mmol, 1 equivalent) and (trans)-3-methoxycyclobutyl-1-amine (60 mg, 0.593 mmol, 1.38 equivalent) in ACN (5 mL). The resulting mixture was stirred at room temperature for 30 min. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution of CH2Cl2 / MeOH (12:1) to give 3-chloro-5-cyano-N-((trans)-3-methoxycyclobutyl)isoquinoline-1-carboxamide (180 mg, 66% yield) as a yellow solid.

[0325] A solution of 3-chloro-5-cyano-N-[(trans)-3-methoxycyclobutyl]isoquinoline-1-carboxamide (50 mg, 0.158 mmol, 1 equivalent), t-BuBrettphos Pd G3 (13 mg, 0.015 mmol, 0.1 equivalent), t-BuBrettphos (15 mg, 0.032 mmol, 0.2 equivalent), Cs2CO3 (150 mg, 0.460 mmol, 2.91 equivalent), and imidazole (25 mg, 0.367 mmol, 2.32 equivalent) in dioxane (3 mL) was stirred at 120°C under a nitrogen atmosphere for 30 min. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 7) to give 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. 1 H 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-difluoropyrrolidone-1-yl)cyclohexyl]isoquinoline-1-carboxamide (compound 165)

[0326] A solution of (trans)-4-(3,3-difluoropyrrolidone-1-yl)cyclohexyl-1-amine (50 mg, 0.245 mmol, 1 equivalent), 5-cyano-3-(imidazol-1-yl)isoquinoline-1-carboxylic acid (71 mg, 0.270 mmol, 1.1 equivalent), TCFH (137 mg, 0.490 mmol, 2 equivalent), and NMI (100 mg, 1.225 mmol, 5 equivalent) in ACN (2 mL) was stirred at room temperature under air for 1 h. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 5) to give 5-cyano-3-(imidazol-1-yl)-N-[(trans)-4-(3,3-difluoropyrrolidone-1-yl)cyclohexyl]isoquinoline-1-carboxamide (12.3 mg, 11% yield) as a white solid. LCMS (ESI) [M+H] + :451.20. 1 H NMR (400 MHz, DMSO-d6) δ9.13 (dt, J = 8.7, 1.1 Hz, 1H), 8.95 - 8.79 (m, 2H), 8.52 (dd, J = 7.2, 1.2Hz, 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 = 6.9Hz, 2H), 2.32 - 2.06 (m, 3H), 1.97 (d, J = 11.2 Hz, 4H), 1.49 (q, J = 11.9Hz, 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)

[0327] A mixture of 3-chloro-5-cyanoisoquinoline-1-carboxylic acid (300 mg, 1.290 mmol, 1 equivalent), N-[(trans)-4-aminocyclohexyl]carbamate tert-butyl ester (331 mg, 1.548 mmol, 1.2 equivalent), TCFH (1.085 g, 3.870 mmol, 3 equivalent), and NMI (317 mg, 3.870 mmol, 3 equivalent) in ACN (10 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give N-[(trans)-4-(3-chloro-5-cyanoisoquinoline-1-amido)cyclohexyl]carbamate tert-butyl ester (220 mg, 40% yield) as a yellow solid.

[0328] A mixture of N-[(trans)-4-(3-chloro-5-cyanoisoquinoline-1-amido)cyclohexyl]carbamate tert-butyl ester (210 mg, 0.490 mmol, 1 equivalent), imidazole (40 mg, 0.588 mmol, 1.2 equivalent), t-BuBrettPhos (23 mg, 0.049 mmol, 0.1 equivalent), t-BuBrettPhos Pd G3 (83 mg, 0.098 mmol, 0.2 equivalent), and Cs₂CO₃ (478 mg, 1.470 mmol, 3 equivalent) in 1,4-dioxane (7 mL) was stirred at 120°C under nitrogen atmosphere for 1 h. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:3) elution to give N-[(trans)-4-[5-cyano-3-(imidazol-1-yl)isoquinoline-1-amido]cyclohexyl] tert-butyl carbamate (160 mg, 71% yield) as a pale yellow solid.

[0329] A solution of N-[(trans)-4-[5-cyano-3-(imidazol-1-yl)isoquinoline-1-amido]cyclohexyl]tert-butyl carbamate (150 mg, 0.326 mmol, 1 equivalent) in 4 M HCl (gas) / 1,4-dioxane (10 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. This yielded 5-cyano-3-(imidazol-1-yl)-N-[(trans)-4-aminocyclohexyl]isoquinoline-1-carboxamide (100 mg, 68% yield) as a yellow solid.

[0330] A mixture of 5-cyano-3-(1H-imidazol-1-yl)-N-[(trans)-4-aminocyclohexyl]isoquinoline-1-carboxamide (46 mg, 0.128 mmol, 1 equivalent), 2,2,2-trifluoroethyl trifluoromethanesulfonate (35 mg, 0.154 mmol, 1.2 equivalent), and TEA (64 mg, 0.640 mmol, 5 equivalent) in ACN (3 mL) was stirred at 70°C under nitrogen atmosphere for 16 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 8) to give 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 pale yellow solid. LCMS (ESI) [M+H] + : 443.15. 1 H 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 = 7.2Hz, 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)

[0331] At 0°C under a nitrogen atmosphere, NaH (583 mg, 14.444 mmol, 2 equivalents, 60% purity) was added partically to a stirred mixture of malononitrile (570 mg, 8.666 mmol, 1.2 equivalents) in THF (10 mL). The mixture was stirred at 0°C under a nitrogen atmosphere for 30 min. At 0°C under a nitrogen atmosphere, 7-bromo-1,3-dichloroisoquinoline (2 g, 7.222 mmol, 1 equivalent) was added partically to the above mixture. The mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was quenched at 0°C with NH4Cl (aqueous solution). The aqueous layer was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:2) elution to give 2-(7-bromo-3-chloroisoquinoline-1-yl)malononitrile (820 mg, 37% yield) as a pale yellow solid.

[0332] A mixture of 2-(7-bromo-3-chloroisoquinoline-1-yl)malononitrile (800 mg, 2.610 mmol, 1 equivalent) and m-CPBA (1.06 g, 5.220 mmol, 2 equivalent, 85% purity) in MeOH (20 mL) was stirred at 0°C for 1 h. The reaction was quenched at 0°C by adding saturated sodium thiosulfate (aqueous solution). The aqueous layer was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:1) elution to give methyl 7-bromo-3-chloroisoquinoline-1-carboxylate (430 mg, 55% yield) as a yellow solid.

[0333] A mixture of methyl 7-bromo-3-chloroisoquinoline-1-carboxylate (410 mg, 1.364 mmol, 1 equivalent), CuCN (244 mg, 2.728 mmol, 2 equivalents), and Pd(PPh3)2Cl2 (95 mg, 0.136 mmol, 0.1 equivalents) in DMSO (10 mL) was stirred at 150°C under a nitrogen atmosphere for 1 h. The residue was purified by reversed-phase rapid chromatography (Method 1) to give methyl 3-chloro-7-cyanoisoquinoline-1-carboxylate (230 mg, 68% yield) as a yellow solid.

[0334] A solution of methyl 3-chloro-7-cyanoisoquinoline-1-carboxylate (220 mg, 0.892 mmol, 1 equivalent) and trimethyltin hydroxide (322 mg, 1.784 mmol, 2 equivalents) in a DCE (10 mL) was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 3-chloro-7-cyanoisoquinoline-1-carboxylic acid (100 mg, 48% yield) as a yellow solid.

[0335] A mixture of 3-chloro-7-cyanoisoquinoline-1-carboxylic acid (90 mg, 0.387 mmol, 1 equivalent), (trans)-4-methoxycyclohexyl-1-amine (59 mg, 0.464 mmol, 1.2 equivalent), DIEA (150 mg, 1.161 mmol, 3 equivalent), and HATU (220 mg, 0.581 mmol, 1.5 equivalent) in DMF (5 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with water at room temperature. The aqueous layer was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:3) elution to give 3-chloro-7-cyano-N-[(trans)-4-methoxycyclohexyl]isoquinoline-1-carboxamide (70 mg, 53% yield) as a yellow solid.

[0336] A mixture of 3-chloro-7-cyano-N-[(trans)-4-methoxycyclohexyl]isoquinoline-1-carboxamide (60 mg, 0.175 mmol, 1 equivalent), imidazole (47 mg, 0.700 mmol, 4 equivalents), t-BuBrettPhos Pd G3 (29 mg, 0.035 mmol, 0.2 equivalents), t-BuBrettPhos (8 mg, 0.017 mmol, 0.1 equivalents), and Cs₂CO₃ (170 mg, 0.525 mmol, 3 equivalents) in dioxane (5 mL) was stirred at 120°C under nitrogen atmosphere for 1 h. The mixture was concentrated under reduced pressure. The crude product was subjected to preparative HPLC (column: XBridge BEH C18 OBD Prep column 19). Purification was performed using a mobile phase of 250 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; wavelength: 254 / 220 nm) to give 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. 1 H NMR (400 MHz, DMSO-d6) δ9.49 (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 = 1.8Hz, 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)

[0337] At 0°C under a nitrogen atmosphere, NaH (867 mg, 21.67 mmol, 3.0 equivalent, 60% purity) was added partically to a stirred solution of malononitrile (954 mg, 14.44 mmol, 2.0 equivalent) in THF (20 mL). The mixture was stirred at 0°C under a nitrogen atmosphere for 10 min. At 0°C under a nitrogen atmosphere, 6-bromo-1,3-dichloroisoquinoline (2 g, 7.22 mmol, 1.0 equivalent) was added partically to the above mixture. The mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated NH4Cl (aqueous solution) at room temperature. The resulting mixture was diluted with water. The aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (7:3) elution to give 2-(6-bromo-3-chloroisoquinoline-1-yl)malononitrile (1.91 g, 86% yield) as a yellow solid.

[0338] At 0°C under a nitrogen atmosphere, m-CPBA (1.33 g, 6.52 mmol, 2.0 equivalent, 85% purity) was added partically to a stirred mixture of 2-(6-bromo-3-chloroisoquinoline-1-yl)malononitrile (1 g, 3.26 mmol, 1.0 equivalent) in MeOH (10 mL). The mixture was stirred at 0°C under a nitrogen atmosphere for 1 h. The reaction was quenched at 0°C with saturated sodium thiosulfate (aqueous solution). The aqueous layer was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:1) elution to give methyl 6-bromo-3-chloroisoquinoline-1-carboxylate (700 mg, 71% yield) as a yellow solid.

[0339] At room temperature, KOAc (261 mg, 2.66 mmol, 2.0 equivalent), H2O (1 mL), K4Fe(CN)6 (562 mg, 1.33 mmol, 1.0 equivalent), and Pd(dpephos)Cl2 (191 mg, 0.27 mmol, 0.2 equivalent) were added partically to a stirred mixture of methyl 6-bromo-3-chloroisoquinoline-1-carboxylate (400 mg, 1.33 mmol, 1.0 equivalent) in dioxane (5 mL). The mixture was stirred at 80°C under a nitrogen atmosphere for 4 h. The reaction was allowed to cool to room temperature. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (2:1) elution to give methyl 3-chloro-6-cyanoisoquinoline-1-carboxylate (200 mg, 33% yield) as a yellow solid.

[0340] At room temperature, trimethylstantanol (264 mg, 1.46 mmol, 2.0 equivalent) was added partically to a mixture of methyl 3-chloro-6-cyanoisoquinoline-1-carboxylate (180 mg, 0.73 mmol, 1 equivalent) in a DCE (3 mL). The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. This yielded 3-chloro-6-cyanoisoquinoline-1-carboxylic acid (150 mg, 88% yield) as a yellow solid.

[0341] At room temperature, (trans)-4-methoxycyclohexyl-1-amine (71 mg, 0.55 mmol, 1.5 equivalent), DIEA (142 mg, 1.10 mmol, 3.0 equivalent), and HATU (208 mg, 0.55 mmol, 1.5 equivalent) were added partically to a stirred mixture of 3-chloro-6-cyanoisoquinoline-1-carboxylic acid (85 mg, 0.37 mmol, 1.0 equivalent) in DMF (5 mL). The mixture was stirred at room temperature for 1 h. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 3-chloro-6-cyano-N-[(trans)-4-methoxycyclohexyl]isoquinoline-1-carboxamide (85 mg, 68% yield) as a white solid.

[0342] At room temperature, imidazole (48 mg, 0.70 mmol, 3.0 equivalent), t-BuBrettphos (23 mg, 0.05 mmol, 0.2 equivalent), t-BuBrettPhos Pd G3 (20 mg, 0.02 mmol, 0.1 equivalent), and Cs2CO3 (227 mg, 0.7 mmol, 3.0 equivalent) were added in portions to a stirred mixture of 3-chloro-6-cyano-N-[(trans)-4-methoxycyclohexyl]isoquinoline-1-carboxamide (80 mg, 0.23 mmol, 1.0 equivalent) in dioxane (2 mL). The mixture was stirred at 120°C under a nitrogen atmosphere for 1 h. The reaction was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was analyzed by preparative HPLC under the following conditions (column: XBridge BEH C18 OBD Prep column 19). Purification was performed at 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; wavelength: 254 / 220 nm to obtain 6-cyano-3-(imidazol-1-yl)-N-[(trans)-4-methoxycyclohexyl]isoquinoline-1-carboxamide (14.7 mg, 17% yield) as a pale 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)

[0343] A solution of 3-chloro-5-cyanoisoquinoline-1-carboxylic acid (150 mg, 0.645 mmol, 1 equivalent), N-[(trans)-3-aminocyclobutyl]carbamate tert-butyl ester (144 mg, 0.774 mmol, 1.2 equivalent), HATU (367 mg, 0.968 mmol, 1.5 equivalent), and 2,4,6-trimethylpyridine (234 mg, 1.935 mmol, 3 equivalent) in DMF (5 mL) was stirred at room temperature under air for 1 h. The residue was purified by reversed-phase rapid chromatography (Method 2) to give N-[(trans)-3-(3-chloro-5-cyanoisoquinoline-1-amido)cyclobutyl]carbamate tert-butyl ester (140 mg, 54% yield) as an off-white solid.

[0344] A solution of N-[(trans)-3-(3-chloro-5-cyanoisoquinoline-1-amido)cyclobutyl]carbamate (130 mg, 0.324 mmol, 1 equivalent), imidazole (66 mg, 0.972 mmol, 3 equivalents), t-BuBrettphos (32 mg, 0.065 mmol, 0.2 equivalents), t-BuBrettphos Pd G3 (27 mg, 0.032 mmol, 0.1 equivalents), and Cs2CO3 (316 mg, 0.972 mmol, 3 equivalents) in dioxane (5 mL) was stirred at 120°C under a nitrogen atmosphere for 1 h. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution of CH2Cl2 / MeOH (8:1) to give N-[(trans)-3-[5-cyano-3-(imidazol-1-yl)isoquinoline-1-amido]cyclobutyl]carbamate tert-butyl ester (80 mg, 57% yield) as a white solid.

[0345] A solution of N-[(trans)-3-[5-cyano-3-(imidazol-1-yl)isoquinoline-1-amido]cyclobutyl]carbamate tert-butyl ester (70 mg, 0.162 mmol, 1 equivalent) in 4 M HCl (gas) / 1,4-dioxane (5 mL) was stirred at room temperature under air for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product (50 mg) was used directly in the next step without further purification.

[0346] A solution of 5-cyano-3-(imidazol-1-yl)-N-[(trans)-3-aminocyclobutyl]isoquinoline-1-carboxamide (40 mg, 0.120 mmol, 1 equivalent), 2,2,2-trifluoroethyl trifluoromethanesulfonate (55 mg, 0.240 mmol, 2 equivalents), and TEA (60 mg, 0.600 mmol, 5 equivalents) in ACN (2 mL) was stirred at 70°C under nitrogen atmosphere for 16 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 10) to give 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 pale 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-oxopyrrolidone-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopentadien[d]pyrimidine-4-carboxamide (compound 198)

[0347] A solution of (trans)-4-(3,3-difluoropyrrolidone-1-yl)cyclohexyl-1-amine (200 mg, 0.979 mmol, 1 equivalent), di-tert-butyl dicarbonate (320 mg, 1.468 mmol, 1.5 equivalent), TEA (297 mg, 2.937 mmol, 3 equivalent), and DMAP (11 mg, 0.098 mmol, 0.1 equivalent) in DCM (5 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:1) elution to give N-[(trans)-4-(3,3-difluoropyrrolidone-1-yl)cyclohexyl]tert-butyl carbamate (110 mg, 37% yield) as a white solid.

[0348] At 0°C, NaIO4 (267 mg, 1.250 mmol, 3.8 equivalents) was added partically to a stirred solution of N-[(trans)-4-(3,3-difluoropyrrolidone-1-yl)cyclohexyl]carbamate (100 mg, 0.329 mmol, 1 equivalent) and ruthenium(III) chloride (4 mg, 0.020 mmol, 0.06 equivalents) in EA (3 mL) and H2O (3 mL). The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 2) to give tert-butyl ((trans)-4-(4,4-difluoro-2-oxopyrrolidone-1-yl)cyclohexyl)carbamate (40 mg, 38% yield) as a white solid.

[0349] A solution of ((trans)-4-(4,4-difluoro-2-oxopyrrolidone-1-yl)cyclohexyl)carbamate tert-butyl ester (40 mg, 0.126 mmol, 1 equivalent) in HCl / 1,4-dioxane (4.0 M) (3 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. This yielded 4,4-difluoro-1-[(trans)-4-aminocyclohexyl]pyrrolidone-2-one (20 mg, crude) as a white solid.

[0350] A solution of 4,4-difluoro-1-[(trans)-4-aminocyclohexyl]pyrrolidone-2-one (20 mg, 0.092 mmol, 1 equivalent), 2-(imidazol-1-yl)-5H,6H,7H-cyclopentadien[d]pyrimidin-4-carboxylic acid (25 mg, 0.110 mmol, 1.2 equivalent), TCFH (51 mg, 0.184 mmol, 2 equivalent), and NMI (37 mg, 0.460 mmol, 5 equivalent) in ACN (2 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 7) to give N-((trans)-4-(4,4-difluoro-2-oxopyrrolidone-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopentadien[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 = 13.3Hz, 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-difluoroazacyclobutane-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopentadien[d]pyrimidine-4-carboxamide (compound 152)

[0351] A solution of N-(4-oxocyclohexyl)carbamate (1 g, 4.044 mmol, 1 equivalent) in DCM (16 mL) was treated at room temperature with 3,3-difluoroazacyclobutane (0.45 g, 4.853 mmol, 1.2 equivalent), followed by dropwise addition of AcOH (0.24 g, 4.044 mmol, 1 equivalent) at room temperature. NaBH3CN (0.51 g, 8.088 mmol, 2 equivalent) was added partically to the mixture at 0°C. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with DCM (3 × 60 mL). 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 with PE / EA (1:1) elution to give benzyl ((trans)-4-(3,3-difluoroazacyclobutane-1-yl)cyclohexyl)carbamate (400 mg, 31% yield) as a white solid.

[0352] In a pressure vessel, Pd(OH)₂ / C (380 mg) was added to a solution of ((trans)-4-(3,3-difluoroazacyclobutan-1-yl)cyclohexyl)carbamate (380 mg, 1.171 mmol, 1 equivalent) in 10 mL of MeOH. The mixture was hydrogenated at 50°C and 4 atm for 16 h, filtered through a diatomaceous earth pad, and concentrated under reduced pressure. The crude product was subjected to preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column 30). Purification was performed at 150 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: isocratic 2% to 6% B over 8 min; wavelength: 254 nm / 220 nm; RT1 (min): 5.75 to give (trans)-4-(3,3-difluoroazacyclobutan-1-yl)cyclohexyl-1-amine (150 mg, 67% yield) as a white solid.

[0353] At room temperature, NMI (78 mg, 0.945 mmol, 3 equivalents) and TCFH (133 mg, 0.473 mmol, 1.5 equivalents) were added to a stirred solution of (trans)-4-(3,3-difluoroazacyclobutan-1-yl)cyclohexyl-1-amine (60 mg, 0.315 mmol, 1 equivalent) and 2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopentadien[d]pyrimidine-4-carboxylic acid (73 mg, 0.315 mmol, 1 equivalent) in ACN (2 mL). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 8) to give N-((trans)-4-(3,3-difluoroazacyclobutan-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopentadien[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) δ8.91 (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-difluoropyrrolidone-1-yl)cyclohexyl)-6-(1H-imidazol-1-yl)-1,3-dihydrofurano[3,4-c]pyridine-4-carboxamide (compound 194)

[0354] A solution of 4,6-dichloro-1H,3H-furano[3,4-c]pyridine (1.5 g, 7.894 mmol, 1 equivalent), tributyl(2-methoxypropyl-2-en-1-yl)stanane (2.57 g, 7.105 mmol, 0.9 equivalent), and Pd(PPh3)2Cl2 (554 mg, 0.789 mmol, 0.1 equivalent) in DMF (15 mL) was stirred at 70°C under a nitrogen atmosphere for 2 h. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (9:1) elution to give 6-chloro-4-(1-ethoxyvinyl)-1H,3H-furano[3,4-c]pyridine (420 mg, 24% yield) as an off-white solid.

[0355] A solution of 6-chloro-4-(1-ethoxyvinyl)-1H,3H-furano[3,4-c]pyridine (410 mg, 1.817 mmol, 1 equivalent) in dioxane (5 mL) and NaIO4 (777 mg, 3.634 mmol, 2.0 equivalent) in H2O (2 mL) was stirred at room temperature for 5 min. KMnO4 (43 mg, 0.273 mmol, 0.15 equivalent) was added to the mixture at room temperature. The resulting mixture was stirred at room temperature for another 2 h. The resulting mixture was filtered, and the filter cake was washed with dioxane (5 mL) (3 × 10 mL). The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:1) elution to give ethyl 6-chloro-1H,3H-furano[3,4-c]pyridine-4-carboxylate (110 mg, 27% yield) as a white solid.

[0356] Ethyl 6-chloro-1H,3H-furano[3,4-c]pyridine-4-carboxylate (100 mg, 0.439 mmol, 1 equivalent) and LiOH . A solution of H2O (37 mg, 0.878 mmol, 2.0 equivalent) in THF (1.2 mL) and H2O (0.4 mL) was stirred at room temperature for 1 h. The mixture was acidified to pH 5 with 1 M HCl (aqueous solution). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 1) to give 6-chloro-1H,3H-furano[3,4-c]pyridine-4-carboxylic acid (50 mg, 57% yield) as a white solid.

[0357] A solution of 6-chloro-1H,3H-furano[3,4-c]pyridine-4-carboxylic acid (20 mg, 0.100 mmol, 1 equivalent), (trans)-4-(3,3-difluoropyrrolidone-1-yl)cyclohexyl-1-amine (25 mg, 0.120 mmol, 1.2 equivalent), TCFH (56 mg, 0.200 mmol, 2.0 equivalent), and NMI (41 mg, 0.500 mmol, 5.0 equivalent) in ACN (1 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (3:2) elution to give 6-chloro-N-[(trans)-4-(3,3-difluoropyrrolidone-1-yl)cyclohexyl]-1H,3H-furano[3,4-c]pyridine-4-carboxamide (28 mg, 72% yield) as a white solid.

[0358] A solution of 6-chloro-N-[(trans)-4-(3,3-difluoropyrrolidone-1-yl)cyclohexyl]-1H,3H-furano[3,4-c]pyridine-4-carboxamide (25 mg, 0.065 mmol, 1 equivalent), imidazole (11 mg, 0.163 mmol, 2.5 equivalent), t-BuBrettphos Pd G3 (5 mg, 0.007 mmol, 0.1 equivalent), t-BuBrettphos (6 mg, 0.013 mmol, 0.2 equivalent), and Cs2CO3 (63 mg, 0.195 mmol, 3.0 equivalent) in dioxane (1.0 mL) was stirred at 100°C under a nitrogen atmosphere for 1 h. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 4) to give N-((trans)-4-(3,3-difluoropyrrolidone-1-yl)cyclohexyl)-6-(1H-imidazol-1-yl)-1,3-dihydrofurano[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-oxopyrrolidone-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopentadien[d]pyrimidine-4-carboxamide (compound 198)

[0359] A solution of (trans)-4-(3,3-difluoropyrrolidone-1-yl)cyclohexyl-1-amine (200 mg, 0.979 mmol, 1 equivalent), di-tert-butyl dicarbonate (320 mg, 1.468 mmol, 1.5 equivalent), TEA (297 mg, 2.937 mmol, 3 equivalent), and DMAP (11 mg, 0.098 mmol, 0.1 equivalent) in DCM (5 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:1) elution to give N-[(trans)-4-(3,3-difluoropyrrolidone-1-yl)cyclohexyl]tert-butyl carbamate (110 mg, 37% yield) as a white solid.

[0360] At 0°C, NaIO4 (267 mg, 1.250 mmol, 3.8 equivalents) was added partically to a stirred solution of N-[(trans)-4-(3,3-difluoropyrrolidone-1-yl)cyclohexyl]carbamate (100 mg, 0.329 mmol, 1 equivalent) and ruthenium(III) chloride (4 mg, 0.020 mmol, 0.06 equivalents) in EA (3 mL) and H2O (3 mL). The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography (Method 2) to give tert-butyl ((trans)-4-(4,4-difluoro-2-oxopyrrolidone-1-yl)cyclohexyl)carbamate (40 mg, 38% yield) as a white solid.

[0361] A solution of ((trans)-4-(4,4-difluoro-2-oxopyrrolidone-1-yl)cyclohexyl)carbamate tert-butyl ester (40 mg, 0.126 mmol, 1 equivalent) in HCl / 1,4-dioxane (4.0 M) (3 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. This yielded 4,4-difluoro-1-[(trans)-4-aminocyclohexyl]pyrrolidone-2-one (20 mg, crude) as a white solid.

[0362] A solution of 4,4-difluoro-1-[(trans)-4-aminocyclohexyl]pyrrolidone-2-one (20 mg, 0.092 mmol, 1 equivalent), 2-(imidazol-1-yl)-5H,6H,7H-cyclopentadien[d]pyrimidin-4-carboxylic acid (25 mg, 0.110 mmol, 1.2 equivalent), TCFH (51 mg, 0.184 mmol, 2 equivalent), and NMI (37 mg, 0.460 mmol, 5 equivalent) in ACN (2 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method 7) to give N-((trans)-4-(4,4-difluoro-2-oxopyrrolidone-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopentadien[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 = 13.3Hz, 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).

[0363] Example 89: Synthesis of N-((trans)-4-(3,3-difluoro-2-oxopyrrolidone-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-6,7-dihydro-5H-cyclopentadien[d]pyrimidine-4-carboxamide (compound 199)

[0364] At 0°C under a nitrogen atmosphere, TsCl (6.64 g, 34.83 mmol, 1.5 equivalent) and DMAP (0.57 g, 4.64 mmol, 0.2 equivalent) were added dropwise to a solution of (cis)-4-hydroxycyclohexyl)carbamate (5 g, 23.22 mmol, 1 equivalent) and TEA (7.05 g, 69.67 mmol, 3 equivalent) in DCM (50 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction was quenched with water at 0°C. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:1) elution to give N-[(cis)-4-[(4-methylbenzenesulfonyl)oxy]cyclohexyl]carbamate tert-butyl ester (3 g, 35% yield) as a white solid.

[0365] Sodium hydride (60% in oil, 290 mg) was added to a solution of N-[(cis)-4-[(4-methylbenzenesulfonyl)oxy]cyclohexyl]carbamate (3 g, 8.12 mmol, 1 equivalent) in DMF (30 mL). The mixture was stirred for 15 min. 1-(chloromethyl)-4-methoxybenzene (2.54 g, 16.24 mmol, 2 equivalents) was added and the mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched at 0°C with saturated NH4Cl (aqueous solution). The aqueous layer was extracted with EtOAc (3 × 30 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (5:1) elution to give N-[(4-methoxyphenyl)methyl]-N-[(cis)-4-[(4-methylbenzenesulfonyl)oxy]cyclohexyl]carbamate tert-butyl ester (1.2 g, 30% yield), which was a yellow oil.

[0366] A solution of 3,3-difluoropyrrolidone-2-one (300 mg, 2.47 mmol, 1 equivalent), N-[(4-methoxyphenyl)methyl]-N-[(cis)-4-[(4-methylbenzenesulfonyl)oxy]cyclohexyl]carbamate tert-butyl ester (1334 mg, 2.72 mmol, 1.1 equivalent), and t-BuOK (556 mg, 4.95 mmol, 2 equivalent) in THF (5 mL) was stirred at 80°C for 16 h. The resulting mixture was diluted with water and extracted with EtOAc, then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reversed-phase rapid chromatography (Method 2) to give N-[(4-methoxyphenyl)methyl]-N-[(trans)-4-(3,3-difluoro-2-oxopyrrolidone-1-yl)cyclohexyl]carbamate tert-butyl ester (180 mg, 17% yield) as a yellow solid.

[0367] Under a nitrogen atmosphere, Pd / C (10%, 180 mg) was added to a solution of N-[(4-methoxyphenyl)methyl]-N-[(trans)-4-(3,3-difluoro-2-oxopyrrolidone-1-yl)cyclohexyl]carbamate (180 mg, 0.41 mmol, 1 equivalent) in MeOH (3 mL). The mixture was hydrogenated at 50°C under a hydrogen atmosphere using a hydrogen balloon for 16 h, filtered through a diatomaceous earth pad, and concentrated under reduced pressure to give N-[(trans)-4-(3,3-difluoro-2-oxopyrrolidone-1-yl)cyclohexyl]carbamate (120 mg, 92% yield) as a white solid.

[0368] A solut...

Claims

1. A compound represented by formula I: (I)； Or its pharmaceutically acceptable salts and / or stereoisomers, wherein: X 1 and X 2 Each is independently selected from N and CH; Y is -C(O)-NR a -or-S(O)2-NR a -; R 1 It is a 5-6 member monocyclic heteroaryl or an 8-10 member bicyclic heteroaryl; wherein R 1 It can be optionally selected by one or more independently chosen from R 11 Substituents of the substituents; R 11 Each time it appears, it is independently selected from the following groups: halogen, hydroxyl, -C. 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, -CN, -CF3, -NR a R b -C(O)-NR a R b -NR a -C(O)-R b , and deuterium; where -C 1-6 Alkyl and -C 1-6 The alkoxy group can optionally be selected by one or more elements, each independently chosen from hydroxyl, halogen, deuterium, and -C. 1-3 Substitution of alkoxy groups; Ring A is a 5-6 membered ring selected from the group consisting of: phenyl, 5-6 membered carbon rings, and 5-6 membered heterocyclic groups; and wherein ring A may optionally be selected independently by one, two, or three groups from R. A Substituents of the substituents; Ring B is selected from the group consisting of: 4-12 member monocyclic, fused bicyclic, bridging bicyclic or spirocyclic carbon rings, and 5-7 member heterocyclic groups; wherein ring B may optionally be selected independently by one, two or three members from R B Substituents of the substituents; R A Each time it appears, it is independently selected from the following groups: halogen, hydroxyl, deuterium, -C. 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, 5-6 membered heterocyclic groups, -CN, -CF3, -OC(O)-C 1-6 Alkyl, -NR a R b -C(O)-NR a R b , and -NR a -C(O)-R b ;where -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, and 5-6 membered heterocyclic groups may optionally be selected independently by one or more groups chosen from hydroxyl, halogen, deuterium, and -C. 1-3 Substitution of alkoxy groups; R B Each time it appears, it is independently selected from the following groups: halogen, hydroxyl, deuterium, -C. 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, 5-6 membered heterocyclic groups, -CN, -CF3, oxo groups, -OC(O)-C 1-6 Alkyl, -NR a R b -C(O)-NR a R b , and -NR a -C(O)-R b ;where -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, and 5-6 membered heterocyclic groups may optionally be selected independently by one or more groups chosen from hydroxyl, halogen, oxo, deuterium, and -C. 1-3 Substitution of alkoxy groups; R a and R b Each occurrence is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups may optionally be substituted by one or more substituents independently selected from the group consisting of halogens, deuterium, hydroxyl groups, and C1-C6 alkoxy groups; or R a and R b The nitrogen atoms attached to them can be linked together to form 4-7 membered heterocyclic groups, which may be optionally substituted by one or more substituents selected independently from the group consisting of: halogen, deuterium, hydroxyl, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy groups; p is 0, 1, or 2; and q can be 0, 1, or 2.

2. The compound of claim 1, wherein, The compound is represented by formula 1A: (IA); Or its pharmaceutically acceptable salts and / or stereoisomers, wherein: X 1 and X 2 Each is independently selected from N and CH; Y is -C(O)-NR a -or-S(O)2-NR a -; R 1 It is a 5-6 member monocyclic heteroaryl or an 8-10 member bicyclic heteroaryl; wherein R 1 It can be optionally selected by one or more independently chosen from R 11 Substituents of the substituents; R 11 Each time it appears, it is independently selected from the following groups: halogen, hydroxyl, -C. 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, -CN, -CF3, -NR a R b -C(O)-NR a R b -NR a -C(O)-R b , and deuterium; where -C 1-6 Alkyl and -C 1-6 The alkoxy group can optionally be selected by one or more elements, each independently chosen from hydroxyl, halogen, deuterium, and -C. 1-3 Substitution of alkoxy groups; Ring A is a 5-6 membered ring selected from the group consisting of: phenyl, 5-6 membered carbon rings, and 5-6 membered heterocyclic groups; and wherein ring A may optionally be selected independently by one, two, or three groups from R. A Substituents of the substituents; R A Each time it appears, it is independently selected from the following groups: halogen, hydroxyl, deuterium, -C. 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, 5-6 membered heterocyclic groups, -CN, -CF3, -OC(O)-C 1-6 Alkyl, -NR a R b -C(O)-NR a R b , and -NR a -C(O)-R b ;where -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, and 5-6 membered heterocyclic groups may optionally be selected independently by one or more groups chosen from hydroxyl, halogen, deuterium, and -C. 1-3 Substitution of alkoxy groups; R 2 Choose from the following groups: halogens, hydroxyl groups, deuterium, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, 5-6 membered heterocyclic groups, -CN, -CF3, oxo groups, -OC(O)-C 1-6 Alkyl, -NR a R b -C(O)-NR a R b , and -NR a -C(O)-R b ;where -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, and 5-6 membered heterocyclic groups may optionally be selected independently by one or more groups chosen from hydroxyl, halogen, oxo, deuterium, and -C. 1-3 Substitution of alkoxy groups; R 3 Choose from the following groups: hydrogen, deuterium, halogen, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, -CN, -NR a R b -C(O)-NR a R b , and -NR a -C(O)-R b ; R 4 and R 5 Each is independently selected from the group consisting of hydrogen and -C atoms optionally substituted with one or more halogens. 1-3 alkyl; R a and R b Each occurrence is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups may optionally be substituted by one or more substituents independently selected from the group consisting of halogens, deuterium, hydroxyl groups, and C1-C6 alkoxy groups; or R a and R b The nitrogen atoms attached to them can be linked together to form 4-7 membered heterocyclic groups, which may be optionally substituted by one or more substituents selected independently from the group consisting of: halogen, deuterium, hydroxyl, -NR. a R b C1-C6 alkyl and C1-C6 alkoxy groups; m is 1 or 2; n is 1, 2, or 3; and p is 0, 1, 2, or 3.

3. The compound according to claim 1 or 2, wherein, m and n are both 2, or m and n are both 1.

4. The compound according to any one of claims 1-3, wherein, The compound is represented by the following: (IB) or (IC).

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

6. The compound according to any one of claims 1-4, wherein, The compound is represented by the following: (ID), (IE), (IF), or (IG).

7. The compound according to any one of claims 1-6, wherein, X 1 It is N and X 2 It is CH.

8. The compound according to any one of claims 1-6, wherein, X 1 It is CH and X 2 It is N.

9. The compound according to any one of claims 1-6, wherein, X 1 It is N and X 2 It is N.

10. The compound according to any one of claims 1-6, wherein, X 1 It is CH and X 2 It is CH.

11. The compound according to any one of claims 1-10, wherein, R 1 It is a 5-6 membered heteroaryl group containing at least one cyclic nitrogen, wherein R 1 It can be optionally selected by one or two independently chosen from R 11 Substituents are substituted.

12. The compound according to any one of claims 1-11, wherein, R 1 Choose from the group consisting of: imidazole, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, and pyridinyl, where R 1 It can be optionally substituted by one or two substituents, each independently selected from the group consisting of -CH2OH, -OH, and -NH2.

13. The compound according to any one of claims 1-12, wherein, R 1 Choose from the following groups: , , , , , , , ,and .

14. The compound according to any one of claims 1-13, wherein, R 1 Choose from the following groups: , ,and .

15. The compound according to any one of claims 2-14, wherein, R 2 Choose from the following groups: -OH, -CN, -CD3, -CF3, -OCH3, -OCD3, -OCH2CH2OCH3, -OCH2CH2OCH2CH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OC(CH3)3, -C(CH3)2OH, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, -NHCH2CF3. , , , ,and .

16. The compound according to any one of claims 2-15, wherein, R 2 Choose from the following groups: -OH, -CN, -CD3, -CF3, -OCH3, -OCD3, -OCH2CH2OCH3, -C(CH3)2OH, -C(O)NH(CH3), -C(O)N(CH3)2, -NHCH2CF3, , , , ,and .

17. The compound according to any one of claims 1-16, wherein, p is 1 and R A Choose from the following groups: -CN, -CH2OH, -OC(O)CH3, morpholino, fluorine, chlorine, and bromine.

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

19. The compound according to any one of claims 2-18, wherein, R 3 and R 5 It appears as hydrogen each time.

20. The compound according to any one of claims 2-19, wherein, R 4 Choose from the following groups: hydrogen, -CH3, and -CH2CH3.

21. A compound represented by formula II: (II); Or its pharmaceutically acceptable salts and / or stereoisomers, wherein: A is phenyl, cyclohexyl, cyclopentyl, or dihydrofuranyl; X 1 It is N and X 2 It is CH; or X 1 It is N and X 2 It is N; R 1 It is a 5-6 membered heteroaryl group containing at least one cyclic nitrogen; wherein R 1 It may optionally be substituted by one, two, or three substituents, each independently selected from the group consisting of: halogen, hydroxyl, deuterium, -NH2, -C 1-3 Alkyl, -C 1-3 Alkyl -OH and -C 1-3 Alkoxy; R 2 Choose from the following groups: halogens, hydroxyl groups, deuterium, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, 5-6 membered heterocyclic groups, -CN, -CF3, oxo groups, -OC(O)-C 1-6 Alkyl, -NR a R b -C(O)-NR a R b , and -NR a -C(O)-R b ;where -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 Cycloalkyl, phenyl, and 5-6 membered heterocyclic groups may optionally be selected independently by one or more groups chosen from hydroxyl, halogen, oxo, deuterium, and -C. 1-3 Substitution of alkoxy groups; R 3 Choose from the following groups: hydrogen, -CH3, and -CH2CH3; R A Each time it appears, it is independently selected from the following groups: halogen, hydroxyl, deuterium, -C. 1-6 Alkyl, -C 1-6 Alkoxy groups, -CN groups, and 5-6 membered heterocyclic groups, wherein -C 1-6 Alkyl and -C 1-6 The alkoxy group 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 the following: (IIA) (IIB), or (IIC), or (IID).

23. The compound of claim 21 or 22, wherein, R 1 Choose from the following groups: , , , , , , , ,and .

24. The compound according to any one of claims 21-23, wherein, R 2 Choose from the following groups: -OH, -CN, -CD3, -CF3, -OCH3, -OCD3, -OCH2CH2OCH3, -OCH2CH2OCH2CH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OC(CH3)3, -C(CH3)2OH, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, -NHCH2CF3. , , , ,and .

25. The compound according to any one of claims 21-24, wherein, p is 1 and R A Choose from the following groups: -CN, -CH2OH, morpholino, fluorine, chlorine, and bromine.

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

27. A compound selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , ,and ; Or its pharmaceutically acceptable salts and / or stereoisomers.

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

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

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

31. A method of treating neurodegenerative diseases in patients in need, comprising administering to the patient an effective amount of the compound as described in any one of claims 1-27 or the pharmaceutical composition as described in claim 28.

32. The method of claim 31, wherein, The neurodegenerative disease mentioned is Parkinson's disease.

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

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

35. A method of treating a patient with fibrosis who requires treatment, comprising administering to the patient an effective amount of the compound as described in any one of claims 1-27 or the pharmaceutical composition as described in claim 28.

36. The method of claim 35, wherein, The patient with fibrosis also had systemic sclerosis.

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

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

39. The method of claim 38, wherein, The fatty liver disease was selected from the following groups: non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

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

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

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