TEAD Inhibitors and Methods of Use

Abstract

The present disclosure relates, in part, to a compound of formula (I): [Formula 1] The present invention provides compounds of formula (I) of JPEG2025513725000262.jpg4948 (wherein the variables are as defined herein), pharmaceutical compositions comprising the compounds, and methods of using the compounds to treat physiological disorders such as proliferative disorders mediated by TEA domain transcription factors.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 322,600, filed March 22, 2022, the contents of which are incorporated herein by reference in their entirety. Summary of the Invention

[0002] Disclosed herein, in some embodiments, is a compound of Formula (I) or Formula (I'), e.g., a compound of Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Ib-1), or Formula (Ib-2), or a pharmaceutically acceptable salt thereof. Also disclosed herein, in some embodiments, is a composition comprising a compound of Formula (I) or Formula (I'), e.g., a compound of Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Ib-1), or Formula (Ib-2), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Also disclosed herein, in certain embodiments, is a method for inhibiting aberrant transcription enhancer-associated (TEA) domain transcription factor (TEAD) transcription complex activity, thereby treating certain diseases or disorders, such as cancer, characterized by aberrant TEAD transcription complex activity (e.g., hyperactivation).

[0003] As used herein, in certain embodiments, compounds of formula (I)

[0004] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0005] As used herein, in certain embodiments, (I')

[0006] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0007] In certain embodiments herein, (Ia)

[0008] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0009] As used herein, in certain embodiments, (Ia')

[0010] [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0011] In some embodiments, the compound of Formula (I), Formula (I'), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Ib-1), or Formula (Ib-2) is selected from Table 1 or a pharmaceutically acceptable salt thereof.

[0012] Also provided herein, in certain embodiments, is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0013] Further disclosed herein, in certain embodiments, are methods of treating a disease or condition mediated by aberrant TEAD activity (e.g., dysregulation) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein. In some embodiments, the disease or condition is cancer characterized by aberrant TEAD transcription complex activity (e.g., hyperactivation). [Brief explanation of the drawings]

[0014] The present disclosure can be more fully understood with reference to the following drawings. [Figure 1] Figure 1 shows the domain architecture of human TEAD1, TEAD2, TEAD3, and TEAD4. Percentage values ​​represent the identity of the N-terminal DNA-binding domain (DNA-BD) and C-terminal YAP / TAZ-binding domain (YAP / TAZ-BD) of TEAD2-4 compared to the respective binding domain of TEAD1. Post-translational modifications, including palmitoylation and phosphorylation, as well as the p38-binding D domain of the DNA-BD, are also shown. [Figure 2A] Diagram showing the upstream signaling and downstream transcriptional output of TEADs in cancer biology, which regulates important functions in tumorigenesis, stem cell maintenance, cancer immunology, and metabolism, as well as the formation of signaling feedback loops. Oncogenic signaling pathways include EGFR signaling, TGFβ signaling, WNt signaling, GPCR signaling, and oncogenes (indicated with *) such as KRAS, BRAF, LKB1, APC, and GNAQ / 11. [Figure 2B] FIG. 1 shows the role of TEADs in multiple stages of tumorigenesis. DETAILED DESCRIPTION OF THE INVENTION

[0015] Provided herein, in some embodiments, is a compound (e.g., a compound of Formula (I) or Formula (I'), e.g., a compound of Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Ib-1), or Formula (Ib-2)), or a pharmaceutically acceptable salt thereof. Further provided herein, in some embodiments, is a composition comprising a compound of Formula (I) or Formula (I'), e.g., a compound of Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Ib-1), or Formula (Ib-2), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Further provided herein, in some embodiments, is a method of using the compounds and compositions disclosed herein. Contemplated compounds and compositions disclosed herein are inhibitors of transcriptional enhancer factor domain (TEAD) activity and are therefore useful in methods of treating certain diseases or disorders, such as cancer, characterized by aberrant TEAD transcription complex activity (e.g., hyperactivation).

[0016] The present disclosure provides compounds (e.g., compounds of Formula (I) or Formula (I'), e.g., compounds of Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Ib-1), or Formula (Ib-2)) that can selectively bind to specific TEAD isoforms (e.g., TEAD1 and / or TEAD4) associated with therapeutic efficacy. Such selective binding is advantageous because less selective and / or non-selective TEAD isoform binding can result in undesirable effects (e.g., increased toxicity and / or cancer cell proliferation).

[0017] Specific Terms Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the claimed subject matter belongs. Generally, the nomenclature and techniques used in immunology, oncology, cell and tissue culture, molecular biology, and protein and oligonucleotide or polynucleotide chemistry and hybridization described herein are well known and commonly used in the art. It will be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not intended to be limiting of any subject matter. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0018] chemical definition Definitions of specific functional groups and chemical terms are described in more detail below.

[0019] In some embodiments, the compounds described herein contain one or more asymmetric centers and therefore exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, in some embodiments, the compounds described herein are in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. In some embodiments, isomers are isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers are prepared by asymmetric synthesis. The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0020] In some embodiments, the compounds described herein further comprise one or more isotopic substitutions. For example, in some embodiments, H is 1 H,2 H (D or deuterium), and 3 Any isotopic form containing H (T or tritium), and C 12 C. 13 C, and 14 Any isotopic form containing C, O 16 O and 18 Any isotopic form containing O, F 18 F and 19 Any isotopic form containing F.

[0021] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.

[0022] When a range of values ​​is expressed, it is intended to encompass each value and subrange within the range. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 Alkyl is intended to be included.

[0023] As used herein, "alkyl" refers to the radical of a straight- or branched-chain saturated hydrocarbon group, e.g., having 1 to 20 carbon atoms ("C 1-20 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C1-8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkyl group has one carbon atom ("C alkyl"). 1-6 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0024] As used herein, "alkylene" refers to a divalent radical of an alkyl group. When a range or number of carbon atoms is provided for a particular "alkylene" group, it is understood that the range or number refers to the range or number of carbon atoms in a linear divalent carbon chain. In some embodiments, an "alkylene" group is substituted or unsubstituted with one or more substituents described herein.

[0025] As used herein, "aryl" refers to an aromatic ring system ("C 6-14 "aryl") refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the cyclic array) having 6 to 14 ring carbon atoms and zero heteroatoms.

[0026] As used herein, "heteroaryl" refers to the radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in the cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, in heteroaryl groups containing one or more nitrogen atoms, the point of attachment is at a carbon or nitrogen atom, valence permitting.

[0027] In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5-6 membered heteroaryl"). In some embodiments, a 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0028] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively.

[0029] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged (e.g., adamantyl) hydrocarbon radical of 3 to 12, 3 to 10, 3 to 8, 4 to 8, or 4 to 6 carbons, e.g., as used herein, "C-C" derived from a cycloalkane. 10 Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclopentane, cyclobutane, and cyclopropane.

[0030] As used herein, "heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("3- to 10-membered heterocyclyl"). In some embodiments, in heterocyclyl groups containing one or more nitrogen atoms, the point of attachment is at a carbon atom or a nitrogen atom, where valence permits. In some embodiments, heterocyclyl groups are either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic heterocyclyl"), saturated or partially unsaturated. In some embodiments, heterocyclyl bicyclic ring systems contain one or more heteroatoms in one or both rings. "Heterocyclyl" further includes ring systems in which a heterocyclyl ring as defined above is fused to one or more cycloalkyl groups, the point of attachment being either on the cycloalkyl or heterocyclyl ring, or in which a heterocyclyl ring as defined above is fused to one or more phenyl or heteroaryl groups, the point of attachment being on the heterocyclyl ring; in such instances, the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably.

[0031] The term "carbocyclyl" or "carbocyclic" refers to the radical of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms (a "3- to 10-membered carbocyclic ring") and zero heteroatoms in a non-aromatic ring system. In some embodiments, a "carbocyclyl" or "carbocyclic" ring is a "3- to 7-membered carbocyclic ring."

[0032] In some embodiments, a heterocyclyl group is a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "3- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 4- to 7-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "4- to 7-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5-6 membered heterocyclyl"). In some embodiments, a 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0033] "Hetero," when used to describe a compound or a group present on a compound, means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. In some embodiments, hetero applies to any of the above hydrocarbyl groups, such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, and the like, having 1 to 5, especially 1 to 3, heteroatoms.

[0034] The terms "halo" and "halogen," as used herein, refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I). In certain embodiments, a halo group is either fluoro or chloro.

[0035] The term "haloalkyl" includes mono-, poly-, and perhaloalkyl groups substituted with one or more halogen atoms, the halogens being independently selected from fluorine, chlorine, bromine, and iodine.

[0036] The term "oxo" refers to =O.

[0037] In general, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.

[0038] Nitrogen atoms are substituted or unsubstituted where valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms.

[0039] These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The present disclosure is not intended to be limited by the above exemplary list of substituents.

[0040] Other definitions As used herein, "pharmaceutically acceptable excipient" refers to any substance in a pharmaceutical formulation other than the active pharmaceutical ingredient. Exemplary pharmaceutical excipients include those that aid in the manufacturing process, protect, support, or enhance stability, increase bioavailability, or increase patient tolerance. They may also aid in product identification or enhance the overall safety or performance of the product during storage or use.

[0041] As used herein, "pharmaceutically acceptable salts" refers to salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Pharmaceutically acceptable salts derived from appropriate bases include: lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0042] As used herein, a "subject" to which administration is contemplated includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, a child, an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or the elderly)) and / or a non-human animal, e.g., a mammal such as a primate (e.g., a cynomolgus monkey, a rhesus monkey), a cow, a pig, a horse, a sheep, a goat, a rodent, a cat, and / or a dog. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," "individual," and "subject" are used interchangeably herein. None of the terms require the supervision of a medical professional.

[0043] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0044] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate an action that occurs while a subject is suffering from a particular disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or slows or slows the progression of the disease, disorder, or condition.

[0045] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. In some embodiments, the term "therapeutically effective amount" encompasses an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effectiveness of another therapeutic agent.

[0046] compound As used herein, in certain embodiments, compounds of formula (I)

[0047] [ka] or a pharmaceutically acceptable salt thereof, wherein X is N or CH; R 1 is -C(O)OR 5 , -C(O)-NR 6 R 2 , -S(O)2-N(R 6 )2, -S(O) m -(C 1-6 alkyl), and -S(O)N(R 6 )2, R 2 is -C1-C6 alkyl, -(one or two -OR 5 -(C1-C6 alkyl substituted with), -(C1-C6 alkylene)-CN, -(C1-C6 alkylene)-S(O) n -(C1-C6 alkyl), -(OR 5 C1-C4 alkylene optionally substituted with -C(O)OR 5 , -(OR 5 C1-C4 alkylene optionally substituted with -C(O)N(R 6 )2, -(C0-C4 alkylene)-phenyl, -(C1-C6 alkylene)-N(R6 )2, 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; -(OR 5 -(C1-C4 alkylene)-(5-6 membered heteroaryl having 1, 2, or 3 heteroatoms each independently selected from N, O, and S), optionally substituted with -(C0-C4 alkylene)-C3-C 10 cycloalkyl, and -(C0-C4 alkylene)-(3- to 10-membered heterocyclyl having 1, 2, 3, or 4 heteroatoms each independently selected from N, O, and S), including any of the aforementioned phenyl, 5- to 6-membered heteroaryl, C3-C4 10 cycloalkyl and 3- to 10-membered heterocyclyl are optionally substituted; m is 1 or 2, n is 0, 1, or 2; R 3 is selected from the group consisting of hydrogen, halogen, —C1-C6 alkyl, —(C1-C6 haloalkyl), —O—(C1-C6 alkyl), and —O—(C1-C6 haloalkyl); R 4 is selected from the group consisting of hydrogen, halogen, and -C1-C6 alkyl; or R 3 and R 4 Together, R 3 and R 4 forms a 3- to 7-membered carbocyclic ring with the carbon to which it is attached, the carbocyclic ring being optionally substituted with one or more halogens; R 5 are each independently hydrogen or -C1-C6 alkyl; R 6 are each independently hydrogen or -C1-C6 alkyl; R x are each independently -C1-C6 alkyl, halogen, or -OR 5 , -CN, and -N(R 6 )2, R yare each independently -C1-C6 alkyl, halogen, or -OR 5 , -CN, and -N(R 6 )2, s is 0, 1, or 2; and t is 0, 1, 2, or 3.

[0048] As used herein, in certain embodiments, the compound of formula (I')

[0049] [ka] or a pharmaceutically acceptable salt thereof, wherein X is N or CH; R 1 is -C(O)OR 5 , -C(O)-NR 6 R 2 , -S(O)2-N(R 6 )2, -S(O) m -(C 1-6 alkyl), and -S(O)N(R 6 )2, R 2 is -C1-C6 alkyl, -(one or two -OR 5 -(C1-C6 alkyl substituted with), -(C1-C6 alkylene)-CN, -(C1-C6 alkylene)-S(O) n -(C1-C6 alkyl), -(OR 5 C1-C4 alkylene optionally substituted with -C(O)OR 5 , -(CN or OR 5 C1-C4 alkylene optionally substituted with -C(O)N(R 6 )2, -(C0-C4 alkylene)-phenyl, -(C1-C6 alkylene)-N(R 6 R 7 ), -(C1-C6 alkylene)-OP(O)(OR 5 )2, 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; -(OR 5-(C1-C4 alkylene)-(5-6 membered heteroaryl having 1, 2, or 3 heteroatoms each independently selected from N, O, and S), optionally substituted with -(C0-C4 alkylene)-C3-C 10 cycloalkyl, and -(C0-C4 alkylene)-(3- to 10-membered heterocyclyl having 1, 2, 3, or 4 heteroatoms each independently selected from N, O, and S), including any of the aforementioned phenyl, 5- to 6-membered heteroaryl, C3-C4 10 Cycloalkyl and 3- to 10-membered heterocyclyl are each independently one or more R w is optionally replaced by m is 1 or 2, n is 0, 1, or 2; R 3 is selected from the group consisting of hydrogen, halogen, —C1-C6 alkyl, —(C1-C6 haloalkyl), —O—(C1-C6 alkyl), and —O—(C1-C6 haloalkyl); R 4 is selected from the group consisting of hydrogen, halogen, and -C1-C6 alkyl; or R 3 and R 4 Together, R 3 and R 4 forms a 3- to 7-membered carbocyclic ring with the carbon to which it is attached, the carbocyclic ring being optionally substituted with one or more halogens; R 5 are each independently hydrogen or -C1-C6 alkyl; R 6 are each independently hydrogen or -C1-C6 alkyl; R 7 is hydrogen, -C1-C6 alkyl, -C(O)-(C 1-6 alkyl), -C(O)N(R 6 )2, -C(O)2-(C 1-6 alkyl), -S(O) n -(C1-C6 alkyl), and -S(O) n NR 6 -(C1-C6 alkyl), R w are each independently -C1-C6 alkyl, halogen, -N(R 6 )2, and oxo, wherein -C1-C6 alkyl is optionally substituted with -OH; R x are each independently -C1-C6 alkyl, halogen, or -OR 5 -CN; R y are each independently -C1-C6 alkyl, halogen, or -OR 5 -CN; s is 0, 1, or 2; and t is 0, 1, 2, or 3.

[0050] In some embodiments, X is N. In some embodiments, X is CH.

[0051] In some embodiments, R 1 -C(O)-NHR 2 In some embodiments, R 1 Ha-S(O)-R 2 In some embodiments, R 1 is —C(O)OH. In some embodiments, R 1 -S(O)2-R 2 In some embodiments, R 1 -S(O)2-NHR 2 In some embodiments, R 1 is —S(O)CH. In some embodiments, R 1 is —S(O)2CH3. In some embodiments, R 1 is -S(O)2NHCH3.

[0052] In some embodiments, R 2 is -C1-C6 alkyl, -(one or two -OR 5-(C1-C6 alkyl substituted with), -(C1-C6 alkylene)-CN, -(C1-C6 alkylene)-S(O) n -(C1-C6 alkyl), -(OR 5 C1-C4 alkylene optionally substituted with -C(O)OR 5 , -(OR 5 C1-C4 alkylene optionally substituted with -C(O)N(R 6 )2, -(C1-C6 alkylene)-N(R 6 )2, and -(OR 5 C1-C4 alkylene optionally substituted with -(5-6 membered heteroaryl having 1, 2, or 3 heteroatoms each independently selected from N, O, and S).

[0053] In some embodiments, R 2 is -(C1-C4 alkylene)-5-6 membered heteroaryl.

[0054] In some embodiments, R 2 is -CH(CH3)-5 to 6-membered heteroaryl.

[0055] In some embodiments, R 2 is -CH2- 5 to 6-membered heteroaryl.

[0056] In some embodiments, the 5-6 membered heteroaryl is C1-C6 alkyl or N(R a )2, optionally replaced by R a are each independently hydrogen or C1-C6 alkyl.

[0057] In some embodiments, the 5-6 membered heteroaryl is pyridyl. In some embodiments, the 5-6 membered heteroaryl is

[0058] [ka] In some embodiments, the 5-6 membered heteroaryl is oxazolyl. In some embodiments, the 5-6 membered heteroaryl is

[0059] [ka] is.

[0060] In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2 is -(C1-C6 alkyl)-OH. In some embodiments, R 2 is -(C1-C6 alkyl)-O-(C1-C6 alkyl). In some embodiments, R 2 is isopropyl. In some embodiments, R 2 -(one or two -OR 5 In some embodiments, R 2 HA-(-OR 5 In some embodiments, R 2 is -(C1-C6 alkyl substituted with -OH). In some embodiments, R 2 is -(C1-C6 alkyl substituted with -OH and -OCH3). In some embodiments, R 2 -(C1-C6 alkylene)-S(O) n -(C1-C6 alkyl). In some embodiments, R 2 is -(C1-C6 alkylene)-CN. In some embodiments, R 2 Is-(OR 5 C1-C4 alkylene optionally substituted with -C(O)OR 5 In some embodiments, R 2 Is-(OR 5 C1-C4 alkylene optionally substituted with -C(O)N(R 6 )2. In some embodiments, R 2-(C1-C6 alkylene)-N(R 6 )2.

[0061] In some embodiments, R 2 is methyl,

[0062] [ka] is selected from the group consisting of:

[0063] In some embodiments, R 2 is methyl,

[0064] [ka] is selected from the group consisting of:

[0065] In some embodiments, R 2 is methyl,

[0066] [ka] is selected from the group consisting of:

[0067] In some embodiments, m is 1. In some embodiments, m is 2.

[0068] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0069] In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2.

[0070] In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3.

[0071] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is -C1-C6 alkyl. In some embodiments, R 3 is methyl.

[0072] In some embodiments, R 3 is -C1-C6 haloalkyl.

[0073] In some embodiments, R 3 is trifluoromethyl.

[0074] In some embodiments, R 3 is halogen. In some embodiments, R 3 is -F.

[0075] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -C1-C6 alkyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is halogen. In some embodiments, R 4 is -F.

[0076] In some embodiments, R 3 is -C1-C6 haloalkyl, and R 4 is H. In some embodiments, R 3 and R 4 are both halogen. In some embodiments, R 3 and R 4 are both -C1-C6 alkyl. In some embodiments, R 3 and R 4 are both H.

[0077] In some embodiments, R 3 and R4 Together, R 3 and R 4 forms a 3- to 7-membered carbocyclic ring with the carbon to which it is attached, and the carbocyclic ring is optionally substituted with one or more halogens. In some embodiments, the halogen is F.

[0078] In some embodiments, R 3 and R 4 together form cyclopropyl or cyclobutyl optionally substituted with one or more halogens. In some embodiments, R 3 and R 4 together form a cyclopropyl or cyclobutyl optionally substituted with one or more fluoro. In some embodiments, R 3 and R 4 together form a cyclopropyl. In some embodiments, R 3 and R 4 taken together form a cyclobutyl optionally substituted with one or more fluoro.

[0079] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is -C1-C6 alkyl. In some embodiments, R 5 is methyl.

[0080] In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is -C1-C6 alkyl.

[0081] In some embodiments, s and t are both 0.

[0082] As used herein, in certain embodiments, compounds of formula (Ia)

[0083] [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 is -C1-C6 alkyl, -(one or two -OR 5 -(C1-C6 alkyl substituted with), -(C1-C6 alkylene)-CN, -(C1-C6 alkylene)-S(O) n -(C1-C6 alkyl), -(CN or OR 5 C1-C4 alkylene optionally substituted with -C(O)OR 5 , -(OR 5 C1-C4 alkylene optionally substituted with -C(O)N(R 6 )2, -(C1-C6 alkylene)-N(R 6 R 7 ), and -(OR 5 and C-C alkylene)-(5-6 membered heteroaryl having 1, 2, or 3 heteroatoms each independently selected from N, O, and S), optionally substituted with one or more R w is optionally replaced by n is 0, 1, or 2; R 3 is selected from the group consisting of halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, and —O—(C1-C6 alkyl); R 4 is selected from the group consisting of hydrogen, halogen, and -C1-C6 alkyl; or R 3 and R 4 Together, R 3 and R 4 forms a 3- to 7-membered carbocyclic ring with the carbon to which it is attached, the 3- to 7-membered carbocyclic ring being optionally substituted with one or more halogens; R 5 is independently at each occurrence hydrogen or -C1-C6 alkyl; and R 6 each occurrence is independently hydrogen or -C1-C6 alkyl; R 7is hydrogen, -C1-C6 alkyl, -C(O)-(C 1-6 alkyl), -C(O)NR 6 , -C(O)2-(C 1-6 alkyl), and -S(O)NR 6 -(C1-C6 alkyl), R w are each independently -C1-C6 alkyl, -N(R 6 )2, and oxo, wherein -C1-C6 alkyl is optionally substituted with -OH.

[0084] As used herein, in certain embodiments, compounds of formula (Ia')

[0085] [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 is -C1-C6 alkyl, -(one or two -OR 5 -(C1-C6 alkyl substituted with), -(C1-C6 alkylene)-CN, -(C1-C6 alkylene)-S(O) n -(C1-C6 alkyl), -(CN or OR 5 C1-C4 alkylene optionally substituted with -C(O)OR 5 , -(OR 5 C1-C4 alkylene optionally substituted with -C(O)N(R 6 )2, -(C1-C6 alkylene)-N(R 6 R 7 ), -(C1-C6 alkylene)-OP(O)(OR 5 )2, and -(OR 5 and C-C alkylene)-(5-6 membered heteroaryl having 1, 2, or 3 heteroatoms each independently selected from N, O, and S), optionally substituted with one or more R w is optionally replaced by n is 0, 1, or 2; R3 is selected from the group consisting of halogen, —C1-C6 alkyl, —C1-C6 haloalkyl, and —O—(C1-C6 alkyl); R 4 is selected from the group consisting of hydrogen, halogen, and -C1-C6 alkyl; or R 3 and R 4 Together, R 3 and R 4 forms a 3- to 7-membered carbocyclic ring with the carbon to which it is attached, the 3- to 7-membered carbocyclic ring being optionally substituted with one or more halogens; R 5 is independently at each occurrence hydrogen or -C1-C6 alkyl; and R 6 each occurrence is independently hydrogen or -C1-C6 alkyl; R 7 is hydrogen, -C1-C6 alkyl, -C(O)-(C 1-6 alkyl), -C(O)N(R 6 )2, -C(O)2-(C 1-6 alkyl), -S(O) n -(C1-C6 alkyl), and -S(O) n NR 6 -(C1-C6 alkyl), R w are each independently -C1-C6 alkyl, -N(R 6 )2, and oxo, wherein -C1-C6 alkyl is optionally substituted with -OH.

[0086] In some embodiments, the compound has the formula (Ib):

[0087] [ka] or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, the compound has the formula (Ic):

[0089] [ka] or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments, the compound has the formula (Ib-1):

[0091] [ka] or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, the compound has the formula (Ib-2):

[0093] [ka] or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments, R 2 is -(C1-C4 alkylene)-5-6 membered heteroaryl.

[0095] In some embodiments, R 2 is -CH(CH3)-5 to 6-membered heteroaryl.

[0096] In some embodiments, R 2 is -CH2- 5 to 6-membered heteroaryl.

[0097] In some embodiments, the 5-6 membered heteroaryl is C1-C6 alkyl or N(R a )2, optionally replaced by R a are each independently hydrogen or C1-C6 alkyl.

[0098] In some embodiments, the 5-6 membered heteroaryl is pyridyl. In some embodiments, the 5-6 membered heteroaryl is

[0099] [ka] In some embodiments, the 5-6 membered heteroaryl is oxazolyl. In some embodiments, the 5-6 membered heteroaryl is

[0100] [ka] is.

[0101] In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2 is -(C1-C6 alkyl)-OH. In some embodiments, R 2 is -(C1-C6 alkyl)-O-(C1-C6 alkyl). In some embodiments, R 2 is isopropyl. In some embodiments, R 2 -(one or two -OR 5 In some embodiments, R 2 HA-(-OR 5 In some embodiments, R 2 is -(C1-C6 alkyl substituted with -OH). In some embodiments, R 2 is -(C1-C6 alkyl substituted with -OH and -OCH3). In some embodiments, R 2 -(C1-C6 alkylene)-S(O) n -(C1-C6 alkyl). In some embodiments, R 2 is -(C1-C6 alkylene)-CN. In some embodiments, R 2 Is -(OR 5 C1-C4 alkylene optionally substituted with -C(O)OR 5 In some embodiments, R 2 Is -(OR5 C1-C4 alkylene optionally substituted with -C(O)N(R 6 )2. In some embodiments, R 2 -(C1-C6 alkylene)-OP(O)(OR 5 )2. In some embodiments, R 2 -(C1-C6 alkylene)-N(R 6 )2.

[0102] In some embodiments, R 2 -(one or two -OR 5 C1-C6 alkyl substituted with), -(C1-C6 alkylene)-S(O) n -(C1-C6 alkyl), -(OR 5 C1-C4 alkylene optionally substituted with -C(O)OR 5 , -(OR 5 C1-C4 alkylene optionally substituted with -C(O)N(R 6 )2, -(C1-C6 alkylene)-N(R 6 R 7 )2, -(C1-C6 alkylene)-OP(O)(OR 5 )2, -(OR 5 and -(C-C alkylene)-(3- to 10-membered heterocyclyl having 1, 2, 3, or 4 heteroatoms each independently selected from N, O, and S), wherein any of the aforementioned 5- to 6-membered heteroaryl and 3- to 10-membered heterocyclyl are optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of methyl, -NH, and oxo.

[0103] In some embodiments, R 2 -(one or two -OR 5 -(C1-C6 alkyl substituted with), -(C1-C6 alkylene)-N(R 6 R7 )2, and -(OR 5 and C-C alkylene)-(5- to 6-membered heteroaryl having 1, 2, or 3 heteroatoms each independently selected from N, O, and S), optionally substituted with, wherein any of the aforementioned 5- to 6-membered heteroaryl and 3- to 10-membered heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of methyl, —NH, and oxo.

[0104] R 2 is methyl,

[0105] [ka] is selected from the group consisting of:

[0106] In some embodiments, R 2 is methyl,

[0107] [ka] is selected from the group consisting of:

[0108] In some embodiments, R 2 is methyl,

[0109] [ka] is selected from the group consisting of:

[0110] In some embodiments, R 3 is -C1-C6 haloalkyl.

[0111] In some embodiments, R 3 is trifluoromethyl.

[0112] In some embodiments, R 3is halogen. In some embodiments, R 3 is -F.

[0113] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is halogen. In some embodiments, R 4 is -F.

[0114] In some embodiments, R 3 and R 4 Together, R 3 and R 4 forms a 3- to 7-membered carbocyclic ring with the carbon to which it is attached, and the carbocyclic ring is optionally substituted with one or more halogens. In some embodiments, the halogen is F.

[0115] In some embodiments, the compound is selected from Table 1.

[0116] [Table 1-1]

[0117] [Table 1-2]

[0118] [Table 1-3]

[0119] [Table 1-4]

[0120] [Table 1-5]

[0121] [Table 1-6]

[0122]

Table 1-7

[0123]

Table 1-8

[0124]

Table 1-9

[0125]

Table 1-10

[0126]

Table 1-11

[0127]

Table 1-12

[0128]

Table 1-13

[0129]

Table 1-14

[0130]

Table 1-15

[0131]

Table 1-16

[0132]

Table 1-17

[0133]

Table 1-18

[0134]

Table 1-19

[0135]

Table 1-20

[0136]

Table 1-21

[0137]

Table 1-22

[0138]

Table 1-23

[0139]

Table 1-24

[0140]

Table 1-25

[0141]

Table 1-26

[0142]

Table 1-27

[0143]

Table 1-28

[0144]

Table 1-29

[0145]

Table 1-30

[0146]

Table 1-31

[0147]

Table 1-32

[0148]

Table 1-33

[0149]

Table 1-34

[0150]

Table 1-35

[0151]

Table 1-36

[0152] [Table 1-37]

[0153] Pharmaceutical Compositions and Routes of Administration Disclosed herein, in certain embodiments, is a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (I), Formula (I'), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Ib-1), or Formula (Ib-2)), or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable excipient. In some embodiments, the excipient is selected from inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizing agents, and adjuvants. In some embodiments, the pharmaceutical composition is administered alone or in combination with other therapeutic agents. Such compositions are prepared by methods well known in the pharmaceutical arts.

[0154] In some embodiments, the pharmaceutical compositions are administered in either single or multiple doses by any of the accepted modes of administration for agents having similar utilities as described in the patents and patent applications incorporated by reference, including, for example, rectal, buccal, intranasal, and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as, for example, a stent, or a cylindrical polymer inserted into an artery.

[0155] One mode of administration is parenteral, particularly by injection. In some embodiments, the novel compositions of the present disclosure may be incorporated into aqueous or oily suspensions or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil for administration by injection, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection, but are less preferred in the context of the present disclosure. In some embodiments, ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils are used. In some embodiments, proper fluidity is maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. In some embodiments, the prevention of microbial action is achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0156] Sterile injectable solution is prepared by incorporating the compound of the present disclosure in the required amount into a suitable solvent together with various other components as listed above as necessary, and then sterilizing by filtration.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains a basic dispersion medium and the other necessary components listed above.For the preparation of sterile injectable powder, the preferred preparation method is vacuum drying and freeze-drying technology, which can obtain powder of active ingredient and any additional desired components from the solution that has been previously sterilized and filtered.

[0157] Oral administration is another route of administration of the compounds of the present disclosure. In some embodiments, administration is via capsules or enteric-coated tablets, etc. In some embodiments, in preparing pharmaceutical compositions containing at least one compound described herein, the active ingredient is typically diluted with an excipient and / or enclosed within such a carrier in the form of a capsule, sachet, paper, or other container. In some embodiments, when an excipient acts as a diluent, the excipient is in the form of a solid, semi-solid, or liquid material (as described above) that acts as a vehicle, carrier, or medium for the active ingredient. Thus, in some embodiments, the composition is in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), e.g., ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0158] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. In some embodiments, the formulation further comprises the following: lubricating agents such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methylbenzoates and propylhydroxybenzoates, sweeteners, and flavoring agents.

[0159] In some embodiments, the compositions of the present disclosure are formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient by utilizing procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Another formulation for use in the methods of the present disclosure uses transdermal delivery devices ("patches"). In some embodiments, such transdermal patches are used to provide continuous or discontinuous infusion of a controlled amount of the compounds of the present disclosure. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. In some embodiments, such patches are constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

[0160] The compositions are preferably formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce a desired therapeutic effect, in association with an appropriate pharmaceutical excipient (e.g., tablet, capsule, ampoule). The compounds are typically administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains 1 mg to 2 g of a compound described herein, and for parenteral administration, preferably 0.1 to 700 mg of a compound described herein. However, it will be understood that the amount of compound actually administered will typically be determined by a physician in light of relevant circumstances, including the condition being treated, the selected route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0161] To prepare solid compositions such as tablets, the primary active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds of the present disclosure. In some embodiments, when these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition such that the composition is easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0162] In some embodiments, tablets or pills of the present disclosure are coated or otherwise compounded to provide a dosage form offering the advantage of prolonged action or to protect against the acidic conditions of the stomach. For example, in some embodiments, the tablet or pill comprises an inner dosage component and an outer dosage component, the latter in the form of an envelope over the former. In some embodiments, the two components are separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. In some embodiments, a variety of materials are used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0163] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. In some embodiments, liquid or solid compositions contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, compositions are administered by oral or nasal respiratory route for local or systemic effect. In some embodiments, compositions in pharmaceutically acceptable solvents are nebulized by the use of inert gases. In some embodiments, nebulized solutions are inhaled directly from a nebulizing device, or the nebulizing device is attached to a face mask tent or intermittent positive pressure breathing machine. In some embodiments, solution, suspension, or powder compositions are administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0164] Treatment method Disclosed herein, in certain embodiments, is a method for treating a disease or disorder regulated by abnormal activity of a TEAD isoform (e.g., TEAD1 and / or TEAD4) (e.g., overactivation of the TEAD transcription complex) in an individual in need thereof, the method comprising administering to the individual a compound of Formula (I), Formula (I'), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Ib-1), or Formula (Ib-2), or a pharmaceutically acceptable salt thereof (e.g., a therapeutically effective amount of a compound of Formula (I), Formula (I'), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Ib-1), or Formula (Ib-2), or a pharmaceutically acceptable salt thereof).

[0165] TEA domain transcription factors (TEADs) are downstream effectors of the Hippo signaling pathway. Currently, four isoforms of TEADs—TEAD1, TEAD2, TEAD3, and TEAD4—have been identified. TEAD isoforms share a highly similar structure. The N-termini of the four isoforms share a highly conserved 68-amino acid TEA / ATTS DNA-binding domain that binds to the MCAT element (50-CATTCCA / T-30). The C-termini contain a transactivation domain that recruits the transcriptional coactivators YAP / TAZ.

[0166] TEAD protein expression is upregulated in many cancer types, including gastric, colon, breast, and prostate cancer. TEAD hyperactivation plays a role in tumor progression, metastasis, cancer metabolism, immunity, and drug resistance, and correlates with poor patient survival.

[0167] Selective binding of TEAD1 and / or TEAD4 is beneficial for optimizing antitumor efficacy while minimizing undesired effects. Inhibition of TEAD3 is associated with off-target toxicity (e.g., nephrotoxicity), whereas inhibition of TEAD2 can be pro-proliferative.

[0168] The TEAD isoform selectivity demonstrated by the compounds disclosed herein is an advantage over TEAD inhibitors known in the art. For example, as demonstrated by Tang and Post using a thermal shift assay, the TEAD inhibitor VT3989 interacts primarily with TEAD1-3. The reported thermal shift data are shown in Table 2 below (Tang and Post, "The TEAD autopalmitoylation inhibitor VT3989 improves efficacy and increases durability of efficacy of osimertinib in preclinical EGFR mutant tumor models," Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr. 8-13. Philadelphia (PA): AACR; Poster #5364). The data provided in Table 2 indicate that VT3989 offers minimal selectivity for TEAD2 and 3, TEAD isoforms for which inhibition is undesirable. Furthermore, VT3989 exhibits low levels of binding to TEAD4, a TEAD isoform for which inhibition is desirable. Each change in ΔTm (°C) of 2.5°C can be associated with an approximately 10-fold difference in binding affinity (Bhayani et al.; “Determination of dissociation constants of protein ligands by thermal shift assay,” Biochemical and Biophysical Research Communications, 2022, 560:1-6.).

[0169] [Table 2]

[0170] In some embodiments, the compounds disclosed herein selectively bind to one or more TEAD isoforms. In certain embodiments, the compounds disclosed herein selectively bind to TEAD1. In certain embodiments, the compounds disclosed herein selectively bind to TEAD4. In certain embodiments, the compounds disclosed herein selectively bind to TEAD1 and TEAD4. In some embodiments, the binding selectivity for TEAD1 is 10-fold, 100-fold, 1,000-fold, or 10,000-fold relative to TEAD2 and / or TEAD3. In some embodiments, the binding selectivity for TEAD4 is 10-fold, 100-fold, 1,000-fold, or 10,000-fold relative to TEAD2 and / or TEAD3. Evidence of the TEAD isoform selectivity demonstrated by the compounds disclosed herein is provided in Example 174 below.

[0171] In some embodiments, the compounds disclosed herein are useful as medical therapies for treating diseases, disorders, or conditions mediated by overactivation of the YAP / TAZ-TEAD (e.g., TEAD1 and / or TEAD4) transcriptional coactivator complex. In some embodiments, the compounds disclosed herein are useful as medical therapies for treating diseases, disorders, or conditions characterized by overactivation of TEAD (e.g., TEAD1, TEAD2, TEAD3, and TEAD4 isoforms). In some embodiments, the disease, disorder, or condition is characterized by TEAD overexpression or genomic fusion or amplification. TEAD1 and TEAD4 undergo recurrent onco-fusions, e.g., TEAD1-PARVA. These fusions can induce higher expression of TEADs, resulting in enhanced transcription of TEAD target genes. TEAD4 amplification (genomic copy number gain) occurs in a variety of cancers, for example, as part of the 12p13 locus in ovarian and uterine cancers and testicular germ cell tumors. These genomic amplifications of TEAD4 are associated with a strong increase in its mRNA expression and can induce high TEAD-YAP / TAZ transcriptional activity.

[0172] In certain embodiments, the TEAD isoform is TEAD1. In certain embodiments, the TEAD isoform is TEAD4. In some embodiments, the disease, disorder, or condition is a cancer characterized by aberrant TEAD transcription complex activity (e.g., hyperactivation). Such cancers include, but are not limited to, breast cancer, lung cancer, gastric cancer, colorectal cancer, pancreatic cancer including pancreatic adenocarcinoma, mesothelioma including malignant mesothelioma, hepatocellular carcinoma, prostate cancer, head and neck cancer, renal cell carcinoma, and medulloblastoma. In some embodiments, the cancer is selected from pancreatic adenocarcinoma, hepatocellular carcinoma, breast cancer, and malignant mesothelioma. In certain embodiments, the cancer is malignant mesothelioma.

[0173] In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is renal cell carcinoma. In some embodiments, the cancer is medulloblastoma. In some embodiments, the cancer is metastatic cancer. In some embodiments, the cancer is medulloblastoma. In some embodiments, the cancer is metastatic cancer. In some embodiments, the cancer is metastatic breast cancer. In some embodiments, the cancer is metastatic lung cancer. In some embodiments, the cancer is metastatic gastric cancer. In some embodiments, the cancer is metastatic colon cancer. In some embodiments, the cancer is metastatic prostate cancer. In some embodiments, the cancer is metastatic head and neck cancer. In some embodiments, the cancer is metastatic renal cell carcinoma. In some embodiments, the cancer is metastatic mesothelioma. In some embodiments, the cancer is metastatic pancreatic cancer. In some embodiments, the cancer is metastatic hepatocellular carcinoma.

[0174] In some embodiments, the present disclosure provides a compound of Formula (I), Formula (I'), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Ib-1), or Formula (Ib-2) for modulating TEAD activity. In some embodiments, the present disclosure provides a pharmaceutically acceptable salt of a compound of Formula (I), Formula (I'), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Ib-1), or Formula (Ib-2) for modulating TEAD activity.

[0175] In some embodiments, the present disclosure provides a compound of Formula (I), Formula (I'), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Ib-1), or Formula (Ib-2), or a pharmaceutically acceptable salt thereof, for use in medical therapy. [Example]

[0176] The present disclosure is further described in the following examples, which are provided for illustrative purposes only and are not intended to limit the disclosure in any way. Abbreviation Boc tert-butyloxycarbonyl DAST Diethylaminosulfur trifluoride DBU 1,8-diazabicyclo(5.4.0)undec-7-ene DCC dicyclohexylcarbodiimide DCE 1,1-dichloroethane DCM dichloromethane DEA Diethanolamine DEAD Diethyl azodicarboxylate DIAD Diisopropyl azodicarboxylate DIBAL Diisobutylaluminum hydride DIPEA N,N-Diisopropylethylamine, Hunig's base DMA N,N-dimethylacetamide DMAP 4-(dimethylamino)pyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc ethyl acetate h time HATU N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide HBTU (1H-benzotriazol-1-yloxy)(dimethylamino)-N,N-dimethylmethaniminium hexafluorophosphate HOBT N-Hydroxybenzotriazole HPLC High Pressure Liquid Chromatography LAH Lithium aluminum hydride IPA Isopropyl Alcohol LCMS Liquid Chromatography-Mass Spectrometry LDA Lithium diisopropylamide LiHMDS Lithium bis(trimethylsilyl)amide mCPBA meta-chloroperoxybenzoic acid MI molecular ion Min MW Microwave NBS N-Bromosuccinamide NCS N-chlorosuccinamide NFOBS N-fluoro-o-benzenedisulfonimide NFSI N-Fluorobenzenesulfonimide NHS N-hydroxysuccinimide NIS N-iodosuccinamide NMM N-methylmorpholine NMP 1-methyl-2-pyrrolidone NMR nuclear magnetic resonance PdCl2(PPh3)2 Bis(triphenylphosphine)palladium chloride Pd(dppf)2Cl2[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)2Cl2.DCM [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (Pd(dba)2) Bis(dibenzylideneacetone)palladium Rbf round bottom flask RT retention time SCX-2 Silica-based adsorbent with chemically bonded propylsulfonic acid functional groups SFC Supercritical Fluid Chromatography TBAF Tetra-n-butylammonium fluoride TBDMS tert-butyldimethylsilyl TFAA Trifluoroacetic anhydride TFA trifluoroacetic acid THF tetrahydrofuran TPP Tripotassium Phosphate Ts Toluenesulfonyl XPhos-Pd-G1 2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) chloride XPhos-Pd-G2 Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0177] Analysis method Commercially available starting materials, reagents, and dry solvents were used as supplied. Flash or glass column chromatography was performed using Merck silica gel 230-400 mesh size. Flash chromatography was also performed on a combi-flash RF Teledyne Isco machine. Preparative TLC was performed on Merck plates.

[0178] Liquid chromatography-mass spectrometry Method A Method Name:-UC02_FAR1, Machine Details:-Water Acquity UPLC-H Class with PDA and Acquity SQ detector, Column: Waters X-bridge C18, 50 * 2.1 mm, 2.5 micron, column temperature: 35 °C, autosampler temperature: 15 °C, mobile phase A: 0.1% formic acid in Milli-Q water (pH = 2.70), mobile phase B: 0.1% formic acid in Milli-Q water:acetonitrile (10:90), mobile phase gradient details: T = 0 min (97% A, 3% B) flow rate: 0.8 mL / min, T = 0.75 min (97% A, 3% B) flow rate: 0.8 mL / min, gradient for T = 2.7 min (2% A, 98% B) flow rate: 0.8 mL / min, gradient for T = 3 min (0% A, 100% B) flow rate: 1 mL / min, T = 3.5 min (0% A, 100% B) Flow rate: 1 mL / min, gradient to T = 3.51 min (97% A, 3% B), flow rate: 0.8 mL / min, end of run at T = 4 min (97% A, 3% B), flow rate: 0.8 mL / min, flow rate: -0.8 mL / min, run time: -4 min, UV detection method: -PDA, wavelength: -200 to 500 nm, mass parameters: probe: -ESI, ionization mode: -positive and negative, cone voltage: -30 V and 10 V, capillary voltage: -3.0 kV, extractor voltage: -1 V, RF lens: -0.1 V, source temperature: -120 °C, desolvation temperature: -400 °C. Cone gas flow: -100 L / h, desolvation gas flow: -800 L / h.

[0179] Method B Method Name:-UC03_ABR2, Machine Details:-Waters Acquity Ultraperfomance LC connected to PDA and equipped with SQ detector, Column:Waters X-bridge C18, 50 *4.6 mm, 3.5 micron, column temperature: 35°C, autosampler temperature: 15°C, mobile phase A: 5 mM ammonium bicarbonate in Milli-Q water (pH = 8.00), mobile phase B: acetonitrile, mobile phase gradient details: T = 0 min (97% A, 3% B) flow rate: 1.0 mL / min, T = 0.20 min (97% A, 3% B) flow rate: 1.0 mL / min, gradient for T = 2.70 min (20% A, 80% B) flow rate: 1.0 mL / min, gradient for T = 3.0 min (0% A, 100% B) flow rate: 1.2 mL / min, T = 3.50 min (0% A, 100% B) flow rate: 1.2 mL / min, gradient for T = 3. .51 min (97% A, 3% B) Flow rate: 1.0 mL / min, End of run at T=4.0 min (97% A, 3% B), Flow rate: 1.0 mL / min, Run time: -4 min, UV detection method: -PDA, Wavelength: -195 nm-500 nm, Mass parameters: Probe: -ESI, Mode of ionization: -positive and negative, Cone voltage: -30 and 10 V, Capillary voltage: -3.0 kV, Extractor voltage: -2 V, Rf lens: -0.1 V, Source temperature: -120 °C, Probe temperature: -400 °C, Cone gas flow: -100 L / hr, Desolvation gas flow: -800 L / hr.

[0180] High-Performance Liquid Chromatography Method Method A Method name: -HP04_BR1 Machine details: -Water alliance e2695 with 2998PDA detector, Column temperature: 25°C, Autosampler temperature: 25°C, Mobile phase A: 0.1% ammonium hydroxide solution in HPLC water, Mobile phase B: 100% acetonitrile, Mobile phase gradient details: T=0 min (10% A, 90% B) flow rate: 1 mL / min, T=7 min (90% A, 10% B) flow rate: 1 mL / min, Gradient for T=9 min (100% A, 0% B), Flow rate: 1 mL / min, gradient to T = 14 min (100% A, 0% B), Flow rate: 1 mL / min, gradient to T = 14.01 min (10% A, 90% B), Flow rate: 1 mL / min, gradient to T = 17 min (10% A, 90% B), Flow rate: 1 mL / min, end of run at T = 17 min (10% A, 90% B), Flow rate: 1 mL / min, Run time: -17 min, UV detection method: -PDA.

[0181] Method B Method name: -HP05_TFAR1. Machine details: AGILENT TECHNOLOGY 1260 Infinity Series with PDA detector, Column temperature: 25°C, Autosampler temperature: 25°C, Mobile phase A: 0.05% trifluoroacetic acid in HPLC water, Mobile phase B: 100% acetonitrile, Mobile phase gradient details: T = 0 min (90% A, 10% B) flow rate: 1 mL / min, T = 7 min (10% A, 90% B) flow rate: 1 mL / min, T = 9 min (0% A, 100% B) Gradient, flow rate: 1 mL / min, T = 14 min (0% A, 100% B), gradient, flow rate: 1 mL / min, T = 14.01 min (90% A, 10% B), flow rate: 1 mL / min, T = 17 min (90% A, 10% B), gradient, flow rate: 1 mL / min, T = 17 min (90% A, 10% B), end of run at T = 17 min (90% A, 10% B), flow rate: 1 mL / min, run time: -17 min, UV detection method: -PDA.

[0182] Method C Method Name:-HP06_TFAR1. Machine Details:-AGILENT TECHNOLOGY 1100 Series with PDA detector, Column Temperature: 25°C, Autosampler Temperature: 25°C, Mobile Phase A: 0.05% trifluoroacetic acid in HPLC water, Mobile Phase B: 100% acetonitrile, Mobile Phase Gradient Details: T=0 min (90% A, 10% B) Flow Rate: 1 mL / min, T=7 min (10% A, 90% B) Flow Rate: 1 mL / min, T=9 min (0% A, 100% B) Gradient, Flow Volume: 1 mL / min, gradient to T = 14 min (0% A, 100% B), flow rate: 1 mL / min, gradient to T = 14.01 min (90% A, 10% B), flow rate: 1 mL / min, gradient to T = 17 min (90% A, 10% B), flow rate: 1 mL / min, end of run at T = 17 min (90% A, 10% B), flow rate: 1 mL / min, run time: -17 min, UV detection method: -PDA.

[0183] NMR 1H nuclear magnetic resonance (NMR) spectroscopy was performed using a Bruker Avance-400 instrument operating at 400 MHz at room temperature using the solvents indicated unless otherwise specified. Samples were prepared as solutions in the appropriate deuterated solvent and referenced to the appropriate internal non-deuterated solvent peak or tetramethylsilane. Chemical shifts were recorded in ppm (δ) downfield of tetramethylsilane. In all cases, the NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts per million (ppm), using conventional abbreviations to designate major peaks, e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet; and br, broadband.

[0184] Purification method Preparative purification by reversed-phase HPLC Preparative HPLC method A Biotage-FC-01 with a binary pump equipped with a UV / visible wavelength detector; Column: YMC, 120 g, 50 μm; Column temperature: room temperature; Mobile phase A: 0.1% formic acid in water; Mobile phase B: acetonitrile; Mobile phase gradient details: t = 0.01 min (100% A, 0% B), t = 3 min (85% A, 15% B), gradient for t = 25 min (55% A, 45% B), t = 35 min (0% A, 100% B), gradient to end of run at t = 45 min (100% A, 0% B); Flow rate: 80 mL / min; Analysis time: 45 min.

[0185] synthesis Several methods for chemical synthesis of the compounds of the present application are described herein. These and / or other well-known methods can be modified and / or adapted in various ways to facilitate the synthesis of additional compounds within the scope of the present application and claims. Such alternative methods and modifications should be understood as being within the spirit and scope of the present application and claims. Therefore, the methods described in the following description, schemes, and examples are intended for illustrative purposes and should not be construed as limiting the scope of the present disclosure.

[0186] In one approach (Scheme 1), compounds of formula [IIb] can be prepared by reacting a substituted Het-aromatic carboxylic acid of formula [II] with an amine of general formula [III] in the presence of a tertiary amine base such as DIPEA, with an amide coupling reagent such as HATU in DMF or DCM as a solvent. The reaction is suitably carried out at room temperature. After workup of the reaction, typically by liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse-phase preparative HPLC, or recrystallization (Method A).

[0187] [ka]

[0188] The following compounds were prepared according to the methods described above using the intermediates indicated.

[0189] Example 1 - Synthesis of N-isopropyl-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 1)

[0190] [ka]

[0191] Process 1a In a 250 mL three-neck RB flask, 4-(trifluoromethyl)cyclohexan-1-one (CAS No.: 75091-99-5) (0.5 g, 3.01 mmol, 1.0 equiv.) in THF (31.5 mL) was added dropwise with stirring at −78 °C for 30 min. Stirring was then continued for an additional 1 h at −78 °C. After 1 h, N-phenyltrifluoromethanesulfonimide (1.0 g, 3.01 mmol, 1.0 equiv.) in THF (4 mL) was added dropwise with stirring over 30 min. The reaction mixture was then stirred at −78 °C for an additional 2 h and slowly warmed to room temperature with stirring over 6 h. The reaction was monitored by TLC (using EA:hexane, 0.1:9.9 as the mobile phase) and was found to be complete after 6 h of stirring at room temperature. The reaction mixture was extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with water, dried over NaSO, and filtered. The filtrate was evaporated, and the residue was purified by silica gel column chromatography (10% EtOAc in hexanes) to give 4-(trifluoromethyl)cyclohex-1-en-1-yl trifluoromethanesulfonate as a white solid (A1, 0.45 g, 1.509 mmol, yield: 50.14%). 1 H NMR (CDCl3, 400 MHz): δ ppm 5.80-5.81 (m, 1H), 2.51-2.47 (m, 2H), 2.43-2.30 (m, 2H), 2.20-2.15 (m, 1H), 1.84-1.73 (m, 1H), 0.83-0.90 (m, 1H). Note: Traces of aliphatic impurities with PhN(OTf)2.

[0192] Process 1b To a solution of 4-(trifluoromethyl)-cyclohex-1-enyl trifluoromethanesulfonate (CAS: 73183-34-3) (A1, 0.1 g, 0.335 mmol, 1.0 equiv.) in dioxane (3.8 mL) in a 250 mL three-necked RB flask, bis(pinacolato)diboron (0.102 g, 0.402 mmol, 1.2 equiv.), potassium acetate (0.109 g, 1.11 mmol, 3.0 equiv.), and PdCl(dppf) (0.074 g, 0.100 mmol, 0.3 equiv.) were added under nitrogen atmosphere. The reaction mixture was heated at 80 °C with stirring for 16 h. The reaction was monitored by TLC (using EA:hexane, 1:9, as the mobile phase) and found to be complete after stirring at 80 °C for 16 h, after which it was cooled to room temperature and filtered through a bed of Celite. The filtrate was evaporated in vacuo, and the residue was purified by silica gel column chromatography (10% EtOAc / hexane) to give 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1,3,2-dioxaborolane (A2, 0.027 g, 0.097 mmol, yield: 29.16%). 1 H NMR (DMSO-d6, 400 MHz): δ ppm 6.54-6.53 (m, 1H), 2.38-2.31 (m, 2H), 2.27-2.25 (m, 1H), 2.21-2.20 (m, 2H), 2.03-1.99 (m, 1H), 1.49-1.47 (m, 1H), 1.30 (s, 12H). Note: Small amounts of aliphatic impurities were observed.

[0193] Process 1 A solution of methyl 8-bromoquinoline-3-carboxylate (A13, 5.0 g, 18.791 mmol, 1.0 equiv.) and NaOH (1.5 g, 37.581 mmol, 2.0 equiv.) in methanol and water (50 mL, 9:1) was stirred at room temperature for 2 h. The reaction mixture was acidified with 1 N HCl (40 mL, pH = 3) and stirred at 0 °C for 30 min to give a pale yellowish solid. The reaction was monitored by TLC (using EA:hexane, 3:7 as the mobile phase) and found to be complete after stirring at room temperature for 2 h. The resulting solid was filtered under high vacuum to give 8-bromoquinoline-3-carboxylic acid (A3, 4.13 g, 16.38 mmol, 87.20% yield). 1 H NMR (DMSO-d6, 400MHz): δ ppm 7.64(t,J=8.0Hz,1H),8.25-8.31(m,2H),9.05(d,J=2.4Hz,1H),9.40(d,J=2.4Hz,1H) LCMS (Method A): 1.736 min, 100.0%, MS: ES+ 252.00[M] +

[0194] Process 2 In a 250 mL three-neck RB flask, 8-bromoquinoline-3-carboxylic acid (A3, 4.0 g, 15.873 mmol, 1.0 equiv.), isopropylamine CAS number: 75-31-0 (1.19 g, 15.873 mmol, 1.0 equiv.), and DIPEA (6.2 g, 47.62 mmol, 3.0 equiv.) were stirred with HATU (6.59 g, 17.46 mmol, 1.1 equiv.) in DMF (40 mL, 10 v) at room temperature for 16 h. The reaction was monitored by TLC (using EA:hexane, 1:1 as the mobile phase) and was found to be complete after stirring at room temperature for 16 h. The resulting reaction mixture was diluted with ice-cold water (200 mL) and stirred for 1 h. The resulting yellowish solid was filtered through a Buchner funnel to give 8-bromo-N-isopropylquinoline-3-carboxamide (A4, 3.05 g, 10.41 mmol, yield: 65.58%). 1H NMR (DMSO-d6, 400MHz): δ ppm 9.34(d,J=2.0Hz,1H),8.87(d,J=2.4Hz,1H),8.67(d,J=8.8Hz,1H),8.26-8.24,(m,1H ),8.16-8.13(m,1H),7.62(d,J=8.0Hz,1H),4.22-4.13(m,1H),1.23(d,J=6.8Hz,6H), LCMS (Method A): 1.852 min, 100.0%, MS: ES+ 293.01 [M+H]

[0195] Process 3 To a stirred solution of 8-bromo-N-isopropylquinoline-3-carboxamide (A4, 1.2 g, 4.093 mmol, 1.0 equiv.) and 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (A2, 1.24 g, 4.503 mmol, 1.1 equiv.) in 1,4-dioxane and water (14.5 mL, 9:1), tripotassium phosphate (1.21 g, 12.28 mmol, 3.0 equiv.) was added and purged with nitrogen for 30 minutes, after which Pd(dppf)Cl (0.94 g, 0.819 mmol, 0.2 equiv.) was added and the resulting reaction mixture was heated at room temperature up to 100 °C for 16 hours. The reaction was monitored by TLC (using EA:hexane, 3:7, as the mobile phase) and was found to be complete after 16 h. The reaction mixture was filtered through a bed of Celite, and the filtrate was concentrated under reduced pressure. The crude residue (2.5 g) was purified using silica gel (60-120 mesh) as the stationary phase (25% EtOAc in hexane) to give N-isopropyl-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 1, 1.0 g, 2.759 mmol, yield: 67.57%). 1H NMR (DMSO-d, 400 MHz): δ ppm 9.24 (d, J = 2.4 Hz, 1H), 8.78 (d, J = 2.4 Hz, 1H), 8.58 (d, J = 7.6 Hz, 1H), 8.01-7.98 (m, 1H), 7.63-7.62 (m, 2H), 5.87 (br s, 1H), 4.18-4.13 (m, 1H), 2.80-2.68 (m, 3H), 2.31-2.27 (m, 1H), 2.09-2.06 (m, 1H), 1.73-1.67 (m, 1H), 1.21 (d, J = 8.0 Hz, 6H). Note: CF-CH protons corresponded to the DMSO solvent peaks clearly observed in MeOD NMR. 1 H NMR (MeOD, 400 MHz): δ ppm 9.24 (d, J = 2.4 Hz, 1H), 8.74 (d, J = 2.4 Hz, 1H), 7.96 (dd, J = 7.6, 2.0 Hz, 1H), 7.68-7.62 (m, 2H), 5.87 (br s, 1H), 4.33-4.26 (m, 1H), 2.79-2.64 (m, 3H), 2.55-2.49 (m, 1H), 2.41-2.36 (m, 1H), 2.18-2.14 (m, 1H), 1.92-1.83 (m, 1H), 1.33 (d, J = 6.8 Hz, 6H). Note: -CONH protons were exchanged in MeOD. LCMS (Method A): 2.239 min, 96.73%, MS: ES+ 363.10[M+H] HPLC (Method B): 8.327 min, 97.65%, @254nm.

[0196] Example 2 - Synthesis of N-((S)-1-hydroxypropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 2)

[0197] [ka]

[0198] Process 1 To a stirred solution of 8-bromoquinoline-3-carboxylic acid (A3, 0.3 g, 1.190 mmol, 1.0 equiv.), 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1,3,2-dioxaborolane (A2, 0.328 g, 1.190 mmol, 1.0 equiv.), and KPO (1.2 g, 5.952 mmol, 5.0 equiv.) in 1,4 dioxane:water (4 mL, 9:1) was added Pd(PPh) (0.137 g, 0.119 mmol, 0.1 equiv.) under N. The resulting mixture was stirred at 100 °C for 2.5 h. The reaction was monitored by TLC (using EA:hexane, 7.0:3.0 as the mobile phase) and was found to be complete after stirring at 100 °C for 2.5 h. The resulting reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.3 g (crude) of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (A5, 0.3 g, 0.934 mmol, yield: crude). Note: The crude compound was used directly in the next step without further purification. LCMS (Method A): 2.464 min, 86.69%, 254.0 nm, MS: ES+ 322.11 (M+1)

[0199] Process 2 A solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (A5, 0.3 g, 0.9345 mmol, 1.0 equiv.), HATU (1.0 g, 2.803 mmol, 3.0 equiv.), and DIPEA (0.180 g, 1.401 mmol, 1.5 equiv.) in DCM (3 mL) was stirred at 0 °C under a N atmosphere for 20 min, followed by the addition of CAS:40154-78-7 (0.2 g, 1.027 mmol, 1.1 equiv.) under nitrogen. The resulting mixture was stirred at room temperature for 5 h. The reaction was monitored by TLC (using EA:hexane, 7.0:3.0 as the mobile phase), which confirmed completion after 5 h. The resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.5 g of crude material, which was purified by flash column chromatography (45% EtOAc in hexanes) using silica gel (230-400 mesh) as the stationary phase to give N-((S)-1-(pyridin-2-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 2, 0.065 g, 0.152 mmol, yield: 12.84% (yield over two steps)). 1 H NMR (DMSO-d6, 400MHz): δ ppm,9.29(br s,1H),9.19(d,J=7.6Hz,1H),8.89(br s,1H),8.54(d,J=4.4Hz,1H),8.02(t,J=4.4Hz,1H),7.78(t,J=7.2Hz,1 H),7.65-7.62(m,2H),7.48(d,J=8.0Hz,1H),7.28(t,J=5.6Hz,1H),5.87 (s,1H),5.28-5.23(m,1H),2.81-2.69(m,3H),2.46-2.42(m,1H),2.32- 2.29(m,1H),2.1-2.07(m,1H),1.71-1.67(m,1H),1.55(d,J=6.8Hz,3H). 1H NMR(MeOD,400MHz):δ ppm,9.27(d,J=2.4Hz,1H),8.85(d,J=2.4Hz,1H),8.56(d,J=1.6Hz,1H),7.9(dd,J=1.6Hz,1H ),7.86(td,J=7.6Hz,1H),7.70(m,2H),7.54(d,J=8.0Hz,1H),7.35(t,J=4.8Hz,1H),5.87(br s,1H),5.35(q,J=7.1Hz,1H),2.83-2.71(m,1H),2.68-2.64(m,2H),2.56-2.50(m,1 H),2.41-2.37(m,1H),2.18-2.15(m,1H),1.81-1.70(m,1H),1.66(d,J=2.0Hz,3H). LCMS (Method A): 2.295 min, 100%, 254.0 nm, MS: ES+ 426.23 (M+1) HPLC (Method B): 6.213 min, 99.75%, 254.0nm Chiral HPLC: 2.28 min, 100%, 245.0 nm

[0200] Example 3 - Synthesis of N-((S)-1-(6-aminopyridin-2-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide formate (Compound 3)

[0201] [ka]

[0202] Process 1 A solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (A5, 0.3 g, 0.93 mmol, 1.0 equiv.), HATU (0.530 g, 1.39 mmol, 1.5 equiv.), and DIPEA (0.48 ml, 2.79 mmol, 3.0 equiv.) in DCM (5 mL) was stirred at 0° C. under a nitrogen atmosphere for 5 minutes, after which CAS:1415303-42-2 (0.265 g, 1.11 mmol, 1.2 equiv.) was added under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC (using EA:hexane, 8:2, as the mobile phase), which confirmed completion after 16 hours. The resulting reaction mixture was quenched with water (10 mL) and extracted with DCM (3×25 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.3 g of crude material, which was purified by flash column chromatography using silica gel (230-400 mesh) as the stationary phase (50% ethyl acetate in hexanes as a gradient) to give N-((S)-1-(6-bromopyridin-2-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (A6, 0.21 g, 0.416 mmol, 44% yield). 1 H NMR (DMSO-d6, 400MHz):δ 9.28-9.25(m,2H),8.89(d,J=2.4Hz,1H),8.03-8.00(m,1H),7.75(t,J=7.6Hz,1H),7.67-7.62(m,2H),7.55-7.51(m,2H),5.88(br s,1H),5.22-5.15(m 1H),2.82-2.60(m,3H),2.51-2.50(m,1H),2.29-2.25(m,1H),2.10-2.07(m,1H),1.75-1.64(m,1H).1.54(d,J=7.2Hz,3H) LCMS (Method A): 2.817 min, 95.22%, 254.0 nm, MS: ES+ 506.04 (M+2)

[0203] Process 2 A solution of N-((S)-1-(6-bromopyridin-2-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (A6, 0.19 g, 0.37 mmol, 1.0 equiv.), Pd(OAc) (0.012 g, 0.037 mmol, 0.1 equiv.), Xantphos (0.021 g, 0.037 mmol, 0.1 equiv.), and CS2CO3 (0.360 g, 1.11 mmol, 3.0 equiv.) in dioxane (10 mL) was prepared at room temperature. The resulting mixture was purged with nitrogen for 5 minutes, and then CAS:4248-19-5 (0.051 g, 0.44 mmol, 1.2 equiv.) was added under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h. The reaction was monitored by TLC (EA:hexane, 70:30, as the mobile phase), which confirmed completion after 16 h. The resulting reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.19 g of crude material. The resulting crude material was purified by flash column chromatography using silica gel (230-400 mesh) as the stationary phase to give the desired product, which was eluted with a gradient of 30% ethyl acetate in hexane to give tert-butyl (6-((1S)-1-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamido)ethyl)pyridin-2-yl)carbamate (A7, 0.15 g, 0.27 mmol, yield: 73.89%). 1 H NMR (DMSO-d6, 400MHz):δ ppm,9.75(s,1H),9.33(d,J=1.6Hz,1H),9.07(d,J=7.6Hz,1H),8.89(d,J=2.4 Hz,1H),8.05-8.03(m,1H),7.74-7.64(m,4H),7.12(d,J=7.2Hz,1H),5.87(br s,1H),5.15-5.12(m,1H),2.80-2.67(m,4H),2.33-2.29(m,1H),2.10-2.08(m,1H),1.73-1.68(m,1H),1.5(d,J=7.2Hz,3H),1.48(s,9H) LCMS (Method A): 2.977 min, 96.51%, 254.0 nm, MS: ES+ 541.3 (M+1)

[0204] Process 3 To a solution of tert-butyl (6-((1S)-1-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamido)ethyl)pyridin-2-yl)carbamate (A7, 0.15 g, 0.277 mmol, 1.0 equiv) in dioxane (10 mL) was added HCl in dioxane [4 M] (5 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC (using EA:hexane, 1:1 as the mobile phase), which confirmed completion of the reaction after 16 hours. The resulting reaction mixture was concentrated under reduced pressure to give 0.15 g of crude product as the HCl salt. The crude material was purified by reverse-phase preparative HPLC purification (Method A 0.1% formic acid in water acetonitrile) to give the desired N-((S)-1-(6-aminopyridin-2-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide format (compound 3, 0.043 g, 0.097 mmol, yield: 35.24%). 1 H NMR (DMSO-d6, 400MHz): δ ppm,9.29(br s,1H),9.13(br s,1H),8.89(br s,1H),8.04-8.01(m,1H),7.66-7.63(m,2H),7.42(t,J=8.0Hz,1H),6.60(d,J=7.2Hz,1H),6.41(d,J=7.6Hz,1H),5.87(br s,1H),5.07-5.04(br s, 1H), 2.80-2.67 (m, 3H), 2.51-2.50 (m, 1H), 2.29-2.25 (m, 1H), 2.10-2.07 (m, 1H), 1.72-1.64 (m, 1H), 1.51 (d, J = 6.8 Hz, 3H). Note: The -NH2 proton is not visible and is not present in the compound in salt format. 1H NMR(MeOD,400MHz):δ ppm,9.28(d,J=2.4Hz,1H),8.86(d,J=2.4Hz,1H),7.99(dd,J=8.0,1.6Hz,1 H),7.70-7.63(m,3H),6.82(d,J=7.2Hz,1H),6.70(d,J=8.4Hz,1H),5.86(br s,1H),5.21-5.15(m,1H 2.78-2.65 (m, 3H), 2.55-2.51 (m, 1H), 2.41-2.34 (m, 1H), 2.18-2.15 (m, 1H), 1.92-1.83 (m, 1H), 1.66 (d, J = 7.2 Hz, 3H). Note: -NH and NH protons are not visible and the compound is not in the form of a salt format. LCMS (Method B): 2.98 min, 99.60%, 254.0 nm, MS: ES+ 441.07 (M+1), HPLC (Method A): 8.772 min, 99.60%, 254.0nm Chiral HPLC: 3.76 min, 100%, 240.0 nm

[0205] Example 4 - Synthesis of N-((S)-1-hydroxypropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 4)

[0206] [ka]

[0207] Process 1 A solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (A5, 0.17 g, 0.529 mmol, 1.0 equiv.), HATU (0.30 g, 0.791 mmol, 1.5 equiv.), and DIPEA (0.20 g, 1.587 mmol, 3.0 equiv.) in DMF (1.7 mL) was stirred at 0° C. under a nitrogen atmosphere for 30 minutes, and CAS:2749-11-3 (0.043 g, 0.582 mmol, 1.1 equiv.) was added under nitrogen. The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC (100% ethyl acetate as the mobile phase), which confirmed completion after 3 hours. The resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.22 g of crude material, which was purified by flash column chromatography using silica gel (230-400 mesh) as the stationary phase (80% ethyl acetate in hexanes as a gradient) to give N-((S)-1-hydroxypropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 4, 0.123 g, 0.325 mmol, yield: 61.43%). 1 H NMR (DMSO-d6, 400MHz): δ ppm,9.25(d,J=2.0Hz,1H),8.80(d,J=2.4Hz,1H),8.47(d,J=8.0Hz,1H),8.01-7.99(m,1H),7.64-7.63(m,2H),5.87(br s, 1H), 4.80 (t, J = 6.0 Hz, 1H), 4.10-4.07 (m, 1H), 3.54-3.50 (m, 1H), 2.80-2.67 (m, 3H), 2.44-2.42 (m, 1H), 2.33-2.25 (m, 1H), 2.10-2.07 (m, 1H), 1.75-1.64 (m, 1H), 1.18 (d, J = 6.8 Hz, 3H). Note: The CF3-CH4 protons corresponded to the DMSO solvent peaks clearly observed in the MeOD NMR spectrum. 1H NMR(MeOD,400MHz):δ ppm,9.25(d,J=2.4Hz,1H),8.78(d,J=2.0Hz,1H),7.96(dd,J=7.6,2.0Hz,1H),7.69-7.62(m,2H),5.87(br s, 1H), 4.32-4.26 (m, 1H), 3.67 (d, J = 5.6 Hz, 2H), 2.81-2.75 (m, 1H), 2.68-2.64 (m, 2H), 2.55-2.51 (m, 1H), 2.40-2.34 (m, 1H), 2.18-2.15 (m, 1H), 1.93-1.82 (m, 1H), 1.32 (d, J = 6.8 Hz, 3H). Note: -OH and -NH protons may exchange in MeOD. LCMS (Method A): 2.236 min, 99.62%, 254.0 nm, MS: ES+ 379.12 (M+1) HPLC (Method A): 7.941 min, 99.26%, 254.0nm Chiral HPLC: 4.73 min, 50.10%, 240.0 nm, 5.10 min, 49.48%, 240.0 nm

[0208] Example 5 - Synthesis of N-(pyridin-2-ylmethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 5)

[0209] [ka]

[0210] Process 1 A solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (A5, 0.15 g, 0.466 mmol, 1.0 equiv.), HATU (0.26 g, 0.700 mmol, 1.5 equiv.), and DIPEA (0.24 ml, 1.400 mmol, 3.0 equiv.) in DMF (1.5 mL) was stirred at 0° C. under a nitrogen atmosphere for 15 minutes, and CAS:3731-51-9 (0.055 g, 0.513 mmol, 1.1 equiv.) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC (100% ethyl acetate as the mobile phase), which confirmed completion after 16 hours. The resulting reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.20 g of crude material, which was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (70% ethyl acetate in hexanes as a gradient) to give N-(pyridin-2-ylmethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 5, 0.057 g, 0.138 mmol, yield: 29.67%). 1 H NMR (DMSO-d6, 400MHz): δ ppm 9.46(t,J=6Hz,1H) 9.31(d,J=2.4Hz,1H),8.89(d,J=2.0Hz,1H) 8.53(d,J=4.0Hz,1H),8.04-8.00(m,1H),7.79 (dt J=7.6,1.6Hz,1H),7.67-7.62(m,2H),7.41 (d J=7.6Hz,1H),7.29(t,J=5.2Hz,1H),5.88(br s,1H),4.65(d,J=6.0Hz,2H),2.81-2.78(m,1H),2.72-2.67(m,2H),2.33-2.25(m,1H),2.10-2.07(m,1H),1.75-1.72(m,1H) 1H NMR(MeOD,400MHz):9.28(d,J=2.0Hz,1H),8.82(d,J=2.4Hz,1H),8.51(d,J=5.2Hz,1H),7.95(dd J=8.0,2.0Hz 1H),7.84(td J=7.6,1.6Hz,1H),7.67-7.60(m,2H),7.49(d,J=8.0Hz,1H),7.34-7.31(m,1H),5.84(br s,1H),4.76(s,2H),2.80-2.73(m,1H),2.67-2.62(m,2H),2.54-2.48(m,1H),2.38-2.30(m,1H),2.15-2.12(m,1H),1.87-1.82(m,1H) LCMS (Method A): 2.145 min, 99.27%, 254.0 nm, MS: ES+ 412.17 (M+1) HPLC (Method A): 8.707 min, 98.45%, 254.0nm

[0211] Example 6 - Synthesis of N-((S)-1-methoxypropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 6)

[0212] [ka]

[0213] Process 1 A solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (A5, 0.15 g, 0.466 mmol, 1.0 equiv.), HATU (0.26 g, 0.700 mmol, 1.5 equiv.), and DIPEA (0.18 g, 1.400 mmol, 3.0 equiv.) in DMF (1.5 mL) was stirred at 0° C. under a nitrogen atmosphere for 30 minutes, after which CAS:99636-32-5 (0.045 g, 0.513 mmol, 1.1 equiv.) was added. The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC (using 100% ethyl acetate as the mobile phase), which confirmed completion after 3 hours. The resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.22 g of crude material, which was purified by flash column chromatography using silica gel (230-400 mesh) as the stationary phase (70% ethyl acetate in hexanes as a gradient) to give N-((S)-1-methoxypropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 6, 0.063 g, 0.160 mmol, yield: 34.38%). 1 H NMR (DMSO-d6, 400MHz):δ ppm,9.24(d,J=2.0Hz,1H),8.80(d,J=2.0Hz,1H),8.60(d,J=8.0Hz,1H),8.02-7.9 9(m,1H),7.64-7.61(m,2H),5.87(s,1H),4.29-4.23(m,1H),3.47-3.43(m,1H),3.3 4-3.31(m,1H),3.30(s,3H),2.80-2.77(m,1H),2.72-2.68(m,2H),2.50-2.46(m,1 H),2.32-2.24(m,1H),2.10-2.07(m,1H),1.73-1.67(m,1H),1.19(d,J=6.8Hz,3H). 1H NMR(MeOD,400MHz):δ ppm,9.24(d,J=2.4Hz,1H),8.77(d,J=2.0Hz,1H),7.97(dd,J=7.6,2.0Hz,1H),7.70-7.63(m,2H),5.87(br s,1H),4.5-4.39(m,1H),3.58-3.54(m,1H),3.50-3.47(m,1H),3.42(s,3H),2.83-2.81(m,1H),2.78-2.75 (m,2H),2.68-2.65(m,1H),2.55-2.41(m,1H),2.18-2.15(m,1H),1.93-1.82(m,1H),1.31(d,J=6.8Hz,3H). LCMS (Method A): 2.505 min, 98.87%, 254.0 nm, MS: ES+ 393.17 (M+1) HPLC (Method A): 9.078 min, 98.54%, 254.0nm Chiral HPLC: 5.31 min, 50.73%, 240.0 nm; 5.63 min, 49.26%, 240.0 nm.

[0214] Example 7 - Synthesis of N-((R)-1-hydroxypropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 7)

[0215] [ka]

[0216] Process 1 A solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (A5, 0.15 g, 0.467 mmol, 1.0 equiv.), HATU (0.35 g, 0.934 mmol, 2.0 equiv.), and DIPEA (0.18 g, 1.400 mmol, 3.0 equiv.) in DMF (1.5 mL) was stirred at 0° C. under a nitrogen atmosphere for 20 minutes, and CAS:35320-23-1 (0.042 g, 0.560 mmol, 1.2 equiv.) was added under nitrogen. The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC (100% EtOAc as the mobile phase), which confirmed completion after 3 hours. The resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.3 g of crude material, which was purified by flash column chromatography using silica gel (230-400 mesh) as the stationary phase (70% ethyl acetate in hexanes as a gradient) to give N-((R)-1-methoxypropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 7, 0.097 g, 0.256 mmol, yield: 54.91%). 1 H NMR (DMSO-d6, 400MHz): δ ppm,9.25(d,J=2.4Hz,1H),8.80(d,J=2.4Hz,1H),8.47(d,J=8.0Hz,1H),8.01-7.98(m,1H),7.64-7.61(m,2H),5.87(br s,1H),4.79(t,J=6.0Hz,1H),4.12-4.01(m,1H),3.54-3.48(m,1H),3.42-3.38(m,1H),2.89-2.77(m,1H),2.73- 2.68(m,2H),2.50-2.46(m,1H),2.33-2.25(m,1H),2.09-2.07(m,1H),1.73-1.67(m,1H),1.18(d,J=6.8Hz,3H). 1H NMR(MeOD,400MHz):δ ppm,9.25(d,J=2.0Hz,1H),8.78(d,J=2.0Hz,1H),7.97(d,J=7.6Hz,1H),7.69-7.62(m,2H),5.86(br s,1H),4.30-4.25(m,1H),3.67(d,J=5.6Hz,1H),2.88-2.65(m,3H),2.55-2.51(m,1 H),2.40-2.37(m,1H),2.17-2.15(m,1H),1.89-1.85(m,1H),1.31(d,J=6.8Hz,3H). LCMS (Method A): 2.237 min, 100%, 254.0 nm, MS: ES+ 379.1 (M+1) HPLC (Method A): 7.930 min, 100%, 254.0nm Chiral HPLC: 6.17 min, 49.36%, 6.99 min, 50.32%, 240.0 nm

[0217] Example 8 - Synthesis of N-((1-methyl-1H-imidazol-2-yl)methyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 8)

[0218] [ka]

[0219] Process 1 A solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (A5, 0.15 g, 0.466 mmol, 1.0 equiv.), HATU (0.26 g, 0.700 mmol, 1.5 equiv.), and DIPEA (0.18 g, 1.400 mmol, 3.0 equiv.) in DMF (1.5 mL) was stirred at 0° C. under a nitrogen atmosphere for 10 minutes, and CAS: 53332-67-5 (0.094 g, 0.513 mmol, 1.1 equiv.) was added under nitrogen. The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC (MeOH:DCM, 1.0:9.0, as the mobile phase), which confirmed completion after 3 hours. The resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.223 g of crude material, which was purified by flash column chromatography using silica gel (230-400 mesh) (5% methanol in DCM) as the stationary phase to give N-((1-methyl-1H-imidazol-2-yl)methyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 8, 0.058 g, 0.139 mmol, yield: 29.97%). 1 H NMR (DMSO-d6, 400MHz): δ ppm,9.30-9.27(m,2H),8.85(s,1H),8.00-7.97(m,1H),7.64-7.62(m,2H),7.11(s,1H),6.82(s,1H),5.86(br s,1H),4.60(d,J=5.2Hz,2H),3.69(s,3H),2.71-2.67(m,3H),2.50-2.45(m,1H),2.25-2.22(m,1H),2.09-2.06(m,1H),1.71-1.65(m,1H) 1H NMR(MeOD,400MHz):δ ppm,9.27(d,J=2.4Hz,1H),8.81(d,J=2.0Hz,1H),7.96(dd,J=7.6,2.0Hz,1 H),7.69-7.62(m,2H),7.09(d,J=1.2Hz,1H),6.93(d,J=1.6Hz,1H),5.86(br s,1H),4.75(s,2H),3.81(s,3H),2.81-2.64(m,3H),2.55-2.50(m,1H),2.40-2.33(m,1H),2.17-2.15(m,1H),1.92-1.84(m,1H). LCMS (Method A): 1.892 min, 100.0%, 210.0 nm, MS: ES+ 415.1 (M+1) HPLC (Method A): 8.081 min, 98.59%, 210.0nm

[0220] Example 9 - Synthesis of N-((R)-1-methoxypropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 9)

[0221] [ka]

[0222] Process 1 A solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (A5, 0.150 g, 0.466 mmol, 1.0 equiv.), HATU (0.26 g, 0.700 mmol, 1.5 equiv.), and DIPEA (0.18 g, 1.400 mmol, 3.0 equiv.) in DMF (1.5 mL) was stirred at 0° C. under a nitrogen atmosphere for 15 minutes, and CAS: 626220-76-6 (0.064 g, 0.513 mmol, 1.1 equiv.) was added under nitrogen. The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC (using 100% EtOAc as the mobile phase), which confirmed completion after 3 hours. The resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.180 g of crude material, which was purified by trituration with ACN to give N-((R)-1-methoxypropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 9, 0.121 g, 0.308 mmol, yield: 66.05%). 1 H NMR (DMSO-d6, 400MHz): δ ppm,9.24(d,J=2.4Hz,1H),8.79(d,J=2.4Hz,1H),8.60(d,J=8.0Hz,1H),8.01-7.99(m,1H),7.64-7.63(m,2H),5.87(br s,1H),4.29-4.23(m,1H),3.47-3.43(m,1H),3.35-3.31(m,1H) 3.29(s,3H),2.80-2.77(m,1H),2.72-2.68(m,2H),2.47-2.46(m,1H),2.32 -2.24(m,1H),2.09-2.07(m,1H),1.73-1.67(m,1H),1.19(d,J=6.8Hz,3H). 1H NMR(MeOD,400MHz):δ ppm,9.23(d,J=2.4Hz,1H),8.75(d,J=2.0Hz,1H),7.96(dd,J=7.6,2.0Hz,1H),7.68-7.62(m,2H),5.86(br s,1H),4.43-4.39(m,1H),3.57-3.50(m,1H),3.49-3.46(m,1H),3.42(s,3H),2.80-2.71(m,1H),2.67-2.55 (m,2H),2.52-2.50(m,1H),2.40-2.33(m,1H),2.18-2.14(m,1H),1.92-1.81(m,1H),1.31(d,J=6.8Hz,3H). LCMS (Method A): 2.480 min, 100.0%, 254.0 nm, MS: ES+ 393.17 (M+1) HPLC (Method A): 9.068 min, 98.51,210.0nm Chiral HPLC: 4.64 min and 4.93 min, 49.45% and 50.54%, 240.0 nm

[0223] Example 10 - Synthesis of N-((4-methyl-1H-pyrazol-5-yl)methyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 10)

[0224] [ka]

[0225] Process 1 A solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (A5, 0.15 g, 0.466 mmol, 1.0 equiv.), HATU (0.26 g, 0.700 mmol, 1.5 equiv.), and DIPEA (0.18 g, 1.400 mmol, 3.0 equiv.) in DMF (1.5 mL) was stirred at 0° C. under a nitrogen atmosphere for 15 minutes, and CAS: 2173991-88-1 (0.094 g, 0.513 mmol, 1.1 equiv.) was added under nitrogen. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (MeOH:DCM, 1.0:9.0, as the mobile phase), which confirmed completion after 2 hours. The resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.194 g of crude material, which was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (70% ethyl acetate in hexanes as a gradient) to give N-((4-methyl-1H-pyrazol-5-yl)methyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 10, 0.073 g, 0.176 mmol, yield: 37.73%). 1 H NMR (DMSO-d6, 400MHz):δ ppm,12.54,12.38(s,1H),9.26(d,J=2.4Hz,1H),9.18-9.09(m,1H),8.83(d,J=2.4Hz,1H),7.99-7.97(m,1H),7.64-7.60(m,2H),7.46(br s,1H),5.86(br s,1H),4.52(d,J=4.8Hz,2H),2.84-2.77(m,2H),2.28-2.24(m,1H),2.09-2.06(m,1H),2.02(s,3H),1.74-1.65(m,1H).Note: Aliphatic 2 protons are MeOD This coincided with the clearly visible DMSO solvent peak in the NMR. 1H NMR(MeOD,400MHz):δ ppm,9.26(d,J=2.4Hz,1H),8.77(d,J=2.0Hz,1H),7.95(d,J=7.6Hz,1H),7.68-7.62(m,2H),7.42(br s,1H),5.86(br s,1H),4.68(s,2H),2.77-2.74(m,1H),2.64(d,J=2.8Hz,2H),2.55-2.50(m,1H),2.40-2.33(m,1H),2.19-2.10(m,4H),1.92-1.81(m,1H). LCMS (Method A): 2.331 min, 100.0%, 210.0 nm, MS: ES+ 415.1 (M+1) HPLC (Method A): 8.273 min, 98.67%, 210.0nm

[0226] Example 11 - Synthesis of N-(oxazol-2-ylmethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 11)

[0227] [ka]

[0228] Process 1 A solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (A5, 0.15 g, 0.466 mmol, 1.0 equiv.), HATU (0.35 g, 0.933 mmol, 2.0 equiv.), and DIPEA (0.24 g, 1.867 mmol, 4.0 equiv.) in DMF (1.5 mL) was stirred at 0° C. under a nitrogen atmosphere for 20 minutes, and CAS: 1041053-44-4 (0.075 g, 0.560 mmol, 1.2 equiv.) was added under nitrogen. The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC (using 8:2 EtOAc:hexane as the mobile phase), which confirmed completion after 3 hours. The resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.2 g of crude material, which was purified by flash column chromatography using silica gel (230-400 mesh) as the stationary phase (75% ethyl acetate in hexanes as a gradient) to give N-(oxazol-2-ylmethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 11, 0.090 g, 0.224 mmol, yield: 48.03%). 1 H NMR (DMSO-d6, 400MHz): δ ppm,9.52(t,J=5.6Hz,1H),9.27(d,J=2.4Hz,1H),8.86(d,J=2.0,Hz,1H),8.09(d,J=0.8Hz,1H),8.02(dd,J=6.8 ,2.8Hz,1H),7.67-7.62(m,2H),7.19(d,J=0.8Hz,1H),5.87(br s, 1H), 4.67 (d, J = 5.6 Hz, 2H), 2.85-2.78 (m, 1H), 2.71-2.67 (m, 2H), 2.33-2.25 (m, 1H), 2.10-2.07 (m, 1H), 1.74-1.67 (m, 1H). Note: The CF3-CH protons coincided with the clearly visible DMSO solvent peaks in MeOD NMR. 1H NMR (MeOD, 400 MHz): δ ppm, 9.29 (d, J = 2.4 Hz, 1H), 8.82 (d, J = 2.4 Hz, 1H), 7.98 (dd, J = 8.0, 2.0 Hz, 1H), 7.93 (d, J = 0.4 Hz, 1H), 7.71-7.64 (m, 2H), 7.18 (s, 1H), 5.87 (br s, 1H), 4.80 (s, 2H), 2.83-2.76 (m, 1H), 2.68-2.64 (m, 2H), 2.55-2.51 (m, 1H), 2.41-2.37 (m, 1H), 2.18-2.15 (m, 1H), 1.92-1.86 (m, 1H). Note: -CONH protons were exchanged in MeOD NMR. LCMS (Method A): 2.341 min, 99.58%, 220.0 nm, MS: ES+ 402.07 (M+1) HPLC (Method A): 8.385 min, 98.13%, 210.0nm

[0229] Example 1 Chiral Separation of 2-N-(oxazol-2-ylmethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compounds 12 and 13)

[0230] [ka] procedure: Compound 11 (0.025 g) racemate was subjected to chiral SFC purification on a (CHIRALPAK IG 250 x 10 mm 5 um) column, which separated two peaks: peak 1 as compound 12 (0.007 g, yield = 28.00%) and peak 2 as compound 13 (0.004 g, yield = 16.00%). Column ID: CHIRALPAK IG, 250×10mm, 5μm Mobile phase A: liquid carbon dioxide Mobile phase B: 0.1% methanolic ammonia in IPA-ACN Flow rate (ML / min): 14 Device ID:SFC INVESTIGATOR Method: Time: Flow rate: %A:%B(0:14:60:40), (7:14:60:40) Compound 12: 1 H NMR (DMSO-d6, 400MHz): δ ppm, 9.53(t,J=5.2Hz,1H),9.28(d,J=1.6Hz,1H),8.86(d,J=1.6Hz,1H),8.09(s,1H),8.02(d,J=5.6Hz,1H),7.66(br s,2H),7.19(s,1H),5.88(s,1H),4.67(d,J=5.2Hz,2H),2.78-2.67(m,3H),2.33-2.29(m,1H),2.10-2.07(m,1H),1.72-1.68(m,1H) LCMS (Method A): 2.368 min, 97.96%, 254.0 nm, MS: ES+ 402.2 (M+1) HPLC (Method A): 8.461 min, 98.53%, 254.0 nm Compound 13: 1 H NMR (DMSO-d6, 400MHz): δ ppm,9.53(t,J=5.2Hz,1H),9.28(d,J=1.6Hz,1H),8.86(d,J=1.6Hz,1H),8.09(s,1H),8.02(d,J=5.6Hz,1H),7.66-7.63(m,2H ),7.20(s,1H),5.88(s,1H),4.67(d,J=5.6Hz,2H),2.81-2.68(m,3H),2.33-2.25(m,1H),2.10-2.07(m,1H),1.75-1.67(m,1H) LCMS (Method A): 2.367 points, 98.83%, 254 nm, MS: ES+ 402.1 (M+1) HPLC (Method A): 8.481 min, 99.19%, 254.0 nm

[0231] Example 13-3-(メチルスルフィニル)-8-(4-(トリフルオロメSynthesis of チル)シクロヘキサ-1-エン-1-イル)キノリン(Compound 14)

[0232]

change

[0233] Process 1 To a stirred solution of 8-bromoquinoline CAS:16567-18-3 (5.0 g, 23.96 mmol, 1.0 equiv.) in acetonitrile (50 mL) was added iodine (12.16 g, 47.93 mmol, 2.0 equiv.) and TBHP (70% aqueous solution), followed by CAS:75-91-2 (30.93 mL, 240.3 mmol, 10.0 equiv.). The resulting mixture was stirred at 80 °C for 16 h. The reaction was monitored by TLC (using 1.0:9.0 EtOAc:hexane as the mobile phase) and found to be complete after stirring at 80 °C for 16 h. The resulting reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 5.5 g of crude product. The resulting crude material was purified by flash column chromatography using silica (230-400 mesh) (1% EtOAc in hexane) as the stationary phase to give 8-bromo-3-iodoquinoline (A8, 4.1 g, 12.27 mmol, yield: 51.09%). 1 H NMR (DMSO-d6, 400MHz):9.16(d,J=2.0Hz,1H),8.97(d,J=2.0Hz,1H),8.18(d,J=7.4Hz,1H),7.98(d,J=7.6Hz,1H),7.56(t,J=7.6Hz,8Hz,1H) LCMS (Method A): 2.516 min, 97.70%, 254.0 nm, MS: ES-336.0 (M+2)

[0234] Process 2 To a stirred solution of 8-bromo-3-iodoquinoline (A8, 4.0 g, 11.98 mmol, 1.0 equiv.) in toluene (40 mL) was added CAS: 5188-07-8 (1.17 g, 16.77 mmol, 1.4 equiv.) under N2. The resulting mixture was stirred at 80 °C for 3 h. The reaction was monitored by TLC (using EA:n-hexane, 1.0:9.0 as the mobile phase) and confirmed to be complete after stirring at 80 °C for 3 h. The resulting reaction mixture was quenched with cold water (40 mL) to precipitate the crude product, which was filtered, washed with 50 mL of water, and dried under reduced pressure to give 2.9 g of crude product. The resulting crude material was triturated with n-hexane to give 8-bromo-3-(methylthio)quinoline (A9, 2.5 g, 9.84 mmol, 84.13% yield). 1 H NMR (DMSO-d6, 400MHz):δ ppm,8.90(d,J=2.4Hz,1H),8.24(d,J=2.0Hz,1H),8.04(dd,J=7.6,1.2Hz,1H),7.95(dd,J=8.2Hz,0.8Hz,1H),7.52(t,J=8.0Hz,1H),2.66(s,3H). LCMS (Method A): 2.295 min, 95.98%, 254.0 nm, MS: ES+ 256.10 (M+2)

[0235] Process 3 To a stirred solution of 8-bromo-3-(methylthio)quinoline (A9, 1.5 g, 5.90 mmol, 1.0 equiv) in DCM (15 mL) at 0 °C under N was added m-CPBA (1.52 g, 8.85 mmol, 1.5 equiv). The resulting mixture was stirred for 2 h at room temperature. The reaction was monitored by TLC (using 7.0:3.0 EtOAc:hexane as the mobile phase) and found to be complete after stirring for 2 h at room temperature. The resulting reaction mixture was quenched with cold water (10 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 1.5 g of crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) (2% MeOH in DCM) as the stationary phase to give 8-bromo-3-(methylsulfinyl)quinoline (A10, 0.55 g, 2.04 mmol, yield: 34.50%). 1 H NMR (DMSO-d6, 400MHz):δ ppm,9.23(d,J=2.0Hz,1H),8.80(d,J=2.4Hz,1H),8.29(dd,J=7.6,2.0Hz,1H),8.23(dd,J=8.0Hz,1.2Hz,1H),7.65(t,J=8.0Hz,1H),2.97(s,3H). LCMS (Method A): 1.553 min, 96.36%, 254.0 nm, MS: ES+ 272.00 (M+2)

[0236] Process 4 To a stirred solution of 8-bromo-3-(methylsulfinyl)quinoline (A10, 0.25 g, 0.925 mmol, 1.0 equiv.), 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1,3,2-dioxaborolane (A2, 0.38 g, 1.388 mmol, 1.5 equiv.), and NaCO (0.29 g, 2.776 mmol, 3.0 equiv.) in dioxane (2.0 mL) and water (0.5 mL) was added Pd(dppf)Cl.DCM (0.075 g, 0.092 mmol, 0.1 equiv.) under N. The resulting mixture was stirred at 100 °C for 3 h. The reaction was monitored by TLC (using EA:hexane, 7.0:3.0, as the mobile phase) and was found to be complete after stirring at 100 °C for 3 h. The resulting reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.4 g of crude product. The resulting crude material was purified by flash column chromatography using silica gel (230-400 mesh) (75% ethyl acetate in n-hexane) as the stationary phase to give 3-(methylsulfinyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline (compound 14, 0.07 g, 0.206 mmol, yield: 22.78%). 1 H NMR (DMSO-d, 400 MHz): δ ppm, 9.11 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.10-8.07 (m, 1H), 7.70-7.67 (m, 2H), 5.86 (br s, 1H), 2.94 (s, 3H), 2.77-2.67 (m, 3H), 2.33-2.28 (m, 1H), 2.10-2.07 (m, 1H), 1.72-1.67 (m, 1H). Note: CF-CH coincided with the DMSO solvent peak clearly observed in MeOD NMR. 1H NMR (MeOD, 400 MHz): δ ppm, 9.10 (d, J = 1.6 Hz, 1H), 8.69 (d, J = 2.4 Hz, 1H), 8.01 (dd, J = 7.6, 2.4 Hz, 1H), 7.74-7.68 (m, 2H), 5.87 (br s, 1H), 3.01 (s, 3H), 2.83-2.78 (m, 1H), 2.72-2.61 (m, 2H), 2.55-2.51 (m, 1H), 2.40-2.33 (m, 1H), 2.18-2.15 (m, 1H), 1.91-1.82 (m, 1H). Note: Small amounts of aliphatic impurities were observed. LCMS (Method A): 2.357 min, 97.92%, 254.0 nm, MS: ES+ 340.06 (M+1) HPLC (Method A): 8.493 min, 98.25%, 254.0nm

[0237] Example 14 - Synthesis of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (Compound 15)

[0238] [ka]

[0239] Process 1 To a solution of 2-amino-3-bromobenzoic acid (CAS: 20776-51-6) (5.0 g, 23.145 mmol, 1.0 equiv) in THF (20 mL) was added BH3.THF (1 M in THF, 81.0 mL, 81.007 mmol, 3.5 equiv) at 0 °C. The mixture was stirred for 12 h at 70 °C. The reaction was monitored by TLC (using EtOAc as the mobile phase) and found to be complete after stirring at 70 °C for 12 h. The reaction mixture was then quenched with MeOH, filtered, and concentrated under reduced pressure to give the crude product. The residue was stirred with water (100 mL) and filtered. The residue was dissolved in DCM, dried over Na2SO4 and evaporated under reduced pressure to give (2-amino-3-bromo-phenyl)methanol (A11, 4.4 g, 21.78 mmol, 94.09% yield) as a light brown solid. 1H NMR (CDCl3, 400 MHz): δ ppm, 7.41 (dd, J = 8.4, 1.6 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.60 (t, J = 8.0 Hz, 1H), 4.68 (s, 2H), 3.65 (br s, 3H). Note: A small amount of aliphatic impurity was observed. LCMS (Method A): 1.667 min, 98.41%, 254.0 nm, MS: ES+ 202.0 (M), 204.0 (M+2)

[0240] Process 2 To a solution of (2-amino-3-bromo-phenyl)methanol (A11, 4.4 g, 21.78 mmol, 1 equiv.) in DCM (40 mL) was added MnO2 (18.93 g, 232.40 mmol, 10 equiv.). The mixture was stirred for 12 h at room temperature. The reaction was monitored by TLC (using EA:hexane, 6.0:4.0 as the mobile phase) and was found to be complete after stirring for 12 h at room temperature. The reaction mixture was filtered and concentrated under reduced pressure to give 2-amino-3-bromobenzaldehyde (A12, 3.5 g, 17.50 mmol, 78.75% yield). 1 H NMR (CDCl3, 400 MHz): δ ppm, 9.85 (s, 1H), 7.64 (dd, J = 7.6, 1.6 Hz, 1H), 7.51 (dd, J = 7.6, 1.6 Hz, 1H), 6.70 (t, J = 7.6 Hz, 1H). Note: -NH2 protons were not observed. LCMS (Method A): 1.966 min, 98.98%, 254.0 nm, MS: ES+ 200.0 (M), 201.99 (M+2)

[0241] Process 3 To a solution of (A12, 380 mg, 1.8996 mmol, 1 equiv) in EtOH (4 mL) was added L-proline (109 mg, 0.9498 mmol, 0.5 equiv) and CAS 922-67-80 (0.22 mL, 2.4695 mmol, 1.3 equiv). The mixture was stirred for 16 h at 80 °C. The reaction was monitored by TLC (using EtOAc:hexane as the mobile phase) and was found to be complete after stirring at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography using silica gel (60-120 mesh) as the stationary phase (100% ethyl acetate in hexane as a gradient) to give methyl 8-bromoquinoline-3-carboxylate (A13, 374 mg, 1.41 mmol, 73.99% yield). 1 H NMR(CDCl3,400MHz):δ ppm,9.59(d,J=2.0Hz,1H),8.89(d,J=2.0Hz,1H),8.20(dd,J=7.6,1.6Hz,1H),7.95(dd,J=8.4,1.2Hz,1H),7.52(t,J=8.0Hz,1H),4.06(s,3H). LCMS (Method B): 2.61 min, 100%, 254.0 nm, MS: ES+ 268.02 (M+2)

[0242] Process 4 To a stirred solution of 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1,3,2-dioxaborolane (A2, 1.14 g, 4.133 mmol, 1.1 equiv.), methyl 8-bromoquinoline-3-carboxylate (A13, 1.0 g, 3.758 mmol, 1.0 equiv.), and KPO (1.59 g, 7.516 mmol, 2.0 equiv.) in dioxane (7 mL) and water (3 mL) was added Pd(dppf)Cl.DCM (0.306 g, 0.375 mmol, 0.1 equiv.) under N. The resulting mixture was stirred at 100 °C for 2 h. The reaction was monitored by TLC (using 2.0:8.0 EtOAc:hexane as the mobile phase) and was found to be complete after stirring at 100 °C for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 1.2 g of crude product. The crude material was purified by flash column chromatography (55% EtOAc in hexane) using silica gel (230-400 mesh) as the stationary phase to give methyl 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylate (A14, 0.72 g, 2.147 mmol, 57.20% yield). 1 H NMR (DMSO-d6, 400MHz): δ ppm,9.29(d,J=2.0Hz,1H),9.00(d,J=2.0Hz,1H),8.13(dd,J=7.6,1.6Hz,1H),7.71-7.64(m,2H),5.86(br s,1H),3.95(s,3H),2.80-2.77(m,1H),2.69-2.66(m,3H),2.31-2.27(m,1H),2.09-2.06(m,1H),1.72-1.66(m,1H). LCMS (Method A): 2.903 min, 100.0%, 210.0 nm, MS: ES+ 336.06 (M+1)

[0243] Process 5 A solution of methyl 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylate (A14, 1.0 g, 2.982 mmol, 1.0 equiv.) and NaOH (0.59 g, 14.912 mmol, 5.0 equiv.) in MeOH:HO (10 mL, 7:3) was prepared at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4 h. The reaction was monitored by TLC (using 6.0:4.0 EtOAc:hexane as the mobile phase) and was found to be complete after 4 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was poured into ice water and then filtered to give the desired product, 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15, 0.8 g, 2.489 mmol, 83.83% yield). 1 H NMR (DMSO-d6, 400MHz): δ ppm,13.54(br s,1H),9.29(d,J=2.4Hz,1H),8.98(d,J=2.4,Hz,1H),8.12(dd,J=7.6,2.0Hz,1H),7.71-7.64(m,2H),5.87(br s,1H),2.84-2.67(m,3H),2.47-2.42(m,1H),2.33-2.24(m,1H),2.10-2.07(m,1H),1.75-1.65(m,1H). 1 H NMR (MeOD, 400 MHz): δ ppm, 9.49 (d, J = 2.0 Hz, 1H), 9.42 (d, J = 2.0 Hz, 1H), 8.29 (dd, J = 8.4, 1.2 Hz, 1H), 8.00 (dd, J = 7.2, 1.2 Hz, 1H), 7.91 (t, J = 8.0 Hz, 1H), 6.02 (br s, 1H), 2.78-2.71 (m, 2H), 2.68-2.57 (m, 2H), 2.47-2.40 (m, 1H), 2.25-2.21 (m, 1H), 1.98-1.88 (m, 1H). Note: -COOH protons were replaced with MeOD. LCMS (Method A): 2.475 min, 100.0%, 254.0 nm, MS: ES+ 322.06 (M+1) HPLC (Method A): 4.280 min, 99.77%, 254.0nm

[0244] Example 15 - Synthesis of 3-(methylsulfonyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline (Compound 16)

[0245] [ka]

[0246] Process 1 To a stirred solution of 5-bromo-3-(methylthio)quinoline (A9, 1.0 g, 3.934 mmol, 1.0 equiv) in DCM (25 mL) was added m-chloroperbenzoic acid (2.10 g, 11.80 mmol, 3.0 equiv) under N. The resulting mixture was stirred for 16 h at room temperature. The reaction was monitored by TLC (using EA:hexane, 1.0:1.0 as the mobile phase) and found to be complete after stirring for 16 h at room temperature. The resulting reaction mixture was diluted with saturated aqueous sodium bicarbonate (200 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.65 g of crude product. The resulting crude material was purified by flash column chromatography using silica gel (230-400 mesh) as the stationary phase (55% ethyl acetate in hexane as gradient) to give 8-bromo-3-(methylsulfonyl)quinoline (A15, 0.50 g, 1.747 mmol, yield: 44.41%). 1 H NMR (DMSO-d6, 400MHz):δ ppm,9.41(d,J=2.4Hz,1H),9.13(d,J=2.4Hz,1H),8.39(dd,J=7.6,1.2Hz,1H),8.33(dd,J=8.0,1.2Hz,1H),7.72(t,J=8.0Hz,1H),3.44(s,3H). LCMS (Method A): 1.807 min, 95.24%, 254.0 nm, MS: ES+ 286.01 (M), 288.01 (M+2)

[0247] Process 2 To a stirred solution of 8-bromo-3-(methylsulfonyl)quinoline (A15, 0.3 g, 1.048 mmol, 1.0 equiv.), 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1,3,2-dioxaborolane (A2, 0.289 g, 1.048 mmol, 1.0 equiv.), and KPO (0.666 g, 3.144 mmol, 3.0 equiv.) in dioxane (15 mL) was added Pd(PPh) (0.242 g, 0.209 mmol, 0.2 equiv.) under N. The resulting mixture was stirred at 100 °C for 2 h. The reaction was monitored by TLC (using EA:hexane, 1.0:1.0 as the mobile phase) and was found to be complete after stirring at 100 °C for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (150 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.35 g of crude product. The crude material was purified by flash column chromatography using silica gel (230-400 mesh) as the stationary phase (15% ethyl acetate in hexanes as a gradient) to give 3-(methylsulfonyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline (compound 16, 0.113 g, 0.317 mmol, yield: 30.37%). 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 9.29 (d, J = 2.4 Hz, 1H), 9.02 (d, J = 2.4 Hz, 1H), 8.20 (dd, J = 7.6, 2.0 Hz, 1H), 7.79-7.73 (m, 2H), 5.88 (br s, 1H), 3.40 (s, 3H), 2.79-2.76 (m, 1H), 2.76-2.70 (m, 1H), 2.29-2.26 (m, 1H), 2.11-2.08 (m, 1H), 1.75-1.65 (m, 1H). Note: 2H was consistent with DMSO solvent clearly visible in MeOD NMR. 1H NMR(MeOD,400MHz):δ ppm,9.28(d,J=2.4Hz,1H),8.96(d,J=2.4Hz,1H),8.08(dd,J=8.0,1.6Hz,1H),7.80(dd,J=7.2,1.6Hz,1H),7.76-7.72(m,1H),5.89(br s,1H),3.30(s,3H),2.83-2.78(m,1H),2.72-2.68(m,1H),2.68-2.61(m,1H) ,2.57-2.52(m,1H),2.41-2.34(m,1H),2.20-2.15(m,1H),1.90-1.80(m,1H). LCMS (Method A): 2.560 min, 95.70%, 254.0 nm, MS: ES+ 356.02 (M+1) HPLC (Method A): 9.069 min, 95.08%, 254.0nm

[0248] Example 16 - Synthesis of N-methyl-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-sulfonamide (Compound 17)

[0249] [ka]

[0250] Step 1a: To a stirred solution of phenylmethanethiol CAS:100-53-8 (10.0 g, 80.645 mmol, 1.0 equiv.) in diethyl ether (100 mL) was added Na metal (0.927 g, 40.257 mmol, 0.5 equiv.). The resulting mixture was stirred for 16 h at room temperature. The reaction was monitored by TLC (using 3.0:7.0 EtOAc:hexane as the mobile phase) and was found to be complete after 16 h. The resulting reaction mixture was filtered using a Buchner funnel, and the solid material was washed with diethyl ether and dried under vacuum to give sodium phenylmethanethiolate as a white solid (A16, 6.0 g, 41.04 mmol, 50.98% yield). 1H NMR (DMSO-d6, 400MHz): δ ppm,7.25(d,J=9.2Hz,2H),7.16-7.11(m,2H),7.01-6.98(m,1H),3.50(br s,2H).

[0251] Process 1 To a solution of 8-bromo-3-iodoquinoline (A8, 3.0 g, 8.983 mmol, 1.0 equiv) in DMF (25 mL) was added sodium phenylmethanethiolate (A16, 1.83 g, 12.576 mmol, 1.4 equiv) under nitrogen. The resulting mixture was stirred at 80 °C for 6 h. The reaction was monitored by TLC (EA:hexane, 1.0:9.0 as the mobile phase), which confirmed completion after 6 h. The resulting reaction mixture was quenched with ice-cold water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 2.0 g of crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (30% ethyl acetate in hexane as gradient) to give 3-(benzylthio)-8-bromoquinoline (A17, 1.5 g, 4.54 mmol, yield: 50.56%). 1 H NMR (DMSO-d6, 400MHz):δ ppm,8.91(d,J=2.4Hz,1H),8.39(d,J=2.4Hz,1H),8.07(dd,J=7.6,1.2Hz,1H),7.92(dd,J=8.0,1.2Hz ,1H),7.51(t,J=7.6Hz,1H),7.41(d,J=7.2Hz,2H),7.32-7.28(m,2H),7.25-7.21(m,1H),4.45(s,2H). LCMS (Method A): 2.780 min, 97.22%, 254.0 nm, MS: ES+ 332.01 (M+2)

[0252] Process 2 To a stirred solution of 3-(benzylthio)-8-bromoquinoline (A17, 1.5 g, 4.542 mmol, 1.0 equiv.) in acetonitrile, acetic acid, and water was added CAS:118-52-5 (1.91 g, 9.084 mmol, 2 equiv.) at 0° C., and the resulting mixture was stirred at 0° C. for 2 hours. The reaction was monitored by TLC (using 3.0:7.0 EtOAc:hexane as the mobile phase), which confirmed completion after stirring at 0° C. for 2 hours. The resulting reaction mixture was concentrated to dryness, then diluted with DCM and cooled to 0° C. 5% aqueous NaHCO3 was added, the reaction mixture was stirred at 0° C. for 15 minutes, and the organic layer was washed with brine solution (50 ml). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 1.5 g of crude 8-bromoquinoline-3-sulfonyl chloride (A18, 1.5 g, 4.893 mmol, yield: crude). Note: The crude product was used directly in the next step without further purification. LCMS (Method A): 2.455 min, 11.07%, 254.0 nm, MS: ES+, 308.0 (M+2)

[0253] Process 3 To a solution of 8-bromoquinoline-3-sulfonyl chloride (A18, 1.5 g, 4.893 mmol, 1.0 equiv) in DCM (20 mL) was added CAS:74-89-5 (4.89 mL, 9.786 mmol, 2.0 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC (using 3.0:7.0 EtOAc:hexane as the mobile phase) and was found to be complete after 2 h. The resulting reaction mixture was quenched with ice-cold water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 1.4 g of crude product. The crude material obtained was purified by flash column chromatography using silica gel (230-400 mesh) as the stationary phase (40% ethyl acetate in hexanes as a gradient) to give 8-bromo-N-methylquinoline-3-sulfonamide (A19, 1.1 g, 3.652 mmol, 80.42% yield over two steps). 1H NMR (DMSO-d6, 400MHz):δ ppm,9.26(d,J=2.4Hz,1H),8.96(d,J=2.0Hz,1H),8.35-8.30(m,2H),7.88(q,J=4.8Hz,1H),7.69(t,J=8.0Hz,1H),2.49(s,3H). LCMS (Method A): 1.859 min, 100%, 254.0 nm, MS: ES+ 302.96 (M+2)

[0254] Process 4 To a stirred solution of 8-bromo-N-methylquinoline-3-sulfonamide (A19, 0.1 g, 0.332 mmol, 1.0 equiv.), 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1,3,2-dioxaborolane (A2, 0.11 g, 0.398 mmol, 1.2 equiv.), and NaCO (0.088 g, 0.83 mmol, 2.5 equiv.) in dioxane (2 mL) and water (0.4 mL) was added Pd(dppf)Cl.DCM (0.013 g, 0.016 mmol, 0.05 equiv.) under N. The resulting mixture was stirred at 100 °C for 2 h. The reaction was monitored by TLC (using EA:hexane, 1.0:1.0, as the mobile phase) and was found to be complete after stirring at 100 °C for 2 h. The resulting reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.120 g of crude product. The resulting crude material was purified by flash column chromatography (30% EtOAc in hexane) using silica (230-400 mesh) as the stationary phase to give N-methyl-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-sulfonamide (compound 17, 0.079 g, 0.213 mmol, yield: 64.23%). 1H NMR (DMSO-d6, 400MHz): δ ppm,9.13(d,J=2.4Hz,1H),8.85(d,J=2.4Hz,1H),8.17(dd,J=6.8,2.8Hz,1H),7.74-7.70(m,3H),5.87(br s,1H),2.80-2.66(m,4H),2.49(s,3H),2.32-2.25(m,1H),2.10-2.07(m,1H),1.74-1.67(m,1H). 1 H NMR (MeOD, 400 MHz): δ ppm, 9.17 (d, J = 2.4 Hz, 1H), 8.80 (d, J = 2.4 Hz, 1H), 8.04 (dd, J = 8.0, 1.6 Hz, 1H), 7.77-7.69 (m, 2H), 5.88 (br s, 1H), 2.83-2.78 (m, 1H), 2.71-2.66 (m, 2H), 2.62 (s, 3H), 2.57-2.51 (m, 1H), 2.40-2.34 (m, 1H), 2.19-2.16 (m, 1H), 1.91-1.89 (m, 1H). Note: -SO2NH protons were exchanged in MeOD. LCMS (Method A): 2.599 min, 100%, 254.0 nm, MS: ES+ 371.12 (M+1) HPLC (Method A): 9.102 min, 100%, 254.0nm

[0255] Example 17 - Synthesis of N-(1-oxazol-2-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 18)

[0256] [ka]

[0257] Process 1 To the oxazole CAS:288-42-6 (0.2 g, 2.896 mmol, 1.0 equiv.) in THF (4 mL) was added n-BuLi (1.81 mL, 2.896 mmol, 1.5 M in hexane, 1.0 equiv.) at −78° C. and stirring was continued at −78° C. for 1 h. Then, CAS:3591-86-8 (0.327 g, 2.896 mmol, 1.0 equiv.) in THF (1 mL) was added under N2. The resulting mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC (using EA:hexane, 1:1, as the mobile phase) and was found to be complete after stirring at room temperature for 16 h. The resulting reaction mixture was quenched with 1 N HCl (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give crude oxazole-2-carbaldehyde (A20, 0.25 g, 2.575 mmol, yield: crude), which was used directly in the next step without further purification. 1 H NMR (DMSO-d6, 400MHz): δ ppm, 9.72 (s, 1H), 7.95 (s, 1H), 7.66 (s, 1H). LCMS (Method A): 0.196 min, 38.56%, 210.0 nm, MS: ES+, 97.9 (M+1)

[0258] Process 2 To a solution of oxazole-2-carbaldehyde (A20, 0.25 g, 2.57 mmol, 1.0 equiv) in THF (3 mL) was added CAS: 146374-27-8 (0.374 g, 3.09 mmol, 1.2 equiv) and CAS: 3087-36-3 (1.17 g, 5.15 mmol, 2.0 equiv). The resulting mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC (using 1:1 EtOAc:hexane as the mobile phase), which confirmed completion after 16 h. The resulting reaction mixture was quenched with brine (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.3 g of crude product. The resulting crude material was purified by flash column chromatography using silica gel (230-400 mesh) as the stationary phase (40% ethyl acetate in hexanes as a gradient) to give (£)-2-methyl-N-(oxazol-2-ylmethylene)propane-2-sulfonamide (A21, 0.15 g, 2.496 mmol, 25.87% yield over two steps). 1 H NMR (DMSO-d6, 400MHz): δ ppm, 8.45 (s, 1H), 8.29 (s, 1H), 7.63 (s, 1H), 1.19 (s, 9H). LCMS (Method A): 1.551 min, 98.61%, 254.0 nm, MS: ES+ 201.10 (M+1)

[0259] Process 3 To a stirred solution of (£)-2-methyl-N-(oxazol-2-ylmethylene)propane-2-sulfonamide (A21, 0.150 g, 0.749 mmol, 1.0 equiv) in DCM (3 mL) at 0 °C under N was added CHMgBr (0.27 mL, 0.823 mmol, 1.1 equiv). The resulting mixture was stirred for 1 h at 0 °C. The reaction was monitored by TLC (using 1.0:1.0 EtOAc:hexane as the mobile phase) and was found to be complete after stirring for 16 h at 0 °C. The resulting reaction mixture was quenched with NH Cl solution (5 mL) and extracted with DCM (3 × 10 mL). The crude material was then dissolved in MeOH (5 mL), and 4 M HCl in dioxane (0.347 mL, 1.388 mmol, 2.0 equiv) was added, and the reaction mixture was stirred for 1 h. The reaction was monitored by TLC (using 4.0:1.0 EtOAc:hexane as the mobile phase) and was found to be complete after 1 h. The reaction mixture was concentrated under reduced pressure to give 0.15 g of crude product. The crude material was purified by trituration to give 1-(oxazol-2-yl)ethan-1-amine (A22, 0.08 g, 0.713 mmol, 71.88% yield). 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 8.81 (s, 2H), 8.24 (d, J = 0.8 Hz, 1H), 7.32 (d, J = 0.8 Hz, 1H), 4.68-4.65 (m, 1H), 1.56 (d, J = 6.8 Hz, 3H). (Trace amount of MeOH observed.)

[0260] Process 4 A solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (A5, 0.2 g, 0.622 mmol, 1.0 equiv.), HATU (0.35 g, 0.933 mmol, 1.5 equiv.), and DIPEA (0.32 mL, 1.867 mmol, 3.0 equiv.) in DMF (5 mL) was stirred at 0° C. under a nitrogen atmosphere for 20 minutes, and 1-(oxazol-2-yl)ethan-1-amine (A22, 0.139 g, 0.933 mmol, 1.5 equiv.) was added under nitrogen. The resulting mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC (using 7:3 EtOAc:hexane as the mobile phase), which indicated completion after 12 hours. The resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.3 g of crude material, which was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (60% ethyl acetate in hexanes as a gradient) to give N-(1-(oxazol-2-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (18, 0.141 g, 0.333 mmol, 54.53% yield). 1 H NMR (DMSO-d, 400 MHz): δ ppm, 9.35 (d, J = 7.6 Hz, 1H), 9.27 (d, J = 2.0 Hz, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.08 (s, 1H), 8.02-8.00 (m, 1H), 7.66-7.62 (m, 2H), 7.19 (s, 1H), 5.87 (br s, 1H), 5.40-5.36 (m, 1H), 2.80-2.67 (m, 3H), 2.32-2.28 (m, 1H), 2.09-2.07 (m, 1H), 1.71-1.65 (m, 1H), 1.61 (d, J = 7.6 Hz, 3H). Note: CF3-CH protons are the same as those in MeOD This coincided with the clearly visible DMSO solvent peak in the NMR. 1H NMR(MeOD,400MHz):δ ppm,9.27(d,J=2.4Hz,1H),8.83(d,J=2.4Hz,1H),7.97(dd,J=8.0,2.0Hz,1H),7.92(d,J=0.4Hz,1H),7.7-7.63(m,2H),7.18(d,J=0.4Hz,1H),5.87(br s, 1H), 5.52-5.46 (m, 1H), 2.75-2.68 (m, 1H), 2.68-2.65 (m, 2H), 2.56-2.51 (m, 1H), 2.40-2.37 (m, 1H), 2.18-2.14 (m, 1H), 1.92-1.83 (m, 1H), 1.73 (d, J = 6.8 Hz, 3H). Note: -CONH protons were exchanged in MeOD. LCMS (Method A): 2.466 min, 100%, 254.0 nm, MS: ES+ 416.18 (M+1) HPLC (Method A): 8.717 min, 99.37%, 254.0nm

[0261] Example 1 Chiral separation of 8-N-(1-oxazol-2-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compounds 19-22)

[0262] [ka]

[0263] procedure Compound 18 (0.131 g) racemate was subjected to chiral SFC purification on a (CHIRALPAK IG 250 x 50 mm 5 um) column, where three peaks were separated: peak 1 (0.051 g, yield = 38.93%), peak 2 (compound 19, 0.0172 g, yield = 13.13%), and peak 3 (compound 20, 0.0142 g, yield = 10.84%). Column ID: CHIRALPAK IG 250X50mm 5um Mobile phase A: liquid carbon dioxide Mobile phase B: 0.1% M NH3 in MEOH-ACN (50-50) Flow rate (ML / min): 170 Instrument ID: 2489 WATERS SFC 350 with UV detector Method: Time: Flow rate: %A:%B(0.01:170:55:45), (17:170:55:45) Compound 19: 1 H NMR (DMSO-d6, 400MHz):δ ppm,9.35(d,J=7.6Hz,1H),9.27(d,J=2.4Hz,1H),8.86(d,J=2.4Hz,1H),8.08(d,J =0.8Hz,1H),8.03-8.00(m,1H),7.67-7.63(m,2H),7.19(d,J=0.4Hz,1H),5.88(br s, 1H), 5.40-5.36 (m, 1H), 2.72-2.67 (m, 4H), 2.33-2.29 (m, 1H), 2.10-2.07 (m, 1H), 1.71-1.67 (m, 1H), 1.61 (d, J = 6.8 Hz, 3H) (Note: - One CF3-CH proton corresponds to the clearly visible DMSO solvent peak in MeOD NMR.) 1 H NMR (MeOD, 400 MHz): δ ppm, 9.28 (d, J = 2.4 Hz, 1H), 8.83 (d, J = 2.0 Hz, 1H), 7.98 (dd, J = 7.6, 1.6 Hz, 1H), 7.92 (d, J = 0.8 Hz, 1H), 7.71-7.64 (m, 2H), 7.18 (s, 1H), 5.87 (br s, 1H), 5.52-5.47 (m, 1H), 2.79-2.66 (m, 4H), 2.56-2.37 (m, 1H), 2.18-2.15 (m, 1H), 1.93-1.82 (m, 1H), 1.73 (d, J = 7.2 Hz, 3H). (Note: -NH protons may be exchanged for deuterium in MeOD.) LCMS (Method A): 2.465 min, 100%, 254.0 nm, MS: ES+ 416.2 (M+1) HPLC (Method A): 8.775 min, 100%, 254.0nm Compound 20: 1H NMR (DMSO-d6, 400MHz):δ ppm,9.35(d,J=7.6Hz,1H),9.27(d,J=2.4Hz,1H),8.86(d,J=2.4Hz,1H),8.08(d,J =0.8Hz,1H),8.03-8.00(m,1H),7.67-7.63(m,2H),7.19(d,J=0.4Hz,1H),5.88(br s, 1H), 5.40-5.36 (m, 1H), 2.72-2.67 (m, 4H), 2.33-2.29 (m, 1H), 2.10-2.07 (m, 1H), 1.71-1.67 (m, 1H), 1.61 (d, J = 6.8 Hz, 3H) (Note: - One CF3-CH proton corresponds to the clearly visible DMSO solvent peak in MeOD NMR.) 1 H NMR (MeOD, 400 MHz): δ ppm, 9.28 (d, J = 2.4 Hz, 1H), 8.83 (d, J = 2.0 Hz, 1H), 7.98 (dd, J = 7.6, 1.6 Hz, 1H), 7.92 (d, J = 0.8 Hz, 1H), 7.71-7.64 (m, 2H), 7.18 (s, 1H), 5.87 (br s, 1H), 5.52-5.47 (m, 1H), 2.79-2.66 (m, 4H), 2.56-2.37 (m, 1H), 2.18-2.15 (m, 1H), 1.93-1.82 (m, 1H), 1.73 (d, J = 7.2 Hz, 3H) (Note: -NH protons may be exchanged for deuterium from MeOD). LCMS (Method A): 2.466 min, 100%, 254.0 nm, MS: ES+ 416.2 (M+1) HPLC (Method A): 8.772 min, 99.71%, 254.0nm

[0264] Chiral separation of compound 21 and compound 22: Procedure: Peak 1 (0.051 g) was further subjected to chiral SFC purification on a (CHIRALPAK IG 250 x 50 mm 5 um) column to give Peak 1 Isomer 1 (Compound 21, 0.0131 g, Yield = 26.20%) and Peak 1 Isomer 2 (Compound 22, 0.0129 g, Yield = 25.80%). Column ID: CHIRALPAK IG 250X50mm 5um Mobile phase A: liquid carbon dioxide Mobile phase B: 0.1% M NH3 in IPA-MEOH (70-30) Flow rate (ML / min): 150 Instrument ID: 2489 WATERS SFC 350 with UV detector Method: Time: Flow rate: %A:%B(0.01:150:70:30), (18:150:70:30) Compound 21: 1 H NMR (DMSO-d6, 400MHz):δ ppm,9.35(d,J=7.6Hz,1H),9.27(d,J=2.4Hz,1H),8.86(d,J=2.4Hz,1H),8.08(d,J =0.8Hz,1H),8.03-8.00(m,1H),7.67-7.63(m,2H),7.19(d,J=0.4Hz,1H),5.88(br s, 1H), 5.40-5.36 (m, 1H), 2.72-2.67 (m, 4H), 2.33-2.29 (m, 1H), 2.10-2.07 (m, 1H), 1.71-1.67 (m, 1H), 1.61 (d, J = 6.8 Hz, 3H) (Note: One CF3-CH proton coincided with the clearly visible DMSO solvent peak in MeOD NMR). 1 H NMR (MeOD, 400 MHz): δ ppm, 9.28 (d, J = 2.4 Hz, 1H), 8.83 (d, J = 2.0 Hz, 1H), 7.98 (dd, J = 7.6, 1.6 Hz, 1H), 7.92 (d, J = 0.8 Hz, 1H), 7.71-7.64 (m, 2H), 7.18 (s, 1H), 5.87 (bs, 1H), 5.52-5.47 (m, 1H), 2.79-2.66 (m, 4H), 2.56-2.37 (m, 1H), 2.18-2.15 (m, 1H), 1.93-1.82 (m, 1H), 1.73 (d, J = 7.2 Hz, 3H). (Note: -NH protons may be exchanged for deuterium in MeOD.) LCMS (Method A): 2.427 min, 100%, 254.0 nm, MS: ES+ 416.2 (M+1) HPLC (Method A): 8.859 min, 100%, 254.0nm Compound 22: 1H NMR (DMSO-d6, 400MHz):δ ppm,9.35(d,J=7.6Hz,1H),9.27(d,J=2.4Hz,1H),8.86(d,J=2.4Hz,1H),8.08(d,J =0.8Hz,1H),8.03-8.00(m,1H),7.67-7.63(m,2H),7.19(d,J=0.4Hz,1H),5.88(br s, 1H), 5.40-5.36 (m, 1H), 2.72-2.67 (m, 4H), 2.33-2.29 (m, 1H), 2.10-2.07 (m, 1H), 1.71-1.67 (m, 1H), 1.61 (d, J = 6.8 Hz, 3H) (Note: One CF3-CH proton coincided with the clearly visible DMSO solvent peak in MeOD NMR). 1 H NMR (MeOD, 400 MHz): δ ppm, 9.28 (d, J = 2.4 Hz, 1H), 8.83 (d, J = 2.0 Hz, 1H), 7.98 (dd, J = 7.6, 1.6 Hz, 1H), 7.92 (d, J = 0.8 Hz, 1H), 7.71-7.64 (m, 2H), 7.18 (s, 1H), 5.87 (br s, 1H), 5.52-5.47 (m, 1H), 2.79-2.66 (m, 4H), 2.56-2.37 (m, 1H), 2.18-2.15 (m, 1H), 1.93-1.82 (m, 1H), 1.73 (d, J = 7.2 Hz, 3H). (Note: -NH protons may be exchanged for deuterium in MeOD.) LCMS (Method A): 2.420 min, 100%, 254.0 nm, MS: ES+ 416.1 (M+1) HPLC (Method A): 8.851 min, 100%, 254.0nm

[0265] Example 19 - Synthesis of N-(2-(methylthio)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 23)

[0266] [ka]

[0267] Process 1 A stirred solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15, 0.1 g, 0.31 mmol, 1.0 equiv.) in DMF (1 mL) was prepared in a 10 mL glass vial at room temperature. DIPEA (0.16 mL, 0.93 mmol, 3.0 equiv.) and HATU (0.17 g, 0.46 mmol, 1.5 equiv.) were added to the reaction solution at 0 °C under a nitrogen atmosphere. After stirring at 0 °C for 30 minutes, 2-(methylthio)ethan-1-amine (CAS: 18542-42-2) (0.028 g, 0.31 mmol, 1.0 equiv.) was added at the same temperature. The resulting reaction mixture was then stirred from 0 °C to room temperature for 16 hours. The reaction was monitored by TLC (using 4.0:6.0 EtOAc:hexane as the mobile phase) and was found to be complete after stirring at room temperature for 16 hours. The resulting reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give 0.11 g of crude product. The resulting crude material was purified by flash column chromatography using silica (230-400 mesh size) as the stationary phase (elution gradient of 20% EtOAc in hexane) to give N-(2-(methylthio)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 23, 0.055 g, 0.13 mmol, yield: 45.08%). 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 9.25 (d, J = 2.4 Hz, 1H), 8.96 (t, J = 5.6 Hz, 1H), 8.79 (d, J = 2.0 Hz, 1H), 8.02-7.99 (m, 1H), 7.65-7.61 (m, 2H), 5.86 (br s, 1H), 3.53 (q, J = 6.4 Hz, 2H), 2.80-2.77 (m, 1H), 2.72-2.67 (m, 4H), 2.32-2.20 (m, 1H), 2.13-2.06 (m, 4H), 1.74-1.67 (m, 1H). (Note: One CF3-CH proton coincided with the clearly visible DMSO solvent peak in MeOD NMR.) 1H NMR (MeOD, 400 MHz): δ ppm, 9.24 (d, J = 2.4 Hz, 1H), 8.75 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.69-7.62 (m, 2H), 5.86 (br s, 1H), 3.68 (t, J = 6.8 Hz, 2H), 2.80 (t, J = 7.2 Hz, 3H), 2.68-2.60 (m, 2H), 2.55-2.50 (m, 1H), 2.40-2.33 (m, 1H), 2.19-2.15 (m, 4H), 1.92-1.81 (m, 1H) (Note: -NH protons may be exchanged for deuterium from MeOD). LCMS (Method A): 2.614 min, 95.77%, 254 nm, MS: ES+ 395.12 (M+1) HPLC (Method B): 9.433 min, 95.17%, 254nm

[0268] Example 20 - Synthesis of N-(2-(methylsulfinyl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 24)

[0269] [ka]

[0270] Process 1 A stirred solution of N-(2-(methylthio)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 23, 0.1 g, 0.25 mmol, 1.0 equiv.) in DCM (1 mL) was prepared in a 10 mL glass vial at room temperature. To the resulting mixture, m-CPBA (60% assay) (0.026 g, 0.25 mmol, 1.0 equiv.) in DCM (0.5 mL) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting reaction mixture was then stirred from 0 °C to room temperature for 16 h. The reaction was monitored by TLC (using MeOH:DCM, 0.5:9.5 as the mobile phase) and found to be complete after stirring at room temperature for 16 h. The resulting reaction mixture was diluted with water (5 mL), basified with a solution of saturated NaHCO (5 mL), and extracted with DCM (3 × 5 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give 0.11 g of crude material, which was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (elution gradient of 3% MeOH in DCM) to give N-(2-(methylsulfinyl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 24, 0.055 g, 0.13 mmol, yield: 52.88%). 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 9.24 (d, J = 2.0 Hz, 1H), 9.13 (t, J = 5.2 Hz, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.02-8.00 (m, 1H), 7.65-7.62 (m, 2H), 5.87 (br s, 1H), 3.77-3.64 (m, 2H), 3.15-3.08 (m, 1H), 2.97-2.91 (m, 1H), 2.79-2.71 (m, 2H), 2.62 (s, 3H), 2.32-2.25 (m, 1H), 2.10-2.07 (m, 1H), 1.74-1.67 (m, 1H). (Note: One CF3-CH proton is present in MeOD.) (This coincided with the clearly visible DMSO solvent peak in the NMR.) 1H NMR (MeOD, 400 MHz): δ ppm, 9.25 (d, J = 2.0 Hz, 1H), 8.76 (d, J = 2.0 Hz, 1H), 7.96 (t, J = 6.4 Hz, 1H), 7.69-7.63 (m, 2H), 5.86 (br s, 1H), 3.95-3.89 (m, 2H), 3.28-3.23 (m, 1H), 3.13-3.07 (s, 1H), 2.76 (s, 4H), 2.68-2.65 (m, 2H), 2.55-2.51 (m, 1H), 2.40-2.37 (m, 1H), 2.18-2.15 (m, 1H), 1.89-1.85 (m, 1H). (Note: -NH protons may be exchanged for deuterium in MeOD.) LCMS (Method A): 2.121 min, 100%, 254 nm, MS: ES+ 411.1 (M+1) HPLC (Method B): 7.334 min, 99.45%, 254nm

[0271] Example 21 - Synthesis of N-(2-(methylsulfonyl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 25)

[0272] [ka]

[0273] Process 1 A stirred solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15, 0.1 g, 0.31 mmol, 1.0 equiv.) in DMF (1 mL) was prepared in a 10 mL glass vial at room temperature. DIPEA (0.27 mL, 1.55 mmol, 5.0 equiv.) and HATU (0.17 g, 0.46 mmol, 1.5 equiv.) were added to the reaction solution at 0° C. under a nitrogen atmosphere. After stirring for 30 minutes at 0° C., 2-(methylsulfonyl)ethan-1-amine (CAS: 104458-24-4) (0.049 g, 0.31 mmol, 1.0 equiv.) was added at the same temperature. The resulting reaction mixture was then stirred from 0° C. to room temperature for 16 hours. The reaction was monitored by TLC (using neat EtOAc as the mobile phase) and was found to be complete after stirring at room temperature for 16 hours. The resulting reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with cold water (3 × 30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give 0.12 g of crude product. The resulting crude material was purified by trituration with diethyl ether to give N-(2-(methylsulfonyl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 25, 0.053 g, 0.12 mmol, yield: 40.15%). 1 H NMR (DMSO-d6, 400MHz): δ ppm,9.24(d,J=2.0Hz,1H),9.09(t,J=5.2Hz,1H),8.79(d,J=1.6Hz,1H),8.02-8.00(m,1H),7.65-7.62(m,2H),5.87(br s, 1H), 3.77 (q, J = 6.4 Hz, 2H), 3.44 (t, J = 6.8 Hz, 2H), 3.07 (s, 3H), 2.80-2.77 (m, 1H), 2.71-2.67 (m, 2H), 2.46-2.43 (m, 1H), 2.32-2.28 (m, 1H), 2.10-2.07 (m, 1H), 1.71-1.67 (m, 1H) (Note: One CF3-CH proton coincided with the clearly visible DMSO solvent peak in MeOD NMR). 1H NMR (MeOD, 400 MHz): δ ppm, 9.24 (d, J = 2.4 Hz, 1H), 8.76 (d, J = 2.0 Hz, 1H), 7.97 (dd, J = 7.6, 3.6 Hz, 1H), 7.69-7.63 (m, 2H), 5.86 (s, 1H), 3.95 (t, J = 6.4 Hz, 2H), 3.51 (t, J = 6.8 Hz, 2H), 3.09 (s, 3H), 2.78-2.74 (m, 1H), 2.68-2.64 (m, 2H), 2.55-2.51 (m, 1H), 2.40-2.37 (m, 1H), 2.18-2.15 (m, 1H), 1.89-1.85 (m, 1H). (Note: The -NH protons may be exchanged for deuterium from MeOD.) LCMS (Method A): 2.290 min, 98.55%, 254 nm, MS: ES+ 427.2 (M+1) HPLC (Method B): 8.152 min, 98.63%, 254nm

[0274] Example 22 - Synthesis of 8-(4,4-difluorocyclohex-1-en-1-yl)-N-isopropylquinoline-3-carboxamide (Compound 26):

[0275] [ka]

[0276] Process 1 A stirred solution of 8-bromoquinoline-3-carboxylic acid (A3, 0.50 g, 1.98 mmol, 1.0 equiv.) in DMF (5.0 mL) was prepared in a 30 mL glass vial at room temperature. DIPEA (0.76 g, 5.95 mmol, 3.0 equiv.) and HATU (1.12 g, 2.97 mmol, 1.5 equiv.) were added to the reaction solution at 0 °C under a nitrogen atmosphere. After stirring for 10 minutes, isopropylamine (CAS: 75-31-0) (0.11 g, 1.98 mmol, 1.0 equiv.) was added at the same temperature. The resulting reaction mixture was then stirred for 16 hours at room temperature. The reaction was monitored by TLC (using 1.0:1.0 EtOAc:hexane as the mobile phase) and confirmed to be complete after stirring for 16 hours at room temperature. The resulting reaction mixture was extracted with 50 mL of EtOAc and 50 mL of HO. The organic layer was dried over NaSO, filtered, and concentrated under high vacuum to give the crude product, which was purified by Combiflash using 230-400 mesh silica and eluted with 12% EtOAc:hexane to give 8-bromo-N-isopropylquinoline-3-carboxamide (A23, 0.323 g, 1.101 mmol, 55.59% yield). 1 H NMR (DMSO-d6, 400MHz):δ ppm,9.33(d,J=2.0Hz,1H),8.86(d,J=2.0Hz,1H),8.67(d,J=4.8Hz,1H),8.24(d,J=6.8Hz, 1H),8.14(d,J=8.0Hz,1H),7.61(t,J=8.0Hz,1H),4.21-4.12(m,1H),1.23(d,J=6.4Hz,6H). LCMS (Method A): 1.866 min, 99.55%, 254 nm, MS: ES+ 294 (M+1)

[0277] Process 2 A stirred solution of A23 (0.1 g, 0.34 mmol, 1 equiv.) in dioxane:HO (3:1) was prepared in a 10 mL glass vial at room temperature. CAS: 1227068-84-9 (0.08 g, 0.33 mmol, 1 equiv.) and NaCO (0.10 g, 1.02 mmol, 3 equiv.) were added to the reaction solution at the same temperature. The mixture was purged with N. Then, Pd(dppf)Cl (0.02 g, 0.03 mmol, 0.1 equiv.) was added and stirred at 110 °C for 2 h. The reaction was then monitored by TLC (50% EtOAc:hexane as mobile phase) and found to be complete after stirring at 110 °C for 2 h. The resulting reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL). The organic layer was dried over NaSO, filtered, and concentrated under high vacuum to give the crude product. The crude product was purified by Combi-Flash column chromatography using 230-400 mesh silica and eluting the product with 10% EtOAc:hexane to give 8-(4,4-difluorocyclohex-1-en-1-yl)-N-isopropylquinoline-3-carboxamide (compound 26, 0.074 g, 0.223 mmol, yield: 66.07%). 1 H NMR (DMSO-d6, 400MHz): δ ppm,9.25(d,J=1.6Hz,1H),8.79(d,J=1.6Hz,1H),8.56(d,J=7.2Hz,1H),8.01(t,J=5.6Hz,1H),7.63(t,J=7.2Hz,2H),5.76(br s,1H),4.18-4.13(m,1H),2.90(br s,2H),2.79(t,J=14.8Hz,2H),2.25-2.18(m,2H),1.21(d,J=6.4Hz,6H). LCMS (Method A): 2.313 min, 96.62%, 254.0 nm, MS: ES+ 331.2 (M+1) HPLC (Method B): 8.486 min, 99.62% at 254.0nm.

[0278] Example 2 Synthesis of 3-(S)-8-(4,4-difluorocyclohex-1-en-1-yl)-N-(1-(pyridin-2-yl)ethyl)quinoline-3-carboxamide (Compound 27)

[0279] [ka]

[0280] Process 1 A stirred solution of methyl 8-bromoquinoline-3-carboxylate (A13, 0.4 g, 1.50 mmol, 1.0 equiv.), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS: 1227068-84-9) (0.36 g, 1.50 mmol, 1.0 equiv.), and NaCO (0.47 g, 4.50 mmol, 3.0 equiv.) in dioxane:water (9:1) was prepared in a 30 mL glass vial under a N atmosphere at room temperature. The reaction solution was degassed with N for 15 minutes at room temperature. PdCl(dppf) (0.10 g, 0.15 mmol, 0.1 equiv.) was added to the reaction solution at the same temperature. The glass vial was sealed with a cap and heated at 110 °C for 16 h. The reaction was monitored by TLC (using 3.0:7.0 EtOAc:hexane as the mobile phase) and was found to be complete after stirring at 110 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with 10 mL of EtOAc, filtered through a bed of Celite, washed with 30 mL of EtOAc, and the filtrate was concentrated under reduced pressure to give 0.7 g of crude product. The crude material was purified by flash column chromatography using silica (230-400 mesh) (10% EtOAc in hexane) as the stationary phase to give methyl 8-(4,4-difluorocyclohex-1-en-1-yl)quinoline-3-carboxylate (A24, 0.3 g, 0.98 mmol, 65.93% yield). 1H NMR (DMSO-d6, 400MHz):δ ppm,9.31(d,J=2.0Hz,1H),9.02(d,J=2.0Hz,1H),8.16(dd,J=8.0Hz,1.2Hz,1H),7.73(dd,J=6.8Hz,1.2Hz,1H),7.68(t,J=7.6Hz,1H),5.76(br s,1H)3.96(s,3H),2.89(br s,2H),2.83-2.75(m,2H),2.27-2.17(m,2H). LCMS (Method A): 2.613 min, 98.28%, 254 nm, MS: ES+ 304.1 (M+1)

[0281] Process 2 A stirred solution of methyl 8-(4,4-difluorocyclohex-1-en-1-yl)quinoline-3-carboxylate (A24, 0.3 g, 0.98 mmol, 1.0 equiv.) in MeOH:water (7:3) was prepared in a 30 mL glass vial at room temperature. NaOH (0.10 g, 2.630 mmol, 2.0 equiv.) was added to the reaction solution at the same temperature. The glass vial was sealed with a cap and heated at 50 °C for 4 h. The reaction was monitored by TLC (using 3.0:7.0 EtOAc:hexane as the mobile phase) and found to be complete after stirring at 110 °C for 4 h. The resulting reaction mixture was cooled to room temperature, diluted with MeOH (5 mL), and concentrated under reduced pressure. Aqueous citric acid was added to the reaction mixture until the pH became acidic, resulting in a precipitate. The resulting precipitate was filtered through a Buchner funnel, washed with water (10 mL), and dried under reduced pressure to give 8-(4,4-difluorocyclohex-1-en-1-yl)quinoline-3-carboxylic acid (A25, 0.24 g, 0.82 mmol, yield: 83.91%). 1H NMR (DMSO-d6, 400 MHz): δ ppm, 9.30 (d, J = 2.0 Hz, 1H), 8.97 (d, J = 2.0 Hz, 1H), 8.13 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.72-7.64 (m, 2H), 5.76 (br s, 1H), 2.89 (br s, 2H), 2.79 (t, J = 14.4 Hz, 2H), 2.27-2.17 (m, 2H). Note: -COOH protons may be exchanged with DMSO moisture. LCMS (Method A): 2.164 min, 98.32%, 254 nm, MS: ES+ 290.1 ​​(M+1)

[0282] Process 3 A stirred solution of 8-(4,4-difluorocyclohex-1-en-1-yl)quinoline-3-carboxylic acid (A25, 0.1 g, 0.34 mmol, 1.0 equiv.) in DMF (1.0 mL) was prepared in a 10 mL glass vial at room temperature. DIPEA (0.30 mL, 1.72 mmol, 5.0 equiv.) and HATU (0.19 g, 0.51 mmol, 1.5 equiv.) were added to the reaction solution at 0 °C under a nitrogen atmosphere. After stirring at 0 °C for 30 minutes, (1S)-1-(pyridin-2-yl)ethan-1-amine hydrochloride (CAS: 40154-78-7) (0.067 g, 0.34 mmol, 1.0 equiv.) was added at the same temperature. The resulting reaction mixture was then stirred from 0 °C to room temperature for 1 hour. The reaction was monitored by TLC (using neat EtOAc as the mobile phase) and was found to be complete after stirring at 0 °C to room temperature for 1 h. The resulting reaction mixture was diluted with cold water (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give 0.12 g of crude product. The resulting crude material was purified by flash column chromatography using silica (230–400 mesh) as the stationary phase (elution gradient: 30% EtOAc in hexanes) to give (S)-8-(4,4-difluorocyclohex-1-en-1-yl)-N-(1-(pyridin-2-yl)ethyl)quinoline-3-carboxamide (compound 27, 0.099 g, 0.25 mmol, yield: 72.79%). 1H NMR (DMSO-d6, 400MHz):δ ppm,9.31(d,J=2.4Hz,1H),9.20(d,J=8.0Hz,1H),8.90(d,J=2.4Hz,1H),8.54(d,J=4.0Hz,1H),8.04(dd,J=7.2, 2.0Hz,1H),7.78(dt,J=8.0Hz,2.0Hz,1H),7.69-7.63(m,2H),7.48(d,J=8.0Hz,1H),7.29-7.26(m,1H),5.77(br s,1H),5.30-5.22(m,1H),2.90-2.89(m,2H),2.79(t,J=15.6Hz,2H),2.26-2.19(m,2H),1.55(d,J=6.8Hz,3H). 1 H NMR(MeOD,400MHz):δ ppm,9.29(d,J=2.4Hz,1H),8.85(d,J=2.4Hz,1H),8.55(d,J=4.4Hz,1H),8.00(d,J=8.0Hz,1 H),7.87-7.83(m,1H),7.70-7.63(m,2H),7.54(d,J=8.0Hz,1H),7.36-7.32(m,1H),5.75(br s, 1H), 5.35 (q, J = 7.2 Hz, 1H), 2.89-2.86 (m, 2H), 2.83-2.74 (m, 2H), 2.32-2.25 (m, 2H), 1.66 (d, J = 7.2 Hz, 3H). (Note: The -NH protons may be exchanged for deuterium from MeOD.) LCMS (Method A): 2.027 min, 95.17%, 210 nm, MS: ES+ 394.2 (M+1) HPLC (Method B): 8.283 min, 98.25%, 254nm Chiral HPLC (Method C): 2.59 min, 98.10%, 240 nm

[0283] Example 2 Synthesis of 4-(S)-8-(4,4-difluorocyclohex-1-en-1-yl)-N-1-(hydroxypropan-2-yl)quinoline-3-carboxamide (Compound 28)

[0284] [ka]

[0285] Process 1 A stirred solution of 8-(4,4-difluorocyclohex-1-en-1-yl)quinoline-3-carboxylic acid (A25, 0.1 g, 0.34 mmol, 1.0 equiv.) in DMF (1.0 mL) was prepared in a 10 mL glass vial at room temperature. DIPEA (0.18 mL, 1.03 mmol, 3.0 equiv.) and HATU (0.19 g, 0.51 mmol, 1.5 equiv.) were added to the reaction solution at 0 °C under a nitrogen atmosphere. After stirring for 30 minutes at 0 °C, (S)-2-aminopropan-1-ol (CAS: 2749-11-3) (0.025 g, 0.34 mmol, 1.0 equiv.) was added at the same temperature. The resulting reaction mixture was then stirred from 0 °C to room temperature for 1 hour. The reaction was monitored by TLC (using neat EtOAc as the mobile phase) and was found to be complete after stirring at 0 °C to room temperature for 1 h. The resulting reaction mixture was diluted with cold water (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give 0.18 g of crude product. The resulting crude material was purified by flash column chromatography (70% EtOAc in hexanes) using silica (230-400 mesh) as the stationary phase to give (S)-8-(4,4-difluorocyclohex-1-en-1-yl)-N-(1-hydroxypropan-2-yl)quinoline-3-carboxamide (compound 28, 0.075 g, 0.21 mmol, yield: 63.02%). 1 H NMR (DMSO-d6, 400MHz):δ ppm,9.26(d,J=2.4Hz,1H),8.81(d,J=2.0Hz,1H),8.47(d,J=7.6Hz,1H),8.02(dd,J=7.6,2.4Hz,1H),7.67-7.62(m,2H),5.76(br s,1H),4.79(t,J=5.6Hz,1H),4.10-4.06(m,1H),3.53-3.48(m,1H),3.42-3.37(m,1H),2.89(br s,2H),2.79(t,J=14.8Hz,2H),2.25-2.18(m,2H),1.18(d,J=6.4Hz,3H). 1 H NMR (MeOD, 400 MHz): δ ppm, 9.26 (d, J = 2.4 Hz, 1H), 8.77 (d, J = 2.0 Hz, 1H), 7.98 (dd, J = 8.0, 1.6 Hz, 1H), 7.69-7.59 (m, 2H), 5.75 (br s, 1H), 4.32-4.24 (m, 1H), 3.68 (dd, J = 17.6 Hz, 11.6 Hz, 2H), 3.67 (s, 1H), 3.01 (br s, 2H), 2.89-2.74 (m, 2H), 2.34-2.24 (m, 2H), 1.39-1.28 (m, 3H). (Note: -NH and -OH protons may exchange for deuterium in MeOD.) LCMS (Method A): 1.970 min, 98.04%, 254 nm, MS: ES+ 347.2 (M+1) HPLC (Method B): 7.064 min, 97.63%, 254nm Chiral HPLC (Method C): 2.79 min, 99.18%, 248 nm

[0286] Example 25 - Synthesis of 8-(4,4-difluorocyclohex-1-en-1-yl)-N-(oxazol-2-ylmethyl)quinoline-3-carboxamide (Compound 29)

[0287] [ka]

[0288] Process 1 A stirred solution of 8-(4,4-difluorocyclohex-1-en-1-yl)quinoline-3-carboxylic acid (A25, 0.1 g, 0.34 mmol, 1.0 equiv.) in DMF (1.0 mL) was prepared in a 10 mL glass vial at room temperature. DIPEA (0.30 mL, 1.72 mmol, 5.0 equiv.) and HATU (0.19 g, 0.51 mmol, 1.5 equiv.) were added to the reaction solution at 0 °C under a nitrogen atmosphere. After stirring at 0 °C for 30 min, oxazol-2-ylmethanamine hydrochloride (0.046 g, 0.34 mmol, 1.0 equiv.) was added at the same temperature. The resulting reaction mixture was then stirred from 0 °C to room temperature for 1 h. The reaction was monitored by TLC (using 10.0% EtOAc as the mobile phase) and confirmed to be complete after stirring from 0 °C to room temperature for 1 h. The reaction mixture was diluted with cold water (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give 0.13 g of crude product. The crude material was purified by flash column chromatography (50% EtOAc in hexanes) using silica (230-400 mesh) as the stationary phase to give 8-(4,4-difluorocyclohex-1-en-1-yl)-N-(oxazol-2-ylmethyl)quinoline-3-carboxamide (compound 29, 0.085 g, 0.23 mmol, yield: 66.92%). 1 H NMR (DMSO-d6, 400MHz):δ ppm,9.53(t,J=5.2Hz,1H),9.28(d,J=2.0Hz,1H),8.87(d,J=2.0Hz,1H),8.09( s,1H),8.04(dd,J=7.6Hz,1.6Hz,1H),7.69-7.63(m,2H),7.19(s,1H),5.77(br s,1H),4.67(d,J=5.6Hz,2H),2.90(br s,2H),2.79(t,J=14.4Hz,2H),2.27-2.17(m,2H). LCMS (Method A): 2.111 min, 97.20%, 254 nm, MS: ES+ 370.1 (M+1) HPLC (Method B): 7.544 min, 98.69%, 254nm

[0289] Example 26 - Synthesis of 8-(4,4-dimethylcyclohex-1-en-1-yl)-N-isopropylquinoline-3-carboxamide (Compound 30):

[0290] [ka]

[0291] Process 1 A stirred solution of A23 (0.1 g, 0.34 mmol, 1 equiv.) in dioxane:HO (3:1) was prepared in a 10 mL glass vial at room temperature. CAS: 859217-67-7 (0.08 g, 0.33 mmol, 1 equiv.) and NaCO (0.10 g, 1.02 mmol, 3 equiv.) were added to the reaction solution at the same temperature. The mixture was purged with N. Then, Pd(dppf)Cl (0.02 g, 0.03 mmol, 0.1 equiv.) was added and stirred at 110 °C for 2 h. The reaction was then monitored by TLC (50% EtOAc:hexane as mobile phase) and found to be complete after stirring at 110 °C for 2 h. The resulting reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (20 mL). The organic layer was dried over NaSO, filtered, and concentrated under high vacuum. The crude product was purified by CombiFlash column chromatography using 230-400 mesh silica. The product was eluted with 7% EtOAc:hexane to give 8-(4,4-dimethylcyclohex-1-en-1-yl)-N-isopropylquinoline-3-carboxamide (compound 30, 0.051 g, 0.158 mmol, 46.40% yield). 1H NMR (DMSO-d6, 400MHz): δ ppm,9.25(d,J=2.0Hz,1H),8.76(d,J=2.0Hz,1H),8.56(d,J=7.6Hz,1H),7.98-7.96(m,1H),7.63-7.59(m,2H),5.73(br s,1H),4.20-4.11(m,1H),2.61(br s,2H),2.01(br s,2H),1.52(t,J=6.4Hz,2H),1.21(d,J=6.4Hz,6H),1.05(s,6H). 1 H NMR (MeOD, 400 MHz): δ ppm, 9.22 (d, J = 2 Hz, 1H), 8.71 (d, J = 2.0 Hz, 1H), 7.93-7.90 (m, 1H), 7.62-7.59 (m, 2H), 5.78 (br s, 1H), 4.32-4.26 (m, 1H), 2.61 (s, 2H), 2.07-2.03 (m, 2H), 1.64 (t, J = 6.4 Hz, 2H), 1.48 (d, J = 6.8 Hz, 6H), 0.94 (s, 6H). (Note: -NH protons may be exchanged for deuterium in MeOD.) LCMS (Method A): 2.797 min, 100%, 254 nm, MS: ES+ 323.2 (M+1). HPLC (Method B): 10.612 min, 100% at 254nm.

[0292] Example 2 Synthesis of 7-(S)-8-(4,4-dimethylcyclohex-1-en-1-yl)-N-(1-(pyridin-2-yl)ethyl)quinoline-3-carboxamide (Compound 31)

[0293] [ka]

[0294] Process 1 A stirred solution of 8-(4,4-dimethylcyclohex-1-en-1-yl)quinoline-3-carboxylic acid (A26, 0.1 g, 0.35 mmol, 1.0 equiv.) in DMF (1.0 mL) was prepared in a 10 mL glass vial at room temperature. DIPEA (0.30 mL, 1.03 mmol, 5.0 equiv.) and HATU (0.20 g, 0.53 mmol, 1.5 equiv.) were added to the reaction solution at 0 °C under a nitrogen atmosphere. After stirring at 0 °C for 30 minutes, (S)-1-(pyridin-2-yl)ethanamine hydrochloride (CAS: 40154-78-7) (0.069 g, 0.35 mmol, 1.0 equiv.) was added at the same temperature. The resulting reaction mixture was then stirred from 0 °C to room temperature for 1 hour. The reaction was monitored by TLC (using neat EtOAc as the mobile phase) and was found to be complete after stirring at 0 °C to room temperature for 1 h. The resulting reaction mixture was diluted with cold water (5 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give 0.14 g of crude product. The resulting crude material was purified by flash column chromatography (40% EtOAc in hexanes) using silica (230-400 mesh) as the stationary phase to give (S)-8-(4,4-dimethylcyclohex-1-en-1-yl)-N-(1-(pyridin-2-yl)ethyl)quinoline-3-carboxamide (compound 31, 0.078 g, 0.20 mmol, yield: 56.93%). 1 H NMR (DMSO-d6, 400MHz):δ ppm,9.31(d,J=2.0Hz,1H),9.18(d,J=7.6Hz,1H),8.86(d,J=2.0Hz,1H),8.54(d,J=4.0Hz,1H),8.00-7.98( m,1H),7.77(dt,J=7.6Hz,1.6Hz,1H),7.64-7.61(m,2H),7.47(d,J=8.0Hz,1H),7.29-7.26(m,1H),5.74(br s,1H),5.27-5.24(m,1H),2.62(br s,2H),2.01(br s,2H),1.56-1.51(m,5H),1.05(s,6H). LCMS (Method A): 2.560 min, 100%, 254 nm, MS: ES+ 386.2 (M+1) HPLC (Method B): 10.376 min, 100%, 254nm Chiral HPLC (Method C): 9.687 min, 100%, 240 nm

[0295] Example 2 Synthesis of 8-(S)-8-(4,4-dimethylcyclohex-1-en-1-yl)-N-1-(hydroxypropan-2-yl)quinoline-3-carboxamide (Compound 32)

[0296] [ka]

[0297] Process 1 A stirred solution of A26 (0.090 g, 0.310 mmol, 1.0 equiv.) in DMF (1.0 mL) was prepared in a 10 mL glass vial at room temperature. DIPEA (0.124 g, 0.950 mmol, 3.0 equiv.) and HATU (0.18 g, 0.470 mmol, 1.5 equiv.) were added to the reaction solution under a nitrogen atmosphere at the same temperature. After stirring for 10 minutes, (S)-2-aminopropan-1-ol (CAS: 2749-11-3) (0.024 g, 0.310 mmol, 1.0 equiv.) was added at the same temperature. The resulting reaction mixture was then stirred for 16 hours at room temperature. The reaction was monitored by TLC (using pure ethyl acetate as the mobile phase) and confirmed to be complete after stirring for 16 hours at room temperature. The resulting reaction mixture was poured into cold water (40 mL) and extracted with ethyl acetate (50 × 2). The organics were dried over NaSO and concentrated under reduced pressure to give the crude product, which was purified by preparative TLC to give (S)-8-(4,4-dimethylcyclohex-1-en-1-yl)-N-(1-hydroxypropan-2-yl)quinoline-3-carboxamide (compound 32, 0.050 g, 0.147 mmol, yield: 46.29%). 1H NMR (DMSO-d6, 400MHz): δ ppm,9.26(s,1H),8.78(s,1H),8.45(d,J=8.0Hz,1H),7.97(t,J=4.8Hz,1H),7.63-7.60(m,2H),5.74(br s,1H),4.79(t,J=5.6Hz,1H),4.11-4.04(m,1H),3.53-3.47(m,1H),3.41-3.35(m,1H),2.61(br s,2H),2.01(br s,2H),1.52(t,J=6.4Hz,2H),1.17(d,J=6.8Hz,3H),1.05(s,6H). LCMS (Method A): 2.411 min, 100%, 254.0 nm, MS: ES+ 339.11 (M+1) HPLC (Method B): 8.906 min, 100%, 254.0nm Chiral HPLC (Method B): 4.01 min, 100%, 260.0 nm

[0298] Example 29 - Synthesis of 8-(4,4-dimethylcyclohex-1-en-1-yl)-N-(oxazol-2-ylmethyl)quinoline-3-carboxamide (Compound 33)

[0299] [ka]

[0300] Process 1 A stirred solution of A26 (0.1 g, 0.35 mmol, 1 equiv.) in DMF (1 mL) was prepared in a 10 mL glass vial at room temperature. DIPEA (0.19 g, 1.053 mmol, 3 equiv.) and HATU (0.20 g, 0.53 mmol, 1.5 equiv.) were added to the reaction solution at 0 °C and stirred for 10 min. Oxazol-2-ylmethanamine (0.03 g, 0.30 mmol, 1 equiv.) was then added, and the resulting reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC (7.0:3.0 EtOAc:hexane as mobile phase) and confirmed to be complete after stirring at room temperature for 16 h. The resulting reaction mixture was extracted with EtOAc (20 mL) and HO (20 mL). The organic layer was dried over NaSO, filtered, and concentrated under high vacuum to give the crude product. The crude product was purified by Combiflash column chromatography using 230-400 mesh silica and the product was eluted with 50% EtOAc:hexane to give 8-(4-dimethylcyclohex-1-en-1-yl)-N-(oxazol-2-ylmethyl)quinoline-3-carboxamide (compound 33, 0.026 g, 0.074 mmol, yield: 20.27%). 1 H NMR (DMSO-d6, 400MHz): δ ppm,9.51(br s,1H),9.27(s,1H),8.84(s,1H),8.08(s,1H),7.98(t,J=4.4 Hz 1H),7.62(d,J=4.4Hz,2H),7.19(s,1H),5.74(br s,1H),4.66(d,J=5.2Hz,2H),2.67-2.33(m,2H),2.01(br s,2H),1.52(t,J=5.6Hz,2H),1.04(s,6H). 1H NMR (MeOD, 400 MHz): δ ppm 9.28 (s, 1H), 8.79 (d, J = 2.0 Hz, 1H), 7.94 (t, J = 4.4 Hz, 2H), 7.66-7.61 (m, 2H), 7.18 (s, 1H), 5.78 (br s, 1H), 4.66 (s, 2H), 2.62 (s, 2H), 2.04 (t, J = 10.0 Hz, 2H), 1.64 (t, J = 6.4 Hz, 2H), 1.10 (s, 6H). (Note: -NH protons may be exchanged for deuterium from MeOD.) LCMS (Method A): 2.569 min, 98.86% at 254nm, MS: ES+ 362 (M+1) HPLC (Method B): 9.413 min, 100% at 254nm.

[0301] Example 30 - Synthesis of 8-(cyclohex-1-en-1-yl)-N-isopropylquinoline-3-carboxamide (Compound 34):

[0302] [ka]

[0303] Process 1 A stirred solution of A13 (1.0 g, 3.750 mmol, 1.0 equiv.) and CAS: 141091-37-4 (0.78 g, 3.750 mmol, 1.0 equiv.) in dioxane:water (4:1) was prepared in a 35 mL glass vial at room temperature. To this reaction solution, Na2CO3 (1.19 g, 11.20 mmol, 3.0 equiv.) was added at the same temperature. The resulting reaction mixture was then stirred at room temperature and purged with nitrogen for 15 minutes. After purging with nitrogen gas, PdCl2(dppf) was added at room temperature, and the reaction was then stirred at 110 °C for 16 hours. The reaction was monitored by TLC (20% ethyl acetate in hexane as the mobile phase) and confirmed to be complete after stirring at 110 °C for 16 hours. The resulting reaction mixture was then cooled to room temperature and poured into cold water (200 mL). After further extraction with ethyl acetate (2 × 200 mL), the organics were dried over NaSO, filtered, and concentrated under reduced pressure to give the crude material, which was purified by column chromatography using hexanes and ethyl acetate. The product was eluted with 7% ethyl acetate in hexane to give methyl 8-(cyclohex-1-en-1-yl)quinoline-3-carboxylate (A27, 0.6 g, 2.244 mmol, 59.72% yield). 1 H NMR (DMSO-d6, 400MHz): δ ppm,9.30(d,J=2.0Hz,1H),8.99(d,J=2.0Hz,1H),8.10(dd,J=8.0Hz,J=2.0Hz,1H),7.69-7.63(m,2H),5.83(br s,1H),3.95(s,3H),2.57(br s,2H),2.22(br s,2H),1.78-1.70(m,4H). LCMS (Method A): 2.821 min, 96.51%, 254.0 nm, MS: ES+ 268.10 (M+1)

[0304] Process 2 A stirred solution of A27 (0.6 g, 2.240 mmol, 1.0 equiv) in MeOH:HO (4.2:1.8 mL) was prepared in a 35 mL glass vial at room temperature. To this reaction solution, NaOH (0.179 g, 4.480 mmol, 2.0 equiv) was added at the same temperature. The resulting reaction mixture was then stirred at 50 °C for 3 h. The reaction was monitored by TLC (using pure ethyl acetate as the mobile phase) and confirmed to be complete after stirring at room temperature for 3 h. The resulting reaction mixture was directly concentrated under reduced pressure and then acidified with citric acid, followed by the addition of water (15 mL) to give a white solid. The precipitate was filtered through a Buchner funnel, washed with water (20 mL), and dried under high vacuum to give 8-(cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (A28, 0.45 g, 1.776 mmol, yield: 79.22%). 1 H NMR (DMSO-d6, 400MHz): δ ppm,13.54(br s,1H),9.29(d,J=2.0Hz,1H),8.93(d,J=2.0Hz,1H),8.07(dd,J=7.6Hz,J=2.0Hz,1H),7.66-7.13(m,2H),5.83(br s,1H),2.58(br s,2H),2.22(br s,2H),1.77-1.70(m,4H). LCMS (Method A): 2.220 min, 99.73%, 254.0 nm, MS: ES+ 254.10 (M+1)

[0305] Process 3 A stirred solution of A28 (0.1 g, 0.390 mmol, 1.0 equiv.) in DMF (1.0 mL) was prepared in a 10 mL glass vial at room temperature. DIPEA (0.153 g, 1.180 mmol, 3.0 equiv.) and HATU (0.225 g, 0.590 mmol, 1.5 equiv.) were added to the reaction solution under a nitrogen atmosphere at the same temperature. After stirring for 10 minutes, propan-2-amine (CAS: 75-31-0) (0.023 g, 0.390 mmol, 1.0 equiv.) was added at 0°C. The resulting reaction mixture was then stirred for 16 hours at room temperature. The reaction was monitored by TLC (using 50% ethyl acetate in hexane as the mobile phase), which confirmed completion after stirring for 16 hours at room temperature. The resulting reaction mixture was poured into cold water (40 mL) and extracted with ethyl acetate (2 × 40 mL). The organics were dried over NaSO and concentrated under reduced pressure to give the crude product, which was purified by conventional column chromatography using hexane and ethyl acetate. The product was eluted with 30% ethyl acetate in hexane to give 8-(cyclohex-1-en-1-yl)-N-isopropylquinoline-3-carboxamide (compound 34, 0.065 g, 0.220 mmol, yield: 56.03%). 1 H NMR (DMSO-d6, 400MHz): δ ppm,9.23(d,J=2.0Hz,1H),8.76(d,J=2.0Hz,1H),8.56(d,J=7.6Hz,1H),7.96(t,J=4.8Hz,1H),7.63-7.60(m,2H),5.83(br s,1H),4.18-4.11(m,1H),2.67(br s,2H),2.22(br s,2H),1.77-1.70(m,4H),1.21(d,J=6.8Hz,6H). LCMS (Method A): 2.397 min, 100%, 254.0 nm, MS: ES+ 295.16 (M+1) HPLC (Method B): 9.316 min, 99.74%, 254.0nm

[0306] Example 31 Synthesis of (S)-8-(cyclohex-1-en-1-yl)-N-(1-(pyridin-2-yl)ethyl)quinoline-3-carboxamide (Compound 35)

[0307] [ka]

[0308] Process 1 A stirred solution of A28 (0.1 g, 0.390 mmol, 1.0 equiv.) in DMF (1.0 mL) was prepared in a 10 mL glass vial at room temperature. DIPEA (0.255 g, 1.900 mmol, 5.0 equiv.) and HATU (0.225 g, 0.590 mmol, 1.5 equiv.) were added to the reaction solution under a nitrogen atmosphere at the same temperature. After stirring for 10 minutes, CAS: 40154-78-7 (0.077 g, 0.390 mmol, 1.0 equiv.) was added at 0°C. The resulting reaction mixture was then stirred for 16 hours at room temperature. The reaction was monitored by TLC (using pure ethyl acetate as the mobile phase) and was found to be complete after stirring for 16 hours at room temperature. The resulting reaction mixture was poured into cold water (40 mL) and extracted with ethyl acetate (2 × 40 mL). The organics were dried over NaSO and concentrated under reduced pressure to give the crude product, which was purified by standard column chromatography using hexane and ethyl acetate. The product was eluted with 35% ethyl acetate in hexane and further purified by preparative TLC to give (S)-8-(cyclohex-1-en-1-yl)-N-(1-(pyridin-2-yl)ethyl)quinoline-3-carboxamide (Compound 35, 0.031 g, 0.086 mmol, yield: 21.98%). 1H NMR (DMSO-d6, 400MHz):δ ppm,9.28(d,J=2.0Hz,1H),9.19(d,J=7.6Hz,1H),8.87(d,J=2.0Hz,1H),8.54(d,J=4.4Hz,1H),7.98(t,J=4.8H z,1H),7.78(dt,J=7.6Hz,1.6Hz,1H),7.62(d,J=4.8Hz,2H),7.47(d,J=8.0Hz,1H),7.29-7.26(m,1H),5.84(br s,1H),5.29-5.22(m,1H),2.59(br s,2H),2.33(br s,2H),1.77-1.70(m,4H),1.55(d,J=7.2Hz,3H). LCMS (Method A): 2.131 min, 100%, 210nm, MS: ES+ 358.12 (M+1) HPLC (Method B): 9.162 min, 99.49%, 254.0nm Chiral HPLC (Method C): 2.88 min, 98.97%, 241.0 nm

[0309] Example 3 Synthesis of 2-(S)-8-(cyclohex-1-en-1-yl)-N-1-(hydroxypropan-2-yl)quinoline-3-carboxamide (Compound 36)

[0310] [ka]

[0311] Process 1 procedure: A stirred solution of A28 (0.1 g, 0.390 mmol, 1.0 equiv.) in DMF (1.0 mL) was prepared in a 10 mL glass vial at room temperature. DIPEA (0.153 g, 1.110 mmol, 3.0 equiv.) and HATU (0.225 g, 0.590 mmol, 1.5 equiv.) were added to the reaction solution under a nitrogen atmosphere at the same temperature. After stirring for 10 minutes, (S)-2-aminopropan-1-ol (CAS: 2749-11-3) (0.030 g, 0.390 mmol, 1.0 equiv.) was added at 0°C. The resulting reaction mixture was then stirred for 16 hours at room temperature. The reaction was monitored by TLC (using pure ethyl acetate as the mobile phase) and was found to be complete after stirring for 16 hours at room temperature. The resulting reaction mixture was poured into cold water (35 mL) and extracted with ethyl acetate (2 × 50 mL). The organics were dried over NaSO and concentrated under reduced pressure to give the crude product, which was purified by standard column chromatography using hexane and ethyl acetate. The product was eluted with 50% ethyl acetate in hexane to give (S)-8-(cyclohex-1-en-1-yl)-N-1-(hydroxypropan-2-yl)quinoline-3-carboxamide (compound 36, 0.055 g, 0.177 mmol, yield: 45.08%). 1 H NMR (DMSO-d6, 400MHz): δ ppm,9.24(d,J=2.0Hz,1H),8.78(d,J=2.0Hz,1H),8.46(d,J=8.0Hz,1H),7.96(t,J=4.8Hz,1H),7.63-7.60(m,2H),5.83(br s,1H),4.79(t,J=6.0Hz,1H),4.11-4.04 (m. 1H),3.53-3.48(m,1H),3.41-3.37(m,1H),2.59(br s,2H),2.22(br s,2H),1.77-1.70(m,4H),1.17(d,J=6.4Hz,3H). LCMS (Method A): 2.006 min, 95.61%, 254 nm, MS: ES+ 311.11 (M+1) HPLC (Method B): 7.558 min, 97.76%, 254.0nm Chiral HPLC (Method C): 2.85 min, 100%, 241.0 nm

[0312] Example 33 - Synthesis of 8-(cyclohex-1-en-1-yl)-N-(oxazol-2-ylmethyl)quinoline-3-carboxamide (compound 37):

[0313] [ka]

[0314] Process 1 A stirred solution of A28 (0.1 g, 0.39 mmol, 1 equiv.) in DMF (1 mL) was prepared in a 10 mL glass vial at room temperature. DIPEA (0.15 g, 1.8 mmol, 3 equiv.) and HATU (0.22 g, 0.58 mmol, 1.5 equiv.) were added to the reaction solution at 0 °C and stirred for 10 min. Oxazol-2-ylmethanamine (0.03 g, 0.39 mmol, 1 equiv.) was then added, and the resulting reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC (MeOH:DCM, 1.0:9.0 as the mobile phase) and confirmed to be complete after stirring at room temperature for 16 h. The resulting reaction mixture was extracted with EtOAc (20 mL) and HO (20 mL). The organic layer was dried over NaSO, filtered, and concentrated under high vacuum to give the crude product. The crude product was purified by Combiflash column chromatography using 230-400 mesh silica and the product was eluted with 12% EtOAc:hexane to give 8-(cyclohex-1-en-1-yl)-N-(oxazol-2-ylmethyl)quinoline-3-carboxamide (compound 37, 0.042 g, 0.125 mmol, yield: 32.06%). 1H NMR (DMSO-d6, 400MHz):δ ppm,9.52(t,J=5.2Hz,1H),9.27(d,J=2.0Hz,1H),8.84(d,J=2.0Hz,1H),8 .09(s,1H),7.99-7.97(m,1H),7.62(d,J=4.0Hz,2H),7.19(s,1H),5.84(br s,1H),4.67(d,J=5.2Hz,2H),2.58(br s,2H),2.22(br s,2H),1.77-1.70(m,4H). 1 H NMR (MeOD, 400 MHz): δ ppm, 9.28 (d, J = 2.4 Hz, 1H), 8.81 (d, J = 2.4 Hz, 1H), 7.95 (t, J = 6.0 Hz, 2H), 7.67-7.62 (m, 2H), 7.18 (s, 1H), 5.86 (br s, 1H), 4.79 (s, 2H), 2.56 (d, J = 1.6 Hz, 2H), 2.31-2.29 (m, 2H), 1.89-1.86 (m, 2H), 1.83-1.80 (m, 2H). (Note: -NH protons may be exchanged for deuterium in MeOD.) LCMS (Method A): 2.209 min, 95.17%, 254 nm, MS: ES+ 334.1 (M+1) HPLC (Method B): 8.202 min, 96.41%, 254nm

[0315] Example 3 Synthesis of 4-N-methyl-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 38)

[0316] [ka]

[0317] Process 1 A solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15, 0.09 g, 0.280 mmol, 1.0 equiv.), HATU (0.159 g, 0.420 mmol, 1.5 equiv.), and DIPEA (0.14 mL, 0.840 mmol, 3.0 equiv.) in DMF (1 mL) was stirred at 0° C. under a nitrogen atmosphere for 10 minutes, and CAS:74-89-5 (0.021 g, 0.420 mmol, 1.5 equiv.) was added under nitrogen. The resulting mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC (using 8:2 EtOAc:hexane as the mobile phase), which confirmed completion after 16 hours. The resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.15 g of crude material, which was purified by flash column chromatography (50% ethyl acetate in hexanes) using silica (230-400 mesh) as the stationary phase to give N-methyl-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 38, 0.035 g, 0.104 mmol, yield: 37.38%). 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 9.24 (d, J = 2.4 Hz, 1H), 8.80-8.74 (m, 2H), 8.01-7.99 (dd, J = 6.0 Hz, J = 4.0 Hz, 1H), 7.64-7.61 (m, 2H), 5.86 (br s, 1H), 2.87 (d, J = 4.8 Hz, 3H), 2.87-2.59 (m, 1H), 2.80-2.50 (m, 2H), 2.33-2.24 (m, 2H), 2.33-2.07 (m, 1H), 1.74-1.64 (m, 1H). (Note: One CF3-CH proton coincided with the clearly visible DMSO solvent peak in MeOD NMR.) 1H NMR (MeOD, 400 MHz): δ ppm, 9.24 (d, J = 2.0 Hz, 1H), 8.74 (t, J = 2.4 Hz, 1H), 7.96 (dd, J = 7.6, 2.0 Hz, 1H), 7.69-7.63 (m, 2H), 5.86 (br s, 1H), 3.02 (s, 3H), 2.76-2.64 (m, 1H), 2.55-2.33 (m, 2H), 2.51 (s, 1H), 2.18-2.03 (m, 1H), 1.92-1.82 (br s, 1H), 1.92-1.82 (m, 1H) (Note: -NH protons may be exchanged for deuterium from MeOD). LCMS (Method A): 2.327 min, 98.92%, 254.0 nm, MS: ES+ 429.3 (M+1) HPLC (Method A): 8.561 min, 97.93%, 210.0nm Chiral HPLC (Method A): Peak-1 3.73 min, 49.03%, 240.0 nm, Peak-2 4.02 min, 50.02%, 240.0 nm

[0318] Example 35 - Synthesis of N-(2-hydroxyethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 39)

[0319] [ka]

[0320] Process 1 A solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15, 0.09 g, 0.280 mmol, 1.0 equiv.), HATU (0.159 g, 0.420 mmol, 1.5 equiv.), and DIPEA (0.14 mL, 0.840 mmol, 3.0 equiv.) in DMF (1 mL) was stirred at 0° C. under a nitrogen atmosphere for 10 minutes, and CAS:141-43-5 (0.025 g, 0.420 mmol, 1.5 equiv.) was added under nitrogen. The resulting mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC (using 8:2 EtOAc:hexane as the mobile phase), which confirmed completion after 16 hours. The resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.15 g of crude material, which was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (elution gradient: 80% ethyl acetate in hexane) to give N-(2-hydroxyethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 39, 0.034 g, 0.093 mmol, yield: 33.32%). 1 H NMR (DMSO-d6, 400MHz): δ ppm,9.25(d,J=2.0Hz,1H),8.81-8.80(m,2H),8.00(,J=5.6,4.7Hz,1H),7.64-7.61(m,2H),5.87(br s, 1H), 4.80 (t, J = 5.6 Hz, 1H), 3.59-3.54 (q, J = 6.0 Hz, 2H), 3.42-3.34 (q, J = 6.0 Hz, 2H), 2.80-2.77 (m, 1H), 2.72-2.67 (m, 2H), 2.32-2.24 (m, 1H), 2.10-2.07 (m, 1H), 1.74-1.64 (m, 1H) (Note: One CF3-CH proton coincided with the clearly visible DMSO solvent peak in MeOD NMR). 1H NMR (MeOD, 400 MHz): δ ppm, 9.26 (d, J = 2.0 Hz, 1H), 8.78 (d, J = 2.4 Hz, 1H), 7.97 (dd, J = 7.6 Hz, 2 Hz, 1H), 7.69-7.63 (m, 2H), 5.86 (s, 1H), 3.78 (t, J = 5.6 Hz, 2H), 3.59 (t, J = 5.6 Hz, 2H), 2.78-2.65 (m, 3H), 2.55-2.51 (m, 1H), 2.40-2.37 (m, 1H), 2.18-2.15 (m, 1H), 1.91-1.85 (m, 1H). (Note: -NH and -OH protons may exchange for deuterium in MeOD.) LCMS (Method A): 2.154 min, 100%, 254.0 nm, MS: ES+ 365 (M+1) HPLC (Method A): 7.651 min, 99.49%, 210.0nm Chiral HPLC (Method A): Peak-1 4.25 min, 49.65%, 240.0 nm; 4.69 min, 49.98%, 240.0 nm

[0321] Example 36 Synthesis of N-(2-methoxyethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 40)

[0322] [ka]

[0323] Process 1 A solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15, 0.09 g, 0.280 mmol, 1.0 equiv.), HATU (0.160 g, 0.420 mmol, 1.5 equiv.), and DIPEA (0.15 mL, 0.840 mmol, 3.0 equiv.) in DMF (2 mL) was stirred at 0° C. under a nitrogen atmosphere for 20 minutes, and CAS:109-85-3 (0.0315 g, 0.420 mmol, 1.5 equiv.) was added under nitrogen. The resulting mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC (using 7.0:3.0 EtOAc:hexane as the mobile phase), which confirmed completion after 16 hours. The resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.08 g of crude material, which was purified by flash column chromatography using silica (230-400 mesh size) as the stationary phase (elution gradient 50% ethyl acetate in hexane) to give N-(2-methoxyethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 40, 0.047 g, 0.124 mmol, yield: 44.34%). 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 9.25 (d, J = 2.0 Hz, 1H), 8.90 (br s, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.02-7.99 (m, 1H), 7.65-7.62 (m, 2H), 5.87 (br s, 1H), 3.51 (s, 4H), 3.30 (s, 3H), 2.81-2.69 (m, 3H), 2.29-2.25 (m, 1H), 2.09-2.07 (m, 1H), 1.74-1.64 (m, 1H). (Note: One CF3-CH proton coincided with the clearly visible DMSO solvent peak in MeOD NMR.) 1H NMR (MeOD, 400 MHz): δ ppm, 9.25 (d, J = 2.0 Hz, 1H), 8.77 (d, J = 2.4 Hz, 1H), 7.97 (dd, J = 1.6, 7.6 Hz, 1H), 7.69-7.63 (m, 2H), 5.87 (br s, 1H), 3.67 (s, 4H), 3.42 (s, 3H), 2.83-2.65 (m, 3H), 2.55-2.51 (m, 1H), 2.41-2.34 (m, 1H), 2.18-2.15 (m, 1H), 1.93-1.82 (m, 1H) (Note: -NH protons may be exchanged for deuterium from MeOD). LCMS (Method A): 2.393 min, 98.83%, 254.0 nm, MS: ES+ 379.1 (M+1) HPLC (Method A): 8.672 min, 97.52%, 254.0nm Chiral HPLC: Peak-1: 5.14 min, 49.67%, 240 nm; Peak-2: 5.57 min, 50.32%, 240 nm

[0324] Example 37 - Synthesis of N-isopropyl-N-methyl-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 41)

[0325] [ka]

[0326] Process 1 To a stirred solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15, 0.09 g, 1.2 mmol, 1.0 equiv.), CAS: 4747-21-1 (0.024 g, 0.336 mmol, 1.2 equiv.), and DIPEA (0.10 g, 0.84 mmol, 3.0 equiv.) in DMF (2 mL) under inert N2 (g) conditions was added HATU (0.159 g, 0.42 mmol, 1.5 equiv.). The reaction was monitored by TLC (using ethyl acetate in hexane (3:7) as the mobile phase) and was found to be complete after stirring at room temperature for 3 h. The resulting reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were extracted with EtOAc (2 × 50 mL), dried over NaSO, and concentrated under reduced pressure to give 0.07 g of crude product, which was purified by reverse-phase HPLC to give N-isopropyl-N-methyl-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 41, 0.023 g, 0.061 mmol, 19.16% yield). 1 H VT-NMR (DMSO-d6, 400 MHz): δ ppm, 8.86 (br s, 1H), 8.36 (br s, 1H), 7.95 (br s, 1H), 7.61 (br s, 1H), 5.89 (br s, 2H), 4.28 (br s, 1H), 2.89-2.70 (m, 6H), 2.34-2.31 (m, 1H), 2.12-2.10 (m, 1H), 1.75-1.73 (m, 1H), 1.26-1.19 (br s, 6H). (Note: One CF3-CH proton coincided with the clearly visible DMSO solvent peak in MeOD NMR.) 1H-NMR(MeOD,400MHz):δ ppm,8.87(d,J=12.4Hz,1H),8.40(d,J=17.2Hz,1H),7.94(dd,J=6.8,7.2Hz,1H),7.67-7.62(m,2H),5.86(br s,1H),4.04-3.95(m,1H),3.36-2.95(s,3H),2.79-2.62(m,3H)2.55-2.50(m,1H),2.40-2. 36(m,1H),2.18-2.15(m,1H),1.92-1.86(m,1H),1.32(d,J=6.8Hz,3H)1.27(d,J=6.8Hz,3H) 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 8.87 (d, J = 12.4 Hz, 1H), 8.46 (br s, 1H), 8.40 (br s, 1H), 7.98-7.96 (m, 1H), 7.64-7.61 (m, 3H), 5.85 (s, 2H), 4.78 (br s, 1H), 3.86 (br s, 1H), 2.90-2.60 (m, 9H), 2.33-2.23 (m, 1H), 2.08-2.05 (m, 1H), 1.74-1.63 (m, 1H), 1.23-1.14 (m, 6H) (Note: Peaks observed later due to rotamers). LCMS (Method A): 2.512 min, (100%), 254 nm, m / z=377.17(M+H)+ HPLC (Method A): 9.81 min, (100%), 210nm

[0327] Example 38 - Synthesis of N-(pyrimidin-2-ylmethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 42)

[0328] [ka]

[0329] Process 1 To a stirred solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15, 0.01 g, 0.31 mmol, 1.0 equiv.), CAS: 372118-67-7 (0.045 g, 0.31 mmol, 1.0 equiv.), and DIPEA (0.12 g, 0.93 mmol, 3.0 equiv.) in DMF (2 mL) under inert N2 (g) conditions, HATU (0.178 g, 0.46 mmol, 1.5 equiv.) was added. The reaction was monitored by TLC (using MeOH in DCM (0.5:9.5) as the mobile phase) and was found to be complete after stirring at room temperature for 3 h. The resulting reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were extracted with EtOAc (2 × 50 mL), dried over NaSO, and concentrated under reduced pressure to give 0.06 g of crude product, which was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (gradient elution in 50% methanol in DCM) to give compound 42 (0.039 g, 0.094 mmol, 32.88% yield). 1 H-NMR(DMSO-d6,400MHz):δ ppm 9.45(t,J=6.0Hz,1H),9.31(d,J=2.4Hz,1H),8.88(d,J=2.4Hz,1H),8.79(d,J=4 .8Hz,2H),8.04-8.01(m,1H),7.66-7.63(m,2H),7.43(t,J=4.8Hz,1H),5.88(br s, 1H), 4.74 (d, J = 6.0 Hz, 2H), 2.82-2.80 (m, 1H), 2.79-2.67 (m, 2H), 2.40-2.25 (m, 2H), 2.10-2.07 (m, 1H), 1.73-1.66 (m, 1H) (Note: One CF3-CH proton coincided with the clearly visible DMSO solvent peak in MeOD NMR). 1H-NMR(MeOD,400MHz):δ ppm,9.32(d,J=2.0Hz,1H),8.87(d,J=2.0Hz,1H),8.80(d,J=5.2Hz,2H),8. 00(dd,J=8.0,7.6Hz,1H),7.71-7.64(m,2H),7.43(t,J=4.8Hz,1H),5.88(br s, 1H), 2.79-2.76(m, 1H), 2.69-2.66(m, 2H), 2.56-2.51(m, 1H), 2.39-2.33(m, 1H), 2.18-2.16(m, 1H), 1.93-1.83(m, 1H), (Note: -NH protons may be exchanged with deuterium from MeOD, and 2H corresponds to the MeOD water peak.) LCMS (Method A): 2.28 min, (98.45%), 254 nm, MS: ES+ 413 (M+1) HPLC (Method A): 8.20 min, (97.7%), 210nm

[0330] Example 39 - Synthesis of N-(pyridazin-3-ylmethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 43)

[0331] [ka]

[0332] Process 1 A solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15, 0.09 g, 0.280 mmol, 1.0 equiv.), HATU (0.159 g, 0.420 mmol, 1.5 equiv.), and DIPEA (0.14 mL, 0.840 mmol, 3.0 equiv.) in DMF (1 mL) was stirred at 0° C. under a nitrogen atmosphere for 10 minutes, and CAS:93319-65-4 (0.036 g, 0.336 mmol, 1.2 equiv.) was added under nitrogen. The resulting mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC (using MDC:MeOH, 9:1, as the mobile phase) and was found to be complete after 16 hours. The resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.15 g of crude material, which was purified by flash column chromatography using silica (230-400 mesh size) (5% MeOH in DCM) as the stationary phase to give N-(2-hydroxyethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (43, 0.076 g, 0.184 mmol, 65.79% yield). 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 9.60 (t, J = 5.2 Hz, 1H), 9.31 (d, J = 2.0 Hz, 1H), 9.16 (d, J = 2.4 Hz, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.03-8.01 (m, 1H), 7.73-7.63 (m, 4H), 5.87 (br s, 1H), 4.85 (d, J = 5.6 Hz, 2H), 2.85-2.71 (m, 2H), 2.28-2.25 (m, 1H), 2.09-2.07 (m, 1H), 1.74-1.67 (m, 1H). (Note: One CF3-CH proton coincided with the clearly visible DMSO solvent peak in MeOD NMR.) 1H NMR(MeOD,400MHz):δ ppm,9.31(d,J=2.4Hz,1H),9.14(d,J=4.0Hz,1H),8.85(d,J=2.4Hz,1H),7.98(dd, J=1.2Hz,1H),7.85(d,J=7.6Hz,1H),7.77-7.74(m,1H),7.69-7.64(m,2H),5.87(br s, 1H), 4.95 (s, 2H), 2.79-2.76 (m, 1H), 2.69-2.65 (m, 2H), 2.55-2.51 (m, 1H), 2.41-2.33 (m, 1H), 2.18-2.15 (m, 1H), 1.88-1.82 (m, 1H). (Note: The -NH protons may be exchanged for deuterium from MeOD.) LCMS (Method A): 2.243 min, 98.55%, 254.0 nm, MS: ES+ 413 (M+1) HPLC (Method A): 7.95 min, 98.09%, 254.0nm Chiral HPLC (Method A): Peak-1 4.25 min, 49.65%, 240.0 nm, Peak-2 4.69 min, 49.98%, 240.0 nm

[0333] Example 40 - Synthesis of N-(pyrazin-2-ylmethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 44)

[0334] [ka]

[0335] Process 1 A solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15, 0.09 g, 0.280 mmol, 1.0 equiv.), HATU (0.160 g, 0.420 mmol, 1.5 equiv.), and DIPEA (0.15 mL, 0.840 mmol, 3.0 equiv.) in DMF (2 mL) was stirred at 0° C. under a nitrogen atmosphere for 20 minutes, and CAS:20010-99-5 (0.046 g, 0.420 mmol, 1.5 equiv.) was added under nitrogen. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (using 100% EtOAc as the mobile phase), which confirmed completion after 2 hours. The resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.072 g of crude material, which was purified by flash column chromatography using silica (230-400 mesh size) as the stationary phase (elution gradient 95% ethyl acetate in hexane) to give N-(pyrazin-2-ylmethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 44, 0.072 g, 0.174 mmol, yield: 62.33%). 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 9.54 (t, J = 5.6 Hz, 1H), 9.30 (d, J = 2.0 Hz, 1H), 8.88 (d, J = 1.6 Hz, 1H), 8.73 (s, 1H), 8.62 (s, 1H), 8.57 (d, J = 2.0 Hz, 1H), 8.03-8.01 (m, 1H), 7.66-7.63 (m, 2H), 5.87 (br s, 1H), 4.71 (d, J = 5.6 Hz, 2H), 2.81-2.68 (m, 3H), 2.32-2.25 (m, 1H), 2.10-2.07 (m, 1H), 1.75-1.67 (m, 1H). (Note: One CF3-CH proton is present in MeOD.) (This coincided with the clearly visible DMSO solvent peak in the NMR.) 1H NMR(MeOD,400MHz):δ ppm,9.30(d,J=2.0Hz,1H),8.83(d,J=2.0Hz,1H),8.75(s,1H),8.62(s,1H),8 .55(d,J=2.0Hz,1H),7.98(dd,J=1.6,8.0Hz,1H),7.70-7.64(m,2H),5.87(br s, 1H), 4.87 (s, 2H), 2.79-2.79-2.77 (m, 1H), 2.69-2.66 (m, 2H), 2.56-2.51 (m, 1H), 2.41-2.34 (m, 1H), 2.18-2.15 (m, 1H), 1.93-1.85 (m, 1H). (Note: The -NH protons may be exchanged for deuterium from MeOD.) LCMS (Method A): 2.305 min, 98.22%, 254.0 nm, MS: ES+ 413.2 (M+1) HPLC (Method A): 8.360 min, 97.65%, 254.0nm

[0336] Example 41 - Synthesis of N-((5-methyloxazol-2-yl)methyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 45)

[0337] [ka]

[0338] Process 1 A solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15, 0.09 g, 0.280 mmol, 1.0 equiv.), HATU (0.160 g, 0.420 mmol, 1.5 equiv.), and DIPEA (0.15 mL, 0.840 mmol, 3.0 equiv.) in DMF (2 mL) was stirred at 0° C. under a nitrogen atmosphere for 20 minutes, and CAS:2173992-46-4 (0.0457 g, 0.420 mmol, 1.5 equiv.) was added under nitrogen. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (using 5% MeOH:DCM as the mobile phase), which confirmed completion after 2 hours. The resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.08 g of crude material, which was purified by flash column chromatography using silica (230-400 mesh) (5% MeOH in DCM) as the stationary phase to give N-((5-methyloxazol-2-yl)methyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (45, 0.038 g, 0.0914 mmol, 32.66% yield). 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 9.49 (br s, 1H), 9.27 (s, 1H), 8.86 (s, 1H), 8.02 (d, J = 3.6 Hz, 1H), 7.66 (s, 2H), 6.79 (s, 1H), 5.87 (br s, 1H), 4.60 (d, J = 4.8 Hz, 2H), 2.81-2.68 (m, 3H), 2.32-2.28 (m, 4H), 2.10-2.07 (m, 1H), 1.71-1.67 (m, 1H). (Note: CF3-CH protons correspond to the DMSO solvent peaks clearly observed in MeOD NMR.) 1H NMR (MeOD, 400 MHz): δ ppm, 9.29 (s, 1H), 8.83 (s, 1H), 7.98 (d, J = 7.2 Hz, 1H), 7.70-7.64 (m, 2H), 6.78 (s, 1H), 5.87 (br s, 1H), 4.73 (s, 2H), 2.79-2.66 (m, 3H), 2.56-2.51 (m, 1H), 2.41-2.34 (m, 4H), 2.18-2.15 (m, 1H), 1.91-1.85 (m, 1H). (Note: -NH protons may be exchanged for deuterium in MeOD.) LCMS (Method A): 2.433 min, 97.16%, 254.0 nm, MS: ES+ 416.1 (M+1) HPLC (Method A): 8.81 min, 97.37%, 254.0nm

[0339] Example 42 - Synthesis of N-(2-hydroxy-1-(pyridin-2-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 46)

[0340] [ka]

[0341] Process 1 A solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15, 0.09 g, 0.280 mmol, 1.0 equiv.), HATU (0.160 g, 0.420 mmol, 1.5 equiv.), and DIPEA (0.15 mL, 0.840 mmol, 3.0 equiv.) in DMF (2 mL) was stirred at 0° C. under a nitrogen atmosphere for 20 minutes, and CAS: 1187930-63-7 (0.065 g, 0.308 mmol, 1.1 equiv.) was added under nitrogen. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (MeOH:DCM, 0.5:9.5, as the mobile phase), which confirmed completion after 2 hours. The resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.08 g of crude material, which was purified by flash column chromatography using silica (230-400 mesh size) as the stationary phase (elution gradient 95% ethyl acetate in hexane) to give N-(2-hydroxy-1-(pyridin-2-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 46, 0.058 g, 0.131 mmol, yield: 46.90%). 1 H NMR (DMSO-d6, 400MHz):δ ppm,9.30(s,1H),9.09(d,J=7.6Hz,1H),8.92(s,1H),8.55(d,J=4.0Hz,1H),8.03(t,J=4.8Hz,1H), 7.78(t,J=6.8Hz,1H),7.66(d,J=4.4Hz,2H),7.49(d,J=8.0Hz,1H),7.29(t,J=5.6Hz,1H),5.88(br s, 1H), 3.90-3.82 (m, 2H), 2.81-2.68 (m, 4H), 2.33-2.26 (m, 1H), 2.10-2.08 (m, 1H), 1.72-1.68 (m, 1H). (Note: The CF3-CH protons corresponded to the DMSO solvent peaks clearly observed in MeOD NMR.) 1H NMR(MeOD,400MHz):δ ppm,9.30(d,J=2.0Hz,1H),8.89(d,J=2.4Hz,1H),8.59(d,J=4.4Hz,1H),8.00(dd,J=2.0,8.0Hz,1H ),7.86(dt,J=1.6,8.0Hz,1H),7.70-7.65(m,2H),7.57(d,J=8.0Hz,1H),7.38-7.35(m,1H),5.88(br s, 1H), 5.39 (t, J = 6.4 Hz, 1H), 4.09-3.99 (m, 2H), 2.83-2.66 (m, 3H), 2.56-2.52 (m, 1H), 2.41-2.34 (m, 1H), 2.19-2.16 (m, 1H), 1.93-1.86 (m, 1H). (Note: -NH and -OH protons may be exchanged for deuterium from MeOD.) LCMS (Method A): 2.171 min, 100%, 210.0 nm, MS: ES+ 442.2 (M+1) HPLC (Method A): 8.19 min, 99.16%, 254.0nm

[0342] Example 43 - Synthesis of N-((1H-pyrazol-5-yl)methyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 47)

[0343] [ka]

[0344] Process 1 A solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15, 0.09 g, 0.280 mmol, 1.0 equiv.), HATU (0.160 g, 0.420 mmol, 1.5 equiv.), and DIPEA (0.15 mL, 0.840 mmol, 3.0 equiv.) in DMF (2 mL) was stirred at 0° C. under a nitrogen atmosphere for 20 minutes, and CAS: 1196153-72-6 (0.041 g, 0.308 mmol, 1.1 equiv.) was added under nitrogen. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (MeOH:DCM, 0.5:9.5, as the mobile phase), which confirmed completion after 2 hours. The resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.08 g of crude material, which was purified by flash column chromatography using silica (230-400 mesh size) as the stationary phase (elution gradient: 5% MeOH in DCM) to give N-((1H-pyrazol-5-yl)methyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 47, 0.038 g, 0.0949 mmol, yield: 33.88%). 1 H NMR (DMSO-d6, 400 MHz) VT NMR: δ ppm, 12.47 (s, 1H), 9.29 (s, 1H), 8.99 (s, 1H), 8.81 (s, 1H), 7.97 (d, J = 6.8 Hz, 1H), 7.64-7.61 (m, 3H), 6.24 (s, 1H), 5.89 (br s, 1H), 4.58 (d, J = 4.8 Hz, 2H), 2.82-2.70 (m, 3H), 2.35-2.28 (m, 1H), 2.13-2.10 (m, 1H), 1.80-1.71 (m, 1H). (Note: One CF3-CH proton coincided with the clearly visible DMSO solvent peak in MeOD NMR.) 1H NMR (MeOD, 400 MHz): δ ppm, 9.28 (d, J = 2.4 Hz, 1H), 8.80 (d, J = 2.0 Hz, 1H), 7.97 (dd, J = 1.6, 8.0 Hz, 1H), 7.69-7.63 (m, 3H), 6.38 (s, 1H), 5.87 (br s, 1H), 4.71 (s, 2H), 2.78-2.65 (m, 3H), 2.56-2.51 (m, 1H), 2.41-2.33 (m, 1H), 2.18-2.15 (m, 1H), 1.93-1.82 (m, 1H). (Note: -NH protons may be exchanged for deuterium in MeOD.) LCMS (Method A): 2.257 min, 98.28%, 254.0 nm, MS: ES+ 401.2 (M+1) HPLC (Method A): 8.02 min, 95.17%, 254.0nm

[0345] Example 44 - Synthesis of N-((1H-1,2,4-triazol-3-yl)methyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 48)

[0346] [ka]

[0347] Process 1 A solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15, 0.09 g, 0.280 mmol, 1.0 equiv.), HATU (0.160 g, 0.420 mmol, 1.5 equiv.), and DIPEA (0.15 mL, 0.840 mmol, 3.0 equiv.) in DMF (2 mL) was stirred at 0° C. under a nitrogen atmosphere for 20 minutes, and CAS: 1197157-75-7 (0.041 g, 0.308 mmol, 1.1 equiv.) was added under nitrogen. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (MeOH:DCM, 0.5:9.5, as the mobile phase), which confirmed completion after 2 hours. The resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.07 g of crude material, which was purified by flash column chromatography using silica (230-400 mesh size) as the stationary phase (elution gradient: 5% MeOH in DCM) to give N-((1H-1,2,4-triazol-3-yl)methyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 48, 0.040 g, 0.0996 mmol, yield: 35.58%). 1 H NMR (DMSO-d6, 400 MHz) VT NMR: δ ppm, 13.70 (s, 1H), 9.29 (d, J = 1.6 Hz, 1H), 9.13 (bs, 1H), 8.83 (d, J = 1.6 Hz, 1H), 8.44 (br s, 1H), 7.98 (d, J = 6.4 Hz, 1H), 7.67-7.61 (m, 2H), 5.91 (br s, 1H), 4.66 (s, 2H), 3.54-3.46 (m, 1H), 2.83-2.68 (m, 4H), 2.35-2.28 (m, 1H), 2.13-2.11 (m, 1H), 1.80-1.71 (m, 1H). (Note: One CF3-CH proton is present in MeOD.) (This coincided with the clearly visible DMSO solvent peak in the NMR.) 1H NMR (MeOD, 400 MHz): δ ppm, 9.30 (s, 1H), 8.84 (s, 1H), 8.48 (br s, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.70-7.63 (m, 2H), 5.87 (br s, 1H), 4.81 (s, 2H), 2.79-2.65 (m, 3H), 2.56-2.51 (m, 1H), 2.41-2.33 (m, 1H), 2.18-2.16 (m, 1H), 1.93-1.83 (m, 1H). (Note: -NH protons may be exchanged for deuterium from MeOD.) LCMS (Method A): 2.069 min, 99.06%, 254.0 nm, MS: ES+ 402.2 (M+1) HPLC (Method A): 6.22 min, 98.60%, 254.0nm

[0348] Example 45 - Synthesis of N-(cyanomethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 49)

[0349] [ka]

[0350] Process 1 A solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15, 0.1 g, 0.3112 mmol, 1.0 equiv.), HATU (0.177 g, 0.466 mmol, 1.5 equiv.), and DIPEA (0.161 g, 1.244 mmol, 4.0 equiv.) in DMF (1 mL) was stirred at 0° C. under a nitrogen atmosphere for 20 minutes, and CAS:6011-14-9 (0.03168 g, 0.342 mmol, 1.1 equiv.) was added under nitrogen. The resulting mixture was stirred at room temperature for 30 minutes. The reaction was monitored by TLC (using 1:1 EtOAc:hexane as the mobile phase), which indicated completion after 30 minutes. The resulting reaction mixture was quenched with ice-cold water (50 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.15 g of crude material, which was purified by flash column chromatography using silica (230-400 mesh size) (30% ethyl acetate in hexane) as the stationary phase to give N-(cyanomethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (49, 0.1 g, 0.278 mmol, 89.41% yield). 1 H NMR (DMSO d6, 400 MHz): δ ppm, 9.58 (t, J = 5.2 Hz, 1H), 9.25 (d, J = 2.0 Hz, 1H), 8.87 (d, J = 2.0 Hz, 1H), 8.04 (dd, J = 7.2 Hz, 2.8 Hz, 7.2 Hz, 1H), 7.69-7.64 (m, 2H), 5.88 (s, 1H), 4.43 (d, J = 5.6 Hz, 2H), 2.81-2.567 (m, 3H), 2.33-2.25 (m, 1H), 2.09 (d, J = 11.6 Hz, 1H), 1.75-1.64 (m, 1H). (Note: One CF3-CH proton coincided with the clearly visible DMSO solvent peak in MeOD NMR.) 1H NMR (MeOD, 400 MHz): δ ppm, 9.27 (d, J = 2.0 Hz, 1H), 8.81 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 8.0 Hz, 1H), 7.72-7.65 (m, 2H), 5.87 (s, 1H), 4.45 (s, 2H), 2.79-2.66 (m, 3H), 2.56-2.51 (m, 1H), 2.41-2.34 (m, 1H), 2.17 (d, J = 12.8 Hz, 1H), 1.93-1.85 (m, 1H). (Note: -NH protons may be exchanged for deuterium from MeOD.) LCMS (Method A): 2.438 min, 100%, 254.0 nm, MS: ES+ 360.07 (M+1) HPLC (Method A): 8.764 min, 100%, 254.0nm Chiral HPLC: Peak 1 = 3.87 min, 49.62%, 240.0 nm, Peak 2 = 4.46 min, 50.38%, 240.0 nm

[0351] Example 4 Synthesis of 6-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carbonyl)-D-alanine (Compound 50)

[0352] [ka]

[0353] Process 1 To a stirred solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15, 0.5 g, 1.5 mmol, 1.0 equiv.), CAS: 14316-06-4 (0.21 g, 1.54 mmol, 1.0 equiv.), and DIPEA (0.8 mL, 4.6 mmol, 3.0 equiv.) in DMF (5 mL) under inert N2 (g) conditions was added HATU (0.88 g, 2.3 mmol, 1.5 equiv.). The reaction was monitored by TLC (using neat ethyl acetate as the mobile phase) and was found to be complete after stirring at room temperature for 4 h. The resulting reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were extracted with EtOAc (2 × 50 mL), dried over Na2SO4, and concentrated under reduced pressure to give 0.45 g of crude product. The crude material was purified by manual column chromatography (gradient elution in 20% ethyl acetate in hexane) using silica (230-400 mesh) as the stationary phase to give methyl (3R)-3-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamido)butanoate (A29, 0.3 g, 0.738 mmol, yield: 47.44%). 1 H NMR (DMSO-d6, 400MHz): δ ppm 9.26(d,J=2.0Hz,1H),9.17(d,J=6.8Hz,1H),8.86(d,J=2.0Hz,1H),8.02(dd,J=6.0,3.6Hz,1H),7.66-7.63(m,2H),5.87(br s,1H),4.59-4.52(m,1H),3.67(s,3H),2.80-2.67(m,3H),2.50-2.46(m,1H), 2.32-2.24(m,1H),2.10-2.07(m,1H),1.74-1.64(m,1H),1.45(d,J=7.6Hz,3H) LCMS: 2.51 min, 100%, 215nm

[0354] Process 2 To a stirred solution of A29 (0.15 g, 0.36 mmol, 1.0 equiv.) and LiOH (0.018 g, 0.44 mmol, 1.2 equiv.) in MeOH:HO (8:2) was added at 0 °C, and the reaction was then carried out at room temperature. The reaction was monitored by TLC (using neat ethyl acetate as the mobile phase) and was found to be complete after stirring at room temperature for 2 h. The resulting reaction mixture was concentrated, acidified using 1 N HCl, and then filtered using a Buchner funnel to give (8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carbonyl)-D-alanine (compound 50, 0.056 g, 0.143 mmol, 38.67% yield). 1 H NMR (DMSO, 400 MHz): δ ppm 9.32 (d, J = 2.0 Hz, 1H), 9.21 (d, J = 6.8 Hz, 1H), 9.04 (s, 1H), 8.08-8.07 (m, 1H), 7.72-7.68 (m, 2H), 5.89 (br s, 1H), 4.53-4.46 (m, 1H), 2.77-2.69 (br s, 2H), 2.65-2.51 (m, 1H), 2.47-2.42 (m, 1H), 2.33-2.26 (m, 1H), 2.10-2.07 (m, 1H), 1.77-1.68 (m, 1H), 1.46 (d, J = 7.2 Hz, 3H). (Note: One CF3-CH proton is present in MeOD.) (This coincided with the clearly visible DMSO solvent peak in the NMR.) 1 H NMR (MeOD, 400 MHz): δ ppm 9.68 (d, J = 1.6 Hz, 1H), 9.49 (d, J = 1.6 Hz, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.13 (dd, J = 6.8 Hz, 1H), 8.05 (t, J = 8.0 Hz, 1H), 6.10 (br s, 1H), 4.75-4.70 (m, 1H), 3.42-2.25 (s, 6H), 2.03-1.91 (m, 1H), 1.63 (d, J = 7.6 Hz, 3H). (Note: -NH and -OH protons may exchange for deuterium in MeOD.) LCMS: 2.28 min, 100%, 210nm HPLC: 4.49 min, 99.17%, 254nm Chiral HPLC: Peak-1 3.58 min, 48.54%, 240 nm, Peak-2: 3.90 min, 49.73%, 240 nm

[0355] Example 47 Synthesis of O-methyl-N-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carbonyl)-D-serine (Compound 51)

[0356] [ka]

[0357] Process 1 In a 250 mL three-necked RB flask, white amorphous 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (Compound 15, 0.250 g, 0.775 mmol), methyl O-methyl-D-serine hydrochloride (CAS1800300-79-1) (0.315 g, 0.934 mmol, 1.2 equiv.), and DIPEA (1.12 mL, 2.35 mmol, 3.0 equiv.) were stirred with HATU (0.89 g, 1.16 mmol, 1.5 equiv.) in DMF (2 mL, 10 v) for 16 h at room temperature. The reaction was monitored by TLC (using 3:7 EtOAc:hexane as the mobile phase) and found to be complete after stirring at room temperature for 16 h. The resulting reaction mixture was diluted with ice-cold water (10 mL) and extracted with DCM. The combined layers were evaporated under vacuum, and the crude residue was purified by silica column chromatography (60–120 mesh, 30% EtOAc and hexanes) to give methyl O-methyl-N-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carbonyl)-D-serinate (A30, 0.185 g, 0.424 mmol, yield: 54.48%). 1H NMR (DMSO-d6, 400MHz): δ ppm 9.25(d,J=2.0Hz,1H),9.21(d,J=7.2Hz,1H),8.88(d,J=4.0Hz,1H),8.03(dd,J=6.4,4.8Hz,1H),7.67-7.63(m,2H),5.88(br s,1H),4.82-4.77(m,1H),3.87-3.50(m,5H),3.26(s,3H),2.81-2.68(m,4H) ,2.33-2.25(m,1H),2.30-2.20(m,1H),2.10-2.1(m,1H),1.74-1.64(m,1H). LCMS (Method A): 2.513 min, 100.0%, MS: ES+ 437.18[M+H]

[0358] Process 2 A suspension of methyl O-methyl-N-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carbonyl)-D-serinate (A30, 0.170 g, 0.3895 mmol, 1.0 equiv) in THF / water (3 mL / 1 mL) was cooled to 0 °C and then treated with LiOH (0.033 g, 0.824 mmol, 2.0 equiv), and the reaction solution was stirred at this temperature for 12 h. The solution was acidified with 1 N HCl. The resulting reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were extracted with EtOAc (2 × 50 mL), washed, and dried to give O-methyl-N-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carbonyl)-D-serine (compound 51, 0.052 g, 0.123 mmol, 31.06% yield) as a gray solid. 1H NMR (400MHz, DMSO-d6)δ ppm: 9.27(d,J=2.0Hz,1H),9.11(d,J=7.6Hz,1H,) 8.93(s,1H),8.03(dd,J=6.4,4.8Hz,1H),7.67-7.64(m,2H),5.88(br s, 1H), 4.72 (q, J = 10.0 Hz, 1H), 3.83-3.68 (m, 1H), 3.32 (s, 3H), 2.81-2.67 (m, 3H), 2.58-2.51 (m, 1H), 2.33-2.26 (m, 1H), 2.10-2.07 (m, 1H), 1.76-1.66 (m, 1H) (Note: One CF3-CH proton coincided with the clearly visible DMSO solvent peak in MeOD NMR). 1 H NMR (400 MHz, MeOD) δ (ppm): 9.48 (s, 1H), 9.42 (d, J = 2.0 Hz, 1H), 8.29 (d, J = 4.0 Hz, 1H), 8.02 (d, J = 4.0 Hz, 1H), 7.96 (t, J = 8.0 Hz, 1H), 6.04 (br s, 1H), 4.00-3.97 (m, 1H), 3.89-3.82 (m, 1H), 3.45 (s, 3H), 3.74 (br s, 2H), 2.65-2.56 (m, 2H), 2.48-2.41 (m, 1H), 2.61-2.24 (m, 1H), 2.01-1.90 (m, 1H) (Note: -NH and -OH protons may be exchanged for deuterium from MeOD). LCMS (Method A): 2.31 min, 95.47%, 254 nm HPLC (Method A): 4.34 min, 96.33%, 254nm Chiral HPLC: Peak-1 6.26 min, 36.05%, 240 nm; Peak-2 6.71 min, 43.16%, 240 nm

[0359] Example 48 - Synthesis of N-((R)-1-(methylamino)-1-oxopropan-2-yl)-8-(4(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 52)

[0360] [ka]

[0361] Process 1 A stirred solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 50, 0.16 g, 0.40 mmol, 1.0 equiv.), CAS: 61302-99-6 (0.027 g, 0.40 mmol, 1.0 equiv.), and DIPEA (0.2 mL, 1.2 mmol, 3.0 equiv.) in DMF (2 mL) was prepared under inert N2 (g) conditions, followed by the addition of HATU (0.232 g, 0.612 mmol, 1.5 equiv.). The reaction was monitored by TLC (using neat ethyl acetate as the mobile phase) and was found to be complete after stirring at room temperature for 16 h. The resulting reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were extracted with EtOAc (2 × 50 mL), dried over NaSO, and concentrated under reduced pressure to give 0.45 g of crude product. The crude product was purified by manual column chromatography (gradient elution of 20% ethyl acetate in hexanes) using silica (230–400 mesh) as the stationary phase, followed by preparative HPLC purification (Method A) to give N-((R)-1-(methylamino)-1-oxopropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 52, 0.023 g, 0.057 mmol, 13.91% yield). 1 H NMR (DMSO-d6, 400 MHz): δ ppm 9.28 (d, J = 2.0 Hz, 1H), 8.91-8.88 (m, 2H), 8.02-7.80 (m, 2H), 7.95 (m, J = 4.4 Hz, 2H), 7.65-7.64 (m, 1H), 5.88 (br s, 1H), 4.51-4.48 (m, 1H), 2.79 (br s, 1H), 2.72-2.68 (m, 2H), 2.62-2.57 (m, 4H), 2.33-2.29 (m, 1H), 2.10-2.07 (m, 1H), 1.72-1.68 (m, 1H), 1.37 (d, J = 7.2 Hz, 3H). (Note: One CF3-CH proton is present in MeOD.) (This coincided with the clearly visible DMSO solvent peak in the NMR.) 1 H NMR (MeOD, 400 MHz): δ ppm 9.28 (d, J = 2.0 Hz, 1H), 8.85 (d, J = 2.0 Hz, 1H), 7.98 (dd, J = 7.8, 1.6 Hz, 1H), 7.70-7.64 (m, 2H), 5.87 (br s, 1H), 4.61 (q, J = 7.2 Hz, 1H), 2.80 (s, 3H), 2.79-2.75 (m, 2H), 2.68-2.65 (m, 1H), 2.56-2.51 (m, 1H), 2.41-2.38 (m, 1H), 2.18-2.15 (m, 1H), 1.53 (d, J = 7.2 Hz, 3H) (Note: -NH protons may be exchanged for deuterium from MeOD). LCMS (Method A): 2.20 min, 100%, 254.0 nm, m / z=406.12(M+H)+ HPLC (Method A): 7.75 min, 99.61%, 210nm Chiral HPLC: Peak-1: 3.55 min, 42.28%, 245 nm; Peak-2: 4.07 min, 43.73%, 245 nm

[0362] Example 49 - Synthesis of N-((R)-1-aminopropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 53)

[0363] [ka]

[0364] Process 1 To a stirred solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15, 0.2 g, 0.62 mmol, 1.0 equiv.), CAS: 333743-54-7 (0.10 g, 0.62 mmol, 1.0 equiv.), and DIPEA (0.3 mL, 1.8 mmol, 3.0 equiv.) in DMF (2 mL) under inert N2 (g) conditions was added HATU (0.35 g, 0.93 mmol, 1.5 equiv.). The reaction was monitored by TLC (using neat ethyl acetate as the mobile phase) and was found to be complete after stirring at room temperature for 4 h. The resulting reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were extracted with EtOAc (2 × 50 mL), dried over Na2SO4, and concentrated under reduced pressure to give 0.3 g of crude product. The crude material was purified by manual column chromatography using silica (230-400 mesh) as the stationary phase (gradient elution in 20% ethyl acetate in hexane) to give tert-butyl ((2R)-2-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamido)propyl)carbamate (A31, 0.22 g, 0.461 mmol, yield: 67.28%). 1 H NMR (DMSO-d6, 400MHz): δ ppm 9.23(d,J=1.6Hz,1H),8.77(d,J=1.6Hz,1H),8.48(d,J=8.4Hz,1H),7.98(t,J=4.8Hz,1H),7.64-7.61(m,2H),7.01(t,J=5.6Hz,1H),5.87(br s,1H),4.15-4.08(m,1H),3.43-3.07(m,2H),2.79-2.68(m,4H),2.31-2.25(m ,1H),2.01-2.07(m,1H),1.74-1.63(m,1H),1.35(s,9H),1.14(d,J=6.8Hz,3H) LCMS (Method A): RT=2.72 min, 100%, 254 nm, m / z=478.24(M+H)+

[0365] Process 2 To a stirred solution of A31 (0.1 g, 0.20 mmol, 1.0 equiv.) in DCM (1 ml) was added 4 M HCl in dioxane at 0 °C, and the reaction was then carried out at room temperature. The reaction was monitored by TLC (using neat ethyl acetate as the mobile phase) and was confirmed to be complete after stirring at room temperature for 16 h. The resulting reaction mixture was concentrated and then triturated with pentane and diethyl ether to give N-((R)-1-aminopropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 53, 0.070 g, 0.18 mmol, 88.57% yield). 1 H NMR (DMSO-d6, 400 MHz): δ ppm 9.33 (s, 1H), 8.96 (s, 1H), 8.90 (d, J = 8.0 Hz, 1H), 8.09 (br s, 2H), 8.04-8.02 (m, 1H), 7.68-7.66 (m, 2H), 5.88 (br s, 1H), 4.35 (t, J = 6.8 Hz, 1H), 3.01 (br s, 2H), 2.76-2.67 (m, 3H), 2.32-2.25 (m, 1H), 2.10-2.07 (m, 1H), 1.72-1.68 (m, 1H), 1.23 (d, J = 6.4 Hz, 3H). (Note: One CF3-CH proton coincided with the clearly visible DMSO solvent peak in MeOD NMR.) 1 H NMR (MeOD, 400 MHz): δ ppm 9.60 (s, 1H), 9.49 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 6.4 Hz, 1H), 8.01 (t, J = 7.6 Hz, 1H), 6.07 (br s, 1H), 4.56-4.52 (m, 1H), 3.33-3.16 (m, 2H), 2.75-2.61 (m, 4H), 2.49-2.42 (m, 1H), 2.28-2.25 (m, 1H), 2.0-1.90 (m, 1H), 1.46 (d, J = 6.8 Hz, 3H) (Note: -NH protons may be exchanged for deuterium from MeOD). LCMS (Method A): 1.86 min, 100%, 210.0 nm, m / z=378.1 HPLC (Method A): 8.34 min, 100%, 210nm Chiral HPLC: Peak-1: 5.27 min, 47.54%, 240 nm; Peak-2: 5.75 min, 52.45%, 240 nm

[0366] Example 50 - Synthesis of N-((R)-4-hydroxybutan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 54)

[0367] [ka]

[0368] Process 1 To a stirred solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15, 0.2 g, 0.62 mmol, 1.0 equiv.), CAS: 61477-40-5 (0.055 g, 0.62 mmol, 1.0 equiv.), and DIPEA (0.3 mL, 1.8 mmol, 3.0 equiv.) in DMF (2 mL) under inert N2 (g) conditions, HATU (0.355 g, 0.934 mmol, 1.5 equiv.) was added. The reaction was monitored by TLC (using neat ethyl acetate as the mobile phase) and was found to be complete after stirring at room temperature for 4 h. The resulting reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were extracted with EtOAc (2 × 50 mL), dried over NaSO, and concentrated under reduced pressure to give 0.45 g of crude product, which was purified by manual column chromatography (gradient elution of 20% ethyl acetate in hexane) using silica (230-400 mesh size) as the stationary phase to give N-((R)-4-hydroxybutan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 54, 0.063 g, 0.161 mmol, yield: 25.79%). 1H NMR (DMSO-d6, 400 MHz): δ ppm 9.23 (d, J = 1.6 Hz, 1H), 8.78 (d, J = 2.0 Hz, 1H), 8.55 (d, J = 8.4 Hz, 1H), 8.00 (t, J = 4.8 Hz, 1H), 7.64 (d, J = 4.4 Hz, 2H), 5.87 (br s, 1H), 4.47 (t, J = 4.8 Hz, 1H), 4.21-4.14 (m, 1H), 3.49-3.46 (m, 2H), 2.80-2.07 (m, 5H), 1.80-1.42 (m, 3H), 1.20 (d, J = 6.4 Hz, 3H). (Note: One CF3-CH proton coincided with the clearly visible DMSO solvent peak in MeOD NMR.) 1 H NMR (MeOD, 400 MHz): δ ppm 9.23 (d, J = 2.0 Hz, 1H), 8.75 (d, J = 2.0 Hz, 1H), 7.97 (d, J = 6.4 Hz, 1H), 7.69-7.63 (m, 2H), 6.87 (br s, 1H), 4.39-4.34 (m, 1H), 3.75-3.66 (m, 2H), 2.88-2.65 (m, 3H), 2.55-2.51 (m, 1H), 2.40-2.34 (m, 1H), 2.18-2.15 (m, 1H), 1.91-1.82 (m, 3H), 1.35 (d, J = 6.8 Hz, 3H). (Note: -NH protons may be exchanged for deuterium in MeOD.) LCMS (Method A): 2.27 min, 98.91%, 254.0nm, m / z= 393.17(m+H)+ HPLC (Method A): 8.25 minutes, 100%, 210nm Chiral HPLC: Peak-1: 4.22 min, 50.06%, 240 nm; Peak-2: 4.53 min, 49.93%, 240 nm

[0369] Example 51 Synthesis of 1-(3R)-3-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamido)butanoic acid (Compound 55)

[0370] [ka]

[0371] Process 1 To a stirred solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15, 0.45 g, 1.4 mmol, 1.0 equiv.), CAS: 139243-54-2 (0.23 g, 1.54 mmol, 1.1 equiv.), and DIPEA (0.542 g, 4.2 mmol, 3.0 equiv.) in DMF (2 mL) under inert N2 (g) conditions, HATU (0.798 g, 2.1 mmol, 1.5 equiv.) was added. The reaction was monitored by TLC (using neat ethyl acetate as the mobile phase) and was found to be complete after stirring at room temperature for 4 h. The resulting reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were extracted with EtOAc (2 × 50 mL), dried over NaSO, and concentrated under reduced pressure to give 0.45 g of crude material, which was purified by manual column chromatography (gradient elution in 20% ethyl acetate in hexanes) using silica (230–400 mesh) as the stationary phase to give methyl (3R)-3-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamido)butanoate (A32, 0.41 g, 0.975 mmol, yield: 69.72%). 1 H NMR(MeOD,400MHz):δ ppm 9.22(d,J=2.4Hz,1H),8.73(d,J=2.0Hz,1H),7.96(dd,J=7.6,1.6 1H),7.69-7.63(m,2H),5.86(br s, 1H), 4.62-4.57 (m, 1H), 3.70 (s, 3H), 2.77-2.72 (m, 2H), 2.68-2.63 (m, 3H), 2.55-2.51 (m, 1H), 2.41-2.37 (m, 1H), 2.18-2.15 (m, 1H), 1.90-1.85 (m, 1H), 1.37 (d, J = 6.8 Hz, 3H). (Note: The -NH protons may be exchanged with deuterium from MeOD, and traces of EA solvent may be observed.) LCMS (Method A): 2.523 min, 100%, 254 nm, (M+H)+=421.12 Chiral HPLC: Peak-1 3.31 min, 49.60%, 240 nm Peak-2 3.52 min, 50.39%, 240 nm

[0372] Process 2 To a stirred solution of (A32, 0.38 g, 0.90 mmol, 1.0 equiv.) LiOH.HO (0.094 g, 1.80 mmol, 2.0 equiv.) in MeOH:HO (8:2) was added at 0 °C, and the reaction was then carried out at room temperature. The reaction was monitored by TLC (using neat ethyl acetate as the mobile phase) and was found to be complete after stirring at room temperature for 2 h. The resulting reaction mixture was concentrated, then acidified using 1 N HCl, and then filtered using a Buchner funnel to give (3R)-3-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamido)-butanoic acid (compound 55, 0.18 g, 0.44 mmol, 49% yield). 1 H NMR (DMSO-d6, 400 MHz): δ ppm 9.24 (d, J = 2.0 Hz, 1H), 8.84 (s, 1H), 8.75 (d, J = 7.6 Hz, 1H), 8.04-8.02 (m, 1H), 7.68-7.66 (m, 3H), 5.87 (br s, 1H), 4.43-4.35 (m, 1H), 2.79-2.61 (m, 4H), 2.47-2.43 (m, 1H), 2.33-2.29 (m, 1H), 2.10-2.07 (m, 1H), 1.73-1.68 (m, 1H), 1.24 (d, J = 8.0 Hz, 3H). (Note: One CF3-CH proton coincided with the clearly visible DMSO solvent peak in MeOD NMR.) 1H NMR (MeOD, 400 MHz): δ ppm 9.52 (d, J = 1.6 Hz, 1H), 9.41 (d, J = 1.6 Hz, 1H), 8.32 (d, J = 7.6 Hz, 1H), 8.08 (d, J = 6.0 Hz, 1H), 8.01 (t, J = 8.0 Hz, 1H), 6.07 (br s, 1H), 4.64-4.59 (m, 1H), 2.80-2.74 (m, 4H), 2.66-2.63 (m, 2H), 2.49-2.46 (m, 1H), 2.28-2.25 (m, 1H), 1.97-1.93 (m, 1H), 1.41 (d, J = 6.8 Hz, 3H) (Note: -NH and -OH protons may exchange for deuterium in MeOD). LCMS (Method A): 2.28 min, 100%, 242.0 nm, (M+H)+=407.12 HPLC (Method A): 4.51 min, 99.47%, 254nm Chiral HPLC: Peak-1 4.97 min, 47.33%, 240 nm, Peak-2 5.52 min, 44.05%, 240 nm

[0373] Example 52 - Synthesis of N-((R)-4-(methylamino)-4-oxobutan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 56)

[0374] [ka]

[0375] Process 1 To a stirred solution of (3R)-3-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamido)-butanoic acid (compound 55, 0.107 g, 0.263 mmol, 1.0 equiv.), CAS: 593-51-1 (0.0195 g, 0.289 mmol, 1.1 equiv.), and DIPEA (0.102 g, 0.789 mmol, 3.2 equiv.) in DMF (2 mL) under inert N2 (g) conditions, EDCI.HCl (0.0757 g, 0.395 mmol, 1.5 equiv.) and HOBt (0.0534 g, 0.39 mmol, 1.5 equiv.) were added. The reaction was monitored by TLC (using neat ethyl acetate as the mobile phase) and was found to be complete after stirring at room temperature for 16 h. The resulting reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were extracted with EtOAc (2 × 50 mL), dried over NaSO, and concentrated under reduced pressure to give 0.07 g of crude product. The crude product was purified by manual column chromatography (gradient elution in neat ethyl acetate) using silica (230–400 mesh) as the stationary phase to give N-((R)-4-(methylamino)-4-oxobutan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 56, 0.045 g, 0.107 mmol, yield: 40.75%). 1 H NMR(MeOD,400MHz):δ ppm 9.22(d,J=2.0Hz,1H),8.74(d,J=2.0Hz,1H),7.97(dd,J=7.4,2.0Hz,1H),7.69-7.63(m,2H),5.87(br s,1H),4.59-4.54(m,1H),2.89-2.75(m,4H),2.68-2.65(m,1H),2.62-2.61(m,1H),2.59-2. 46(m,3H),2.41-2.34(m,1H),2.41-2.34(m,1H),1.93-1.83(m,1H),1.38(d,(d,J=6.8Hz,3H) 1H NMR (CD3CN,400MHz):δ ppm 9.20(d,J=2.0Hz,1H),8.63(d,J=2.0Hz,1H),7.94(dd,J=7.6,1.6Hz,1H),7.71(d,J=7.6Hz,1H),7.66-7.60(m,2H),6.51(br s,1H),5.89(br s,1H),4.51-4.45(m,1H),2.83-2.48(m,2H),2.43(d,J=6.4Hz,3H),2.40 -2.32(m,4H),1.83-1.77(m,2H),1.96-1.78(m,1H),1.29(d,J=6.8Hz,3H) LCMS (Method A): 2.22 min, 99.89%, 254 nm, (M+H)+=420.18 HPLC (Method A): 7.69 min, 99.53%, 210nm Chiral HPLC: Peak-1 11.21 min, 52.16%, 225 nm, Peak-2 11.81 min, 47.84%, 225 nm

[0376] Example 53 - Synthesis of 5-(4,4-difluorocyclohex-1-en-1-yl)-N-isopropyl-2-naphthamide (Compound 57):

[0377] [ka]

[0378] Process 1 A solution of 5-bromo-2-naphthoic acid CAS:1013-83-8 (1.0 g, 3.982 mmol, 1.0 equiv.), HATU (2.27 g, 5.974 mmol, 1.5 equiv.), and DIPEA (1.36 mL, 7.965 mmol, 2.0 equiv.) in DCM (10 mL) was stirred at 0 °C under a nitrogen atmosphere for 20 min, and propan-2-amine CAS:75-31-0 (0.258 g, 4.389 mmol, 1.1 equiv.) was added under nitrogen. The resulting mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC (using 3:7 EtOAc:hexane as the mobile phase), which confirmed completion after 16 h. The resulting reaction mixture was quenched with ice-cold water (20 mL) and extracted with DCM (3 × 25 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 1.3 g of crude material, which was purified by flash column chromatography (0-20% ethyl acetate in hexanes) using silica (230-400 mesh) as the stationary phase to give 5-bromo-N-isopropyl-2-naphthamide (A33) (0.95 g, 3.251 mmol, 81.64% yield). 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 8.51-8.48 (m, 2H), 8.17 (d, J = 8.8 Hz, 1H), 8.09 (dd, J = 8.8, 1.6 Hz, 2H), 7.98 (d, J = 7.6 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 4.19-4.14 (m, 1H), 1.27-1.17 (m, 6H). Note: Some aliphatic impurities related to SM are present. LCMS (Method A): 2.286 min, 97.67%, 254.0nm, MS: ES+ 292.1(M), 294.1(M+2)

[0379] Process 2 A stirred solution of 5-bromo-N-isopropyl-2-naphthamide (A33) (0.3 g, 1.229 mmol, 1.0 equiv.), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, CAS: 1227068-84-9 (purchased from commercial source combi block) (0.32 g, 1.106 mmol, 0.9 equiv.), and potassium phosphate tripotassium (0.78 g, 3.687 mmol, 3.0 equiv.) in 1,4-dioxane (3 mL) was purged with nitrogen for 30 minutes, after which Pd(PPh3)4 (0.143 g, 0.123 mmol, 1.3 equiv.) was added and the resulting reaction mixture was heated to 100 °C for 16 hours. The reaction was monitored by TLC (using EA:hexane, 3:7 as the mobile phase) and was found to be complete after stirring at 100 °C for 16 h. The resulting reaction mixture was filtered through a Celite bed, and the filtrate was concentrated under reduced pressure to give a crude residue (0.4 g), which was purified using silica gel (60-120 mesh) as the stationary phase (25% EtOAc in hexane) to give 5-(4,4-dithiolocyclohex-1-en-1-yl)-N-isopropyl-2-naphthamide (compound 57) (0.14 g, 0.425 mmol, yield: 34.65%). 1 H NMR (DMSO-d6, 400MHz): δ ppm 8.45(s,1H),8.39(d,J=7.6Hz,1H),7.97-7.91(m,3H),7.55(t,J=8.0Hz,1H),7.40(d,J=6.8Hz,1H),5.64(br s,1H),4.18-4.13(m,1H),2.82(t,J=14.8Hz,2H),2.65-2.55(m,2H),2.34-2.24(m,2H),1.21(d,J=6.4Hz,6H). LCMS (Method A): 2.398 min, 98.32%, MS: ES+ 330.16[M+H] HPLC (Method C): 8.357 min, 96.83%, 210nm

[0380] Example 54 - Synthesis of N-((S)-1-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-2-naphthamide (Compound 58)

[0381] [ka]

[0382] Process 1 A solution of 2-naphthoic acid CAS:93-09-4 (24.0 g, 139.4 mmol, 1.0 equiv), Br (22.2 g, 139.4 mmol, 1.0 equiv), and I (0.706 g, 2.788 mmol, 0.02 equiv) in AcOH (240 mL) was stirred at 120 °C for 5 h. The reaction was monitored by TLC (using EA:hexane, 2.0:8.0 as the mobile phase) and was found to be complete after stirring at 120 °C for 5 h. The resulting reaction mixture was cooled to room temperature. The resulting solid was filtered and washed with AcOH (50 mL) and water (200 mL) to give 20.0 g of crude product. The crude material was then triturated by using MeOH (2×50 mL) to give 5-bromo-2-naphthoic acid (A34) (15.0 g, 59.74 mmol, yield: 42.86%). 1 H NMR (DMSO-d6, 400MHz): δ ppm,13.31(br s,1H),8.68(d,J=1.6Hz,1H),8.21(t,J=8.4Hz,2H),8.14(dd,J=8.8,1.6Hz,1H),8.03(dd,J=7.6,1.2Hz,1H),7.54(t,J=7.6Hz,1H).

[0383] Process 2 To a stirred solution of 5-bromo-2-naphthoic acid (A34) (0.25 g, 0.996 mmol, 1.0 equiv.), 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1,3,2-dioxaborolane (CAS: 683242-93-5) (0.41 g, 1.195 mmol, 1.2 equiv.), and KPO (1.05 g, 4.980 mmol, 5.0 equiv.) in dioxane (2 mL) and water (1 mL) was added Pd(dppf)Cl.DCM (0.081 g, 0.099 mmol, 0.1 equiv.) under N. The resulting mixture was stirred at 100 °C for 2 h. The reaction was monitored by TLC (using EA:hexane, 8.0:2.0 as the mobile phase) and was found to be complete after stirring at 100 °C for 2 h. The resulting reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.320 g of crude product. The resulting crude material was purified by flash column chromatography (69% EA in hexane) using silica gel (230-400 mesh) as the stationary phase to give 5-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-2-naphthoic acid (A35) (0.30 g, 0.936 mmol, yield: 94.06%). 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 13.11 (br s, 1H), 8.60 (d, J = 1.6 Hz, 1H), 8.06 (t, J = 11.2 Hz, 2H), 7.96 (dd, J = 8.8, 2.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.42 (dd, J = 7.2, 1.2 Hz, 1H), 5.73 (br s, 1H), 3.94 (br s, 1H), 2.80-2.77 (m, 1H), 2.56-2.54 (m, 1H), 2.49-2.27 (m, 2H), 2.10-2.07 (m, 1H), 1.77-1.73 (m, 1H). Note: Minor peaks of aliphatic impurities were observed. LCMS (Method A): 2.732 min, 92.64%, 280.0 nm, MS: ES-319.4 (M-1)

[0384] Process 3 A solution of 5-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-2-naphthoic acid (A35) (0.15 g, 0.468 mmol, 1.0 equiv.), HATU (0.26 g, 0.703 mmol, 1.5 equiv.), and DIPEA (0.17 g, 1.370 mmol, 3.0 equiv.) in DMF (2 mL) was stirred at 0 °C under a nitrogen atmosphere for 15 min, and CAS: 40154-78-7 (0.068 g, 0.562 mmol, 1.2 equiv.) was added under a N atmosphere. The resulting mixture was stirred at room temperature for 4 h. The reaction was monitored by TLC (using EA:hexane, 5.0:5.0 as the mobile phase) and was found to be complete after 4 h. The resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.250 g of crude material, which was purified by flash column chromatography (35% ethyl acetate in hexanes) using silica (230-400 mesh) as the stationary phase to give N-((S)-1-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-2-naphthamide (compound 58) (0.063 g, 0.148 mmol, yield: 15.85%). 1 H NMR(DMSO,400MHz):δ ppm,9.01(d,J=8.0Hz,1H),8.56-8.53(m,2H),8.04(d,J=9.2Hz,1H),7.96-7.94(m,2H),7.76 (td,J=8.0,1.6Hz,1H),7.56(t,J=8.0Hz,1H),7.46-7.38(m,2H),7.28-7.25(m,1H),5.74(br s,1H),5.28-5.24(m,1H),2.79(br s,1H),2.52-2.51(m,1H),2.45-2.33(m,3H),2.11-2.08(m,1H),1.83-1.73(m,1H),1.55(d,J=7.2Hz,3H). 1H NMR(MeOD,400MHz):δ ppm,8.56-8.54(m,1H),8.47(d,J=1.6Hz,1H),8.06(d,J=8.8Hz,1H),7.94-7.92(m,2H),7.85(t d,J=7.6,2.0Hz,1H),7.56-7.52(m,2H),7.40(dd,J=6.8,1.2Hz,1H),7.35-7.31(m,1H),5.79(br s,1H),5.35(q,J=7.2Hz,1H),2.67-2.38(m,5H),2.22-2.18(m,1H),1.89-1.85(m,1H) 1.65 (d, J = 7.2 Hz, 3H). Note: The amide -NH was not observed. LCMS (Method A): 2.572 min, 97.37%, 210.0 nm, MS: ES+ 425.23 (M+1) HPLC (Method B): 6.907 min, 95.34%, 210.0nm Chiral HPLC (Method A): 2.51 min, 95.16%, 230.0 nm

[0385] Example 55 Synthesis of N-isopropyl-8-(spiro[2.5]oct-5-en-6-yl)quinoline-3-carboxamide (Compound 59)

[0386] [ka]

[0387] Process 1 To a stirred solution of 1,4-dioxaspiro[4.5]decan-8-one (CAS: 4746-97-8) (25 g, 160.07 mmol, 1.0 equiv.), CAS: 1779-49-3 (57.1 g, 160.07 mmol, 1.0 equiv.) in toluene (200 mL) was added KO tBu (21.5 g, 192.08 mmol, 1.2 equiv.) was added to the reaction mixture under a N2 atmosphere. The resulting mixture was then stirred at room temperature for 16 h at 110 °C. The reaction was monitored by TLC (using EA:hexane, 1:9 as the mobile phase) and confirmed to be complete after stirring at room temperature for 16 h. The resulting reaction mixture was quenched with NH4Cl and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give 25 g of crude product. The crude product was purified by manual column chromatography (gradient elution in 4% EA in hexane) using silica (60–120 mesh) as the stationary phase to give 8-methylene-1,4-dioxaspiro[4.5]decane (A36) (18 g, 116.88 mmol, 72.92% yield). 1 H NMR (CDCl3,400MHz): δ ppm 4.69(s,2H),3.98(s,4H),2.30(t,J=6.4Hz,4H),1.72(t,J=6.8Hz,4H).

[0388] Process 2 A stirred solution of A36 (5.2 g, 34 mmol, 1.0 equiv.) and diethylzinc (87.9 mL, 87.9 mmol, 2.56 equiv.) in toluene (52 mL) was added to the reaction mixture under a N atmosphere at −40° C. The resulting mixture was then stirred at −40° C. for 20 minutes. CHCl (46.06 g, 172 mmol, 5.2 equiv.) was added at −40° C., and the reaction mixture was stirred overnight. The reaction was monitored by TLC (EA:hexane, 1:9 as mobile phase) and confirmed to be complete after stirring at room temperature for 18 hours. The resulting reaction mixture was quenched with NHCl and extracted with diethyl ether (4 × 30 mL). The combined organic layers were washed with sodium thiosulfate (3 × 40 ml), dried over NaSO, and then concentrated under reduced pressure to give 5.3 g of crude product. The crude material was purified by manual column chromatography using silica (230–400 mesh) as the stationary phase (gradient elution of 3% ethyl acetate in hexane) to give 7,10-dioxadispiro[2.2.4.2]dodecane (A37) (3 g, 17.85 mmol, 52% yield). 1 H NMR (CDCl3,400MHz): δ ppm 3.98(s,4H),1.71(t,J=6.0Hz,4H),1.45-1.42(m,4H),0.30(s,4H).

[0389] Process 3 To a stirred solution of A37 (1.1 g, 6.54 mmol, 1.0 equiv) in THF:HO (8.33 mL, 3:2) was added TFA (1.67 mL, 21.58 mmol, 3.3 equiv) to the reaction mixture under a N atmosphere at 0 °C. The resulting mixture was stirred for 18 h at 0 °C. The reaction was monitored by TLC (diethyl ether:pentane, 1:9 as mobile phase) and confirmed to be complete after stirring at room temperature for 18 h. Upon completion, the reaction mixture was quenched with aqueous NaCO and extracted with diethyl ether (4 × 30 mL). The combined organic layers were washed with NaSO (3 × 40 ml), dried over NaSO, and concentrated under reduced pressure to give 5.3 g of crude product. The crude material was purified by manual column chromatography (2% ethyl acetate in hexane) using silica (230–400 mesh) as the stationary phase to give spiro[2.5]octan-6-one (A38) (0.2 g, 1.61 mmol, 24.63% yield). 1 H NMR (CDCl3,400MHz): δ ppm 2.54-2.42(m,4H),1.70(t,J=6.8Hz,4H),0.51(s,4H).

[0390] Process 4 To a stirred solution of A38 (0.2 g, 1.61 mmol, 1.0 equiv) in THF (4 mL) under a N atmosphere at −78 °C, LiHMDS (1.7 mL, 1.77 mmol, 1.1 equiv, 1.0 M in THF) was added dropwise. The resulting mixture was then stirred at −78 °C for 1 h. After 1 h, N-phenyl-bis(trifluoromethanesulfonimide) CAS: 37595-74-7 (0.68 g, 1.93 mmol, 1.2 equiv) was added to the reaction mixture, and the reaction was allowed to proceed overnight. The reaction was monitored by TLC (ethyl acetate:hexane, 1:9 as mobile phase) and confirmed to be complete after stirring at room temperature for 18 h. The resulting reaction mixture was quenched with HO and extracted with ethyl acetate (4 × 30 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.25 g of crude product. The crude material was purified by manual column chromatography (gradient elution in 5% ethyl acetate in hexane) using silica (230–400 mesh) as the stationary phase to give spiro[2.5]oct-5-en-6-yl trifluoromethanesulfonate (A39) (0.19 g, 0.74 mmol, 46.04% yield). 1 H NMR(CDCl3,400MHz):δ ppm 5.81-5.79(m,1H),2.45-2.40(m,2H),2.07-2.04(m,2H),1.57(t,J=6.4Hz,2H),0.41(s,4H).

[0391] Process 5 To a stirred solution of A39 (1.4 g, 5.46 mmol, 1.0 equiv.) in dioxane (14 mL) was added B2Pin2 (CAS: 73183-34-3) (1.52 g, 6.0 mmol, 1.1 equiv.), followed by KOAc (1.62 g, 16.54 mmol, 3.03 equiv.) and PdCl2(dppf) (0.39 g, 0.54 mmol, 0.1 equiv.). The reaction mixture was purged with N2 for 10 minutes and then stirred at 100 °C overnight. TLC (ethyl acetate:hexane 1:9 as mobile phase) confirmed the reaction was complete. The resulting reaction mixture was filtered through Celite and extracted with ethyl acetate (4 × 30 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give 0.41 g of crude product. The crude material was purified by manual column chromatography (10% ethyl acetate in hexane) using silica (230–400 mesh) as the stationary phase to give 4,4,5,5-tetramethyl-2-(spiro[2.5]oct-5-en-6-yl)-1,3,2-dioxaborolane (A40) (0.6 g, 2.56 mmol, 46.90% yield). 1 H NMR (CDCl3,400MHz): δ ppm 6.61-6.60(m,1H),2.25-2.21(m,2H),2.01-1.99(m,2H),1.39-1.36(m,2H),1.29(s,1H),0.32-0.28(m,4H).

[0392] Process 6 To a stirred solution of A40 (0.07 g, 0.29 mmol, 1.1 equiv.) and A23 (0.08 g, 0.27 mmol, 1.0 equiv.) in dioxane:HO (8:2) was added KPO (0.173 g, 0.81 mmol, 3.0 equiv.), PdCl(dppf).DCM (0.11 g, 0.31 mmol, 0.5 equiv.), and the reaction mixture was stirred at 110 °C overnight. The reaction was monitored by TLC (ethyl acetate:hexane, 5:5 as mobile phase) and found to be complete after stirring at 110 °C for 16 h. The resulting reaction mixture was filtered through Celite and extracted with ethyl acetate (4 × 30 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.078 g of crude product. The crude material was purified by manual column chromatography (gradient of 35% ethyl acetate in hexane) using silica (230–400 mesh) as the stationary phase to give N-isopropyl-8-(spiro[2.5]oct-5-en-6-yl)quinoline-3-carboxamide (A59) (0.03 g, 0.09 mmol, 31.32% yield). 1 H NMR (MeOD, 400 MHz): δ ppm 9.23 (d, J = 2.4 Hz, 1H), 8.72 (d, J = 2.4 Hz, 1H), 7.93 (dd, J = 8.0 and 1.6 Hz, 1H), 7.68-7.61 (m, 2H), 5.90-5.88 (m, 1H), 4.33-4.26 (m, 1H), 2.69-2.65 (m, 2H), 2.20-2.18 (m, 2H), 1.68-1.65 (m, 2H), 1.33-1.30 (m, 6H), and 0.44 (s, 4H). Note: -CONH protons were exchanged during MeOD NMR. LCMS (Method A) - 2.57 min, 100%, 254.0nm MS, ES+ 321.2(M+H) HPLC (Method A) - 9.81 min, 95.41%, 210nm

[0393] Example 5 Synthesis of 6-(S)-N-(1-pyridin-2-yl)ethyl)-8-(spiro[2.5]oct-5-en-6-yl)quinoline-3-carboxamide (Compound 60)

[0394] [ka]

[0395] Process 1 To a stirred solution of methyl 8-bromoquinoline-3-carboxylate (A13) (1.8 g, 6.76 mmol, 1.0 equiv.) and A40 (1.74 g, 7.44 mmol, 1.1 equiv.) in dioxane:HO (8:2), KPO (4.28 g, 20.2 mmol, 3.0 equiv.) was added and purged with N for 15 min. PdCl(dppf) (0.24 g, 0.338 mmol, 0.05 equiv.) was then added to the reaction mixture, which was stirred at 110 °C for 16 h. TLC (EA:hexane 1:1 as mobile phase) showed the reaction was complete. The resulting reaction mixture was filtered through Celite, and the filtrate was then extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 1.75 g of crude product. The crude material was purified by manual column chromatography (gradient elution in 30% ethyl acetate in hexane) using silica (60–120 mesh) as the stationary phase to give methyl 8-(spiro[2.5]oct-5-en-6-yl)quinoline-3-carboxylate (A41) (1.15 g, 3.91 mmol, 57.95% yield). 1 H NMR(MeOD,400MHz):δ ppm 9.36(d,J=2.0Hz,1H),8.96(d,J=2.0Hz,1H),7.98(dd,J=8.0Hz,1.6Hz,1H),7.72(dd,J=6.8Hz,1.2Hz,1H),7.65(t,J= 8.0Hz,1H),5.90-5.88(m,1H),4.03(s,3H),2.68-2.67(m,2H),2.20-2.18(m,2H),1.67(t,J=6.0Hz,2H),0.45(s,4H). LCMS (Method A): 2.982 min, 99.11%, 254.0 nm, MS: ES+ 294.2 (M+1)

[0396] Process 2 To a stirred solution of A41 (1.1 g, 3.74 mmol, 1.0 equiv) in MeOH:HO (8:1) (11 ml) was added NaOH (0.74 g, 18.74 mmol, 5.0 equiv) at room temperature. The resulting mixture was then stirred at room temperature for 16 h. The reaction was monitored by TLC (using 100% ethyl acetate as the mobile phase) and confirmed to be complete after stirring at room temperature for 16 h. The resulting reaction mixture was concentrated in vacuo, and the residue was then acidified with dilute hydrochloric acid (pH = 3). The resulting solid was filtered and dried under vacuum to give 8-(spiro[2.5]oct-5-en-6-yl)quinoline-3-carboxylic acid (A42) (0.73 g, 2.61 mmol, 69.70% yield). 1 H NMR (DMSO, 400 MHz): δ ppm 9.36 (d, J = 2.0 Hz, 1H), 8.94 (d, J = 2.0 Hz, 1H), 7.97 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.70 (dd, J = 6.8 Hz, 1.2 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 5.90-5.88 (m, 1H), 2.68-2.65 (m, 2H), 2.20-2.18 (m, 2H), 1.66 (t, J = 6.0 Hz, 2H), 0.44 (s, 4H). Note: -COOH protons may be exchanged in MeOD NMR. LCMS (Method A): 2.510 min, 99.38%, 254.0 nm, MS: ES+ 280.11 (M+1)

[0397] Process 3 To a stirred solution of A42 (0.09 g, 0.322 mmol, 1.0 equiv.) in DCM (1 mL) was added HATU (0.18 g, 0.48 mmol, 1.5 equiv.), followed by DIPEA (0.12 g, 0.96 mmol, 3.0 equiv.) under a N atmosphere. After 10 min, CAS: 40154-78-7 (S)-1-(pyridin-2-yl)ethanamine dihydrochloride (0.037 g, 0.35 mmol, 1.1 equiv.) was added, and the resulting mixture was stirred at room temperature for 18 h. The reaction was monitored by TLC (100% EA mobile phase), which indicated completion of the reaction. The resulting reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude product. The crude material was purified by manual column chromatography (gradient elution in 100% ethyl acetate) using silica (100-200 mesh) as the stationary phase to give (S)—N-(1-(pyridin-2-yl)ethyl)-8-(spiro[2.5]oct-5-en-6-yl)quinoline-3-carboxamide (compound 60) (0.034 g, 0.088 mmol, 27.52% yield). 1 H NMR (MeOD, 400 MHz): δ ppm 9.28(d,J=2.4Hz,1H),8.83(d,J=2.4Hz,1H),8.55(d,J=4.0Hz,1H),7.95(d,J=8 .0Hz,2.0Hz,1H),7.85(dt,J=7.6Hz,1.6Hz,1H),7.69-7.64(m,2H),7.54(d,J=7 .6Hz,1H),7.35-7.32(m,1H),5.90-5.88(m,1H),5.35(q,J=7.2Hz,1H),2.69-2. 65(m,2H),2.20-2.18(m,2H),1.68-1.65(m,5H),0.44(s,4H).Note: -CONH proton is MeOD Exchanged during NMR. LCMS (Method A): 2.273 min, 100%, 254.0 nm, MS: ES+ 384.2 (M+1) HPLC (Method A): 9.67 min, 99.33%, 254.0 nm. Chiral HPLC (Method A): 7.82 min, 94.27%, 300 nm.

[0398] Example 57 - Synthesis of N-(oxazol-2-ylmethyl)-8-(spiro[2.5]oct-5-en-6-yl)quinoline-3-carboxamide (Compound 61)

[0399] [ka]

[0400] Process 1 To a stirred solution of oxazole-2-carbaldehyde (5.0 g, 51.5 mmol, 1.0 equiv.) in DMF (10 mL), 2-methylpropane-2-sulfinamide CAS: 146374-27-8 (7.4 g, 61.8 mmol, 1.2 equiv.) and piperidine-1-carbaldehyde CAS: 3087-36-3 (25.5 mL, 10.3 mmol, 2.0 equiv.) were added under a nitrogen atmosphere at 0°C. The reaction mixture was then stirred at room temperature for 16 h. TLC (50% EtOAc in hexanes as mobile phase) indicated completion of the reaction. The resulting reaction mixture was poured into water (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give the crude product. The obtained crude product was purified by column chromatography using silica gel 230-400 mesh size, and the desired product was eluted with 40% EtOAc in hexane to give (£)-2-methyl-N-(oxazol-2-ylmethylene)propane-2-sulfonamide (A43) (4.9 g, 24.46 mmol, yield: 47.50%). 1 H NMR (DMSO, 400MHz): δ ppm 8.45(s,1H),8.28(s,1H),7.62(s,1H),1.27(s,9H). LCMS (Method A): LCMS does not confirm the mass of the desired product.

[0401] Process 2 To a stirred solution of (£)-2-methyl-N-(oxazol-2-ylmethylene)propane-2-sulfinamide (A43) (4.9 g, 29.9 mmol, 1.0 equiv) in MeOH (20 mL) was added NaBH (1.7 g, 44.9 mmol, 2.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 30 min and monitored by TLC (5% DCM:MeOH as mobile phase). The resulting reaction mixture was poured into water (400 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give the crude product. The resulting crude product was purified by column chromatography (desired product eluted with 2% MeOH in DCM) to give 2-methyl-N-(oxazol-2-ylmethyl)propane-2-sulfinamide (A44) (4.1 g, 20.26 mmol, yield: 82.84%). LCMS (Method A): 1.303 min, 100.0%, 210.0nm MS: ES+ 203.0(M+1). 1 H NMR (DMSO, 400MHz): δ ppm 7.64(s,1H),7.09(s,1H),4.49-4.37(m,2H),3.94(t,J=8.8 Hz 1H),1.24(s,9H).

[0402] Process 3 To a stirred solution of 2-methyl-N-(oxazol-2-ylmethyl)propane-2-sulfonamide (A44) (9.0 g, 44.4 mmol, 1.0 equiv) in MeOH (90 mL) was added 4 M HCl in dioxane (11.68 g, 31.1 mmol, 7.0 v) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC using 5% DCM:MeOH as the mobile phase. Upon completion, the reaction mixture was directly concentrated under reduced pressure to give the crude material, which was triturated with pentane to give oxazol-2-ylmethanamine hydrochloride (A45) (7.0 g, 52.02 mmol, 87.88% yield). LCMS (Method A): LCMS does not confirm the mass of the desired product. 1H NMR (DMSO, 400MHz): δ ppm 8.94(s,3H),8.23(s,1H),7.30(s,1H),4.22(s,2H).

[0403] Process 4 To a stirred solution of A42 (0.2 g, 0.71 mmol, 1.0 equiv) in DCM (2 mL) was added HATU (0.40 g, 1.07 mmol, 1.5 equiv) and DIPEA (0.27 g, 2.1 mmol, 3.0 equiv) at 0 °C. After 10 min, (A45) (0.12 g, 0.93 mmol, 1.3 equiv) was added to the reaction mixture under a N atmosphere. The resulting reaction mixture was stirred at room temperature for 16 h. TLC (100% EA as mobile phase) indicated completion of the reaction. The resulting reaction mixture was poured into ice-water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give 0.21 g of crude product. The crude material was purified by manual column chromatography using silica (100–200 mesh) as the stationary phase (gradient elution with 100% ethyl acetate) to give N-(oxazol-2-ylmethyl)-8-(spiro[2.5]oct-5-en-6-yl)quinoline-3-carboxamide (compound 61) (0.09 g, 0.25 mmol, 34.97% yield). 1 H NMR (MeOD, 400 MHz): δ ppm 9.29 (d, J = 2.4 Hz, 1H), 8.80 (d, J = 2 Hz, 1H), 7.96-7.93 (m, 2H), 7.70-7.62 (m, 2H), 7.18 (s, 1H), 5.89 (br s, 1H), 4.80 (s, 2H), 2.68-2.67 (m, 2H), 2.19 (d, J = 3.2 Hz, 2H), 1.67 (t, J = 6.0 Hz, 2H), 0.44 (s, 4H). Note: -CONH protons were exchanged during MeOD NMR. 1H NMR(DMSO,400MHz):δ ppm 9.51(t,J=5.6Hz,1H),9.28(d,J=2.0Hz,1H),8.84(d,J=2.0Hz,1H),8.09(s,1H),8.00-7.98(m,1H),7.67-7.61(m,2H),7.19(s,1H),5.89(br s,1H),4.67(d,J=5.6Hz,2H),2.69(br s,2H),2.13(br s,2H),1.55(t,J=6.0Hz,2H),0.40(s,4H). LCMS (Method A) - 2.38 min, 100%, 254.0nm, MS:ES+ 360.3(M+1) HPLC (Method A) - 8.76 min, 97.68%, 210nm

[0404] Example 58-N-((S)-1-hydroxy-3-methoxypropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 62):

[0405] [ka]

[0406] Process 1 A solution of benzonitrile CAS100-47-0 (15 g, 145.63 mmol, 1.0 equiv) and acetyl chloride (83 mL, 1165.04 mmol, 8.0 equiv) in EtOH (75 mL) was stirred at room temperature for 16 h. The reaction was monitored by TLC (using 3:7 EtOAc:hexane as the mobile phase) and was found to be complete after 16 h. The resulting reaction mixture was quenched with saturated NaHCO3 (30 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give 20.0 g of crude product. The resulting crude material was purified by manual column chromatography (gradient elution in 10% EA in hexane) using silica (100–200 mesh) as the stationary phase to give ethyl benzimidate (A46) (14 g, 93.95 mmol, 64.52% yield). 1 H NMR (DMSO-d6, 400MHz): δ ppm,8.89(s,1H),7.83-7.81(m,2H),7.51-7.42(m,3H),4.24(q,J=7.2Hz,2H),1.31(t,J=7.2Hz,3H) LCMS (Method A): 1.081 min, 91%, 254.0 nm, MS: ES+149 (M+1)

[0407] Process 2 A solution of ethyl benzimidate (A46) (14 g, 93.95 mmol, 1.0 equiv.) and L-methyl serine hydrochloride CAS 5680-80-8 (16 g, 103.35 mmol, 1.1 equiv.) in 1,2-DCE (140 mL) was stirred at 80 °C for 20 h. TLC (EA:hexane, 1:1 as mobile phase) showed the reaction was complete. The reaction mixture was then filtered through a Celite bed, and the filtrate was concentrated under reduced pressure to give a residue. The crude residue was purified by manual column chromatography (gradient elution in 30% EA in hexane) using silica (100-200 mesh) as the stationary phase to give (S)-2-phenyl-4,5-dihydrooxazole-4-carboxylate (A47) (14 g, 68.292 mmol, 72% yield). 1 H NMR (DMSO-d6, 400MHz):δ ppm,7.9-7.86(m,2H),7.61-7.57(m,1H),7.52-7.48(m,2H),4.99-4.95(dd,J=10Hz,8Hz,1H),4.64-4.56(m,2H),3.71(s,3H), LCMS (Method A): 1.799 min, 99.47%, 254.0 nm, MS: ES+ 206 (M+1)

[0408] Process 3 To a stirred solution of (S)-2-phenyl-4,5-dihydrooxazole-4-carboxylate (A47) (14 g, 68.292 mmol, 1.0 equiv) in THF (1.8 mL) was added DIBAL-H (204 ml, 204.87 mmol, 3.0 equiv) at 0 °C. The resulting reaction mixture was stirred at room temperature for 3 h. The reaction was monitored by TLC (EA:hexane, 7:2 as mobile phase) and found to be complete after 3 h. The resulting reaction mixture was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give 15 g of crude product. The obtained crude material was purified by manual column (70% EA in hexane) using silica (100-200 mesh) as the stationary phase to give (R)-(2-phenyl-4,5-dihydrooxazol-4-yl)methanol (A48) (8.0 g, 45.197 mmol, yield: 66%). 1 H NMR (DMSO-d6, 400MHz): δ ppm,7.86(d,J=7.2Hz,2H),7.56-7.45(m,3H),4.9(t,J=5.6Hz,1H),4.32-4.24(s,3H),3.62-3.44(m,2H). LCMS (Method A): 1.006 min, 94%, 254.0 nm, MS: ES+ 178 (M+1)

[0409] Process 4 To a stirred solution of (R)-(2-phenyl-4,5-dihydrooxazol-4-yl)methanol (A48) (8.0 g, 45.197 mmol, 1.0 equiv.) in THF (1 ml) was added NaH (3.6 g, 90.39 mmol, 2.0 equiv.) and MeI (16.04 g, 112.9 mmol, 2.5 equiv.) at 0 °C, and the reaction mixture was then stirred at room temperature for 16 h. The reaction was monitored by TLC (EA:hexane, 1:1 as mobile phase), which indicated completion of the reaction. The resulting reaction mixture was poured into ice-cold water (50 mL), extracted with EtOAc (3 × 100 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product. The obtained crude material was purified by manual column chromatography (gradient elution in 50% EA in hexane) using silica (100-200 mesh) as the stationary phase to give (R)-4-(methoxymethyl)-2-phenyl-4,5-dihydrooxazole (A49) (3.5 g, 18.324 mmol, yield: 40%). 1 H NMR (DMSO-d6, 400MHz):δ ppm,7.87-7.85(m,2H),7.57-7.46(m,3H),4.49-4.39(m,2H),4.21(t,J=7. 2Hz,1H),3.52(dd,J=9.6,4Hz,1H),3.42(dd,J=9.6,4Hz,1H),3.29(s,3H). LCMS (Method A): 1.345 min, 88%, 254.0 nm, MS: ES+ 192 (M+1)

[0410] Process 5 A solution of (R)-4-(methoxymethyl)-2-phenyl-4,5-dihydrooxazole (A49) (14.0 g, 73.210 mmol, 1.0 equiv.) in 4.0 M aqueous HCl (420 mL) was stirred at room temperature for 5 minutes, and then the resulting reaction mixture was heated at 110° C. for 20 hours. TLC (5% MeOH in DCM as mobile phase) indicated the reaction was complete. The resulting reaction mixture was cooled to room temperature and then filtered through a Buchner funnel. The filtrate was extracted with ether (4×100 mL) to remove impurities, and then the combined aqueous layers were concentrated under reduced pressure to give 12.0 g of (S)-2-amino-3-methoxypropan-1-ol hydrochloride (A50) (12.0 g, 114.12 mmol, quantitative yield). 1 H NMR (DMSO-d6, 400MHz): δ ppm 8.31(br s,3H),3.57-3.47(m,5H),3.27(s,3H),3.21-3.20(m,1H), LCMS (Method A): 0.197 min, 70.29%, 210.0 nm, MS: ES+ 106.0 (M+1)

[0411] Process 6 A solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15) (0.5 g, 1.557 mmol, 1.0 equiv.), HATU (0.887 g, 2.334 mmol, 1.5 equiv.), and DIPEA (0.8 mL, 4.669 mmol, 3.0 equiv.) in DMF (5 mL) was stirred at 0° C. under a nitrogen atmosphere for 20 minutes, and (S)-2-amino-3-methoxypropan-1-ol (A50) (0.327 g, 3.115 mmol, 2.0 equiv.) was added under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 hours. TLC indicated completion of the reaction, and the resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude product. The crude material obtained was purified by flash column chromatography (70% ethyl acetate in hexane) using silica (230-400 mesh) as the stationary phase to give N-((S)-1-hydroxy-3-methoxypropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 62) (0.15 g, 0.367 mmol, yield: 23.60%). 1 H NMR (DMSO-d6, 400 MHz): δ ppm, 9.25 (m, 1H), 8.28 (m, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.01-7.99 (m, 1H), 7.64-7.63 (m, 2H), 5.87 (br s, 1H), 4.83 (t, J = 5.6 Hz, 1H), 4.21-4.18 (m, 1H), 3.55-3.50 (m, 1H), 3.31 (s, 3H), 2.72-2.68 (m, 3H), 2.32-2.07 (m, 3H), 1.71-1.67 (m, 1H). Note: CF3 CH protons corresponded to the DMSO solvent peaks. 1H NMR (MeOD, 400 MHz): δ ppm, 9.25 (m, 1H), 8.79 (m, 1H), 7.97 (dd, J = 7.6 Hz, J = 8.0 Hz, 1H), 7.69-7.63 (m, 2H), 5.87 (br s, 1H), 4.39 (t, J = 5.6 Hz, 1H), 3.80-3.76 (m, 2H), 3.67-3.64 (m, 2H), 3.63 (s, 3H), 2.78-2.15 (m, 6H), 1.91-1.85 (m, 1H). Note: -CONH and -OH protons were exchanged in MeOD NMR. LCMS (Method A): 2.215 min, 100%, 254.0 nm, MS: ES+ 409.42 (M+1) HPLC (Method A): 7.84 min, 100%, 254.0nm

[0412] Example 59 Synthesis of N-(R)-4-aminobutan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 63)

[0413] [ka]

[0414] Process 1 A solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15) (0.2 g, 0.62 mmol, 1.0 equiv.), HATU (0.35 g, 0.93 mmol, 1.5 equiv.), and DIPEA (0.24 g, 1.86 mmol, 3.0 equiv.) in DMF (2 mL) was stirred at 0° C. under a nitrogen atmosphere for 15 minutes, and CAS: 1187927-71-4 (0.12 g, 0.68 mmol, 1.1 equiv.) was added under nitrogen. The resulting mixture was stirred at room temperature for 30 minutes. The reaction was monitored by TLC (using 7:3 EtOAc:hexane as the mobile phase), which indicated completion after 30 minutes. The resulting reaction mixture was quenched with ice-cold water (50 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (40% ethyl acetate in hexanes) using silica (230-400 mesh) as the stationary phase to give tert-butyl ((3R)-3-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamido)butyl)carbamate (A51) (0.2 g, 0.40 mmol, yield: 65.38%). 1 H NMR(DMSO d6,400MHz):δ ppm,9.24(d,J=2.0Hz,1H),8.78(d,J=2.0Hz,1H),8.56(d,J=8.4Hz,1H),8.00(t,J=4.8Hz,1H),7.64-7.61(m,2H),6.82-6.79(m,1H),5.86(br s,1H),4.13-4.06(m,1H),3.04-2.95(m,2H),2.80-2.67(m,3H),2.31-2.24(m,1H),2.09-2.06(m,1H),1.74-1.61 (m ,3H),1.36(s,9H),1.19(d,J=6.4Hz,4H). LCMS (Method A): 2.781 min, 100%, 254.0 nm, MS: ES+ 492.2 (M+1)

[0415] Process 2 To a solution of tert-butyl ((3R)-3-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamido)butyl)carbamate (A51) (0.19 g, 0.387 mmol, 1.0 equiv) in DCM (1.9 ml) was added 4 M HCl in dioxane (1 ml) dropwise at 0° C. under a nitrogen atmosphere and stirred at room temperature for 4 hours. The reaction was monitored by TLC (MeOH:DCM, 0.5:9.5 as the mobile phase) and was found to be complete after 4 hours. The resulting reaction mixture was evaporated to give the crude product. The crude material obtained was purified by flash column chromatography (15% MeOH:DCM) using silica (230-400 mesh) as the stationary phase to give N-(R)-4-aminobutan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 63) (0.062 g, 0.15 mmol, yield: 41.11%). 1 H NMR(MeOD,400MHz):δ ppm,9.45(m,2H),9.05(d,J=7.6Hz,1H),8.28(d,J=8.0Hz,1H),8.03(d,J=6.8Hz,1H),7.98-7.94(m,2H),6.04(br s,1H),4.37-4.34(m,1H),3.15-3.06(m,2H),2.75-2.64(m,3H),2.63-2.60(m,1H),2.48-2.45(m,1H),2.26-2.23(m,1H),2.04-1.92 (m ,3H),1.44 (d ,J=6.8Hz,3H). 1H NMR(DMSO d6,400MHz):δ ppm,9.28(d,J=1.6Hz,1H),8.88(s,1H),8.79(d,J=8.0Hz,1H),8.03(t,J=5.6Hz,1H),7.89(s,3H),7.67-7.66(m,2H),5.875(br s,1H),4.19-4.16(m,1H),2.87-2.84(m,2H),2.79-2.68(m,3H),2.33-2.29(m,1H) ),2.10-2.07(m,1H),1.86-1.82(m,2H),1.72-1.68(m,1H),1.25(d,J=6.4Hz,3H). LCMS (Method A): 1.886 min, 100%, 254.0 nm, MS: ES+ 392.2 (M+1) HPLC (Method A): RT=5.51 min, 100%, 270nm. Chiral HPLC: Peak 1 RT = 8.56 min, 39.00%, 241 nm, Peak 2 = RT: 9.92 min, 60.09%, 241 nm

[0416] Example 60 - Synthesis of N-((S)-1-(dimethylamino)-3-hydroxy-1-oxopropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 64)

[0417] [ka]

[0418] Process 1 To a stirred solution of ((benzyloxy)carbonyl)-L-serine (CAS: 1145-80-8) (2.00 g, 8.36 mmol, 1.0 equiv.) in DCM (20 mL) was added 1.0 M dimethylamine CAS: 124-40-3 (0.843 mL, 12.54 mmol, 1.5 equiv.), followed by DIPEA (4.36 mL, 25.08 mmol, 3.0 equiv.) and HATU (4.765 g, 12.54 mmol, 1.5 equiv.). The resulting mixture was stirred at room temperature for 16 hours. TLC indicated completion of the reaction, and the resulting reaction mixture was concentrated under reduced pressure to give the crude product. The resulting crude material was purified by flash column chromatography using silica gel (230-400 mesh) as the stationary phase (desired product eluted with 3% MeOH in DCM) to give benzyl (S)-(1-(dimethylamino)-3-hydroxy-1-oxopropan-2-yl)carbamate (A52) (0.358 g, 1.34 mmol, 16% yield). 1 H NMR (DMSO-d6, 400MHz):δ ppm,7.38-7.29(m,6H),5.01(s,2H),4.87(t,J=6.0Hz,1H),4.54(m,1H),3.57-3.53(m,1H),3.46-3.42(m,1H),3.05(s,3H),2.82(s,3H). LCMS (Method A): 1.495 min, 95.91%, 220.0 nm, MS: ES+ 267.15

[0419] Process 2 To a solution of benzyl (S)-(1-(dimethylamino)-3-hydroxy-1-oxopropan-2-ylcarbamate (A52) (0.15 g, 0.56 mmol, 1.0 equiv.) in MeOH (5 mL) at room temperature under a nitrogen atmosphere, Pd / C (0.075 g, 50 wt%) was added and stirred at room temperature under a H atmosphere for 5 hours. TLC showed the reaction was complete. The resulting reaction mixture was filtered through a bed of Celite and concentrated under reduced pressure to give the desired product A53 (S)-2-amino-3-hydroxy-N,N-dimethylpropanamide (0.078 g, 0.59 mmol, 7.44% yield). 1H NMR (DMSO-d6, 400MHz):δ ppm,4.77-4.68(bs,1H),3.67(t,J=7.6Hz,1H),3.42-3.36(m,1H),3.26-3.2(m,1H),3.03(s,3H),2.85(s,3H),1.81-1.76(bs,2H), LCMS (Method B): 0.70 min, 100%, 220.0 nm, MS: ES+ 133.1

[0420] Process 3 To a stirred solution of 8-bromo-6-methoxyquinoline-3-carboxylic acid (compound 15) (0.606 g, 1.89 mmol, 1.0 equiv.) in DMF (10 mL) was added (S)-2-amino-3-hydroxy-N,N-dimethylpropanamide (A53) (0.150 mg, 1.89 mmol, 1.0 equiv.), DIPEA (0.736 g, 5.66 mmol, 3.0 equiv.), and HATU (1.07 g, 2.83 mmol, 1.5 equiv.). The resulting mixture was stirred at room temperature for 16 h. TLC indicated completion of the reaction, and the resulting reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 × 125 mL). The combined organic phase was dried over NaSO and concentrated under reduced pressure to give the crude product. The resulting crude material was purified by preparative HPLC (Method A) to give N-((S)-1-(dimethylamino)-3-hydroxy-1-oxopropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 64) (0.055 g, 0.694 mmol, 6.69%). 1H NMR (DMSO-d6, 400 MHz): δ ppm, 9.25 (d, J = 2.0 Hz, 1H), 8.88 (m, 2H), 8.01-7.98 (m, 1H), 7.64 (m, 2H), 5.87 (br s, 1H), 5.08-5.03 (m, 1H), 4.98 (t, J = 6.0 Hz, 1H), 3.79-3.73 (m, 1H), 3.67-3.62 (m, 1H), 3.15 (s, 3H), 2.97-2.87 (m, 4H), 2.87-2.80 (1H), 2.33-2.29 (m, 1H), 2.10-2.07 (m, 1H), 1.74-1.67 (m, 1H). (Note: Two protons coincide with the DMSO solvent peak.) 1 H NMR(MeOD,400MHz):δ ppm,9.27(d,J=2.0Hz,1H),8.84(d,J=2.0Hz,2H),7.98(dd,J=6.0,1.6,Hz 1H),7.70-7.63(m,2H),5.87(bs,1H),5.26(t,J=4.0Hz,1H),3.97-3.86(m,2H),3.29(s,3H),3.03( s,3H),2.78-2.65(m,2H),2.55-2.51(1H),2.40-2.22(m,1H),1.92-1.89(m,1H),1.88-1.86(m,1H). HPLC (Method A): 7.419 min, 100%, 254.0 nm. LCMS (Method A): 2.164 min, 100%, 254.0 nm, MS: ES+ 436.2 Chiral HPLC: Peak-1: 3.96, 49.9%, Peak-2: 4.90, 50% 250nm

[0421] Example 61 - Synthesis of N-(2-hydroxy-1-(oxazol-2-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 65)

[0422] [ka]

[0423] Process 1 A stirred solution of DMSO (2.1 g, 27.21 mmol, 2.4 equiv) in DCM (40 mL) was prepared in a 100 mL three-neck RBF at −78 °C. To this solution, oxalyl chloride (1.43 g, 11.34 mmol, 1.0 equiv) was added at the same temperature and stirred for 30 min. Then, 2-((tert-butyldimethylsilyl)oxy)ethan-1-ol (CAS: 102229-10-7) (2.0 g, 11.34 mmol, 1.0 equiv) was added and stirred again at the same temperature for another 30 min. After 30 min, EtN (5.7 g, 56.71 mmol, 5.0 equiv) was added at −78 °C, and the resulting reaction mixture was stirred at room temperature for 3 h. TLC indicated the reaction was complete, and the resulting reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give crude 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (A54) (2.2 g, 0.126 mmol, quantitative yield). (The crude product was used directly in the next step without further purification due to the volatile nature of the product.)

[0424] Process 2 A stirred solution of 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (A54) (2.0 g, 11.47 mmol, 1.0 equiv.) and 2-methylpropane-2-sulfinamide (CAS: 146374-27-8) (1.6 g, 13.76 mmol, 1.2 equiv.) in THF (50 mL) was prepared in a 100 mL three-neck RBF at 0 °C. To this solution was added Ti(OCH) (CAS: 3087-36-3) (5.2 g, 22.94 mmol, 2.0 equiv.) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. TLC showed the reaction was complete. The resulting reaction mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL). The mixture was then filtered through a Buchner funnel, and the two layers were separated. The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography on silica gel (100-200 mesh) using 50% EtOAc in hexane as the mobile phase to give N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide (A55) (0.6 g, 2.162 mmol, yield: 18.86%). 1 H NMR (DMSO-d6, 400MHz): δ ppm,7.90(s,1H),4.60(d,J=2.8Hz,2H),1.12(s,9H),0.89(s,9H),0.07(s,6H). LCMS (Method A): 2.853 min, 99.01%, 254.0 nm, MS: ES+ 278.15 (M+1)

[0425] Process 3 A stirred solution of oxazole (CAS: 288-42-6) (0.024 g, 0.360 mmol, 1.0 equiv.) in THF (2 mL) was prepared in a 30 mL glass vial at -78 °C. To this solution, n-BuLi (2.5 M in hexanes) (0.14 mL, 0.360 mmol, 1.0 equiv.) was added at -78 °C and stirred for 1 h. N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide (A55) (0.1 g, 0.360 mmol, 1.0 equiv.) was then added, and the reaction mixture was stirred at room temperature for 16 h. TLC indicated completion of the reaction, and the resulting reaction mixture was quenched with aqueous NH4Cl (1 mL), diluted with water (10 mL), and further extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography on silica gel (100-200 mesh) using 60% EtOAc in hexane as the mobile phase to give N-(2-((tert-butyldimethylsilyl)oxy)-1-(oxazol-2-yl)ethyl)-2-methylpropane-2-sulfinamide (A56) (0.03 g, 0.086 mmol, yield: 24.19%). 1 H NMR (DMSO-d6, 400MHz):δ ppm,8.34(s,1H),7.96(s,1H),5.38(d,J=8.0Hz,1H),4.23-4.21(m,1H),3. 87-3.83(m,1H),3.77-3.72(m,1H),1.08(s,9H),0.85(s,9H),0.01(s,6H). LCMS (Method A): 2.550 min, 97.60%, 220.0 nm, MS: ES+ 347.11 (M+1)

[0426] Process 4 A stirred solution of N-(2-((tert-butyldimethylsilyl)oxy)-1-(oxazol-2-yl)ethyl)-2-methylpropane-2-sulfonamide (A56) (0.03 g, 0.086 mmol, 1.0 equiv.) in MeOH (0.3 mL) was prepared in a 5 mL single-port RBF at room temperature. To this solution, 4 M HCl in dioxane (0.3 mL) was added at room temperature, and the resulting reaction mixture was stirred for 16 h. TLC showed the reaction was complete, and the resulting reaction mixture was directly concentrated under reduced pressure to give 2-amino-2-(oxazol-2-yl)ethan-1-ol hydrochloride (A57) (0.02 g, quantitative yield). (The crude product was used directly in the next step without further purification.) LCMS (Method B): 0.70 min, 100.00%, 210.0 nm, MS: ES+ 129.1 (M+1)

[0427] Process 5 A stirred solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15) (0.175 g, 0.547 mmol, 1.0 equiv.) in DMF (2 mL) was prepared in a 10 mL glass vial at room temperature. To this solution, HATU (0.311 g, 0.820 mmol, 1.5 equiv.) and DIPEA (0.212 g, 1.641 mmol, 3.0 equiv.) were added at 0 °C. The reaction mixture was stirred for 10–15 min. Then, A57 (0.090 g, 0.547 mmol, 1.0 equiv.) was added at room temperature and stirred for 16 h. TLC showed the reaction was complete, and the resulting reaction mixture was diluted with water (30 mL) and EtOAc (2 × 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography using silica gel (230:400 mesh) (5% MeOH in DCM as mobile phase) to give N-(2-hydroxy-1-(oxazol-2-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 65) (0.019 g, 0.044 mmol, yield: 15.83%). 1 H NMR (DMSO-d6, 400MHz):δ ppm,9.28(d,J=1.6Hz,1H),8.96(d,J=8.4Hz,1H),8.87(d,J=2.0Hz,1H),8 .35(s,1H),8.05(s,1H),8.00(t,J=5.6Hz,1H),7.65-7.62(m,2H),5.87(br s, 1H), 5.19-5.14 (m, 1H), 5.01 (t, J = 5.6 Hz, 1H), 3.84-3.73 (m, 2H), 2.81-2.67 (m, 3H), 2.29-2.25 (m, 1H), 2.09 (m, 1H), 1.74-1.64 (m, 1H). (Note: The CF3CH- protons coincided with the DMSO solvent peak.) 1 H NMR (MeOD, 400 MHz): δ ppm, 9.28 (d, J = 2.4 Hz, 1H), 8.83 (d, J = 2.0 Hz, 1H), 8.22 (s, 1H), 7.98-7.96 (m, 2H), 7.70-7.63 (m, 2H), 5.86 (br s, 1H), 5.36 (t, J = 6.0 Hz, 1H), 4.02-3.99 (m, 2H), 2.78-2.75 (m, 1H), 2.68-2.65 (m, 2H), 2.55-2.51 (m, 1H), 2.40-2.37 (m, 1H), 2.18-2.14 (m, 1H), 1.89-1.85 (m, 1H). Note: -NH and -OH protons were exchanged with MeOD. LCMS (Method A): 2.196 min, 97.78%, 254.0 nm, MS: ES+ 432.23 (M+1) HPLC (Method A): 7.61 min, 96.07%, 254.0nm

[0428] Example 62 Synthesis of N-((5-oxopyrrolidin-2-yl)methyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 66)

[0429] [ka]

[0430] Process 1 A stirred solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15) (0.05 g, 0.15 mmol, 1.0 equiv.) in DMF (0.5 mL) was prepared in a 10 mL glass vial and cooled to 0° C. To this reaction solution, HATU (0.088 g, 0.23 mmol, 1.5 equiv.) was added at 0° C. under a nitrogen atmosphere. After stirring for 30 minutes, DIPEA (0.06 g, 0.46 mmol, 3.0 equiv.) and 5-(aminomethyl)pyrrolidin-2-one hydrochloride (CAS: 115307-13-6) (0.02 g, 0.15 mmol, 1.0 equiv.) were added. The resulting reaction mixture was stirred at room temperature for 4 hours. TLC showed the reaction was complete, and the resulting reaction mixture was poured into cold water (20 mL) to precipitate, which was filtered, washed with water (50 mL), and dried under reduced pressure to give the crude product, which was purified by normal phase column chromatography (desired product eluted with 7% MeOH in DCM) to give N-((5-oxopyrrolidin-2-yl)methyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 66) (0.046 g, 0.11 mmol, yield: 70.81%). 1 H NMR (DMSO-d6, 400MHz):δ ppm,9.26(d,J=2.0Hz,1H),8.87(t,J=5.6Hz,1H),8.82(d,J=2.4Hz,1H),8.02-7.99(m,1H),7.84(s,1H),7.65-7.64(m,2H),5.87(br s, 1H), 3.78-3.75 (m, 1H), 3.42-3.38 (m, 2H), 2.80-2.67 (m, 2H), 2.42-2.39 (m, 2H), 2.33-2.21 (m, 2H), 2.19-2.07 (m, 2H), 1.82-1.79 (m, 1H), 1.72-1.67 (m, 1H). Note: The CF3-CH4 protons corresponded to the DMSO solvent peak clearly observed in MeOD. 1H NMR(MeOD,400MHz):δ ppm,9.26(d,J=2.0Hz,1H),8.79(d,J=2.0Hz,1H),7.97(dd,J=7.6Hz,1.6Hz,1H),7.70-7.64(m,2H),5.87(br s, 1H), 4.03-4.00 (m, 1H), 3.65-3.58 (m, 2H), 3.55-3.50 (m, 1H), 2.78-2.75 (m, 1H), 2.68-2.65 (m, 2H), 2.55-2.51 (m, 1H), 2.46-2.34 (m, 3H), 2.18-2.15 (m, 1H), 2.00-1.85 (m, 2H). Note: -CONH protons are exchanged into MeOD solvent. LCMS (Method A): 2.156 min, 99.55%, 254.0 nm, MS: ES+ 418.2 (M+1) HPLC (Method A): 7.39 min, 99.49%, 254.0nm Chiral HPLC: Peak-1: 3.57 min, 21.70%, 240.0 nm; Peak-2: 3.81 min, 27.86%, 240.0 nm; Peak-3: 5.05 min, 25.38%, 240.0 nm; Peak-4: 6.30 min, 25.0414%, 240.0 nm

[0431] Example 63 - Synthesis of N-((6-oxo-1,6-dihydropyridin-2-yl)methyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 67)

[0432] [ka]

[0433] Process 1 To a stirred solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15) (0.05 g, 0.155 mmol, 1.0 equiv.) in DMF (1.0 mL) was added HATU (0.088 g, 0.233 mmol, 1.5 equiv.) at 0 °C and stirred for 10 min. Then, DIPEA (0.07 mL, 0.466 mmol, 3.0 equiv.) and 6-(aminomethyl)pyridin-2(1H)-one hydrochloride (CAS: 95878-02-7) (0.027 g, 0.171 mmol, 1.1 equiv.) were added at 0 °C. The resulting reaction mixture was then stirred at room temperature for 4 h. TLC showed the completion of the reaction. The resulting reaction mixture was poured into cold water (5 mL), and a precipitate was obtained. The resulting precipitate was filtered through a Buchner funnel, washed with water (20 mL), and then dried under reduced pressure. The crude was purified by column chromatography (the desired product was eluted with 0-2% MeOH in DCM) to give N-((6-oxo-1,6-dihydropyridin-2-yl)methyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 67) (0.021 g, 0.049 mmol, yield: 31.57%). 1 H NMR (DMSO-d6, 400MHz): δ ppm,11.62(br s,1H),9.32(t,J=6.0Hz,1H),9.29(d,J=2.0Hz,1H),8.86(d,J=2.0Hz,1H),8.04- 8.01(m,1H),7.66-7.63(m,2H),7.39(t,J=7.6Hz,1H),6.23-6.14(m,2H),5.87(br s,1H),4.39(d,J=5.2Hz,2H),2.81-2.67(m,4H),2.33-2.25(m,1H),2.10-2.07(m,1H),1.75-1.67(m,1H). 1H NMR (MeOD, 400 MHz): δ ppm, 9.29 (d, J = 2.0 Hz, 1H), 8.83 (d, J = 2.4 Hz, 1H), 7.98 (dd, J = 7.6, 1.2 Hz, 1H), 7.71-7.64 (m, 2H), 7.58 (t, J = 8.8 Hz, 1H), 6.48-6.41 (m, 2H), 5.87 (br s, 1H), 4.56 (s, 2H), 2.85-2.75 (m, 1H), 2.69-2.65 (m, 2H), 2.55-2.51 (m, 1H), 2.40-2.33 (m, 1H), 2.18-2.15 (m, 1H), 1.92-1.85 (m, 1H). Note: -CONH protons were exchanged during MeOD NMR. LCMS (Method A): 2.189 min, 100.00%, 254 nm, MS: ES+ 428.23 (M+1) HPLC (Method A): 7.37 min, 99.08%, 254nm Chiral HPLC: Peak-1 6.07 min, 49.36%, 242 nm, Peak-2 6.53 min, 49.55%, 242 nm

[0434] Example 64 - Synthesis of N-((2-oxo-1,2-dihydropyridin-3-yl)methyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 68)

[0435] [ka]

[0436] Process 1 A stirred solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15) (0.05 g, 0.15 mmol, 1.0 equiv.) in DMF (0.5 mL) was prepared in a 10 mL glass vial and cooled to 0 °C. HATU (0.09 g, 0.23 mmol, 1.5 equiv.) was added to the reaction solution at 0 °C under a nitrogen atmosphere. After stirring for 30 min, DIPEA (0.06 g, 0.46 mmol, 3.0 equiv.) and 3-(aminomethyl) 171 yridine-2(1H)-one hydrochloride (CAS: 85468-38-8) (0.02 g, 0.15 mmol, 1.0 equiv.) were added. The resulting reaction mixture was stirred at room temperature for 3 h. TLC showed the reaction was complete, and the resulting reaction mixture was poured into cold water (20 mL) to precipitate, which was filtered, washed with water (50 mL), and dried under reduced pressure to give the crude product, which was purified by reverse-phase column chromatography, and the desired product was eluted with 50% water in acetonitrile to give N-((2-oxo-1,2-dihydropyridin-3-yl)methyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 68) (0.037 g, 0.09 mmol, yield: 55.63%). 1 H NMR (DMSO-d6, 400MHz):δ ppm,11.69(s,1H),9.29(d,J=1.6Hz,1H),9.16(t,J=5.6Hz,1H),8.87(d,J=2.0Hz,1H),8.02 -8.00(m,1H),7.65-7.64(m,2H),7.35(dd,J=6.4,24.0Hz,2H),6.18(t,J=6.4,1H),5.87(br s, 1H), 4.31 (d, J = 5.6 Hz, 2H), 2.81-2.67 (m, 3H), 2.33-2.25 (m, 1H), 2.10-2.08 (m, 1H), 1.75-1.66 (m, 1H). Note: The CFCH- protons coincided with the DMSO solvent peak. 1H NMR (MeOD, 400 MHz): δ ppm, 9.29 (s, 1H), 8.81 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.69-7.63 (m, 3H), 7.41 (d, J = 6.4 Hz, 1H), 6.43 (t, J = 6.8 Hz, 1H), 5.87 (br s, 1H), 4.52 (s, 2H), 2.78-2.75 (m, 1H), 2.68-2.65 (m, 2H), 2.55-2.51 (m, 1H), 2.40-2.34 (m, 1H), 2.18-2.15 (m, 1H), 1.93-1.85 (m, 1H). Note: -CONH protons were exchanged during MeOD NMR. LCMS (Method A): 2.266 min, 95.77%, 254.0 nm, MS: ES+ 428.2 (M+1) HPLC (Method A): 7.56 min, 100%, 254.0nm Chiral HPLC: Peak-1: 7.75 min, 49.18%, 240.0 nm, Peak-2: 8.57 min, 50.81%, 240.0 nm

[0437] Example 65 - Synthesis of N-(1-(hydroxymethyl)cyclopropyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 69)

[0438] [ka]

[0439] Process 1 A stirred solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15) (0.1 g, 0.31 mmol, 1.0 equiv.) in DMF (1.0 mL) was prepared in a 10 mL glass vial and cooled to 0 °C. DIPEA (0.12 g, 0.93 mmol, 3.0 equiv.) was added to the reaction solution and stirred for 5 minutes. HATU (0.17 g, 0.46 mmol, 1.5 equiv.) was then added at 0 °C under a nitrogen atmosphere. After stirring for 30 minutes, CAS:115652-52-3 1-amino-cyclopropanemethanol hydrochloride (0.04 g, 0.37 mmol, 1.2 equiv.) was added, and the resulting reaction mixture was stirred at room temperature for 3 hours. TLC indicated the reaction was complete, and the resulting reaction mixture was poured into cold water (20 mL) and extracted with ethyl acetate. The organic layer was dried over N2SO4 and concentrated under reduced pressure to give the crude material, which was purified by normal phase flash column chromatography on silica gel (230-400 mesh) (desired product eluted with 40% ethyl acetate in hexanes) to give N-(1-(hydroxymethyl)cyclopropyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 69) (0.047 g, 0.12 mmol, yield: 38.84%). 1 H NMR (MeOD 400 MHz): δ ppm, 9.24 (d, J = 2.4 Hz, 1H), 8.76 (d, J = 2.0 Hz, 1H), 9.96 (dd, J = 7.6, 1.6 Hz, 1H), 7.69-7.62 (m, 2H), 5.86 (br s, 1H), 3.74 (s, 2H), 2.77-2.74 (m, 1H), 2.67-2.64 (m, 2H), 2.55-2.50 (m, 1H), 2.33-2.15 (m, 1H), 2.17-2.15 (m, 1H), 1.89-1.85 (m, 1H), 0.95 (s, 4H). Note: -CONH and -OH protons were exchanged in MeOD NMR. 1H NMR (DMSO-d6400MHz): δ ppm,9.23(d,J=2.0Hz,1H),9.01(s,1H),8.80(d,J=1.6Hz,1H),7.98-7.96(m,1H),7.63-7.60(m,2H),5.87(br s,1H),4.82(t,J=5.6Hz,1H),3.57(d,J=5.6Hz,2H),2.80-2.67(m,3H),2 .32-2.25(m,2H),2.09-2.06(m,1H),1.74-1.65(m,1H),0.82-.74(m,4H). LCMS (Method A): 2.244 min, 100%, 254.0 nm, MS: ES+ 391.17 (M+1) HPLC (Method A): 7.99 min, 99.74%, 254.0nm Chiral HPLC: Peak-1: 3.06 min, 49.18%, 240.0 nm, Peak-2: 3.50 min, 49.9%, 240.0 nm

[0440] Example 66: Synthesis of N-((R)-1-acetamidopropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 70)

[0441] [ka]

[0442] Process 1 To a stirred solution of N-((R)-1-aminopropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 53) (0.115 g, 0.30 mmol, 1.0 equiv.) in DCM (2 mL) was added acetyl chloride (0.040 g, 0.36 mmol, 1.2 equiv.) under N2 atmosphere. Then, TEA (0.08 mL, 0.61 mmol, 2.0 equiv.) was added, and the reaction mixture was stirred at room temperature for 1 h. TLC showed the reaction was complete, and the resulting reaction mixture was diluted with water (10 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude product. The crude material was purified by manual column chromatography (gradient elution in 20% ethyl acetate in hexane) using silica gel (230–400 mesh) as the stationary phase to give N-((R)-1-acetamidopropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 70) (0.053 g, 0.128 mmol, 41.47% yield). 1 H NMR (DMSO-d, 400 MHz): δ ppm 9.24 (d, J = 2.0 Hz, 1H), 8.78 (d, J = 2.0 Hz, 1H), 8.56 (d, J = 8.0 Hz, 1H), 8.02-7.99 (m, 2H), 7.64-7.63 (m, 2H), 5.87 (br s, 1H), 4.15-4.11 (m, 1H), 3.30-3.17 (m, 2H), 2.79-2.60 (m, 3H), 2.32-2.25 (m, 1H), 2.10-2.07 (m, 1H), 1.82 (s, 3H), 1.73-1.67 (m, 1H), 1.15 (d, J = 6.8 Hz, 3H). Note: CFCH protons coincided with DMSO solvent peaks. 1H NMR (MeOD, 400 MHz): δ ppm 9.23 (d, J = 2.0 Hz, 1H), 8.74 (d, J = 2.0 Hz, 1H), 7.98 (dd, J = 5.6, 2.0 Hz, 1H), 7.69-7.63 (m, 2H), 5.86 (br s, 1H), 4.35-4.30 (m, 1H), 3.47-3.32 (m, 2H), 2.78-2.68 (m, 3H), 2.65-2.55 (m, 1H), 2.51-2.40 (m, 1H), 2.17-2.09 (m, 1H), 1.97 (s, 3H), 1.39-1.29 (m, 1H), 0.93 (d, J = 6.8 Hz, 3H). Note: -CONH protons were exchanged in MeOD NMR. LCMS (Method A): 2.22 min, 100%, 220nm, MS: ES+ 420.13 (M+1) HPLC (Method A): 7.75 min, 99.80%, 210nm Chiral HPLC: 6.74 min, 7.06 min, 48.93%, 51.06%, 240 nm Example 67 Chiral Separation of N-((S)-1-(pyridin-2-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide formate (Compound 71 and Compound 72)

[0443] [ka] Column ID: CHIRALCEL ODH (250X4.6mm 5um) Mobile phase A: liquid carbon dioxide Mobile phase B: M.NH3-MEOH-ACN(50-50) Flow rate (ML / min):3 Device ID:SFC INVESTIGATOR Method: Time: Flow rate: %A:%B(0:14:60:40), (7:14:60:40) Input amount: 0.060g. Output: Compound 71 = 0.015 g (% yield = 33.33%) and Compound 72 = 0.013 g (% yield = 25%) Compound 71: 1H NMR(MeOD,400MHz):δ ppm,9.27(d,J=2.4Hz,1H),8.86(d,J=2Hz,1H),8.56(d,J=4.8Hz,1H),7.99(dd,J=7.6,1 .6Hz,1H),7.86(td,J=7.6,1.6Hz,1H),7.70-7.64(m,2H),7.55(d,J=8Hz,1H),7.36-7.33 (m,1H),5.87(s,1H),5.36-5,32(m,1H),2.78-2.65(m,3H),2.55-2.51(m,1H),2.40-2.3 7(m,1H),2.18-2.15(m,1H),1.92-1.85(m,1H),1.66(d,J=6.8Hz,3H). Note:-CONHプロトンをMeOD Exchange in NMR. 1 H NMR (DMSO-d6, 400MHz): δ ppm,9.29(d,J=2.4Hz,1H),9.21(d,J=7.6Hz,1H),8.89(d,J=2.0Hz,1H),8.54(d,J=4.4Hz,1H),8.02(dd,J=5.2 ,4.0Hz,1H),7.80-7.75(m,1H),7.65-7.62(m,2H),7.48(d,J=8.0Hz,1H),7.29(dd,J=7.2,5.2Hz,1H),5.87(br s,1H),5.29-5.22(m,1H),2.81-2.67(m,3H),2.33-2.29(m,1H),2.10-2.07(m,1H),1.74-1.65(m,1H),1.55(d,J=7.2Hz,3H). LCMS (Method A): 2.321 min, 100%, 254.0 nm, MS: ES+ 426.3 (M+1) HPLC (Method A): 9.18 min, 100%, 254.0 nm KIRAL HPLC: 2.29 minutes, 100%, 246nm Compound 72: 1H NMR(MeOD,400MHz):δ ppm,9.27(d,J=2.4Hz,1H),8.86(d,J=2Hz,1H),8.56(d,J=4.8Hz,1H),7.99(dd,J=7.6,1 .6Hz,1H),7.86(td,J=7.6,1.6Hz,1H),7.70-7.64(m,2H),7.55(d,J=8Hz,1H),7.36-7.33 (m, 1H), 5.87 (s, 1H), 5.36-5.32 (m, 1H), 2.78-2.65 (m, 3H), 2.55-2.51 (m, 1H), 2.40-2.37 (m, 1H), 2.18-2.15 (m, 1H), 1.92-1.85 (m, 1H), 1.66 (d, J = 6.8 Hz, 3H). Note: -CONH protons were exchanged during MeOD NMR. 1 H NMR (DMSO-d6, 400MHz):δ ppm,9.29(d,J=2.4Hz,1H),9.21(d,J=7.6Hz,1H),8.89(d,J=2.0Hz,1H),8.54(d,J=4.4Hz,1H),8.02(dd,J=5.2 ,4.0Hz,1H),7.80-7.75(m,1H),7.65-7.62(m,2H),7.48(d,J=8.0Hz,1H),7.29(dd,J=7.2,5.2Hz,1H),5.87(br s,1H),5.29-5.22(m,1H),2.81-2.67(m,3H),2.33-2.29(m,1H),2.10-2.07(m,1H),1.74-1.65(m,1H),1.55(d,J=7.2Hz,3H). LCMS (Method A): 2.321 min, 100%, 254.0 nm, MS: ES+ 426.3 (M+1) HPLC (Method A): 9.20 minutes, 100%, 254.0nm Chiral HPLC (Method A): 2.32 min, 100%, 246 nm

[0444] Example 68: Synthesis of N-((R)-1-(oxazol-2-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 73)

[0445] [ka]

[0446] Process 1 To a stirred solution of oxazole CAS:288-42-6 (10.0 g, 144.80 mmol, 1.0 equiv) in dry THF (50 mL) at −78 °C, n-BuLi (90.50 mL, 144.80 mmol, 1.0 equiv) was added and stirred for 1 h. Then, CAS:2591-86-8 (16.36 g, 144.80 mmol, 1.0 equiv) was added under a N atmosphere. The resulting reaction mixture was stirred at room temperature for 16 h. TLC showed the reaction was complete. The resulting reaction mixture was quenched with 1 N HCl (200 mL) and extracted with DCM (3 × 300 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give crude oxazole-2-carbaldehyde (A58) (12.8 g, 131.86 mmol, 91.07% yield). The resulting crude material was used directly in the next reaction. (Note: Due to the volatile nature of the compound, the organic layer was concentrated on a rotary evaporator below 25° C., but the solvent was not completely removed.) 1 H NMR (DMSO-d6, 400MHz): δ ppm, 9.73 (s, 1H), 8.50 (s, 1H), 7.66 (s, 1H).

[0447] Process 2 To a solution of oxazole-2-carbaldehyde (A58) (5.0 g, 51.509 mmol, 1.0 equiv.) in THF (50 mL) was added CAS: 343338-28-3 (7.49 g, 61.811 mmol, 1.2 equiv.) and Ti(OCH) CAS: 3087-36-3 (22.988 g, 103.06 mmol, 2.0 equiv.), and the reaction mixture was stirred at room temperature for 16 h. TLC indicated the reaction was complete, and the resulting reaction mixture was quenched with saturated brine (100 mL) and extracted with EtOAc (3 × 300 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude product. The crude material was purified by flash column chromatography using silica (100-200 mesh) as the stationary phase (the desired product was eluted with 40% ethyl acetate in hexane) to give (S,E)-2-methyl-N-(oxazol-2-ylmethylene)propane-2-sulfinamide (A59) (4.0 g, 19.974 mmol, yield: 38.78%). 1 H NMR (DMSO-d6, 400MHz): δ ppm, 8.46 (s, 1H), 8.29 (s, 1H), 7.64 (s, 1H), 1.19 (s, 9H). LCMS (Method A): 1.547 min, 100%, 285.0 nm, MS: ES+ 201.0 (M+1)

[0448] Process 3 To a stirred solution of (E)-2-methyl-N-(oxazol-2-ylmethylene)propane-2-sulfonamide (A59) (4.0 g, 19.974 mmol, 1.0 equiv) in DCM (40 mL) was added CHClMgBr (3 M in EtO) (7.989 mL, 23.969 mmol, 1.2 equiv) under N at −78 °C. The resulting mixture was stirred at −78 °C for 1.5 h and then warmed to room temperature for 1.5 h. A second portion of CHClMgBr (3 M in EtO) (7.989 mL, 23.969 mmol, 1.2 equiv) was added, and the reaction mixture was again stirred at −78 °C for 1 h. After 1 h, it was warmed to room temperature for 3 h. A third portion (3.99 mL, 11.984 mmol, 0.6 equiv) of CHMgBr (3 M in EtO) was added at −78 °C, and the reaction mixture was then warmed to room temperature for 16 h. TLC showed the reaction was complete, and the resulting reaction mixture was slowly poured into aqueous NHCl (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude product. The resulting crude material was purified by trituration with pentane to give (S)-2-methyl-N-((R)-1-(oxazol-2-yl)ethyl)propane-2-sulfinamide (A60) (3.0 g, 13.868 mmol, yield: 69.44%). 1 H NMR (DMSO-d6, 400MHz):8.07(s,1H),7.16(s,1H),5.93(d,J=7.6Hz,1H),4.56-4.48(m,1H),1.50(d,J=6.8Hz,3H),1.09(s,9H). LCMS (Method A): 1.404 min, 100%, 220.0 nm, MS: ES+ 217.1 (M+1). Chiral HPLC: 4.14 min, 100%, 216.0 nm.

[0449] Process 4 To a solution of (S)-2-methyl-N-((R)-1-(oxazol-2-yl)ethyl)propane-2-sulfinamide (A60) (3.0 g, 13.870 mmol, 1.0 equiv) in MeOH (30 mL) was added 4 M HCl in dioxane (7.28 mL, 29.126 mmol, 2.1 equiv) and stirred at room temperature for 1 h. TLC showed the reaction was complete, and the mixture was then concentrated under reduced pressure to give (R)-1-(oxazol-2-yl)ethan-1-amine hydrochloride (A61) (2.77 g, 18.642 mmol, quantitative yield). 1 H NMR (DMSO-d6, 400MHz): δ ppm,8.78(br s,2H),8.25(s,1H),7.33(s,1H),4.70-4.64(m,1H),1.56(d,J=6.8Hz,3H). LCMS (Method A): 0.196 min, 94.57%, 210.0 nm, MS: ES+ 112.9 (M+1)

[0450] Process 5 A solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid compound 15 (5.0 g, 15.562 mmol, 1.0 equiv.), HATU (8.876 g, 23.343 mmol, 1.5 equiv.), and DIPEA (8.045 mL, 46.685 mmol, 3.0 equiv.) in DMF (50 mL) was stirred at 0 °C under a nitrogen atmosphere for 20 min. A61 (2.77 g, 18.674 mmol, 1.2 equiv.) was added, and the reaction mixture was stirred at room temperature for 3 h. TLC showed the reaction was complete, after which water (100 mL) was added and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude product. The crude material obtained was purified by flash column chromatography using silica gel (230-400 mesh) as the stationary phase (desired product eluted with 60% ethyl acetate in hexane) to give N-((R)-1-(oxazol-2-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 73) (4.6 g, 11.073 mmol, yield: 71.16%). 1 H NMR (DMSO-d6, 400MHz):δ ppm,9.36(d,J=7.6Hz,1H),9.27(d,J=2.0Hz,1H),8.86(d,J=2.0Hz,1H),8.08(s,1H),8.03-8.00(m,1H),7.66-7.63(m,2H),7.19(s,1H),5.88(br s,1H),5.40-5.36(m,1H),2.80-2.67(m,4H),2.33-2.29(m,1H),2.10-2.07(m,1H),1.73-1.65(m,1H),1.61(d,J=6.8Hz,3H). 1 H NMR (MeOD, 400 MHz): δ ppm, 9.27 (d, J = 2.0 Hz, 1H), 8.83 (d, J = 2.0 Hz, 1H), 7.99-7.92 (m, 2H), 7.70-7.63 (m, 2H), 7.18 (s, 1H), 5.88 (br s, 1H), 5.52-5.46 (m, 1H), 2.78-2.75 (m, 1H), 2.68-2.65 (m, 2H), 2.55-2.51 (m, 1H), 2.40-2.37 (m, 1H), 2.18-2.15 (m, 1H), 1.91-1.85 (m, 1H), 1.73 (d, J = 6.8 Hz, 3H). Note: -CONH protons were exchanged during MeOD NMR. LCMS (Method A): 2.460 min, 98.73%, 254.0 nm, MS: ES+ 416.2 (M+1) HPLC (Method A): 8.77 min, 99.01%, 254.0nm. Chiral HPLC: Peak-1 (5.02 min, 47.83%, 245.0 nm), Peak-2 (6.08 min, 49.16%, 245.0 nm)

[0451] Example 69 - Synthesis of N-((R)-4-(dimethylamino)-4-oxobutan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 74)

[0452] [ka]

[0453] Process 1 A solution of (3R)-3-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamido)butanoic acid) (Compound 55) (0.15 g, 0.36 mmol, 1.0 equiv.), EDCI.HCl (0.106 g, 0.553 mmol, 1.5 equiv.), HOBt (0.075 g, 0.553 mmol, 1.5 equiv.), and DIPEA (0.143 g, 1.107 mmol, 3.0 equiv.) in DCM (20 v) was stirred at 0 °C under a nitrogen atmosphere for 15 min, and dimethylamine (2 M in THF) CAS:124-40-3 (0.067 g, 1.476 mmol, 4.0 equiv.) was added under nitrogen. The resulting mixture was stirred at room temperature for 16 h. TLC showed the reaction was complete, and the reaction mixture was quenched with ice-cold water (50 mL) and extracted with DCM (3 × 15 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude product. The crude material was purified by trituration with n-pentane to give N-((R)-4-(dimethylamino)-4-oxobutan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 74, 0.04 g, 0.0922 mmol, yield: 25%). 1 H NMR(MeOD,400MHz) δ ppm 9.22(d,J=2.4Hz,1H),8.74(d,J=2.4Hz,1H),7.95(dd,J=7.6,2.0Hz,1H),7.68-7.65(m,2H),5.87(br s, 1H), 4.62-4.57 (m, 1H), 3.17 (s, 3H), 2.96 (s, 3H), 2.88-2.83 (m, 1H), 2.77-2.75 (m, 1H), 2.69-2.64 (m, 3H), 2.55-2.51 (m, 1H), 2.40-2.38 (m, 1H), 2.18-2.15 (m, 1H), 1.92-1.85 (m, 1H), 1.41 (d, J = 5.4 Hz, 3H). Note: -CONH protons were exchanged during MeOD NMR. 1H NMR (DMSO-d6,400MHz) δ ppm 9.23(d,J=2.4Hz,1H),8.77(d,J=2.4Hz,1H),8.64(d,J=7.6Hz,1H),8.02-7.99(m,1H),7.65-7.63(m,2H),5.88(br s,1H),4.42-4.39(m,1H),3.02(s,3H),2.83(s,3H),2.76-2.71(m,2H),2.69-2.61(m,2H),2.57-2.53 (m,1H),2.51-2.43(m,1H),2.35-2.32(m,1H),2.07(m,1H),1.75-1.67(m,1H),1.25(d,J=6.4Hz,3H). LCMS (Method A): 2.290 min, 100%, 210.0 nm, MS: ES+ 434.3 (M+1) HPLC (Method A): 8.26 min, 98.29%, 210.0nm. Chiral HPLC (Method A): Peak 1: 8.12 min, 45.66%, 240 nm; Peak 2: 8.49 min, 53.04%, 240 nm.

[0454] Example 70 - Synthesis of N-(3-(dimethylamino)-3-oxopropyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 75)

[0455] [ka]

[0456] Process 1 To a stirred solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15) (0.5 g, 1.55 mmol, 1.0 equiv.) in DMF (5.0 mL) was added HATU (0.88 g, 2.33 mmol, 1.5 equiv.) at 0 °C. DIPEA (0.8 mL, 4.67 mmol, 3.0 equiv.) was then added and stirred at 0 °C. After stirring for 10 min, CAS: 3196-73-4 β-alanine methyl ester hydrochloride (0.239 g, 1.71 mmol, 1.1 equiv.) was added at 0 °C. The resulting reaction mixture was stirred at room temperature for 4 h. TLC indicated completion of the reaction. The resulting reaction mixture was diluted with ice-cold water (10 mL) and extracted with EtOAc (20 mL). The combined organic layers were evaporated under vacuum and the crude residue was purified by silica column chromatography (60-120 mesh, 50% EtOAc and hexanes) to give methyl 3-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamido)propanoate (A62) (0.34 g, 0.862 mmol, yield: 55.34%). 1 H NMR (DMSO-d6, 400MHz): δ ppm 9.23(d,J=2.0Hz,1H),8.92(t,J=6.8Hz,1H),8.78(d,J=1.6Hz,1H),8.01-7.99(m,1H),7.64-7.61(m,2H),5.86(br s,1H),3.62(s,3H),3.57(q,J=5.6Hz,2H),2.80-2.64(m,5H),2.45-2.40(m,1H),2.31-2.24(m,1H),2.09-2.06(m,1H),1.74-1.63(m,1H). LCMS (Method A): 2.418 min, 99.31%, MS: ES+ 407.22[M+H].

[0457] Process 2 To a solution of methyl 3-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamido)propanoate (A62) (0.340 g, 0.832 mmol) in MeOH:HO (3:1 mL) was added LiOH.HO (0.068 g, 1.67 mmol, 2 equiv.) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. TLC showed the reaction was complete. The resulting reaction mixture was acidified with 1 N HCl and extracted with ethyl acetate (15 mL × 3). The combined organic layers were concentrated under reduced pressure to give 3-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamido)propanoic acid as a white amorphous solid (A63) (0.32 g, 0.765 mmol, yield: 32.82%). 1 H NMR (DMSO-d6, 400MHz): δ ppm 9.24(d,J=2.4Hz,1H),8.92(t,J=5.2Hz,1H),8.81(d,J=2.0Hz,1H),8.02-7.99(m,1H),7.65-7.62(m,2H),5.87(br s,1H),3.53(q,J=6.8Hz,2H),2.80-2.67(m,3H),2.59-2.56(m,2H),2.50 -2.46(m,1H),2.32-2.25(m,1H),2.10-2.07(m,1H),1.74-1.65.(m,1H). LCMS (Method A): 2.191 min, 100%, MS:ES+ 393.17[M+H]+

[0458] Process 3 To a stirred solution of 3-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamido)propanoic acid (A63) (0.15 g, 0.38 mmol, 1.0 equiv.) in DMF (1.5 mL) was added HATU (0.21 g, 0.57 mmol, 1.5 equiv.) at 0 °C. After 10 min at the same temperature, DIPEA (0.2 mL, 1.14 mmol, 3.0 equiv.) was added and stirred for 10 min. After stirring for 10 min, dimethylamine (2 M in THF) CAS:124-40-3 (0.018 g, 0.42 mmol, 1.1 equiv.) was added at 0 °C. The resulting reaction mixture was stirred at room temperature for 4 h. TLC showed the reaction was complete. The reaction mixture was diluted with ice-cold water (10 mL) and extracted with EtOAc (10 mL x 2). The combined layers were evaporated in vacuo, and the crude residue was purified by column chromatography on silica gel (60-120 mesh, 50% EtOAc and hexane) to give N-(3-(dimethylamino)-3-oxopropyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (75) (0.064 g, 0.155 mmol, 43.13% yield). 1 H NMR (DMSO-d, 400 MHz): δ ppm 9.24 (d, J = 2.0 Hz, 1H), 8.84 (t, J = 5.2 Hz, 1H), 8.78 (d, J = 2.4 Hz, 1H), 8.01-7.98 (m, 1H), 7.64-7.61 (m, 2H), 5.86 (br s, 1H), 3.52 (q, J = 5.6 Hz, 2H), 2.97 (s, 3H), 2.88-2.77 (m, 5H), 2.71-2.62 (m, 3H), 2.32-2.24 (m, 1H), 2.09-2.07 (m, 1H), 1.74-1.63 (m, 1H). Note: CFCH protons coincided with DMSO solvent peaks. 1H NMR (MeOD, 400 MHz): δ ppm 9.24 (d, J = 2.0 Hz, 1H), 8.74 (d, J = 2.4 Hz, 1H), 7.96 (dd, J = 1.6 Hz, 7.6 Hz, 1H), 7.68-7.63 (m, 2H), 5.86 (br s, 1H), 3.73 (t, J = 6.8 Hz, 2H), 3.11 (s, 3H), 2.98 (s, 3H), 2.80 (t, J = 6.8 Hz, 3H), 2.75-2.64 (m, 2H), 2.55-2.50 (m, 1H), 2.40-2.37 (m, 1H), 2.17-2.15 (m, 1H), 1.92-1.88 (m, 1H). Note: -CONH protons were exchanged during MeOD NMR. LCMS (Method A): 2.22 min, 99.25%, MS: ES+ 420.3[M+H] HPLC (Method A): 7.98 min. 99.11%, 254nm Chiral HPLC (Method A): 6.46 + 7.39 min. 49.63 + 49.80%, 242 nm

[0459] Example 71 - Synthesis of N-(3-(methylamino)-3-oxopropyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 76)

[0460] [ka]

[0461] Process 1 To a stirred solution of 3-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamido)propanoic acid (A63) (0.15 g, 0.38 mmol, 1.0 equiv.) in DMF (1.5 mL) was added HATU (0.21 g, 0.57 mmol, 1.5 equiv.) at 0 °C. Then, DIPEA (0.2 mL, 1.14 mmol, 3.0 equiv.) and CAS:74-89-5 methylamine 2M in THF (0.28 mL, 0.57 mmol, 1.5 equiv.) were added. The resulting reaction mixture was stirred at room temperature for 16 h. TLC indicated completion of the reaction, and the resulting reaction mixture was diluted with ice-cold water (10 mL) and extracted with EtOAc (25 mL). The combined layers were evaporated under vacuum and the crude residue (60–120 mesh, 50% EtOAc and hexanes) was purified by silica column chromatography to give N-(3-(methylamino)-3-oxopropyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 76) (0.065 g, 0.155 mmol, yield: 40.65%). 1 H NMR (DMSO-d6, 400MHz): δ ppm 9.23(d,J=2.0Hz,1H),8.88(t,J=5.6Hz,1H),8.78(d,J=2.0Hz,1H),8.01-7.98(m,1H),7.88-7.87(m,1H),7.64-7.61(m,2H),5.86(br s, 1H), 3.55 (q, J = 7.2 Hz, 2H), 2.85-2.75 (m, 1H), 2.74-2.65 (m, 1H), 2.58 (d, J = 4.8 Hz, 3H), 2.42-2.39 (m, 3H), 2.18-2.07 (m, 1H), 1.74-1.63 (m, 1H). Note: 3H protons were matched in the DMSO solvent peak. 1H NMR (MeOD, 400 MHz): δ ppm 9.23 (d, J = 2.0 Hz, 1H), 8.74 (d, J = 2.4 Hz, 1H), 7.98-7.95 (m, 1H), 7.69-7.63 (m, 2H), 5.86 (br s, 1H), 3.72 (t, J = 6.8 Hz, 2H), 2.75 (s, 3H), 2.68-2.64 (m, 2H), 2.57 (t, J = 6.8 Hz, 2H), 2.51-2.49 (m, 1H), 2.40-2.34 (m, 1H), 2.18-2.15 (m, 1H), 1.89-1.85 (m, 1H). Note: -CONH protons were exchanged during MeOD NMR. LCMS (Method A): 2.12 min, 98.87%, MS: ES+ 406.37 [M+H] HPLC (Method A): 7.49 min. 99.45%, 254nm

[0462] Example 72 - Synthesis of N-((R)-4-acetamidobutan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 77)

[0463] [ka]

[0464] Process 1 To a solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15) (0.2 g, 0.622 mmol, 1.0 equiv.) in DMF (3 mL) was added HATU (0.355 g, 0.933 mmol, 1.5 equiv.) and DIPEA (0.32 mL, 1.867 mmol, 3.0 equiv.) under a nitrogen atmosphere at 0 °C, followed by stirring for 5 minutes. Then, CAS: 1187927-71-4(R)-1-Boc-amino-butyl-3-amine (0.129 g, 0.685 mmol, 1.1 equiv.) was added under nitrogen. The resulting mixture was stirred at room temperature for 4 hours. TLC indicated completion of the reaction, and the resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography using silica (230-400 mesh) (50% EtOAc in hexanes) as the stationary phase to give tert-butyl ((3R)-3-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamido)butyl)carbamate (A64) (0.22 g, 0.448 mmol, yield: 71.90%). 1 H NMR (DMSO-d6, 400MHz):9.24(d,J=2.0Hz,1H),8.78(d,J=2.0Hz,1H),8.55(d,J=8.0Hz,1H),8.00(t,J=4.8Hz,1H),7.65-7.63(m,2H),6.80(br s,1H),5.87(br s,1H),4.11-4.08(m,1H),3.02-2.97(m,2H),2.73-2.68(m,3H),2.33-2.25(m, 2H),2.09-2.07(m,1H),1.73-1.65(m,3H),1.36(s,9H),1.20(d,J=6.8Hz,3H). LCMS (Method A): 2.725 min, 96.87%, 254.0 nm, MS: ES+ 492.4 (M+1).

[0465] Process 2 To a solution of tert-butyl ((3R)-3-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide)butyl)carbamate (A64) (0.22 g, 0.448 mmol, 1.0 equiv) in MeOH (2 mL) was added 4 M HCl in dioxane (0.22 mL, 0.895 mmol, 2.0 equiv) and stirred at room temperature for 3 h. TLC showed the reaction was complete, and the reaction mixture was concentrated under reduced pressure to give the crude product. The resulting crude material was purified by trituration with diethyl ether (5 mL) to give N-((R)-4-aminobutan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (A65) (0.2 g, 0.511 mmol, quantitative). 1 H NMR (DMSO-d6, 400MHz): δ ppm,9.28(s,1H),8.87(s,1H),8.78(d,J=8.0Hz,1H),8.03(t,J=5.2Hz,3H),7.87(br s,2H),7.67-7.64(m,2H),5.88(br s, 1H), 4.19-4.16 (m, 1H), 3.72-3.46 (m, 5H), 2.89-2.86 (m, 2H), 2.76-2.68 (m, 2H), 2.33-2.25 (m, 1H), 2.10-2.07 (m, 1H), 1.86-1.82 (m, 2H), 1.75-1.69 (m, 1H), 0.85 (d, J = 6.8 Hz, 3H). Note: The compound was isolated as the HCl salt. LCMS (Method A): 1.853 min, 97.76%, 254.0 nm, MS: ES+ 392 (M+1)

[0466] Process 3 A solution of N-((R)-4-aminobutan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (A65) (0.18 g, 0.460 mmol, 1.0 equiv) and TEA (0.2 mL, 1.379 mmol, 3.0 equiv) in DCM (2 mL) was stirred at 0 °C under a nitrogen atmosphere for 10 min. CHCOCl (0.036 mL, 0.460 mmol, 1.0 equiv) was added, and the reaction mixture was stirred at room temperature for an additional 4 h. TLC showed the reaction was complete. The resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with DCM (10 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude product. The crude material obtained was purified by flash column chromatography (50% EtOAc in hexanes) using silica (230-400 mesh) as the stationary phase to give N-((R)-4-acetamidobutan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 77) (0.087 g, 0.201 mmol, yield: 43.65%). 1 H NMR (DMSO-d6400MHz): δ ppm,9.24(s,1H),8.78(s,1H),8.58(d,J=7.6Hz,1H),8.01(s,1H),7.85(s,1H),7.63(d,J=3.6Hz,2H),5.87(br s,1H),4.12-4.09(m,1H),3.11-3.09(m,2H),2.77-2.68(m,3H),2.32-2.29(m, 2H),2.10-2.07(m,1H),1.84(s,3H),1.78-1.64(m,3H),1.20(d,J=6.4Hz,3H). LCMS (Method A): 2.198 min, 98.97%, 242.0 nm, MS: ES+ 434.3 (M+1) HPLC (Method A): 7.87 min, 97.93%, 254.0nm Chiral HPLC: 4.93 min. 98%, 242 nm

[0467] Example 73 - Synthesis of N-(3-acetamidopropyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 78)

[0468] [ka]

[0469] Process 1 A solution of propane-1,3-diamine (CAS: 109-76-2) (0.1 g, 1.348 mmol, 1.0 equiv.), CHCOCl (0.105 g, 1.348 mmol, 1.0 equiv.), and DIPEA (0.704 mL, 4.047 mmol, 3.0 equiv.) in DCM (1 mL) was stirred at −78 °C under a nitrogen atmosphere for 10 min, then warmed to room temperature, and stirring was continued at room temperature for 16 h. TLC indicated completion of the reaction. The resulting reaction mixture was quenched with 5% HCl (2 mL), basified with saturated NaHCO (3 × 10 mL), and then extracted with DCM (10 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude product. The resulting crude material was purified by trituration with n-pentane to give N-(3-aminopropyl)acetamide (A66) (0.1 g, 0.862 mmol, yield: 63.79%). 1 H NMR (DMSO-d6, 400MHz): δ ppm,7.97-7.88(m,1H),3.07-2.98(m,2H),2.70(t,J=6.8Hz,4H),1.78(s,3H),1.62-1.54(m,2H). LCMS (Method B): 1.25 min, 78%, 210.0 nm, MS: ES+ 117 (M+1)

[0470] Process 2 A stirred solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15) (0.1 g, 0.311 mmol, 1.0 equiv.), HATU (0.17 g, 0.467 mmol, 1.5 equiv.), and DIPEA (0.16 mL, 0.934 mmol, 3.0 equiv.) in DMF (1 mL) was stirred at 0 °C for 10 min under a nitrogen atmosphere. A66 (0.039 g, 0.342 mmol, 1.1 equiv.) was added and stirred at room temperature for 7 h. TLC indicated the reaction was complete, and the resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude product. The crude material obtained was purified by flash column chromatography (5% MDC in MeOH) using silica (230-400 mesh) as the stationary phase to give N-(3-acetamidopropyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 78, 0.033 g, 0.078 mmol, yield: 25.28%). 1 H NMR (MeOD, 400 MHz): δ ppm, 9.25 (d, J = 2.0 Hz, 1H), 8.76 (d, J = 2.0 Hz, 1H), 7.97 (dd, J = 2.0 Hz J = 7.6 Hz, 1H), 7.69-7.63 (m, 2H), 5.86 (br s, 1H), 3.51 (t, J = 6.8 Hz, 2H), 2.78-2.75 (m, 1H), 2.68-2.65 (m, 2H), 2.55-2.51 (m, 1H), 2.40-2.33 (m, 1H), 2.17-2.14 (m, 1H), 1.98 (s, 3H), 1.92-1.82 (m, 3H). Note: -CONH protons were exchanged during MeOD NMR. 1H NMR (DMSO-d, 400 MHz): 9.24 (d, J = 2.0 Hz, 1H), 8.80-8.78 (m, 1H), 8.02-7.99 (m, 1H), 7.90 (br s, 1H), 7.64-7.61 (m, 2H), 5.86 (br s, 1H), 3.12 (q, J = 6.8 Hz, 2H), 2.80-2.67 (m, 3H), 2.33-2.32 (m, 1H), 2.10-2.07 (m, 1H), 1.81 (s, 3H), 1.76-1.64 (m, 3H). Note: CFCH protons corresponded to DMSO solvent peaks. LCMS (Method A): 2.150 min, 97.87%, 254.0 nm, MS: ES+ 420.38 (M+1) HPLC (Method A): 7.62 min, 97.0%, 254.0nm

[0471] Example 74 Synthesis of N-(2-acetamidopropyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 79)

[0472] [ka]

[0473] Process 1 To a solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15) (0.1 g, 0.311 mmol, 1.0 equiv.) in DMF (1 mL) was added HATU (0.17 g, 0.467 mmol, 1.5 equiv.) and DIPEA (0.16 mL, 0.934 mmol, 3.0 equiv.) under a nitrogen atmosphere at 0 °C. The mixture was stirred for 10 min, and CAS:1001-53-2 N-acetylethylenediamine (0.034 g, 0.342 mmol, 1.1 equiv.) was added under nitrogen. The mixture was stirred at room temperature for 7 h. TLC indicated completion of the reaction, and the reaction mixture was quenched with ice-cold water (10 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (5% MDC in MeOH) using silica (230-400 mesh) as the stationary phase to give N-(2-acetamidoethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 79) (0.038 g, 0.093 mmol, yield: 30.12%). 1 H NMR (MeOD, 400 MHz): δ ppm, 9.24 (d, J = 2.0 Hz, 1H), 8.74 (d, J = 2.4 Hz, 1H), 7.97 (dd, J = 8.0 Hz, 7.6 Hz, 1H), 7.69-7.63 (m, 2H), 5.86 (br s, 1H), 3.59-3.56 (m, 2H), 3.48-3.45 (m, 2H), 2.78-2.75 (m, 1H), 2.68-2.65 (m, 2H), 2.55-2.51 (m, 1H), 2.40-2.37 (m, 1H), 2.17-2.15 (m, 1H), 1.98 (s, 3H), 1.89-1.85 (m, 1H). Note: -CONH protons were exchanged during MeOD NMR. 1H NMR (DMSO-d6, 400MHz): δ ppm,9.24(d,J=2.0Hz,1H),8.86(t,J=5.2Hz,1H),8.79(d,J=2.0Hz,1H),8.04-7.98(m,2H),7.64-7.61(m,2H),5.87(br s,1H),3.39-3.34(m,2H),3.28-3.23(m,2H),2.80-2.67(m,3H),2.50-2.46( m,1H),2.33-2.24(m,1H),2.10-2.07(m,1H),1.82(s,3H),1.74-1.65(m,1H). LCMS (Method A): 2.122 min, 100%, 242.0 nm, MS: ES+ 406.22 (M+1) HPLC (Method A): 7.45 min, 99.69%, 254.0nm

[0474] Example 75 - Synthesis of N-(1-(1H-pyrazol-5-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 80)

[0475] [ka]

[0476] Process 1 To a stirred solution of 1-(1H-pyrazol-5-yl)ethan-1-one (CAS: 20583-33-9) (0.2 g, 1.81 mmol, 1.0 equiv.) in 7 M NH in MeOH (2.0 mL) was added Ti(O i pr)4 (1.0 g, 3.63 mmol, 2.0 equiv.) was added at 0 °C and stirred for 4 h. Sodium borohydride (0.13 g, 3.63 mmol, 2.0 equiv.) was then added and stirred at room temperature for 6 h. TLC showed the reaction was complete, and the resulting reaction mixture was concentrated in vacuo to give the crude product 1-(1H-pyrazol-5-yl)ethan-1-amine (A67) (0.22 g, 1.97 mmol, quantitative yield). LCMS (Method B): 1.22 min, 10.93%, 254 nm, MS: ES+ 112.2 (M+1)

[0477] Process 2 To a stirred solution of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (compound 15) (0.1 g, 0.31 mmol, 1.0 equiv.) in DMF (1.0 mL) was added HATU (0.17 g, 0.46 mmol, 1.5 equiv.) at 0 °C. DIPEA (0.16 mL, 0.934 mmol, 3.0 equiv.) was then added and stirred for an additional 10 min. After stirring for 10 min, 1-(1H-pyrazol-5-yl)ethan-1-amine (A67) (0.038 g, 0.342 mmol, 1.1 equiv.) was added, and the reaction mixture was stirred at room temperature for 4 h. TLC showed the reaction was complete. The resulting reaction mixture was poured into cold water (5 mL), giving a precipitate. The precipitate was filtered through a Buchner funnel, washed with water (20 mL), dried under high vacuum, and then purified by column chromatography (the desired product was eluted with 80% EtOAc in hexanes) to give N-(1-(1H-pyrazol-5-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 80) (0.018 g, 0.043 mmol, yield: 13.95%). 1 H NMR (DMSO-d6, 400MHz): δ ppm ,12.57(br s,1H),9.27(d,J=2.0,1H),9.04(br s,1H),8.84(d,J=2.0Hz,1H),8.01-7.98(m,1H),7.64-7.63(m,3H),6.25(s,1H),5.87(s,1H),5.39-5.31(m,1H),2. 81-2.67(m,2H),2.50-2.46(m,2H),2.33-2.29(m,1H),2.10-2.07(m,1H),1.73-1.67(m,1H),1.54(d,J=6.8Hz,3H). LCMS (Method A): 2.293 min, 97.06%, 254 nm, MS: ES+ 415.2 (M+1) HPLC (Method A): 8.25 min, 95.14%, 254nm

[0478] Example 7 Chiral Separation of 6-N-((R)-1-hydroxypropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 81 and Compound 82)

[0479] [ka] Column ID: CHIRALPAK IG 250X50 mm 5um Mobile phase A: liquid carbon dioxide Mobile phase B: MeOH Flow rate (ML / min): 150 Instrument ID: 2489 WATERS SFC 350 with UV detector Method: Time: Flow rate: %A:%B(0.01:150:70:30),(24:150:70:30) Input amount: 0.1206g. Output: Compound 81 = 0.044 g (% yield = 36.48%) and Compound 82 = 0.040 g (% yield = 33.17%) Compound 81: 1 H NMR (DMSO-d6, 400MHz): δ ppm, δ 9.25(d,J=2.0Hz,1H),8.81(d,J=2.0Hz,1H),8.47(d,J=7.6Hz,1H),8.01-7.99(m,1H),7.64-7.63(m,2H),5.88(br s,1H),4.79(t,J=5.6Hz,1H),4.10-4.07(m,1H),3.53-3.49(m,1H),3.42-3.37(m,1H),2.73- 2.68(m,3H),2.33-2.29(m,1H),2.10-2.07(m,1H),1.72-1.67(m,1H),1.18(d,J=6.8Hz,3H). 1H NMR (MeOD, 400MHz): δ ppm, δ 9.25(d,J=2.4Hz,1H),8.78(d,J=2.4Hz,1H),7.97(dd,J=7.6,2.0Hz,1H),7.69-7.63(m,2H),5.87(br s,1H),4.31-4.26(m,1H),3.71-3.68(m,2H),2.78-2.65(m,3H),2.56-2.51(m,1H),2.41-2.34 (m,1H),2.18-2.15(m,1H),1.93-1.83(m,1H),1.32(d,J=6.8Hz,3H).Note:-CONHおよび-OHロトンをMeOD NMR exchange rate LCMS (Method A): 2.212 min, 99.64%, 254.0 nm, MS: ES+ 379.2 (M+1) HPLC (Method A): 7.88 min, 99.59%, 254.0 nm Kura HPLC (method A): 5.88 min, 99.76%, 240nm Compound 82: 1 H NMR (DMSO-d6, 400MHz): δ ppm, δ 9.25(d,J=2.0Hz,1H),8.81(d,J=2.4Hz,1H),8.47(d,J=7.6Hz,1H),8.01-7.99(m,1H),7.64-7.63(m,2H),5.87(br s,1H),4.79(t,J=5.6Hz,1H),4.10-4.07(m,1H),3.52-3.48(m,1H),3.42-3.38(m,1H),2.81- 2.68(m,3H),2.33-2.29(m,2H),2.10-2.07(m,1H),1.72-1.67(m,1H),1.18(d,J=6.8Hz,3H). 1H NMR (MeOD, 400 MHz): δ ppm, δ 9.25 (d, J = 2.0 Hz, 1H), 8.78 (d, J = 2.4 Hz, 1H), 7.97 (dd, J = 7.6, 2.0 Hz, 1H), 7.69-7.63 (m, 2H), 5.87 (br s, 1H), 4.31-4.26 (m, 1H), 3.71-3.68 (m, 2H), 2.78-2.65 (m, 3H), 2.56-2.51 (m, 1H), 2.41-2.34 (m, 1H), 2.18-2.15 (m, 1H), 1.93-1.82 (m, 1H), 1.32 (d, J = 6.8 Hz, 3H). Note: -CONH and -OH protons were exchanged in MeOD NMR. LCMS (Method A): 2.214 min, 100%, 254.0 nm, MS: ES+ 379.2 (M+1) HPLC (Method A): 7.87 min, 98.49%, 254.0nm Chiral HPLC (Method A): 6.79 min, 98.70%, 240 nm

[0480] Example 77 - Synthesis of N-((R)-1-cyano-3-(methylamino)-3-oxopropyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 83)

[0481] [ka]

[0482] Process 1 To a stirred solution of CAS: 51186-58-4 (0.5 g, 1.54 mmol, 1.0 equiv) in DMF (5.0 mL) was added HATU (0.88 g, 2.32 mmol, 1.5 equiv) at 0 °C and stirred for 1 h, after which aqueous NHOH (0.37 mL 28%) was added. The resulting reaction mixture was stirred at room temperature for 12 h. TLC showed the reaction was complete, and the resulting reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by manual column chromatography (eluting the desired product with 35% ethyl acetate in hexanes) to give benzyl (R)-4-amino-3-((tert-butoxycarbonyl)amino)-4-oxobutanoate (A68) (0.238, 0.739 mmol, 47.75% yield). 1 H NMR(MeOD,400MHz):δ ppm 7.37-7.30(m,5H),7.27(s,1H),7.10(s,1H),7.05(d,J=8.4Hz,1H),5.12-5.05(m,2H),4.31-4.26(m, 1H),2.78-2.73(dd,J=5.6Hz,16.0Hz,1H),2.61-2.47(dd,J=5.2,16.0Hz,1H),1.33(d,J=24.0Hz,9H). LCMS (Method A): 1.821 min, 100.0% 210nm, MS: ES+ 323.2(M+1)

[0483] Process 2 To a stirred solution of benzyl (R)-4-amino-3-((tert-butoxycarbonyl)amino)-4-oxobutanoate (A68) (4.0 g, 12.4 mmol, 1.0 equiv) in 1,4 dioxane (40.0 mL) was added pyridine (4.0 mL, 13.6 mmol, 1.1 equiv) at room temperature and stirred for 10 minutes. After 10 minutes, TFAA (2.8 mL, 55.9 mmol, 4.5 equiv) was added dropwise, and the resulting reaction mixture was stirred at room temperature for 12 hours. TLC showed the reaction was complete, and the resulting reaction mixture was diluted with NaHCO3 (100 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude material. The crude material was purified by manual column chromatography on silica gel (100-200 mesh) (the desired product was eluted with 30% ethyl acetate in hexanes) to give benzyl (R)-3-((tert-butoxycarbonyl)amino)-3-cyanopropanoate (A69) (3.6 g, 11.82 mol, 95.70% yield). 1 H NMR (MeOD, 400MHz): δ ppm 7.84(d,J=7.6Hz,1H),7.38-7.30(m,5H),5.12(s,2H),4.70(d,J=6.8Hz,1H),3.02-2.87(m,2H),1.30(s,9H). LCMS (Method A): 2.32 min, 90.42%, 220nm, MS: ES+ 305.2 (M+1)

[0484] Process 3 To a stirred solution of benzyl (R)-3-((tert-butoxycarbonyl)amino)-3-cyanopropanoate (A69) (3.6 g, 11.82 mmol, 1.0 equiv) in THF (30 mL) was added CHSOH (5.22 mL, 59.14 mmol, 5.0 equiv) at room temperature, and the resulting reaction mixture was stirred at room temperature for 5 h. TLC showed the reaction was complete, and the resulting reaction mixture was diluted with aqueous NaHCO (100 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by manual column chromatography silica gel (100-200 mesh) (desired product eluted with 30% ethyl acetate in hexane) to give benzyl (R)-3-amino-3-cyanopropanoate hydrochloride (A70) (1.2 g, 4.98 mmol, 42.15% yield). 1 H NMR (DMSO, 400MHz): δ ppm 7.39-7.31(m,5H),5.14(s,2H),4.01(t,J=6.8Hz,1H),2.88-2.74(m,2H). LCMS (Method A): Did not confirm desired mass.

[0485] Process 4 A stirred solution of benzyl (R)-3-amino-3-cyanopropanoate hydrochloride (A70) (0.5 g, 2.08 mmol, 1.0 equiv.) in DMF (5.0 mL) was prepared. To this solution, DIPEA (1.15 mL, 6.24 mmol, 3.0 equiv.) and HATU (1.18 g, 3.12 mmol, 1.5 equiv.) were added at room temperature under a nitrogen atmosphere and stirred for 10 minutes. After 10 minutes, 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (Compound 15) (0.801 g, 2.28 mmol, 1.1 equiv.) was added at the same temperature, and the resulting reaction mixture was again stirred at room temperature for 16 hours. TLC showed the reaction was complete, and the resulting reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product, which was purified by manual column chromatography on silica gel (100-200 mesh) (desired product eluted with 35% ethyl acetate in hexanes) to give benzyl (3R)-3-cyano-3-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamido)propanoate (A71) (0.475, 0.936 mmol, yield: 97.23%). 1 H NMR(DMSO,400MHz):δ ppm 9.60(d,J=7.2Hz,1H),9.22(d,J=1.6Hz,1H),8.81(d,J=1.6Hz,1H),8.04-8.02(dd,J=2.4Hz,& 6.8Hz,1H),7.66(t,J=7.2Hz,2H),7.37(d,J=6.8Hz,2H),7.33-7.27(m,3H),5.88(br s,1H),5.32-5.27(m,1H),5.18(s,2H),3.34-3.15(m,2H),2.81-2.78(m,1H),2.70-2.65(m,2H),2.46(br s,1H),2.32-2.29(m,1H),2.08-2.06(m,1H),1.75-1.64(m,1H). LCMS (Method A): 2....

Claims

1. Chemical formula (I) 【Chemistry 1】 A compound having, or a pharmaceutically acceptable salt thereof, wherein, X is N or CH, R １ is -C(O)OR ５ -C(O)-NR ６ R ２ -S(O) ２ -N(R ６ ) ２ -S(O) ｍ -(C １－６ alkyl), and -S(O)N(R ６ ) ２ is selected from the group consisting of R ２ is, -C １ -C ６ Alkyl, - (one or two - OR ５ C is replaced by １ -C ６ Alkyl), -(C １ -C ６ Alkylene)-CN,-(C １ -C ６ Alkylene)-S(O) ｎ - (C １ -C ６ Alkyl), - (OR ５ C is replaced by optional selection. １ -C ４ Alkylene)-C(O)OR ５ , - ( OR ５ C is replaced by optional selection. １ -C ４ Alkylene)-C(O)N(R) ６ ) ２ , - (C ０ -C ４ Alkylene)-phenyl,-(C) １ -C ６ Alkylene)-N(R) ６ ) ２ , 5-6 member heteroaryls having one, two, or three heteroatoms independently selected from N, O, and S, - (OR ５ C is replaced by optional selection. １ -C ４ Alkylene)-(5-6 membered heteroaryl having one, two, or three heteroatoms independently selected from N, O, and S),-(C ０ -C ４ Alkylene)-C ３ -C １０ Cycloalkyl, and -(C ０ -C ４ A selection from the group consisting of alkylenes (3-10 membered heterocyclines having one, two, three, or four heteroatoms independently selected from N, O, and S), and any of the aforementioned phenyl, 5-6 membered heteroaryl, C ３ -C １０ Cycloalkyl groups and 3- to 10-membered heterocyclines are optionally substituted. m is either 1 or 2. n is 0, 1, or 2, R ３ is hydrogen, halogen, -C １ -C ６ Alkyl, -(C １ -C ６ Haloalkyl), -O-(C １ -C ６ Alkyl), and -O-(C １ -C ６ Selected from the group consisting of haloalkyls, R ４ These are hydrogen, halogens, and -C １ -C ６ Selected from the group consisting of alkyl groups, or, R ３ and R ４ They become one, R ３ and R ４ A carbon atom bonded to it forms a 3- to 7-membered carbon ring, and the carbon ring is optionally substituted with one or more halogens. R ５ Each of them independently represents hydrogen or -C １ -C ６ It is alkyl, R ６ Each of them independently represents hydrogen or -C １ -C ６ It is alkyl, R ｘ Each is independent of -C １ -C ６ Alkyl, halogen, -OR ５ Selected from the group consisting of , and -CN, R ｙ Each is independent of -C １ -C ６ Alkyl, halogen, -OR ５ , -CN, and -N(R ６ ) ２ Selected from the group consisting of, s is 0, 1, or 2, and also, A compound, or a pharmaceutically acceptable salt thereof, where t is 0, 1, 2, or 3.

2. Chemical formula (I') 【Chemistry 2】 A compound having, or a pharmaceutically acceptable salt thereof, wherein, X is N or CH, R1 is selected from the group consisting of -C(O)OR5, -C(O)-NR6R2, -S(O)2-N(R6)2, -S(O)m-(C1-6 alkyl), and -S(O)N(R6)2. R2 is -C1-C6 alkyl, -(C1-C6 alkyl substituted with one or two -OR5), -(C1-C6 alkylene)-CN, -(C1-C6 alkylene)-S(O)n, -(C1-C6 alkyl), -(C1-C4 alkylene optionally substituted with OR5)-C(O)OR5, -(C1-C4 alkylene optionally substituted with CN or OR5)-C(O)N(R6)2, -(C0-C4 alkylene)-phenyl, -(C1-C6 alkylene)-N(R6)(R7), -(C1-C6 Selected from the group consisting of -(C1-C4 alkylene)-OP(O)(OR 5)2, having one, two, or three heteroatoms independently selected from N, O, and S, -(C0-C4 alkylene)-(5-6 membered heteroaryl having one, two, or three heteroatoms independently selected from N, O, and S), -(C0-C4 alkylene)-C3-C10 cycloalkyl, and -(C0-C4 alkylene)-(3-10 membered heterocyclil having one, two, three, or four heteroatoms independently selected from N, O, and S), any of the aforementioned phenyl, 5-6 membered heteroaryl, C3-C10 cycloalkyl, and 3-10 membered heterocyclil may have one or more R w Replaced by optional selection, m is either 1 or 2. n is 0, 1, or 2, R3 is selected from the group consisting of hydrogen, halogen, -C1-C6 alkyl, -(C1-C6 haloalkyl), -O-(C1-C6 alkyl), and -O-(C1-C6 haloalkyl). R4 is selected from the group consisting of hydrogen, halogens, and -C1-C6 alkyl groups, or R3 and R4 together form a 3- to 7-membered carbon ring with the carbon to which R3 and R4 are bonded, and the carbon ring is optionally substituted with one or more halogens. Each R5 is independently either hydrogen or a -C1-C6 alkyl group. Each R6 is independently either hydrogen or a -C1-C6 alkyl group. R7 is selected from the group consisting of hydrogen, -C1-C6 alkyl, -C(O)-(C1-6 alkyl), -C(O)N(R6)2, -C(O)2-(C1-6 alkyl), -S(O)n-(C1-C6 alkyl), and -S(O)nNR6-(C1-C6 alkyl). Each R and w is independently selected from the group consisting of -C1-C6 alkyl, halogen, -N(R6)2, and oxo, and the -C1-C6 alkyl is optionally substituted with -OH. Each R x is independently selected from the group consisting of -C1-C6 alkyl, halogen, -OR5, and -CN. Each of R and y is independently selected from the group consisting of -C1-C6 alkyl, halogen, -OR5, and -CN. s is 0, 1, or 2, and also, A compound, or a pharmaceutically acceptable salt thereof, where t is 0, 1, 2, or 3.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is N.

4. The compound according to either claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(O)-NHR 2.

5. The compound according to either claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1 is -C(O)OH.

6. The compound according to either claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1 is -S(O)CH3.

7. The compound according to either claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1 is -S(O)2CH3.

8. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is -S(O) 2 NHCH 3.

9. R2 is -C1-C6 alkyl, -(C1-C6 alkyl substituted with one or two -OR5), -(C1-C6 alkylene)-CN, -(C1-C6 alkylene)-S(O)n, -(C1-C6 alkyl), -(C1-C4 alkylene optionally substituted with OR5)-C(O)OR5, -(C1-C4 alkylene optionally substituted with OR5)-C(O)N(R6)2, -(C1-C6 alkylene)-N(R6)2, and -(C1-C4 alkylene optionally substituted with OR5) A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from the group consisting of alkylene-(a 5-6 membered heteroaryl having one, two, or three heteroatoms independently selected from N, O, and S).

10. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2 is a -(C1-C4 alkylene)-5 to 6-membered heteroaryl.

11. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2 is a -CH(CH3)-5 to 6-membered heteroaryl.

12. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2 is a -CH2-5 to 6-membered heteroaryl.

13. The compound according to any one of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the 5-6 member heteroaryl is optionally substituted with C1-C6 alkyl or N(Ra)2, and Ra is independently hydrogen or C1-C6 alkyl.

14. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the 5-6 member heteroaryl is pyridyl.

15. The 5-6 member heteroaryl is 【Transformation 3】 The compound according to either claim 1 or 2, or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the 5-6 member heteroaryl is oxazolyl.

17. The 5-6 member heteroaryl is 【Chemistry 4】 The compound according to either claim 1 or 2, or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2 is a -C1-C6 alkyl group.

19. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2 is isopropyl.

20. The compound according to either claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2 is -(a C1-C6 alkyl substituted with one or two -OR5 groups).

21. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2 is - (a C1-C6 alkyl substituted with - OR 5).

22. The compound according to either claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2 is -(C1-C6 alkyl substituted with -OH).

23. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2 is a C1-C6 alkyl substituted with -OH and -OCH3.

24. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2 is -(C1-C6 alkylene)-S(O)n-(C1-C6 alkyl).

25. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2 is -(C1-C6 alkylene)-CN.

26. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2 is -(C1-C4 alkylene optionally substituted with OR 5)-C(O)OR 5.

27. ​​The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 2 is -(C 1-C 4 alkylene optionally substituted with OR 5)-C(O)N(R 6) 2.

28. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2 is -(C1-C6 alkylene)-N(R6)2.

29. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R3 is -(C1-C6 haloalkyl).

30. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R3 is trifluoromethyl.

31. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R3 is a halogen.

32. The compound according to either claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R3 is F.

33. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen.

34. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R4 is a halogen.

35. The compound according to either claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R4 is F.

36. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 together form a 3- to 7-membered carbon ring with the carbon to which R3 and R4 are bonded, and the carbon ring is optionally substituted with one or more halogens.

37. The compound according to claim 36, or a pharmaceutically acceptable salt thereof, wherein the carbon ring is optionally substituted with one or more F atoms.

38. The compound according to either claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein both s and t are 0.

39. Formula (Ia) 【Transformation 5】 A compound of or a pharmaceutically acceptable salt thereof, wherein the formula is R2 is -C1-C6 alkyl, -(C1-C6 alkyl substituted with one or two -OR5), -(C1-C6 alkylene)-CN, -(C1-C6 alkylene)-S(O)n, -(C1-C6 alkyl), -(C1-C4 alkylene optionally substituted with OR5)-C(O)OR5, -(C1-C4 alkylene optionally substituted with OR5)-C(O)N(R6)2, -(C1-C6 alkylene)-N(R6)2, and -(C1-C4 alkylene optionally substituted with OR5) A group consisting of alkylenes (5-6 member heteroaryls having one, two, or three heteroatoms independently selected from N, O, and S) is selected, and the 5-6 member heteroaryls are optionally substituted. n is 0, 1, or 2, R3 is selected from the group consisting of halogens, -C1-C6 alkyls, -C1-C6 haloalkyls, and -O-(C1-C6 alkyls). R4 is selected from the group consisting of hydrogen, halogens, and -C1-C6 alkyl groups, or R3 and R4, together, form a 3- to 7-membered carbon ring with the carbon to which R3 and R4 are bonded, and the 3- to 7-membered carbon ring is optionally substituted with one or more halogens. Each R5 is independently either hydrogen or a -C1-C6 alkyl group, and, A compound, or a pharmaceutically acceptable salt thereof, in which each R6 is independently hydrogen or a -C1-C6 alkyl group.

40. Formula (Ia') 【Transformation 6】 A compound of or a pharmaceutically acceptable salt thereof, wherein the formula is R2 is -C1-C6 alkyl, -(C1-C6 alkyl substituted with one or two -OR5), -(C1-C6 alkylene)-CN, -(C1-C6 alkylene)-S(O)n, -(C1-C6 alkyl), -(C1-C4 alkylene optionally substituted with CN or OR5)-C(O)OR5, -(C1-C4 alkylene optionally substituted with OR5)-C(O)N(R6)2, -(C1-C6 alkylene)-N(R6)(R7), -(C1-C6 alkylene)-OP(O)(OR5)2, and -(OR5 A C1-C4 alkylene is optionally substituted with a 5-6 member heteroaryl having one, two, or three heteroatoms independently selected from N, O, and S, and the 5-6 member heteroaryl is optionally substituted with one or more Rw. n is 0, 1, or 2, R3 is selected from the group consisting of halogens, -C1-C6 alkyls, -C1-C6 haloalkyls, and -O-(C1-C6 alkyls). R4 is selected from the group consisting of hydrogen, halogens, and -C1-C6 alkyl groups, or R3 and R4, together, form a 3- to 7-membered carbon ring with the carbon to which R3 and R4 are bonded, and the 3- to 7-membered carbon ring is optionally substituted with one or more halogens. Each R5 is independently either hydrogen or a -C1-C6 alkyl group, and, Each R6 is independently either hydrogen or a -C1-C6 alkyl group whenever it appears. R7 is selected from the group consisting of hydrogen, -C1-C6 alkyl, -C(O)-(C1-6 alkyl), -C(O)N(R6)2, -C(O)2-(C1-6 alkyl), -S(O)n-(C1-C6 alkyl), and -S(O)nNR6-(C1-C6 alkyl). Rw is independently selected from the group consisting of -C1-C6 alkyl, -N(R6)2, and oxo, and the -C1-C6 alkyl is optionally substituted with -OH, the compound or a pharmaceutically acceptable salt thereof.

41. The compound is of formula (Ib) 【Transformation 7】 The compound according to claim 39 or 40, or a pharmaceutically acceptable salt thereof.

42. The compound is of formula (Ic) 【Transformation 8】 The compound according to claim 39 or 40, or a pharmaceutically acceptable salt thereof.

43. The compound according to any one of claims 39 or 40, or a pharmaceutically acceptable salt thereof, wherein R2 is a -(C1-C4 alkylene)-5 to 6-membered heteroaryl.

44. The compound according to any one of claims 39 or 40, or a pharmaceutically acceptable salt thereof, wherein R2 is a -CH(CH3)-5 to 6-membered heteroaryl.

45. The compound according to claim 39 or 40, or a pharmaceutically acceptable salt thereof, wherein R2 is a -CH2-5 to 6-membered heteroaryl.

46. The compound according to any one of claims 39 or 40, or a pharmaceutically acceptable salt thereof, wherein the 5- to 6-membered heteroaryl is optionally substituted with -C1-C6 alkyl or -N(Ra)2, and Ra is independently hydrogen or C1-C6 alkyl.

47. The compound according to any one of claims 39 or 40, wherein the 5-6 member heteroaryl is pyridyl, or a pharmaceutically acceptable salt thereof.

48. The 5-6 member heteroaryl is 【Chemistry 9】 The compound according to any one of claims 39 or 40, or a pharmaceutically acceptable salt thereof.

49. The compound according to claim 39 or 40, or a pharmaceutically acceptable salt thereof, wherein the 5-6 member heteroaryl is oxazolyl.

50. The 5-6 member heteroaryl is 【Chemistry 10】 The compound according to any one of claims 39 or 40, or a pharmaceutically acceptable salt thereof.

51. R2 is -(C1-C6 alkyl substituted with one or two -OR5), -(C1-C6 alkylene)-S(O)n -(C1-C6 alkyl), -(C1-C4 alkylene optionally substituted with OR5)-C(O)OR5, -(C1-C4 alkylene optionally substituted with OR5)-C(O)N(R6)2, -(C1-C6 alkylene)-N(R6)(R7), -(C1-C6 alkylene)-OP(O)(OR5)2, -(C1-C4 alkylene optionally substituted with OR5) A compound according to claim 40, or a pharmaceutically acceptable salt thereof, selected from the group consisting of alkylene)-(a 5-6 member heteroaryl having one, two, or three heteroatoms independently selected from N, O, and S), wherein any of the aforementioned 5-6 member heteroaryls is optionally substituted with one, two, three, or four substituents independently selected from the group consisting of methyl, -NH2, and oxo.

52. The compound according to claim 40, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of -(C1-C6 alkyl substituted with one or two -OR5), -(C1-C6 alkylene)-N(R6)(R7), and -(C1-C4 alkylene optionally substituted with OR5)-(a 5-6 membered heteroaryl having one, two, or three heteroatoms independently selected from N, O, and S), and any of the aforementioned 5-6 membered heteroaryls is optionally substituted with one, two, three, or four substituents independently selected from the group consisting of methyl, -NH2, and oxo.

53. The compound according to any one of claims 39 or 40, or a pharmaceutically acceptable salt thereof, wherein R2 is a -C1-C6 alkyl group.

54. The compound according to any one of claims 39 or 40, or a pharmaceutically acceptable salt thereof, wherein R2 is isopropyl.

55. The compound according to any one of claims 39 or 40, or a pharmaceutically acceptable salt thereof, wherein R2 is -(a C1-C6 alkyl substituted with one or two -OR5 groups).

56. The compound according to any one of claims 39 or 40, or a pharmaceutically acceptable salt thereof, wherein R2 is - (a C1-C6 alkyl substituted with - OR 5).

57. The compound according to any one of claims 39 or 40, or a pharmaceutically acceptable salt thereof, wherein R2 is -(C1-C6 alkyl substituted with -OH).

58. The compound according to any one of claims 39 or 40, or a pharmaceutically acceptable salt thereof, wherein R2 is a C1-C6 alkyl substituted with -OH and -OCH3.

59. The compound according to claim 39 or 40, or a pharmaceutically acceptable salt thereof, wherein R2 is -(C1-C6 alkylene)-S(O)n-(C1-C6 alkyl).

60. The compound according to any one of claims 39 or 40, or a pharmaceutically acceptable salt thereof, wherein R2 is -(C1-C6 alkylene)-CN.

61. The compound according to any one of claims 39 or 40, or a pharmaceutically acceptable salt thereof, wherein R2 is C1-C4 alkylene (optionally substituted with OR 5)-C(O)OR 5.

62. The compound according to any one of claims 39 or 40, or a pharmaceutically acceptable salt thereof, wherein R 2 is -(C 1-C 4 alkylene optionally substituted with OR 5)-C(O)N(R 6) 2.

63. The compound according to any one of claims 39 or 40, or a pharmaceutically acceptable salt thereof, wherein R2 is -(C1-C6 alkylene)-N(R6)2.

64. The compound according to any one of claims 39 or 40, or a pharmaceutically acceptable salt thereof, wherein R3 is a -C1-C6 haloalkyl group.

65. The compound according to any one of claims 39 or 40, or a pharmaceutically acceptable salt thereof, wherein R3 is trifluoromethyl.

66. The compound according to any one of claims 39 or 40, or a pharmaceutically acceptable salt thereof, wherein R3 is a halogen.

67. The compound according to any one of claims 39 or 40, or a pharmaceutically acceptable salt thereof, wherein R3 is -F.

68. The compound according to any one of claims 39 or 40, or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen.

69. The compound according to either claim 39 or 40, or a pharmaceutically acceptable salt thereof, wherein R4 is a halogen.

70. The compound according to either claim 39 or 40, or a pharmaceutically acceptable salt thereof, wherein R4 is -F.

71. The compound according to claim 39 or 40, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 together form a 3- to 7-membered carbon ring with the carbon to which R3 and R4 are bonded, and the carbon ring is optionally substituted with one or more halogens.

72. The compound according to either claim 39 or 40, or a pharmaceutically acceptable salt thereof, wherein the carbon ring is optionally substituted with one or more F atoms.

73. The compound is 【Chemistry 11-1】 【Chemistry 11-2】 【Chemistry 11-3】 【Chemistry 11-4】 【Chemistry 11-5】 【Chemistry 11-6】 【Chemistry 11-7】 【Chemistry 11-8】 【Chemistry 11-9】 【Chemistry 11-10】 【Chemistry 11-11】 [Chemistry 11-12] [Chemistry 11-13] [Chemistry 11-14] 【Chemistry 11-15】 A compound according to any one of claims 1 to 2 or 39 to 40, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

74. A pharmaceutical composition comprising a compound according to any one of claims 1 to 2 or 39 to 40, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

75. Use of a compound according to any one of claims 1 to 2 or 39 to 40, or a pharmaceutically acceptable salt thereof, in the manufacture of a compound for use in a method of treating a disease or illness mediated by hyperactivation of a TEAD isoform selected from TEAD1 and TEAD4 of a subject requiring treatment, wherein the method comprises the step of administering the compound according to any one of claims 1 to 2 or 39 to 40, or a pharmaceutically acceptable salt thereof, to the subject.

76. The use according to claim 75, wherein the disease or illness is a cancer characterized by hyperactivation of a TEAD isoform selected from TEAD1 and TEAD4.

77. The use according to claim 76, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, gastric cancer, colorectal cancer, pancreatic cancer including pancreatic adenocarcinoma, mesothelioma including malignant mesothelioma, hepatocellular carcinoma, prostate cancer, head and neck cancer, renal cell carcinoma, and medulloblastoma.

78. The use according to claim 76, wherein the cancer is selected from the group consisting of hepatocellular carcinoma, breast cancer, pancreatic adenocarcinoma, and malignant mesothelioma.

79. The use according to claim 76, wherein the cancer is malignant mesothelioma.

80. The use according to claim 76, wherein the cancer is metastatic.

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