TEAD inhibitors and methods of use

Abstract

The present disclosure provides, in part, compounds of Formula (I): # imgabs0 # wherein the variables are as defined herein, pharmaceutical compositions comprising the compounds, and methods of using the compounds in the treatment of physiological disorders mediated by TEA domain transcription factors, such as proliferative disorders.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 322,600, filed on March 22, 2022, the contents of which are hereby incorporated by reference in their entirety.

[0003] Overview of public content

[0004] In certain embodiments, disclosed herein are compounds of Formula (I) or Formula (I'), such as compounds of Formula (Ia), (Ia'), (Ib), (Ic), (Ib-1), or (Ib-2), or pharmaceutically acceptable salts thereof. In addition, disclosed herein are compositions comprising compounds of Formula (I) or Formula (I'), such as compounds of Formula (Ia), (Ia'), (Ib), (Ic), (Ib-1), or (Ib-2), or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient. In certain embodiments, disclosed herein are methods of inhibiting the activity of an aberrant transcriptional enhancer-associated (TEA) domain transcription factor (TEAD) transcription complex and thereby treating certain diseases or disorders, such as cancer, characterized by aberrant TEAD transcription complex activity (e.g., hyperactivation).

[0005] In certain embodiments, disclosed herein are compounds of Formula (I):

[0006]

[0007] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0008] Furthermore, in certain embodiments, disclosed herein are compounds of formula (I'):

[0009]

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

[0011] Furthermore, in certain embodiments, disclosed herein are compounds of Formula (Ia):

[0012]

[0013] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0014] Furthermore, in certain embodiments, disclosed herein are compounds of Formula (Ia'):

[0015]

[0016] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

[0017] 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.

[0018] Also provided herein, in certain embodiments, are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0019] In certain embodiments, disclosed herein are methods of treating a disease or condition mediated by abnormal 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 a cancer characterized by abnormal TEAD transcription complex activity (e.g., hyperactivation). BRIEF DESCRIPTION OF THE DRAWINGS

[0021] The present disclosure can be more completely understood with reference to the following drawings.

[0022] Figure 1 Figure 1 is a diagram showing the domain structure of human TEAD1, TEAD2, TEAD3, and TEAD4. The 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-TEAD4 compared to the corresponding 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.

[0023] Figure 2A Figure 1 is a diagram showing the upstream signaling and downstream transcriptional output of TEAD in cancer biology. TEAD regulates key 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 by *), such as KRAS, BRAF, LKB1, APC, and GNAQ / 11.

[0024] Figure 2B Graphs showing the role of TEAD in multiple stages of tumorigenesis.

[0025] Detailed description

[0026] In certain embodiments, provided herein are compounds (e.g., compounds of Formula (I) or Formula (I'), e.g., compounds of Formula (Ia), (Ia'), (Ib), (Ic), (Ib-1), or (Ib-2)), or pharmaceutically acceptable salts thereof. In certain embodiments, provided herein are compositions comprising compounds of Formula (I) or Formula (I'), e.g., compounds of Formula (Ia), (Ia'), (Ib), (Ic), (Ib-1), or (Ib-2), or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient. In certain embodiments, provided herein are methods of using the compounds and compositions disclosed herein. The contemplated compounds and compositions disclosed herein are inhibitors of transcription enhancer 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).

[0027] 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 certain TEAD isoforms associated with therapeutic efficacy (e.g., TEAD1 and / or TEAD4). Such selective binding is advantageous because less selective and / or non-selective TEAD isoform binding may lead to increased undesirable effects (e.g., toxicity and / or cancer cell proliferation).

[0028] Certain terms

[0029] Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as those generally understood by those skilled in the art of the claimed subject matter. In general, the nomenclature used in conjunction with immunology, oncology, cell and tissue culture, molecular biology, and protein and oligonucleotide or polynucleotide chemistry and hybridization described herein, and the techniques of immunology, oncology, cell and tissue culture, molecular biology, and protein and oligonucleotide or polynucleotide chemistry and hybridization are those well known in the art and commonly used. It should be understood that the foregoing general description and the following detailed description are only exemplary and illustrative and do not limit any claimed subject matter. The section headings used herein are only for organizational purposes and are not to be construed as limiting the described subject matter.

[0030] Chemical definition

[0031] Definitions of specific functional groups and chemical terms are described in more detail below.

[0032] In some embodiments, the compounds described herein contain one or more asymmetric centers and therefore exist in various isomeric forms, for example, 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 a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. In some embodiments, isomers are separated from the mixture 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 compounds described herein as individual isomers that are substantially free of other isomers and, optionally, as mixtures of various isomers.

[0033] In some embodiments, the compounds described herein further comprise one or more isotopic substitutions. For example, in some embodiments, H is in any isotopic form, including 1 H. 2 H (D or deuterium) and 3 H (T or tritium); C in any isotopic form, including 12 C. 13 C and 14 C; O in any isotopic form, including 16 O and 18 O; F in any isotopic form, including 18 F and 19 F; etc.

[0034] The articles "a" and "an" are used herein to refer to one or to more than one (ie, to at least one) of the grammatical object of the article.

[0035] When a range of values ​​is listed, it is intended to encompass every value and subrange within that range. For example, "C 1-6 "Alkyl" is intended to include 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.

[0036] As used herein, "alkyl" refers to a group such as a straight-chain or branched saturated hydrocarbon group 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 ("C 1-8 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, an alkyl group has 1 carbon atom ("C1 alkyl"). 1-6 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0037] As used herein, "alkylene" refers to a divalent radical of an alkyl group. When a range or number of carbons is provided for a particular "alkylene" group, it is understood that the range or number refers to the range or number of carbons in a linear carbon divalent chain. In some embodiments, the "alkylene" group is substituted or unsubstituted with one or more substituents as described herein.

[0038] As used herein, "aryl" refers to 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) radical having 6-14 ring carbon atoms and zero heteroatoms ("C 6-14 "aryl").

[0039] As used herein, "heteroaryl" refers to a group 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 provided in the aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is 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 a carbon atom or a nitrogen atom when valence permits.

[0040] In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl group has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0041] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. 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.

[0042] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group having 3-12, 3-10, 3-8, 4-8, or 4-6 carbon atoms derived from cycloalkanes, referred to herein as, for example, "C3-C 10 Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclopentane, cyclobutane, and cyclopropane.

[0043] As used herein, "heterocyclyl" or "heterocycle" refers to a group of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-10 membered heterocyclyl"). In some embodiments, in a heterocyclyl group comprising one or more nitrogen atoms, when valence permits, the point of attachment is a carbon atom or a nitrogen atom. In some embodiments, the heterocyclyl group is a monocyclic ("monocyclic heterocyclyl") or fused ring system, a bridged ring system, or a spirocyclic ring system, such as a bicyclic system ("bicyclic heterocyclyl"), and is saturated or partially unsaturated. In some embodiments, the heterocyclyl bicyclic ring system comprises one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl or heterocyclyl ring; or a heterocyclyl ring as defined above is fused to one or more phenyl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such cases, the number of ring members continues to refer to 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.

[0044] The term "carbocyclyl" or "carbocycle" refers to a group of non-aromatic cyclic hydrocarbon groups having 3 to 10 ring carbon atoms ("3-10 membered carbocycle") and zero heteroatoms in the non-aromatic ring system. In some embodiments, the "carbocyclyl" or "carbocyclic" ring is a "3-7 membered carbocycle."

[0045] In some embodiments, a heterocyclyl group is a 3-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 4-7 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“4-7 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 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, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“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, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("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 one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0046] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group have been replaced by nitrogen, oxygen, or sulfur heteroatoms. In some embodiments, hetero applies to any of the hydrocarbyl groups described above, such as alkyl, e.g., heteroalkyl; cycloalkyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; and similar groups having 1 to 5, and particularly 1 to 3, heteroatoms.

[0047] As used herein, the terms "halo" and "halogen" refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodine, -I). In certain embodiments, the halogen group is fluorine or chlorine.

[0048] The term "haloalkyl" includes monohaloalkyl, polyhaloalkyl, and perhaloalkyl groups substituted with one or more halogen atoms, wherein the halogen is independently selected from fluorine, chlorine, bromine, and iodine.

[0049] The term "oxo" refers to =0.

[0050] In general, the term "substituted," whether or not 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 a permitted substituent, such as a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as 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 at each position may be the same or different.

[0051] The nitrogen atoms may be substituted or unsubstituted as valence permits, and include primary, secondary, tertiary and quaternary nitrogen atoms.

[0052] These and other exemplary substituents are described in greater detail in the Detailed Description, Examples, and Claims.This disclosure is not intended to be limited in any way by the above exemplary list of substituents.

[0053] Other definitions

[0054] As used herein, a "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; improve bioavailability; or increase patient acceptability. They may also aid product identification or enhance the overall safety or function of the product during storage or use.

[0055] As used herein, "pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, and which 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 formed by 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, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, 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, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Where appropriate, additional pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0056] As used herein, a "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. 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 these terms require the supervision of medical personnel.

[0057] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0058] As used herein, and unless otherwise indicated, the terms "treat," "treating," and "treatment" contemplate actions that occur in a subject suffering from a particular disease, disorder, or condition to reduce the severity of the disease, disorder, or condition, or to slow or slow the progression of the disease, disorder, or condition.

[0059] As used herein, and unless otherwise indicated, 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 the disease, disorder, or condition. In some embodiments, the term "therapeutically effective amount" encompasses an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0060] Compound

[0061] In certain embodiments, disclosed herein are compounds of Formula (I):

[0062] or a pharmaceutically acceptable salt thereof, wherein:

[0063] X is N or CH;

[0064] R 1 Selected from -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;

[0065] R 2 Selected from the group consisting of: -C1-C6 alkyl, -(surrounded by one or two -OR 5 substituted C1-C6 alkyl), -(C1-C6 alkylene)-CN, -(C1-C6 alkylene)-S(O) n -(C1-C6 alkyl), -(optionally replaced by OR 5 Substituted C1-C4 alkylene)-C(O)OR 5 ,-(optionally OR5 Substituted C1-C4 alkylene)-C(O)N(R 6 )2,-(C0-C4 alkylene)-phenyl,-(C1-C6 alkylene)-N(R 6 )2, a 5-6 membered heteroaryl group having one, two or three heteroatoms each independently selected from N, O and S, -(optionally replaced by OR 5 substituted C1-C4 alkylene)-(5-6 membered heteroaryl having one, two or three heteroatoms each independently selected from N, O and S), -(C0-C4 alkylene)-C3-C 10 Cycloalkyl, and -(C0-C4 alkylene)-(3-10 membered heterocyclic group having one, two, three or four heteroatoms each independently selected from N, O and S), wherein any of the aforementioned phenyl, 5-6 membered heteroaryl, C3-C 10 Cycloalkyl and 3-10 membered heterocyclyl are optionally substituted;

[0066] m is 1 or 2;

[0067] n is 0, 1, or 2;

[0068] R 3 Selected from the group consisting of hydrogen, halogen, -C1-C6 alkyl, -(C1-C6 haloalkyl), -O-(C1-C6 alkyl) and -O-(C1-C6 haloalkyl);

[0069] R 4 is selected from the group consisting of hydrogen, halogen and -C1-C6 alkyl; or

[0070] R 3 and R 4 With R 3 and R 4 The attached carbons together form a 3-7 membered carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more halogens;

[0071] Each R 5 are independently hydrogen or -C1-C6 alkyl;

[0072] Each R 6 are independently hydrogen or -C1-C6 alkyl;

[0073] Each R x Independently selected from -C1-C6 alkyl, halogen, -OR 5 , -CN and -N(R 6 )2;

[0074] Each R y Independently selected from -C1-C6 alkyl, halogen, -OR 5 , -CN and -N(R6 )2;

[0075] s is 0, 1, or 2; and

[0076] t is 0, 1, 2, or 3.

[0077] In certain embodiments, disclosed herein are compounds of formula (I'):

[0078] or a pharmaceutically acceptable salt thereof, wherein:

[0079] X is N or CH;

[0080] R 1 Selected from -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;

[0081] R 2 Selected from the group consisting of: -C1-C6 alkyl, -(surrounded by one or two -OR 5 substituted C1-C6 alkyl), -(C1-C6 alkylene)-CN, -(C1-C6 alkylene)-S(O) n -(C1-C6 alkyl), -(optionally replaced by OR 5 Substituted C1-C4 alkylene)-C(O)OR 5 ,-(optionally replaced by CN or OR 5 Substituted C1-C4 alkylene)-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, a 5-6 membered heteroaryl group having one, two or three heteroatoms each independently selected from N, O and S, -(optionally replaced by OR 5 substituted C1-C4 alkylene)-(5-6 membered heteroaryl having one, two or three heteroatoms each independently selected from N, O and S), -(C0-C4 alkylene)-C3-C 10 Cycloalkyl, and -(C0-C4 alkylene)-(3-10 membered heterocyclic group having one, two, three or four heteroatoms each independently selected from N, O and S), wherein any of the aforementioned phenyl, 5-6 membered heteroaryl, C3-C10 Cycloalkyl and 3-10 membered heterocyclic groups are optionally substituted by one or more R w replace;

[0082] m is 1 or 2;

[0083] n is 0, 1, or 2;

[0084] R 3 Selected from the group consisting of hydrogen, halogen, -C1-C6 alkyl, -(C1-C6 haloalkyl), -O-(C1-C6 alkyl) and -O-(C1-C6 haloalkyl);

[0085] R 4 is selected from the group consisting of hydrogen, halogen and -C1-C6 alkyl; or

[0086] R 3 and R 4 With R 3 and R 4 The attached carbons together form a 3-7 membered carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more halogens;

[0087] Each R 5 are independently hydrogen or -C1-C6 alkyl;

[0088] Each R 6 are independently hydrogen or -C1-C6 alkyl;

[0089] R 7 Selected from the group consisting of: 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);

[0090] Each R w independently selected from -C1-C6 alkyl, halogen, -N(R 6 ) 2 and oxo, wherein the -C1-C6 alkyl group is optionally substituted by -OH;

[0091] Each R x Independently selected from -C1-C6 alkyl, halogen, -OR 5 and -CN group;

[0092] Each R y Independently selected from -C1-C6 alkyl, halogen, -OR 5and -CN group;

[0093] s is 0, 1, or 2; and

[0094] t is 0, 1, 2, or 3.

[0095] In some embodiments, X is N. In some embodiments, X is CH.

[0096] In some embodiments, R 1 Yes-C(O)-NHR 2 In some embodiments, R 1 Yes-S(O)-R 2 In some embodiments, R 1 is -C(O)OH. In some embodiments, R 1 Yes-S(O)2-R 2 In some embodiments, R 1 Yes -S(O)2-NHR 2 In some embodiments, R 1 is -S(O)CH3. In some embodiments, R 1 is -S(O)2CH3. In some embodiments, R 1 It is -S(O)2NHCH3.

[0097] In some embodiments, R 2 Selected from the group consisting of: -C1-C6 alkyl, -(surrounded by one or two -OR 5 substituted C1-C6 alkyl), -(C1-C6 alkylene)-CN, -(C1-C6 alkylene)-S(O) n -(C1-C6 alkyl), -(optionally replaced by OR 5 Substituted C1-C4 alkylene)-C(O)OR 5 ,-(optionally OR 5 Substituted C1-C4 alkylene)-C(O)N(R 6 )2, -(C1-C6 alkylene)-N(R 6 )2 and -(optionally OR 5 substituted C1-C4 alkylene)-(5-6 membered heteroaryl having one, two or three heteroatoms each independently selected from N, O and S).

[0098] In some embodiments, R 2 It is -(C1-C4 alkylene)-5-6 membered heteroaryl.

[0099] In some embodiments, R 2 It is -CH(CH3)-5-6 membered heteroaryl.

[0100] In some embodiments, R 2 It is -CH2-5-6 membered heteroaryl.

[0101] In some embodiments, the 5-6 membered heteroaryl is optionally replaced by a C1-C6 alkyl or N(R a )2 substituted, wherein each R a are independently hydrogen or C1-C6 alkyl.

[0102] In some embodiments, the 5-6 membered heteroaryl is pyridinyl. In some embodiments, the 5-6 membered heteroaryl is In some embodiments, the 5-6 membered heteroaryl is oxazolyl. In some embodiments, the 5-6 membered heteroaryl is

[0103] 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 In some embodiments, R 2 is -(by one or two -OR 5 In some embodiments, R 2 is-(be-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 is -(C1-C6 alkylene)-S(O) n -(C1-C6 alkyl). In some embodiments, R 2 is -(C1-C6 alkylene)-CN. In some embodiments, R 2 Yes - (optionally OR 5 Substituted C1-C4 alkylene)-C(O)OR 5 In some embodiments, R 2 Yes - (optionally OR 5 Substituted C1-C4 alkylene)-C(O)N(R 6 )2. In some embodiments, R 2 is -(C1-C6 alkylene)-N(R 6 )2.

[0104] In some embodiments, R 2 Selected from the group consisting of: methyl,

[0105] In some embodiments, R 2 Selected from the group consisting of: methyl,

[0106] In some embodiments, R 2 Selected from the group consisting of: methyl,

[0107] In some embodiments, m is 1. In some embodiments, m is 2.

[0108] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0109] In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2.

[0110] In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3.

[0111] In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 It's methyl.

[0112] In some embodiments, R 3 It is -C1-C6 haloalkyl.

[0113] In some embodiments, R 3 It is trifluoromethyl.

[0114] In some embodiments, wherein R 3 In some embodiments, R 3 Yes -F.

[0115] In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 Yes -F.

[0116] In some embodiments, R 3 is -C1-C6 haloalkyl, and R 4 is H. In some embodiments, R 3 and R 4 In some embodiments, R 3 and R 4 In some embodiments, R 3 and R 4 All are H.

[0117] In some embodiments, R 3 and R 4 With R 3 and R 4 The attached carbons together form a 3-7 membered carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more halogens. In some embodiments, the halogen is F.

[0118] In some embodiments, R 3 and R 4 Together they form a cyclopropyl or cyclobutyl group optionally substituted with one or more halogens. 3 and R 4 Together they form a cyclopropyl or cyclobutyl group optionally substituted with one or more fluorine groups. 3 and R 4 Together they form a cyclopropyl group. In some embodiments, R 3 and R 4 Together they form a cyclobutyl group optionally substituted with one or more fluorine groups.

[0119] In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5 It's methyl.

[0120] In some embodiments, R 6 In some embodiments, R 6 It is a -C1-C6 alkyl group.

[0121] In some embodiments, s and t are both 0.

[0122] In certain embodiments, disclosed herein are compounds of Formula (Ia):

[0123]

[0124] or a pharmaceutically acceptable salt thereof, wherein:

[0125] R 2 Selected from the group consisting of: -C1-C6 alkyl, -(surrounded by one or two -OR 5 substituted C1-C6 alkyl), -(C1-C6 alkylene)-CN, -(C1-C6 alkylene)-S(O) n -(C1-C6 alkyl), -(optionally replaced by CN or OR 5 Substituted C1-C4 alkylene)-C(O)OR 5 ,-(optionally OR 5 Substituted C1-C4 alkylene)-C(O)N(R 6 )2, -(C1-C6 alkylene)-N(R 6 R 7 ) and -(optionally OR 5 substituted C1-C4 alkylene)-(5-6 membered heteroaryl having one, two or three heteroatoms each independently selected from N, O and S), wherein the 5-6 membered heteroaryl is optionally substituted by one or more R w replace;

[0126] n is 0, 1, or 2;

[0127] R 3 Selected from the group consisting of halogen, -C1-C6 alkyl, -C1-C6 haloalkyl and -O-(C1-C6 alkyl);

[0128] R 4 is selected from the group consisting of hydrogen, halogen and -C1-C6 alkyl; or

[0129] R 3 and R 4 With R 3 and R 4 The attached carbons together form a 3-7 membered carbocyclic ring, wherein the 3-7 membered carbocyclic ring is optionally substituted with one or more halogens;

[0130] Each R 5 Each occurrence is independently hydrogen or -C1-C6 alkyl; and

[0131] Each R 6 Each occurrence is independently hydrogen or -C1-C6 alkyl;

[0132] R 7 Selected from the group consisting of: hydrogen, -C1-C6 alkyl, -C(O)-(C 1-6 Alkyl), -C(O)NR 6 、-C(O)2-(C 1-6 Alkyl) and -S(O)2NR 6 -(C1-C6 alkyl);

[0133] Each R w independently selected from -C1-C6 alkyl, -N(R 6 )2 and oxo, wherein the -C1-C6 alkyl group is optionally substituted by -OH.

[0134] In certain embodiments, disclosed herein are compounds of Formula (Ia'):

[0135]

[0136] or a pharmaceutically acceptable salt thereof, wherein:

[0137] R 2 Selected from the group consisting of: -C1-C6 alkyl, -(surrounded by one or two -OR 5 substituted C1-C6 alkyl), -(C1-C6 alkylene)-CN, -(C1-C6 alkylene)-S(O) n -(C1-C6 alkyl), -(optionally replaced by CN or OR 5 Substituted C1-C4 alkylene)-C(O)OR 5 ,-(optionally OR 5 Substituted C1-C4 alkylene)-C(O)N(R 6 )2, -(C1-C6 alkylene)-N(R 6 R 7 ), -(C1-C6 alkylene)-OP(O)(OR 5 )2 and -(optionally OR 5 substituted C1-C4 alkylene)-(5-6 membered heteroaryl having one, two or three heteroatoms each independently selected from N, O and S), wherein the 5-6 membered heteroaryl is optionally substituted by one or more R w replace;

[0138] n is 0, 1, or 2;

[0139] R 3 Selected from the group consisting of halogen, -C1-C6 alkyl, -C1-C6 haloalkyl and -O-(C1-C6 alkyl);

[0140] R 4 is selected from the group consisting of hydrogen, halogen and -C1-C6 alkyl; or

[0141] R 3 and R 4 With R 3 and R 4 The attached carbons together form a 3-7 membered carbocyclic ring, wherein the 3-7 membered carbocyclic ring is optionally substituted with one or more halogens;

[0142] Each R 5 Each occurrence is independently hydrogen or -C1-C6 alkyl; and

[0143] Each R 6 Each occurrence is independently hydrogen or -C1-C6 alkyl;

[0144] R 7 Selected from the group consisting of: 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);

[0145] Each R w independently selected from -C1-C6 alkyl, -N(R 6 )2 and oxo, wherein the -C1-C6 alkyl group is optionally substituted by -OH.

[0146] In some embodiments, the compound is of Formula (Ib):

[0147] or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments, the compound is of Formula (Ic):

[0149] or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, the compound is of Formula (Ib-1):

[0151] or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, the compound is of Formula (Ib-2):

[0153] or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments, R 2 It is -(C1-C4 alkylene)-5-6 membered heteroaryl.

[0155] In some embodiments, R 2 It is -CH(CH3)-5-6 membered heteroaryl.

[0156] In some embodiments, R2 It is -CH2-5-6 membered heteroaryl.

[0157] In some embodiments, the 5-6 membered heteroaryl is optionally replaced by a C1-C6 alkyl or N(R a )2 substituted, wherein each R a are independently hydrogen or C1-C6 alkyl.

[0158] In some embodiments, the 5-6 membered heteroaryl is pyridinyl. In some embodiments, the 5-6 membered heteroaryl is In some embodiments, the 5-6 membered heteroaryl is oxazolyl. In some embodiments, the 5-6 membered heteroaryl is

[0159] 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 In some embodiments, R 2 is -(by one or two -OR 5 In some embodiments, R 2 is-(be-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 is -(C1-C6 alkylene)-S(O) n -(C1-C6 alkyl). In some embodiments, R 2 is -(C1-C6 alkylene)-CN. In some embodiments, R 2 Yes - (optionally OR 5 Substituted C1-C4 alkylene)-C(O)OR 5 In some embodiments, R 2 Yes - (optionally OR 5 Substituted C1-C4 alkylene)-C(O)N(R 6 )2. In some embodiments, R 2 is -(C1-C6 alkylene)-OP(O)(OR 5 )2. In some embodiments, R 2 is -(C1-C6 alkylene)-N(R6 )2.

[0160] In some embodiments, R 2 Selected from the group consisting of: -(one or two -OR 5 Substituted C1-C6 alkyl), -(C1-C6 alkylene)-S(O) n -(C1-C6 alkyl), -(optionally replaced by OR 5 Substituted C1-C4 alkylene)-C(O)OR 5 ,-(optionally OR 5 Substituted C1-C4 alkylene)-C(O)N(R 6 )2, -(C1-C6 alkylene)-N(R 6 R 7 )2, -(C1-C6 alkylene)-OP(O)(OR 5 )2, -(optionally OR 5 substituted C1-C4 alkylene)-(5-6 membered heteroaryl having one, two or three heteroatoms each independently selected from N, O and S) and -(C0-C4 alkylene)-(3-10 membered heterocyclyl having one, two, three or four heteroatoms each independently selected from N, O and S), wherein any of the aforementioned 5-6 membered heteroaryl and 3-10 membered heterocyclyl are optionally substituted by 1, 2, 3 or 4 substituents each independently selected from the group consisting of methyl, -NH2 and oxo.

[0161] In some embodiments, R 2 Selected from the group consisting of: -(one or two -OR 5 Substituted C1-C6 alkyl), -(C1-C6 alkylene)-N(R 6 R 7 )2 and -(optionally OR 5 substituted C1-C4 alkylene)-(5-6 membered heteroaryl having one, two or three heteroatoms each independently selected from N, O and S), wherein any of the aforementioned 5-6 membered heteroaryl and 3-10 membered heterocyclyl are optionally substituted by 1, 2, 3 or 4 substituents each independently selected from the group consisting of methyl, -NH2 and oxo.

[0162] In some embodiments, R 2 Selected from the group consisting of: methyl,

[0163]

[0164] In some embodiments, R 2 Selected from the group consisting of: methyl,

[0165] In some embodiments, R 2 Selected from the group consisting of: methyl,

[0166] In some embodiments, R 3 It is -C1-C6 haloalkyl.

[0167] In some embodiments, R 3 It is trifluoromethyl.

[0168] In some embodiments, R 3 In some embodiments, R 3 Yes -F.

[0169] In some embodiments, R 4 In some embodiments, R 4 In some embodiments, R 4 Yes -F.

[0170] In some embodiments, R 3 and R 4 With R 3 and R 4 The attached carbons together form a 3-7 membered carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more halogens. In some embodiments, the halogen is F.

[0171] In some embodiments, the compound is selected from Table 1:

[0172] Table 1. List of compounds.

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215] Pharmaceutical compositions and routes of administration

[0216] In certain embodiments, disclosed herein are pharmaceutical compositions comprising a compound disclosed herein (e.g., a compound of Formula (I), (I'), (Ia), (Ia'), (Ib), (Ic), (Ib-1), or (Ib-2)), or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable excipient. In some embodiments, the excipient is selected from the group consisting of inert solid diluents and fillers, diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers, and excipients. In some embodiments, the pharmaceutical composition is administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art.

[0217] In some embodiments, the pharmaceutical composition is administered in single or multiple doses by any accepted mode of administration for agents with similar utilities, e.g., as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal, and transdermal routes, by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent or, for example, an arterially inserted cylindrical polymer.

[0218] A mode of administration is parenteral, particularly by injection. In some embodiments, the form of the novel composition of the present disclosure incorporated therein for administration by injection comprises aqueous or oily suspension or emulsion, has sesame oil, corn oil, cottonseed oil or peanut oil, and elixir, mannitol, dextrose or sterile aqueous solution and similar pharmaceutical vehicles. The aqueous solution in saline is also usually used for injection, but is less preferred in the context of the present disclosure. In some embodiments, ethanol, glycerol, propylene glycol, liquid polyethylene glycol etc. (and suitable mixtures thereof), cyclodextrin derivatives and vegetable oils are used. In some embodiments, for example, by using a coating such as lecithin, by maintaining required particle size and by using a surfactant in the case of dispersion, suitable fluidity is maintained. In some embodiments, the effect of preventing microorganisms is realized by various antibacterial and antifungal agents, for example parabens, chlorobutanol, phenol, sorbic acid, thimerosal etc.

[0219] Sterile injectable solutions are prepared by mixing the desired amount of a compound according to the present disclosure with various other ingredients as enumerated above in an appropriate solvent, followed by filtration sterilization. Typically, dispersions are prepared by mixing various sterilized active ingredients into a sterile vehicle comprising a basic dispersion medium and the desired other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, preferred preparation methods are vacuum drying and freeze drying techniques, which produce powders from a sterile filtered solution of the active ingredient plus any additional desired ingredients.

[0220] Oral administration is another route of administration of the compound of the present disclosure. In some embodiments, administration is via capsules or enteric-coated tablets, etc. In some embodiments, when preparing a pharmaceutical composition comprising at least one compound described herein, the active ingredient is typically diluted by an excipient and / or encapsulated in such a carrier in the form of a capsule, pouch, paper or other container. In some embodiments, when an excipient is used as a diluent, it is in the form of a solid, semi-solid or liquid material (such as above), which is used as a vehicle, carrier or medium for the active ingredient. Therefore, in some embodiments, the composition is in the form of tablets, pills, powders, lozenges, pouches, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing, for example, up to 10% by weight of an active compound, soft gelatin capsules and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.

[0221] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, gum tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, sterile water, syrup and methylcellulose. In some embodiments, the formulations additionally comprise: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners; and flavoring agents.

[0222] In some embodiments, the compositions of the present disclosure are prepared by adopting procedures known in the art so that the quick, continuous or delayed release of active ingredients is provided after being used to the patient. The controlled release drug delivery system for oral administration includes an osmotic pump system and a reservoir containing a polymer coating or a dissolution system of a drug-polymer matrix formulation. The another preparation used in the method for the present disclosure adopts a transdermal delivery device (" patch "). In some embodiments, such a transdermal patch is used to provide a continuous or discontinuous infusion of a compound of the present disclosure of a controlled amount. The construction and use of the transdermal patch for delivering medicament are well known in the art. In some embodiments, such a patch is constructed for continuous, pulsed or on-demand delivery of medicament.

[0223] The composition is preferably formulated into a unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable for use as a single dose for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect in combination with a suitable pharmaceutical excipient (e.g., tablet, capsule, ampoule). The compound is typically administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains 1 mg to 2 g of the compound described herein, and for parenteral administration, preferably contains 0.1 mg to 700 mg of the compound described herein. However, it will be understood that the amount of the compound actually administered will typically be determined by the doctor based on the relevant circumstances, including the condition to be 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, etc.

[0224] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure. In some embodiments, when referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0225] In some embodiments, tablet or pill of the present disclosure are coated or otherwise compounded, to provide the dosage form with the advantage of prolonged effect, or to protect it from the acidic condition of stomach.For example, in some embodiments, tablet or pill comprise inner dosage component and outer dosage component, and the latter is in the form of the envelope covering the former.In some embodiments, two kinds of components are separated by enteric layer, and this enteric layer is used for resisting the disintegration in the stomach and allows inner component to enter duodenum intact or delay release.In some embodiments, multiple materials are used for such enteric layer or coating, and such material comprises the mixture of multiple polymeric acid and polymeric acid and the material such as shellac, cetyl alcohol and cellulose acetate.

[0226] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. In some embodiments, the liquid or solid composition contains a suitable pharmaceutically acceptable excipient as described above. In some embodiments, the composition is administered by oral or nasal respiratory route to obtain a local or systemic effect. In some embodiments, the composition in a pharmaceutically acceptable solvent is atomized by using an inert gas. In some embodiments, the atomized solution is inhaled directly from the atomizing device, or the atomizing device is attached to a face mask inhaler (facemask tent) or intermittent positive pressure breathing machine. In some embodiments, the solution, suspension or powder composition is administered orally or nasally from a device for delivering the formulation in an appropriate manner.

[0227] Treatment

[0228] In certain embodiments, disclosed herein are methods of treating a disease or disorder modulated by aberrant activity of a TEAD isoform (e.g., TEAD1 and / or TEAD4) (e.g., hyperactivation of the TEAD transcription complex) in an individual in need thereof, the method comprising administering to the individual a compound of Formula (I)-(II), (Ia)-(II), (Ia')-(Ib), (Ic)-(Ib-1), or (Ib-2), or a pharmaceutically acceptable salt thereof (e.g., a therapeutically effective amount of a compound of Formula (I)-(II), (Ia)-(Ia'), (Ib)-(Ic), (Ib-1), or (Ib-2), or a pharmaceutically acceptable salt thereof).

[0229] TEA domain transcription factors (TEADs) are downstream effectors of the Hippo signaling pathway. Currently, four TEAD isoforms have been identified: TEAD1, TEAD2, TEAD3, and TEAD4. 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-terminus contains a transactivation domain that recruits the transcriptional coactivators YAP / TAZ.

[0230] TEAD protein expression is upregulated in many cancer types, including gastric, colorectal, breast, and prostate cancers. TEAD hyperactivation plays a role in tumor progression, metastasis, cancer metabolism, immunity, and drug resistance, and is associated with poor patient survival.

[0231] Selective binding of TEAD1 and / or TEAD4 is beneficial for optimizing antitumor efficacy while minimizing undesirable effects. Inhibition of TEAD3 is associated with off-target toxicities (e.g., nephrotoxicity), while inhibition of TEAD2 may be pro-proliferative.

[0232] The TEAD isoform selectivity demonstrated by the compounds disclosed herein is superior to TEAD inhibitors known in the art. For example, as demonstrated by Tang and Post using a thermal shift assay, TEAD inhibitor VT3989 primarily interacts with TEAD1-TEAD3. The reported thermal shift data are provided in Table 2 below (Tang and Post, "The TEAD autopalmitoylation inhibitor VT3989 improves efficacy and increases durability of efficacy ofosimertinib in preclinical EGFR mutant tumor models," Proceedings of the American Association for Cancer Research Annual Meeting 2022; April 8-13, 2022. Philadelphia (PA): AACR; Poster #5364). The data provided in Table 2 show that VT3989 provides minimal selectivity for TEAD2 and TEAD3, which are TEAD isoforms that are not expected to be inhibited. In addition, VT3989 shows a lower level of binding to TEAD4, which is a TEAD isoform that is expected to be inhibited. Each change in ΔTm (°C) of 2.5°C can be associated with approximately a 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.).

[0233] Table 2. Thermal shift assays of TEAD isoforms 1-4 treated with the TEAD inhibitor VT3989 compared to an inactive analog control.

[0234] Isotype VT3989 Inactive analogs TEAD1ΔTm(℃) 11.6 0.2 TEAD2ΔTm(℃) 8.8 0.5 TEAD3ΔTm(℃) 8.5 0.2 TEAD4ΔTm(℃) 4.6 0.2

[0235] 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 greater than for TEAD2 and / or TEAD3. In some embodiments, the binding selectivity for TEAD4 is 10-fold, 100-fold, 1,000-fold, or 10,000-fold greater than for TEAD2 and / or TEAD3. Evidence of TEAD isoform selectivity demonstrated by the compounds disclosed herein is provided in Example 174 below.

[0236] In some embodiments, the compounds disclosed herein can be used as medical therapies for treating diseases, disorders, or conditions mediated by hyperactivation of YAP / TAZ-TEAD (e.g., TEAD1 and / or TEAD4) transcriptional coactivator complexes. In some embodiments, the compounds disclosed herein can be used as medical therapies for treating diseases, disorders, or conditions characterized by hyperactivation of TEAD (e.g., TEAD1, TEAD2, TEAD3, and TEAD4 isoforms). In some embodiments, the disease, disorder, or condition is characterized by overexpression or genomic fusion or amplification of TEAD. TEAD1 and TEAD4 undergo recurrent tumor fusion; for example, TEAD1-PARVA. These fusions drive higher expression of TEAD and can result in enhanced transcription of TEAD target genes. Amplification of TEAD4 (increased genomic copy number) occurs in a variety of cancers as part of the 12p13 locus, for example, in ovarian and uterine cancers and testicular germ cell tumors. These genomic amplifications of TEAD4 correlated with a robust increase in its mRNA expression and could drive high TEAD-YAP / TAZ transcriptional activity.

[0237] 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 abnormal 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.

[0238] 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 colorectal 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 colorectal 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.

[0239] In some embodiments, the present disclosure provides compounds of Formula (I), Formula (I'), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Ib-1), or Formula (Ib-2) for use in modulating TEAD activity. In some embodiments, the present disclosure provides pharmaceutically acceptable salts of compounds of Formula (I), Formula (I'), Formula (Ia), Formula (Ia'), Formula (Ib), Formula (Ic), Formula (Ib-1), or Formula (Ib-2) for use in modulating TEAD activity.

[0240] 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

[0241] The present disclosure is further illustrated in the following examples, which are provided for illustrative purposes only and are not intended to limit the present disclosure in any way.

[0242] abbreviation

[0243] Boc, tert-butyloxycarbonyl

[0244] DAST, diethylaminosulfur trifluoride

[0245] DBU, 1,8-diazabicyclo(5.4.0)undec-7-ene

[0246] DCC, dicyclohexylcarbodiimide

[0247] DCE, 1,1-dichloroethane

[0248] DCM, dichloromethane

[0249] DEA, diethanolamine

[0250] DEAD, diethyl azodicarboxylate

[0251] DIAD, diisopropyl azodicarboxylate

[0252] DIBAL, diisobutylaluminum hydride

[0253] DIPEA, N,N-diisopropylethylamine, Hünig's base

[0254] DMA, N,N-dimethylacetamide

[0255] DMAP, 4-(dimethylamino)pyridine

[0256] DMF, N,N-dimethylformamide

[0257] DMSO, dimethyl sulfoxide

[0258] EDC, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0259] EtOAc, ethyl acetate

[0260] h, hours

[0261] HATU, N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanium hexafluorophosphate N-oxide

[0262] HBTU, (1H-benzotriazol-1-yloxy)(dimethylamino)-N,N-dimethylformamidine hexafluorophosphate

[0263] HOBT, N-hydroxybenzotriazole

[0264] HPLC, high pressure liquid chromatography

[0265] LAH, lithium aluminum hydride

[0266] IPA, isopropyl alcohol

[0267] LCMS, liquid chromatography-mass spectrometry

[0268] LDA, lithium diisopropylamide

[0269] LiHMDS, lithium bis(trimethylsilyl)amide

[0270] mCPBA, meta-chloroperbenzoic acid

[0271] MI, molecular ion

[0272] Min, minutes

[0273] MW, microwave

[0274] NBS, N-bromosuccinamide

[0275] NCS, N-chlorosuccinamide

[0276] NFOBS, N-fluoro-o-benzenedisulfonimide

[0277] NFSI, N-fluorobenzenesulfonimide

[0278] NHS, N-hydroxysuccinimide

[0279] NIS, N-iodosuccinamide

[0280] NMM, N-methylmorpholine

[0281] NMP, 1-methyl-2-pyrrolidone

[0282] NMR, nuclear magnetic resonance

[0283] PdCl2(PPh3)2, bis(triphenylphosphine)palladium chloride

[0284] Pd(dppf)2Cl2, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0285] Pd(dppf)2Cl2.DCM, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride complex with DCM

[0286] (Pd(dba)2), bis(dibenzylideneacetone)palladium

[0287] Rbf, round bottom flask

[0288] RT, retention time

[0289] SCX-2, a silica-based adsorbent with chemically bonded propanesulfonic acid functional groups

[0290] SFC, supercritical fluid chromatography

[0291] TBAF, tetra-n-butylammonium fluoride

[0292] TBDMS, tert-butyldimethylsilyl

[0293] TFAA, trifluoroacetic anhydride

[0294] TFA, trifluoroacetic acid

[0295] THF, tetrahydrofuran

[0296] TPP, tripotassium phosphate

[0297] Ts, tosyl

[0298] XPhos-Pd-G1,2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride

[0299] XPhos-Pd-G2, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0300] Analytical methods

[0301] Commercially available starting materials, reagents, and dry solvents were used as supplied. Flash column chromatography or glass column chromatography was performed using Merck silica gel of 230-400 mesh size. Flash chromatography was also performed on a combi-flash RF Teledyne Isco machine. Preparative TLC was performed on Merck plates.

[0302] Liquid chromatography-mass spectrometry

[0303] Method-A

[0304] Method name: UC02_FAR1, Machine details: Water Acquity UPLC-H Class, equipped with PDA and Acquity SQ detector, Column: Waters X-bridge C18, 50*2.1 mm, 2.5 μm, 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 change to T=2.7 min (2% A, 98% B) Flow rate: 0.8 mL / min; Gradient change to 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 change to T = 3.51 min (97% A, 3% B) flow rate: 0.8 mL / min; End 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: -200-500 nm; Quality 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 rate: -100 L / hour, Desolvation gas flow rate: -800 L / hour.

[0305] Method B

[0306] 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 (pH=8.00) in Milli Q water, 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 change to T=2.70 min (20% A, 80% B) flow rate=1.0 ml / min; Gradient change to T=3.0 min (0% A, 100% B) flow rate=1.2 ml / min; T=3.50 min (0% A, 100% B) flow = 1.2 ml / min; T = 3.51 min (97% A, 3% B) flow = 1.0 ml / min; end run at T = 4.0 min (97% A, 3% B) flow = 1.0 ml / min, run time: -4 min, UV detection method: -PDA, wavelength: -195 nm -500 nm; quality parameters: probe: -ESI, ionization mode: -positive and negative, cone voltage: -30 V 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.

[0307] High-performance liquid chromatography

[0308] Method-A

[0309] Method name: HP04_BR1, Machine details: Water alliance e2695 with 2998 PDA 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 change to T = 9 min (100% A, 0% B) flow rate: 1 mL / min; Gradient change to T = 14 min (100% A, 0% B) flow rate: 1 mL / min; T = 14.01 min (10% A, 90% B) flow rate: 1 mL / min; Gradient change to T = 17 min (10% A, 90% B) flow rate: 1 mL / min; End run at T = 17 min (10% A, 90% B), flow rate: 1 mL / min, running time: -17 min, UV detection method: -PDA.

[0310] Method-B

[0311] 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; gradient change to T = 9 min (0% A, 100% B) flow rate: 1 mL / min; gradient change to T = 14 min (0% A, 100% B) flow rate: 1 mL / min; T = 14.01 min (90% A, 10% B) flow rate: 1 mL / min; gradient change 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.

[0312] Method-C

[0313] 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; Gradient change to T = 9 min (0% A, 100% B) flow rate: 1 mL / min; Gradient change to T = 14 min (0% A, 100% B) flow rate: 1 mL / min; T = 14.01 min (90% A, 10% B) flow rate: 1 mL / min; Gradient change 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.

[0314] NMR

[0315] Unless otherwise stated, all analyses were performed using a Bruker Avance-400 instrument operating at 400 MHz and the stated solvents at room temperature. 1 H nuclear magnetic resonance (NMR) spectroscopy. Samples were prepared as solutions in suitable deuterated solvents and referenced to suitable internal non-deuterated solvent peaks or tetramethylsilane. Chemical shifts were recorded in ppm (δ) downfield from tetramethylsilane. In all cases, the NMR data were consistent with the proposed structure. Characteristic chemical shifts (δ) are given in parts per million, using conventional abbreviations for indicating major peaks: for example, s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublet; dt, doublet of triplet; m, multiplet; br, broad.

[0316] Purification method

[0317] Preparative purification by reverse phase HPLC

[0318] Preparative HPLC Method-A

[0319] Biotage-FC-01, with binary pump, with 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 change to t=25 min (55% A, 45% B); t=35 min (0% A, 100% B); gradient change to t=45 min (100% A, 0% B) at the end of the run; flow rate: 80 mL / min, analysis time 45 min.

[0320] synthesis

[0321] Several chemical synthesis methods of the compounds of the present application are described herein. These methods and / or other well-known methods can be modified and / or adjusted in various ways to promote the synthesis of other compounds within the scope of the present application and claims. Such selectable methods and modifications should be understood to be within the spirit and scope of the present application and claims. Therefore, the methods set forth in the following description, schemes, and examples are intended to be used for illustrative purposes and should not be construed as limiting the scope of this disclosure.

[0322] In one method (Scheme 1), the compound of formula [IIb] can be prepared by reacting a substituted Het-aromatic carboxylic acid of formula [II] with an amide coupling reagent such as HATU in DMF or DCM as a solvent with an amine of general formula [III] in the presence of a tertiary amine base such as DIPEA. The reaction is suitably carried out at RT. After post-reaction treatment (usually by liquid-liquid extraction), the reaction product is purified by flash column chromatography, reversed-phase preparative HPLC or recrystallization (Method A).

[0323] Plan-1

[0324]

[0325] The following compounds were prepared according to the methods described above using the indicated intermediates.

[0326] Example 1 - Synthesis of N-isopropyl-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 1)

[0327]

[0328] Step-1a:

[0329] In a 250mL three-necked RB flask, to 4-(trifluoromethyl)cyclohexane-1-one CAS number: 75091-99-5 (0.5g, 3.01mmol, 1.0 equivalent) in THF (31.5mL) at -78 DEG C of stirring over a period of 30min, lithium bis(trimethylsilyl)amide (3.6mL, 3.61mmol, a 1M solution in THF) was added dropwise, then allowed to continue stirring at -78 DEG C for another 1h, after 1h, a solution of N-phenyltrifluoromethanesulfonyl imide (1.0g, 3.01mmol, 1.0 equivalent) in THF (4mL) was added dropwise over a period of 30min under stirring. The reaction mixture was then stirred at -78 DEG C for another 2h, and slowly warmed to room temperature over a period of 6h under stirring. The reaction was monitored on TLC (using EA: hexane; 0.1: 9.9 as mobile phase), which confirmed that the reaction was complete after stirring at room temperature for 6h. The reaction mixture was extracted with EtOAc (3 × 10mL). The combined organic extracts were washed with water, dried over Na2SO4 and filtered. The filtrate was evaporated, and the residue was purified by silica gel column chromatography (10% EtOAc in hexane) to produce 4- (trifluoromethyl) cyclohex-1-ene-1-yl trifluoromethanesulfonate (A1, 0.45g, 1.509mmol, yield: 50.14%) as a white solid.

[0330] 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: There is a trace amount of aliphatic impurity of PhN(OTf)2.

[0331] Step-1b:

[0332] In a 250 mL three-necked RB flask, to a solution of 4-(trifluoromethyl)-cyclohex-1-enyl trifluoromethanesulfonate CAS: 73183-34-3 (A1, 0.1 g, 0.335 mmol, 1.0 eq) in dioxane (3.8 mL) was added bis(pinacolato)diboron (0.102 g, 0.402 mmol, 1.2 eq), potassium acetate (0.109 g, 1.11 mmol, 3.0 eq), PdCl2(dppf) (0.074 g, 0.100 mmol, 0.3 eq) under a nitrogen atmosphere. The reaction mixture was heated at 80° C. with stirring for 16 h, and the reaction was monitored on TLC (using EA: hexane; 1:9 as mobile phase), which confirmed that the reaction was complete after stirring at 80° C. for 16 h, and then cooled to room temperature and filtered through a celite bed. The filtrate was evaporated in vacuo, and the residue was purified by silica gel column chromatography (10% EtOAc / hexanes) 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%).

[0333] 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: A small amount of aliphatic impurities was observed.

[0334] Step-1:

[0335] By 8-bromoquinoline-3-methyl formate (A13, 5.0g, 18.791mmol, 1.0 equivalent) and NaOH (1.5g, 37.581mmol, 2.0 equivalent) in methanol and water (50mL, 9: 1) solution stirring at room temperature for 2h.Reactant mixture is acidified with 1N HCl (40mL; pH=3), and allowed to stir at 0 DEG C for 30 minutes, to provide light yellow solid.By TLC (using EA: hexane; 3: 7 as mobile phase) monitoring reaction, this confirmed that after stirring at room temperature for 2h, complete.The resulting solid is filtered with high vacuum, and produces 8-bromoquinoline-3-formic acid (A3, 4.13g, 16.38mmol, yield: 87.20%).

[0336] 1H NMR (DMSO-d6, 400MHz): δppm 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)

[0337] LCMS (method A): 1.736 min, 100.0%, MS: ES+252.00 [M] +

[0338] Step-2:

[0339] In 250mL three-necked RB flask, by 8-bromoquinoline-3-formic acid (A3, 4.0g, 15.873mmol, 1.0 equivalent), isopropylamine CAS number: 75-31-0 (1.19g, 15.873mmol, 1.0 equivalent) and DIPEA (6.2g, 47.62mmol, 3.0 equivalent) and HATU (6.59g, 17.46mmol, 1.1 equivalent) in DMF (40mL, 10v), stirring at room temperature continues 16h. On TLC (using EA: hexane; 1: 1 is as mobile phase), upper monitoring reaction, this confirmed that after stirring at room temperature 16h, reaction is completed. Obtained reaction mixture is diluted with ice-cold water (200mL) and allowed to stir and continue 1h. The obtained yellow 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%).

[0340] 1 H NMR(DMSO-d6,400MHz): δppm 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).

[0341] LCMS (method A): 1.852 min, 100.0%, MS: ES+293.01 [M+H]

[0342] Step-3:

[0343] 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) was added potassium phosphate (1.21 g, 12.28 mmol, 3.0 equiv) and purged with nitrogen for 30 min, followed by the addition of Pd(dppf)Cl (0.94 g, 0.819 mmol, 0.2 equiv) and the resulting reaction mixture was heated at room temperature up to 100 °C for 16 h. At 4 DEG C, 1h 20min, 1h 20min and 1h 20min, stir in 40min, stir 5min, stir 1h, stir 2h, stir 3h, stir 5min.Then, add 4-isopropyl-8-(4-(trifluoromethyl)cyclohex-1-ene-1-yl)quinoline-3-carboxamide (compound 1,1.0g, 2.759mmol, yield: 67.57%).

[0344] 1 H NMR (DMSO-d6, 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: The CF3-CH3 protons merge with the DMSO solvent peak, which is clearly observed in the MeOD NMR.

[0345] 1H 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 are exchanged in MeOD.

[0346] LCMS (method A): 2.239 min, 96.73%, MS: ES+363.10 [M+H]

[0347] HPLC (Method B): 8.327 min, 97.65%, @254 nm.

[0348] Example 2 - Synthesis of N-((S)-1-hydroxypropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 2)

[0349]

[0350] Step-1:

[0351] 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 K PO (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 on TLC (using EA: hexane; 7.0: 3.0 as mobile phase), which confirmed that the reaction was 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 Na SO and concentrated under reduced pressure to provide 0.3 g (crude) 8-(4-(trifluoromethyl)cyclohex-1-ene-1-yl)quinoline-3-carboxylic acid (A5, 0.3 g, 0.934 mmol, yield: crude). Note: the crude compound was used in the next step as is without further purification.

[0352] LCMS (Method A): 2.464 min, 86.69%, 254.0 nm, MS: ES+322.11 (M+1)

[0353] Step-2:

[0354] 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 an N atmosphere for 20 min, and then CAS: 40154-78-7 (0.2 g, 1.027 mmol, 1.1 equiv) was added under nitrogen. The resulting mixture was stirred at room temperature for 5 h. The reaction was monitored on TLC (using EA: hexane; 7.0: 3.0 as the mobile phase), which confirmed that the reaction was complete 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 provide 0.5 g of crude product. The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) as the stationary phase (45% EtOAc in hexane) to produce N-((S)-1-(pyridin-2-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-ene-1-yl)quinoline-3-carboxamide (compound 2, 0.065 g, 0.152 mmol, yield: 12.84% (yield over 2 steps)).

[0355] 1 H NMR(DMSO-d6,400MHz): δppm,9.29(br s,1H),9.19(d,J=7.6Hz,1H),8.89(brs,1H),8.54(d,J=4.4Hz,1H),8.02(t,J=4. 4Hz,1H),7.78(t,J=7.2Hz,1H),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,1 H), 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).

[0356] 1H NMR (MeOD, 400MHz): δppm, 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).

[0357] LCMS (Method A): 2.295 min, 100%, 254.0 nm, MS: ES+426.23 (M+1)

[0358] HPLC (Method B): 6.213 min, 99.75%, 254.0 nm

[0359] Chiral HPLC: 2.28 min, 100%, 245.0 nm

[0360] 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)

[0361]

[0362] Step-1:

[0363] 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 min, and then 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 h. The reaction was monitored on TLC (using EA: hexane; 8:2 as the mobile phase), which confirmed that the reaction was complete after 16 h. The resulting reaction mixture was quenched with water (10 mL) and extracted with DCM (3×25 mL). The combined organic layers were dried over Na SO and concentrated under reduced pressure to provide 0.3 g of crude product. The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) as the stationary phase (50% ethyl acetate in hexane as a gradient) to produce N-((S)-1-(6-bromopyridin-2-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-ene-1-yl)quinoline-3-carboxamide (A6, 0.21 g, 0.416 mmol, yield: 44%).

[0364] 1 H NMR (DMSO-d 6 ,400MHz): δ9.28-9.25(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)

[0365] LCMS (Method A): 2.817 min, 95.22%, 254.0 nm, MS: ES+506.04 (M+2)

[0366] Step-2:

[0367] 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 CsCO (0.360 g, 1.11 mmol, 3.0 equiv) in dioxane (10 mL) was prepared at RT. The resulting mixture was purged with nitrogen for 5 min, 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. In 40 DEG C of 40 DEG C, 1H-dextrin ...

[0368] 1 H NMR (DMSO-d6, 400MHz): δppm, 9.75 (s, 1H), 9.33 (d, J = 1.6Hz, 1H), 9.07 (d, J = 7.6Hz, 1H), 8 .89(d,J=2.4Hz,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)

[0369] LCMS (Method A): 2.977 min, 96.51%, 254.0 nm, MS: ES+541.3 (M+1)

[0370] Step-3:

[0371] 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 [4M] (5 mL) in dioxane at RT under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC (using EA:hexane; 1:1 as mobile phase), which confirmed that the reaction was complete after 16 h. The resulting reaction mixture was concentrated under reduced pressure to provide 0.15 g of the crude product as the HCl salt. The crude material was purified by reverse phase preparative HPLC (Method-A 0.1% formic acid in water / acetonitrile) to afford the desired N-((S)-1-(6-aminopyridin-2-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide formate (Compound 3, 0.043 g, 0.097 mmol, yield: 35.24%).

[0372] 1 H NMR(DMSO-d6,400MHz): δppm,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: -NH2 protons are not visible and the compound is in the form of a formate salt.

[0373] 1H NMR (MeOD, 400MHz): δppm, 9.28 (d, J = 2.4Hz, 1H), 8.86 (d, J = 2.4Hz, 1H), 7.99 (dd, J = 8.0, 1.6Hz, 1H), 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 NH2 protons are not visible and the compound is in the form of a formate salt.

[0374] LCMS (Method B): 2.98 min, 99.60%, 254.0 nm, MS: ES+ 441.07 (M+1).

[0375] HPLC (Method A): 8.772 min, 99.60%, 254.0 nm

[0376] Chiral HPLC: 3.76 min, 100%, 240.0 nm

[0377] Example 4 - Synthesis of N-((S)-1-hydroxypropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 4)

[0378]

[0379] Step-1:

[0380] To 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) stirred at 0° C. under a nitrogen atmosphere for 30 min was added CAS: 2749-11-3 (0.043 g, 0.582 mmol, 1.1 equiv). The resulting mixture was stirred at room temperature for 3 h. The reaction was monitored by TLC (using 100% ethyl acetate as the mobile phase), which confirmed that the reaction was complete after 3 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 Na SO and concentrated under reduced pressure to provide 0.22 g of crude product. The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) as the stationary phase (80% ethyl acetate in hexane as a gradient) to produce 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%).

[0381] 1 H NMR (DMSO-d6, 400MHz): δppm, 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=6.0Hz,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-CH protons merge with the DMSO solvent peak, which is clearly observed in the MeOD NMR spectrum.

[0382] 1H NMR (MeOD, 400MHz): δppm, 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=5.6Hz,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=6.8Hz,3H). Note: -OH and -NH protons can be exchanged in MeOD.

[0383] LCMS (Method A): 2.236 min, 99.62%, 254.0 nm, MS: ES+379.12 (M+1)

[0384] HPLC (Method A): 7.941 min, 99.26%, 254.0 nm

[0385] Chiral HPLC: 4.73 min, 50.10%, 240.0 nm; 5.10 min, 49.48%, 240.0 nm

[0386] Example 5 - Synthesis of N-(pyridin-2-ylmethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 5)

[0387]

[0388] Step-1:

[0389] To 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) stirred at 0 ° C. under a nitrogen atmosphere for 15 min was added CAS: 3731-51-9 (0.055 g, 0.513 mmol, 1.1 equiv). The resulting mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC (using 100% ethyl acetate as mobile phase), which confirmed that the reaction was complete after 16 h. The resulting reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to provide 0.20 g of crude product. The obtained crude material was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (70% ethyl acetate in hexane as a gradient) to produce 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%).

[0390] 1 H NMR (DMSO-d6, 400MHz): δppm 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)

[0391] 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)

[0392] LCMS (Method A): 2.145 min, 99.27%, 254.0 nm, MS: ES+ 412.17 (M+1)

[0393] HPLC (Method A): 8.707 min, 98.45%, 254.0 nm

[0394] Example 6 - Synthesis of N-((S)-1-methoxyprop-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 6)

[0395]

[0396] Step-1:

[0397] 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 min, and then 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 h. The reaction was monitored by TLC (using 100% ethyl acetate as mobile phase), which confirmed that the reaction was complete after 3 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 Na2SO4 and concentrated under reduced pressure to provide 0.22 g of crude product. The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) as the stationary phase (70% ethyl acetate in hexane as a gradient) to produce N-((S)-1-methoxyprop-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 6, 0.063 g, 0.160 mmol, yield: 34.38%).

[0398] 1 H NMR (DMSO-d6, 400MHz): δppm, 9.24 (d, J = 2.0Hz, 1H), 8.80 (d, J = 2.0Hz, 1H), 8.60(d,J=8.0Hz,1H),8.02-7.99(m,1H),7.64-7.61(m,2H),5.87(s,1H),4 .29-4.23(m,1H),3.47-3.43(m,1H),3.34-3.31(m,1H),3.30(s,3H),2.80- 2.77(m,1H),2.72-2.68(m,2H),2.50-2.46(m,1H),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).

[0399] 1H NMR (MeOD, 400MHz): δppm, 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).

[0400] LCMS (Method A): 2.505 min, 98.87%, 254.0 nm, MS: ES+393.17 (M+1)

[0401] HPLC (Method A): 9.078 min, 98.54%, 254.0 nm

[0402] Chiral HPLC: 5.31 min, 50.73%, 240.0 nm; 5.63 min, 49.26%, 240.0 nm.

[0403] Example 7 - Synthesis of N-((R)-1-hydroxypropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 7)

[0404]

[0405] Step-1:

[0406] To 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) stirred at 0° C. under a nitrogen atmosphere for 20 min was added CAS: 35320-23-1 (0.042 g, 0.560 mmol, 1.2 equiv). The resulting mixture was stirred at room temperature for 3 h. The reaction was monitored on TLC (using 100% EtOAc as the mobile phase), which confirmed that the reaction was complete after 3 h. 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 Na2SO4 and concentrated under reduced pressure to provide 0.3 g of crude product. The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) as the stationary phase (70% ethyl acetate in hexane as a gradient) to produce N-((R)-1-hydroxypropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 7, 0.097 g, 0.256 mmol, yield: 54.91%).

[0407] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[0408] 1H NMR (MeOD, 400MHz): δppm, 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).

[0409] LCMS (Method A): 2.237 min, 100%, 254.0 nm, MS: ES+379.1 (M+1)

[0410] HPLC (Method A): 7.930 min, 100%, 254.0 nm

[0411] Chiral HPLC: 6.17 min, 49.36%, 6.99 min, 50.32%, 240.0 nm

[0412] 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)

[0413]

[0414] Step-1:

[0415] To 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) stirred at 0 ° C. under a nitrogen atmosphere for 10 min was added CAS: 53332-67-5 (0.094 g, 0.513 mmol, 1.1 equiv). The resulting mixture was stirred at room temperature for 3 h. The reaction was monitored by TLC (using MeOH:DCM; 1.0:9.0 as the mobile phase), which confirmed that the reaction was complete after 3 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 Na2SO4 and concentrated under reduced pressure to provide 0.223 g of crude product. The crude material obtained was purified by flash column chromatography using silica gel (230-400 mesh) as the stationary phase (5% methanol in DCM) to produce 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%).

[0416] 1 H NMR(DMSO-d6,400MHz): δppm,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)

[0417] 1H NMR (MeOD, 400MHz): δppm, 9.27 (d, J = 2.4Hz, 1H), 8.81 (d, J = 2.0Hz, 1H), 7.96 (dd, J = 7. 6,2.0Hz,1H),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)

[0418] LCMS (Method A): 1.892 min, 100.0%, 210.0 nm, MS: ES+415.1 (M+1)

[0419] HPLC (Method A): 8.081 min, 98.59%, 210.0 nm

[0420] Example 9 - Synthesis of N-((R)-1-methoxyprop-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 9)

[0421]

[0422] Step-1:

[0423] To 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) stirred at 0 ° C. under a nitrogen atmosphere for 15 min was added CAS: 626220-76-6 (0.064 g, 0.513 mmol, 1.1 equiv). The resulting mixture was stirred at room temperature for 3 h. The reaction was monitored by TLC (using 100% EtOAc as the mobile phase), which confirmed that the reaction was complete after 3 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 Na2SO4 and concentrated under reduced pressure to provide 0.180 g of crude product. The crude material obtained was purified by trituration with ACN to produce N-((R)-1-methoxyprop-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 9, 0.121 g, 0.308 mmol, yield: 66.05%).

[0424] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[0425] 1H NMR (MeOD, 400MHz): δppm, 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).

[0426] LCMS (Method A): 2.480 min, 100.0%, 254.0 nm, MS: ES+393.17 (M+1)

[0427] HPLC (method A): 9.068 min, 98.51, 210.0 nm

[0428] Chiral HPLC: 4.64 min and 4.93 min, 49.45% and 50.54%, 240.0 nm

[0429] 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)

[0430]

[0431] Step-1:

[0432] To 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) stirred at 0 ° C. under a nitrogen atmosphere for 15 min was added CAS: 2173991-88-1 (0.094 g, 0.513 mmol, 1.1 equiv). The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC (using MeOH:DCM; 1.0:9.0 as mobile phase), which confirmed that the reaction was complete after 2 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 Na2SO4 and concentrated under reduced pressure to provide 0.194 g of crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (70% ethyl acetate in hexane as a gradient) to produce 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%).

[0433] 1 H NMR (DMSO-d6, 400MHz): δppm, 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(brs,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: The aliphatic 2 protons merge with the DMSO solvent peak, which is clearly visible in the MeOD NMR.

[0434] 1H NMR (MeOD, 400MHz): δppm, 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).

[0435] LCMS (Method A): 2.331 min, 100.0%, 210.0 nm, MS: ES+415.1 (M+1)

[0436] HPLC (Method A): 8.273 min, 98.67%, 210.0 nm

[0437] Example 11 - Synthesis of N-(oxazol-2-ylmethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 11)

[0438]

[0439] Step-1:

[0440] To 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) stirred at 0 ° C. under a nitrogen atmosphere for 20 min was added CAS: 1041053-44-4 (0.075 g, 0.560 mmol, 1.2 equiv). The resulting mixture was stirred at room temperature for 3 h. The reaction was monitored by TLC (using EtOAc: hexane; 8:2 as the mobile phase), which confirmed that the reaction was complete after 3 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 Na2SO4 and concentrated under reduced pressure to provide 0.2 g of crude product. The obtained crude material was purified by flash column chromatography using silica gel (230-400 mesh) as the stationary phase (75% ethyl acetate in hexane as a gradient) to produce 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%).

[0441] 1 H NMR(DMSO-d6,400MHz): δppm,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=5.6Hz,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 merge with the DMSO solvent peak, which is clearly visible in the MeOD NMR.

[0442] 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 (brs, 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 are exchanged in MeOD NMR.

[0443] LCMS (Method A): 2.341 min, 99.58%, 220.0 nm, MS: ES+402.07 (M+1)

[0444] HPLC (Method A): 8.385 min, 98.13%, 210.0 nm

[0445] Example 12 - Chiral Separation of N-(Oxazol-2-ylmethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 12 and Compound 13)

[0446]

[0447] program:

[0448] Compound 11 (0.025 g) racemate was subjected to chiral SFC purification on a (CHIRALPAK IG 250×10 mm 5 μm) column, where two peaks were separated: Peak 1 (0.007 g, yield = 28.00%) was compound 12, and Peak 2 (0.004 g, yield = 16.00%) was compound 13.

[0449] Column ID: CHIRALPAK IG, 250×10 mm, 5 μm

[0450] Mobile phase A: liquid CO2

[0451] Mobile phase B: 0.1% methanolic ammonia in IPA-ACN (70-30)

[0452] Flow rate (ML / MIN): 14

[0453] Instrument ID: SFC INVESTIGATOR

[0454] Method: Time: Flow: %A:%B (0:14:60:40), (7:14:60:40)

[0455] Compound 12:

[0456] 1 H NMR (DMSO-d6, 400MHz): δppm, 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)

[0457] LCMS (Method A): 2.368 min, 97.96%, 254.0 nm, MS: ES+402.2 (M+1)

[0458] HPLC (Method A): 8.461 min, 98.53%, 254.0 nm

[0459] Compound 13:

[0460] 1 H NMR (DMSO-d6, 400MHz): δppm, 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)

[0461] LCMS (Method A): 2.367 min, 98.83%, 254 nm, MS: ES+402.1 (M+1)

[0462] HPLC (Method A): 8.481 min, 99.19%, 254.0 nm

[0463] Example 13-Synthesis of 3-(methylsulfinyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline (Compound 14)

[0464]

[0465] Step-1:

[0466] To a stirred solution of 8-bromoquinoline CAS: 16567-18-3 (5.0 g, 23.96 mmol, 1.0 eq) in acetonitrile (50 mL) was added iodine (12.16 g, 47.93 mmol, 2.0 eq) and TBHP (70% aqueous solution), followed by CAS: 75-91-2 (30.93 mL, 240.3 mmol, 10.0 eq). The resulting mixture was stirred at 80 ° C for 16 h. The reaction was monitored on TLC (using EtOAc: hexane; 1.0: 9.0 as the mobile phase), which confirmed that the reaction was 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 Na SO and concentrated under reduced pressure to provide 5.5 g of crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) as stationary phase (1% EtOAc in hexanes) to give 8-bromo-3-iodoquinoline (A8, 4.1 g, 12.27 mmol, yield: 51.09%).

[0467] 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)

[0468] LCMS (Method A): 2.516 min, 97.70%, 254.0 nm, MS: ES-336.0 (M+2)

[0469] Step-2:

[0470] To a stirred solution of 8-bromo-3-iodoquinoline (A8, 4.0 g, 11.98 mmol, 1.0 equivalent) in toluene (40 mL) was added CAS: 5188-07-8 (1.17 g, 16.77 mmol, 1.4 equivalents) under N2. The resulting mixture was stirred at 80 ° C for 3 h. The reaction was monitored on TLC (using EA: n-hexane; 1.0: 9.0 as mobile phase), which confirmed that the reaction was complete after stirring at 80 ° C for 3 h. The resulting reaction mixture was quenched with cold water (40 mL) to precipitate a crude product, which was filtered off and washed with 50 mL of water and dried under reduced pressure to provide 2.9 g of crude product. The obtained crude material was triturated with n-hexane to produce 8-bromo-3-(methylthio)quinoline (A9, 2.5 g, 9.84 mmol, yield: 84.13%).

[0471] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[0472] LCMS (Method A): 2.295 min, 95.98%, 254.0 nm, MS: ES+256.10 (M+2)

[0473] Step-3:

[0474] To a stirred solution of 8-bromo-3-(methylthio)quinoline (A9, 1.5 g, 5.90 mmol, 1.0 equivalent) in DCM (15 mL) was added m-CPBA (1.52 g, 8.85 mmol, 1.5 equivalents) at 0 ° C under N2. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored on TLC (using EtOAc: hexane; 7.0: 3.0 as mobile phase), which confirmed that the reaction was complete after stirring at room temperature for 2 h. 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 Na2SO4 and concentrated under reduced pressure to provide 1.5 g of crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) as stationary phase (2% MeOH in DCM) to yield 8-bromo-3-(methylsulfinyl)quinoline (A10, 0.55 g, 2.04 mmol, yield: 34.50%).

[0475] 1H NMR (DMSO-d6, 400MHz): δppm, 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).

[0476] LCMS (Method A): 1.553 min, 96.36%, 254.0 nm, MS: ES+272.00 (M+2)

[0477] Step-4:

[0478] To a stirred solution of 8-bromo-3-(methylsulfinyl)quinoline (A10, 0.25 g, 0.925 mmol, 1.0 eq), 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 eq) and NaCO (0.29 g, 2.776 mmol, 3.0 eq) in dioxane (2.0 mL) and water (0.5 mL) was added Pd(dppf)Cl.DCM (0.075 g, 0.092 mmol, 0.1 eq) under N. The resulting mixture was stirred at 100° C. for 3 h. By TLC (using EA: hexane; 7.0: 3.0 as mobile phase) monitoring reaction, this confirmed that after stirring 3h at 100 ℃, the reaction was complete. The resulting reaction mixture was diluted with water (10mL) and extracted with EtOAc (3 × 20mL). The combined organic layer was dried over Na SO and concentrated under reduced pressure to provide 0.4g crude product. The crude material obtained was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase (75% ethyl acetate in n-hexane), producing 3-(methylsulfinyl)-8-(4-(trifluoromethyl) cyclohex-1-ene-1-yl) quinoline (compound 14, 0.07g, 0.206mmol, yield: 22.78%).

[0479] 1H NMR (DMSO-d6, 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: CF3-CH3 merges with the DMSO solvent peak, which is clearly observed in the MeOD NMR.

[0480] 1 H 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: A small amount of aliphatic impurities was observed.

[0481] LCMS (Method A): 2.357 min, 97.92%, 254.0 nm, MS: ES+340.06 (M+1)

[0482] HPLC (Method A): 8.493 min, 98.25%, 254.0 nm

[0483] Example 14-Synthesis of 8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxylic acid (Compound 15)

[0484]

[0485] Step-1:

[0486] At 0 ° C, to a solution of 2-amino-3-bromobenzoic acid (CAS: 20776-51-6) (5.0 g, 23.145 mmol, 1.0 equivalent) in THF (20 mL) was added BH .THF (1 M in THF, 81.0 mL, 81.007 mmol, 3.5 equivalents). The mixture was stirred at 70 ° C for 12 h. The reaction was monitored on TLC (using EtOAc as a mobile phase), which confirmed that the reaction was complete after stirring at 70 ° C for 12 h. The reaction mixture was then quenched with MeOH, filtered and concentrated under reduced pressure to obtain a crude product. The residue was stirred with water (100 mL) and filtered. The residue was dissolved in DCM and dried over Na SO , 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.

[0487] 1 H 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 impurities was observed.

[0488] LCMS (Method A): 1.667 min, 98.41%, 254.0 nm, MS: ES+202.0 (M), 204.0 (M+2)

[0489] Step-2:

[0490] To a solution of (2-amino-3-bromo-phenyl)methanol (A11, 4.4 g, 21.78 mmol, 1 eq) in DCM (40 mL) was added MnO 2 (18.93 g, 232.40 mmol, 10 eq). The mixture was stirred at room temperature for 12 h. The reaction was monitored on TLC (using EA: hexane; 6.0: 4.0 as mobile phase), which confirmed that the reaction was complete after stirring at room temperature for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give 2-amino-3-bromobenzaldehyde (A12, 3.5 g, 17.50 mmol, yield: 78.75%).

[0491] 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.

[0492] LCMS (Method A): 1.966 min, 98.98%, 254.0 nm, MS: ES+200.0 (M), 201.99 (M+2)

[0493] Step-3:

[0494] To a solution of A12 (380 mg, 1.8996 mmol, 1 eq) in EtOH (4 mL) was added L-proline (109 mg, 0.9498 mmol, 0.5 eq) and CAS 922-67-80 (0.22 mL, 2.4695 mmol, 1.3 eq). The mixture was stirred at 80 ° C for 16 h. The reaction was monitored on TLC (using EtOAc: hexane as the mobile phase), which confirmed that the reaction was 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).

[0495] 1 H NMR (CDCl3, 400MHz): δppm, 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).

[0496] LCMS (Method B): 2.61 min, 100%, 254.0 nm, MS: ES+268.02 (M+2)

[0497] Step-4:

[0498] 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 K3PO4 (1.59 g, 7.516 mmol, 2.0 equiv) in dioxane (7 mL) and water (3 mL) under N2 was added Pd(dppf)Cl2 .The obtained mixture was stirred at 100 ° C for 2 h. The reaction was monitored on TLC (using EtOAc: hexane; 2.0: 8.0 as mobile phase), which confirmed that the reaction was complete after stirring at 100 ° C for 2 h. The obtained reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to provide 1.2 g of crude product. The crude material obtained was purified by flash column chromatography using silica gel (230-400 mesh) as a stationary phase (55% EtOAc in hexane) to produce 8- (4- (trifluoromethyl) cyclohex-1-ene-1-yl) quinoline-3-carboxylic acid methyl ester (A14, 0.72 g, 2.147 mmol, yield: 57.20%).

[0499] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[0500] LCMS (Method A): 2.903 min, 100.0%, 210.0 nm, MS: ES+336.06 (M+1)

[0501] Step-5:

[0502] 8-(4-(trifluoromethyl)cyclohex-1-ene-1-yl)quinoline-3-formic acid methyl ester (A14, 1.0 g, 2.982 mmol, 1.0 equivalent) and NaOH (0.59 g, 14.912 mmol, 5.0 equivalent) in MeOH:HO (10 mL, 7:3) were 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 EtOAc: hexane; 6.0: 4.0 as mobile phase), which confirmed that the reaction was complete after 4 h. The resulting reaction mixture was concentrated under reduced pressure, and the obtained residue was poured into ice water, then filtered to provide the desired product 8-(4-(trifluoromethyl)cyclohex-1-ene-1-yl)quinoline-3-formic acid (compound 15, 0.8 g, 2.489 mmol, yield: 83.83%).

[0503] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[0504] 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 are exchanged with MeOD.

[0505] LCMS (Method A): 2.475 min, 100.0%, 254.0 nm, MS: ES+322.06 (M+1)

[0506] HPLC (Method A): 4.280 min, 99.77%, 254.0 nm

[0507] Example 15-Synthesis of 3-(methylsulfonyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline (Compound 16)

[0508]

[0509] Step-1:

[0510] Under N2, meta-chloroperbenzoic acid (2.10 g, 11.80 mmol, 3.0 equivalents) was added to a stirred solution of 5-bromo-3-(methylthio)quinoline (A9, 1.0 g, 3.934 mmol, 1.0 equivalents) in DCM (25 mL). The resulting mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC (using EA: hexane; 1.0: 1.0 as mobile phase), which confirmed that the reaction was complete after stirring at room temperature for 16 h. The resulting reaction mixture was diluted with saturated sodium bicarbonate aqueous solution (200 mL) and extracted with DCM (2 × 100 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to provide 0.65 g of crude product. The crude material obtained was purified by flash column chromatography using silica gel (230-400 mesh) as the stationary phase (55% ethyl acetate in hexane as a gradient) to give 8-bromo-3-(methylsulfonyl)quinoline (A15, 0.50 g, 1.747 mmol, yield: 44.41%).

[0511] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[0512] LCMS (Method A): 1.807 min, 95.24%, 254.0 nm, MS: ES+ 286.01 (M), 288.01 (M+2)

[0513] Step-2:

[0514] 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 K PO (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 mobile phase), which confirmed that the reaction was complete after stirring at 100 ° C for 2 h. The resulting reaction mixture was diluted with water (100 mL) and extracted with EtOAc (150 mL). The organic layer merged was dried over Na SO and concentrated under reduced pressure to provide 0.35 g of crude product. The crude material obtained was purified by flash column chromatography using silica gel (230-400 mesh) as stationary phase (15% ethyl acetate in hexane as gradient) to produce 3-(methylsulfonyl)-8-(4-(trifluoromethyl) cyclohex-1-ene-1-yl) quinoline (compound 16, 0.113 g, 0.317 mmol, yield: 30.37%).

[0515] 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 combined with DMSO solvent, which is clearly visible in MeOD NMR.

[0516] 1H NMR (MeOD, 400MHz): δppm, 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).

[0517] LCMS (Method A): 2.560 min, 95.70%, 254.0 nm, MS: ES+356.02 (M+1)

[0518] HPLC (Method A): 9.069 min, 95.08%, 254.0 nm

[0519] Example 16 - Synthesis of N-methyl-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-sulfonamide (Compound 17)

[0520]

[0521] Step-1a:

[0522] To a stirred solution of phenylmethylmercaptan CAS: 100-53-8 (10.0 g, 80.645 mmol, 1.0 equivalent) in ether (100 mL) was added Na metal (0.927 g, 40.257 mmol, 0.5 equivalent). The resulting mixture was stirred at RT for 16 h. The reaction was monitored by TLC (using EtOAc: hexane; 3.0: 7.0 as mobile phase), which confirmed that the reaction was complete after 16 h. The resulting reaction mixture was filtered using a Buchner funnel, the solid material was washed with ether and dried under vacuum to produce sodium phenylmethylmercaptan (A16, 6.0 g, 41.04 mmol, yield: 50.98%) as a white solid.

[0523] 1 H NMR (DMSO-d 6 , 400MHz): δppm, 7.25 (d, J = 9.2Hz, 2H), 7.16-7.11 (m, 2H), 7.01-6.98 (m, 1H), 3.50 (br s, 2H).

[0524] Step-1:

[0525] Under nitrogen, to a solution of 8-bromo-3-iodoquinoline (A8, 3.0 g, 8.983 mmol, 1.0 equivalent) in DMF (25 mL) was added sodium phenylmethylmercaptide (A16, 1.83 g, 12.576 mmol, 1.4 equivalents). The resulting mixture was stirred at 80 ° C for 6 h. The reaction was monitored on TLC (using EA: hexane; 1.0: 9.0 as mobile phase), which confirmed that the reaction was complete 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 layer was dried over Na SO and concentrated under reduced pressure to provide 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 a gradient) to yield 3-(benzylthio)-8-bromoquinoline (A17, 1.5 g, 4.54 mmol, yield: 50.56%).

[0526] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[0527] LCMS (Method-A): 2.780 min, 97.22%, 254.0 nm, MS: ES+332.01 (M+2)

[0528] Step-2:

[0529] To a stirred solution of 3-(benzylthio)-8-bromoquinoline (A17, 1.5 g, 4.542 mmol, 1.0 eq) in acetonitrile, acetic acid and water was added CAS: 118-52-5 (1.91 g, 9.084 mmol, 2 eq) at 0°C, and the resulting mixture was stirred at 0°C for 2 h. The reaction was monitored by TLC (using EtOAc: hexane; 3.0: 7.0 as the mobile phase), which confirmed that the reaction was complete after stirring at 0°C for 2 h. The resulting reaction mixture was concentrated to dryness, then diluted with DCM and cooled to 0°C, 5% NaHCO3 aqueous solution was added and 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 Na2SO4 and concentrated under reduced pressure to provide 1.5 g of crude 8-bromoquinoline-3-sulfonyl chloride (A18, 1.5 g, 4.893 mmol, yield: crude). Note: The crude product obtained was used as such in the next step without further purification.

[0530] LCMS (Method A): 2.455 min, 11.07%, 254.0 nm, MS: ES+, 308.0 (M+2)

[0531] Step-3:

[0532] At 0 ° C, CAS: 74-89-5 (4.89 mL, 9.786 mmol, 2.0 equivalents) was added to a solution of 8-bromoquinoline-3-sulfonyl chloride (A18, 1.5 g, 4.893 mmol, 1.0 equivalents) in DCM (20 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored on TLC (using EtOAc: hexane; 3.0: 7.0 as mobile phase), which confirmed that the reaction was 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 Na2SO4 and concentrated under reduced pressure to provide 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 hexane as a gradient) to yield 8-bromo-N-methylquinoline-3-sulfonamide (A19, 1.1 g, 3.652 mmol, yield: 80.42% (yield over 2 steps)).

[0533] 1 H NMR (DMSO-d 6, 400MHz): δppm, 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).

[0534] LCMS (Method A): 1.859 min, 100%, 254.0 nm, MS: ES+ 302.96 (M+2)

[0535] Step-4:

[0536] To a stirred solution of 8-bromo-N-methylquinoline-3-sulfonamide (A19, 0.1 g, 0.332 mmol, 1.0 eq), 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 eq) and NaCO (0.088 g, 0.83 mmol, 2.5 eq) in dioxane (2 mL) and water (0.4 mL) was added Pd(dppf)Cl.DCM (0.013 g, 0.016 mmol, 0.05 eq) under N. The resulting mixture was stirred at 100° C. for 2 h. At 4 DEG C, 1H-dextrose is stirred at 4 DEG C for 2h, and 30 DEG C of 4-nitro-1H-dextrose is stirred at 4 DEG C for 2h.The reaction is monitored on TLC (using EA: hexane; 1.0: 1.0 as mobile phase), and this confirms that the reaction is complete after stirring 2h at 100 DEG C. The resulting reaction mixture is diluted with water (10mL) and extracted with EtOAc (3 × 20mL).The organic layer combined is dried over Na SO and concentrated under reduced pressure to provide 0.120g crude product. The crude material obtained uses silica (230-400 mesh) as stationary phase purification (30% EtOAc in hexane) by flash column chromatography to produce N-methyl-8-(4-(trifluoromethyl) cyclohex-1-ene-1-yl) quinoline-3-sulfonamide (compound 17, 0.079g, 0.213mmol, yield: 64.23%).

[0537] 1 H NMR (DMSO-d 6 ,400MHz): δppm,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).

[0538] 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 are exchanged in MeOD.

[0539] LCMS (Method A): 2.599 min, 100%, 254.0 nm, MS: ES+371.12 (M+1)

[0540] HPLC (Method A): 9.102 min, 100%, 254.0 nm

[0541] Example 17 - Synthesis of N-(1-(oxazol-2-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 18)

[0542]

[0543] Step-1:

[0544] At -78 ° C, to a stirred solution of oxazole CAS: 288-42-6 (0.2 g, 2.896 mmol, 1.0 equivalent) in THF (4 mL) was added n-BuLi (1.81 mL, 2.896 mmol, 1.5 M in hexane, 1.0 equivalent), and stirring was continued at -78 ° C for 1 h, then CAS: 3591-86-8 (0.327 g, 2.896 mmol, 1.0 equivalent) in THF (1 mL) was added under N2. The resulting mixture was stirred at RT for 16 h. The reaction was monitored by TLC (using EA: hexane; 1: 1 as mobile phase), which confirmed that the reaction was complete after stirring for 16 h at RT. The resulting reaction mixture was quenched with 1N HCl (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford crude oxazole-2-carbaldehyde (A20, 0.25 g, 2.575 mmol, yield: crude).The obtained crude material was used directly in the next step without further purification.

[0545] 1 H NMR (DMSO-d6, 400MHz): δppm, 9.72 (s, 1H), 7.95 (s, 1H), 7.66 (s, 1H).

[0546] LCMS (Method A): 0.196 min, 38.56%, 210.0 nm, MS: ES+, 97.9 (M+1)

[0547] Step-2:

[0548] To a solution of oxazole-2-carboxaldehyde (A20, 0.25 g, 2.57 mmol, 1.0 equivalent) in THF (3 mL) was added CAS: 146374-27-8 (0.374 g, 3.09 mmol, 1.2 equivalents) and CAS: 3087-36-3 (1.17 g, 5.15 mmol, 2.0 equivalents). The resulting mixture was stirred at room temperature for 16 h. The reaction was monitored on TLC (using EtOAc: hexane; 1: 1 as mobile phase), which confirmed that the reaction was complete 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 Na2SO4 and concentrated under reduced pressure to provide 0.3 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 hexane as a gradient) to produce (E)-2-methyl-N-(oxazol-2-ylmethylene)propane-2-sulfenamide (A21, 0.15 g, 2.496 mmol, yield: 25.87% (yield over 2 steps)).

[0549] 1 H NMR (DMSO-d6, 400MHz): δppm, 8.45 (s, 1H), 8.29 (s, 1H), 7.63 (s, 1H), 1.19 (s, 9H).

[0550] LCMS (Method A): 1.551 min, 98.61%, 254.0 nm, MS: ES+201.10 (M+1)

[0551] Step-3:

[0552] At 0 ° C under N2, to a stirred solution of (E)-2-methyl-N-(oxazol-2-ylmethylene)propane-2-sulfinamide (A21, 0.150 g, 0.749 mmol, 1.0 equiv) in DCM (3 mL) was added CH3MgBr (0.27 mL, 0.823 mmol, 1.1 equiv). The resulting mixture was stirred at 0 ° C for 1 h. The reaction was monitored on TLC (using EtOAc: hexane; 1.0: 1.0 as mobile phase), which confirmed that the reaction was complete after stirring at 0 ° C for 16 h. The resulting reaction mixture was quenched with NH4Cl solution (5 mL) and extracted with DCM (3×10 mL). The crude material was then dissolved in MeOH (5 mL), 4M HCl (0.347 mL, 1.388 mmol, 2.0 equiv) in dioxane was added and the reaction mixture was stirred for 1 h. The reaction was monitored on TLC (using EtOAc: hexane; 4.0: 1.0 as mobile phase), which confirmed that the reaction was complete after 1 h. The reaction mixture was concentrated under reduced pressure to provide 0.15 g of crude product. The crude material obtained was purified by grinding to produce 1- (oxazol-2-yl) second -1- amine (A22, 0.08 g, 0.713 mmol, yield: 71.88%).

[0553] 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, 1H), 4.68-4.65 (m, 1H), 1.56 (d, J = 6.8 Hz, 3H). (Trace amount of MeOH observed).

[0554] Step-4:

[0555] To a solution of 8-(4-(trifluoromethyl)cyclohex-1-ene-1-yl)quinoline-3-carboxylic acid (A5, 0.2 g, 0.622 mmol, 1.0 equivalent), HATU (0.35 g, 0.933 mmol, 1.5 equivalents) and DIPEA (0.32 mL, 1.867 mmol, 3.0 equivalents) in DMF (5 mL) stirred at 0 ° C. under a nitrogen atmosphere for 20 min was added 1-(oxazol-2-yl)ethyl-1-amine (A22, 0.139 g, 0.933 mmol, 1.5 equivalents). The resulting mixture was stirred at room temperature for 12 h. The reaction was monitored on TLC (using EtOAc: hexane; 7: 3 as mobile phase), which confirmed that the reaction was complete after 12 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 Na2SO4 and concentrated under reduced pressure to provide 0.3 g of crude product. The obtained crude material was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (60% ethyl acetate in hexane as a gradient) to produce N-(1-(oxazol-2-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 18, 0.141 g, 0.333 mmol, yield: 54.53%).

[0556] 1 H NMR (DMSO-d6, 400MHz): δppm, 9.35 (d, J = 7.6Hz, 1H), 9.27 (d, J = 2.0Hz, 1H), 8.85 (d, J =2.0Hz,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=7.6Hz,3H). Note: The CF3-CH protons merge with the DMSO solvent peak, which is clearly visible in the MeOD NMR.

[0557] 1H NMR (MeOD, 400MHz): δppm, 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 exchanged with MeOD.

[0558] LCMS (Method A): 2.466 min, 100%, 254.0 nm, MS: ES+416.18 (M+1)

[0559] HPLC (Method A): 8.717 min, 99.37%, 254.0 nm

[0560] Example 18 - Chiral Separation of N-(1-(oxazol-2-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 19-Compound 22)

[0561]

[0562] program:

[0563] Compound 18 (0.131 g) racemate was purified by chiral SFC on a (CHIRALPAK IG 250×50 mm 5 μm) 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%).

[0564] Column ID: CHIRALPAK IG 250×50mm 5μm

[0565] Mobile phase A: liquid CO2

[0566] Mobile phase B: 0.1% M.NH3 in MEOH-ACN (50-50)

[0567] Flow rate (ML / MIN): 170

[0568] Instrument ID: WATERS SFC 350 with 2489 UV detector

[0569] Method: Time: Flow: %A:%B (0.01:170:55:45), (17:170:55:45)

[0570] Compound 19:

[0571] 1 H NMR (DMSO-d6, 400MHz): δppm, 9.35 (d, J = 7.6Hz, 1H), 9.27 (d, J = 2.4Hz, 1H), 8.86 (d, J = 2.4Hz, 1 H),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-CH3 proton merges with the DMSO solvent peak and is clearly visible in the MeOD NMR)

[0572] 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 (brs, 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 can exchange with deuterium from MeOD)

[0573] LCMS (Method A): 2.465 min, 100%, 254.0 nm, MS: ES+416.2 (M+1)

[0574] HPLC (Method A): 8.775 min, 100%, 254.0 nm

[0575] Compound 20:

[0576] 1 H NMR (DMSO-d6, 400MHz): δppm, 9.35 (d, J = 7.6Hz, 1H), 9.27 (d, J = 2.4Hz, 1H), 8.86 (d, J = 2.4Hz, 1 H),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-CH3 proton merges with the DMSO solvent peak and is clearly visible in the MeOD NMR)

[0577] 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 (brs, 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 can exchange with deuterium from MeOD)

[0578] LCMS (Method A): 2.466 min, 100%, 254.0 nm, MS: ES+416.2 (M+1)

[0579] HPLC (Method A): 8.772 min, 99.71%, 254.0 nm

[0580] Chiral separation of compound 21 and compound 22:

[0581] program: Peak 1 (0.051 g) was further subjected to chiral SFC purification on a (CHIRALPAK IG 250×50 mm 5 μm) column to obtain 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%).

[0582] Column ID: CHIRALPAK IG 250×50mm 5μm

[0583] Mobile phase A: liquid CO2

[0584] Mobile phase B: 0.1% M.NH3 in IPA-MEOH (70-30)

[0585] Flow rate (ML / MIN): 150

[0586] Instrument ID: WATERS SFC 350 with 2489 UV detector

[0587] Method: Time: Flow: %A:%B (0.01:150:70:30), (18:150:70:30)

[0588] Compound 21:

[0589] 1 H NMR (DMSO-d6, 400MHz): δppm, 9.35 (d, J = 7.6Hz, 1H), 9.27 (d, J = 2.4Hz, 1H), 8.86 (d, J = 2.4Hz, 1 H),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-CH3 proton merges with the DMSO solvent peak and is clearly visible in the MeOD NMR)

[0590] 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 can exchange with deuterium from MeOD)

[0591] LCMS (Method A): 2.427 min, 100%, 254.0 nm, MS: ES+416.2 (M+1)

[0592] HPLC (Method A): 8.859 min, 100%, 254.0 nm

[0593] Compound 22:

[0594] 1 H NMR (DMSO-d6, 400MHz): δppm, 9.35 (d, J = 7.6Hz, 1H), 9.27 (d, J = 2.4Hz, 1H), 8.86 (d, J = 2.4Hz, 1 H),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-CH3 proton merges with the DMSO solvent peak and is clearly visible in the MeOD NMR)

[0595] 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 (brs, 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 can exchange with deuterium from MeOD)

[0596] LCMS (Method A): 2.420 min, 100%, 254.0 nm, MS: ES+416.1 (M+1)

[0597] HPLC (Method A): 8.851 min, 100%, 254.0 nm

[0598] Example 19 - Synthesis of N-(2-(methylthio)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 23):

[0599]

[0600] Step-1:

[0601] A stirred solution of 8-(4-(trifluoromethyl)cyclohex-1-ene-1-yl)quinoline-3-carboxylic acid (compound 15, 0.1 g, 0.31 mmol, 1.0 equivalent) in DMF (1 mL) was prepared in a 10 mL glass vial at room temperature. DIPEA (0.16 mL, 0.93 mmol, 3.0 equivalents) and HATU (0.17 g, 0.46 mmol, 1.5 equivalents) were added to the reaction solution at 0 ° C under a nitrogen atmosphere. After stirring at 0 ° C for 30 min, (CAS: 18542-42-2) 2-(methylthio)ethyl-1-amine (0.028 g, 0.31 mmol, 1.0 equivalents) was added at the same temperature. The resulting reaction mixture was then stirred from 0 ° C to RT for 16 h. The reaction was monitored by TLC (using EtOAc: hexane; 4.0: 6.0 as mobile phase), which confirmed that the reaction was complete after stirring for 16 h at RT. The resulting reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 5 mL). The organic layer combined was dried over Na SO Drying, filtered and concentrated under reduced pressure to provide 0.11 g of crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh size) as stationary phase (elution gradient, 20% EtOAc in hexane) to produce N-(2-(methylthio) ethyl)-8-(4-(trifluoromethyl) cyclohex-1-ene-1-yl) quinoline-3-carboxamide (compound 23, 0.055 g, 0.13 mmol, yield: 45.08%).

[0602] 1H 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-CH3 proton is merged with the DMSO solvent peak and is clearly visible in the MeOD NMR.)

[0603] 1 H 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 can exchange with deuterium from MeOD)

[0604] LCMS (Method A): 2.614 min, 95.77%, 254 nm, MS: ES+395.12 (M+1)

[0605] HPLC (Method B): 9.433 min, 95.17%, 254 nm

[0606] Example 20: Synthesis of N-(2-(methylsulfinyl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 24):

[0607]

[0608] Step-1:

[0609] A stirred solution of N-(2-(methylthio)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-ene-1-yl)quinoline-3-carboxamide (compound 23, 0.1g, 0.25mmol, 1.0 equivalent) in DCM (1mL) was prepared at room temperature in a 10mL glass vial. At 0°C under a nitrogen atmosphere, m-CPBA (60% determination) (0.026g, 0.25mmol, 1.0 equivalent) in DCM (0.5mL) was added dropwise to the resulting mixture. The resulting reaction mixture was then stirred from 0°C to RT for 16h. The reaction was monitored by TLC (using MeOH:DCM; 0.5:9.5 as mobile phase), which confirmed that the reaction was complete after stirring for 16h at RT. The resulting reaction mixture was diluted with water (5mL), alkalized with saturated NaHCO solution (5mL) and extracted with DCM (3×5mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to provide 0.11 g of crude product. The obtained crude material was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (elution gradient, 3% MeOH in DCM) to produce 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%).

[0610] 1 H NMR (DMSO-d6, 400MHz): δppm, 9.24 (d, J = 2.0Hz, 1H), 9.13 (t, J = 5.2Hz, 1H), 8.80 (d, J = 2.0Hz, 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 merges with the DMSO solvent peak and is clearly visible in the MeOD NMR)

[0611] 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 can exchange with deuterium from MeOD)

[0612] LCMS (Method A): 2.121 min, 100%, 254 nm, MS: ES+411.1 (M+1)

[0613] HPLC (Method B): 7.334 min, 99.45%, 254 nm

[0614] Example 21 - Synthesis of N-(2-(methylsulfonyl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 25):

[0615]

[0616] Step-1:

[0617] A stirred solution of 8-(4-(trifluoromethyl)cyclohex-1-ene-1-yl)quinoline-3-carboxylic acid (compound 15, 0.1 g, 0.31 mmol, 1.0 equivalent) in DMF (1 mL) was prepared in a 10 mL glass vial at room temperature. DIPEA (0.27 mL, 1.55 mmol, 5.0 equivalents) and HATU (0.17 g, 0.46 mmol, 1.5 equivalents) were added to the reaction solution at 0 ° C under a nitrogen atmosphere. After stirring at 0 ° C for 30 min, 2-(methylsulfonyl)ethyl-1-amine (CAS: 104458-24-4) (0.049 g, 0.31 mmol, 1.0 equivalents) was added at the same temperature. The resulting reaction mixture was then stirred for 16 h from 0 ° C to RT. The reaction was monitored by TLC (using pure EtOAc as mobile phase), which confirmed that the reaction was complete after stirring for 16 h at RT. The resulting reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layer was washed with cold water (3 × 30 mL), through Na SO Drying was filtered and concentrated under reduced pressure to provide 0.12 g of crude product. The crude material obtained was purified by grinding with ether to produce N-(2-(methylsulfonyl) ethyl)-8-(4-(trifluoromethyl) cyclohex-1-ene-1-yl) quinoline-3-carboxamide (compound 25, 0.053 g, 0.12 mmol, yield: 40.15%).

[0618] 1 H NMR (DMSO-d6, 400MHz): δppm, 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-CH3 proton merges with the DMSO solvent peak and is clearly visible in the MeOD NMR)

[0619] 1H NMR (MeOD, 400MHz): δppm, 9.24 (d, J = 2.4Hz, 1H), 8.76 (d, J = 2.0Hz, 1H), 7.97 (dd,J=7.6,3.6Hz,1H),7.69-7.63(m,2H),5.86(s,1H),3.95(t,J=6.4Hz,2H ),3.51(t,J=6.8Hz,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: -NH protons can be exchanged with deuterium from MeOD)

[0620] LCMS (Method A): 2.290 min, 98.55%, 254 nm, MS: ES+427.2 (M+1)

[0621] HPLC (method B): 8.152 min, 98.63%, 254 nm

[0622] Example 22-Synthesis of 8-(4,4-difluorocyclohex-1-en-1-yl)-N-isopropylquinoline-3-carboxamide (Compound 26):

[0623]

[0624] Step-1:

[0625] A stirred solution of 8-bromoquinoline-3-formic acid (A3, 0.50 g, 1.98 mmol, 1.0 equivalent) in DMF (5.0 mL) was prepared at room temperature in a 30 mL glass vial. At 0 ° C under a nitrogen atmosphere, DIPEA (0.76 g, 5.95 mmol, 3.0 equivalents) and HATU (1.12 g, 2.97 mmol, 1.5 equivalents) were added to the reaction solution. After stirring for 10 min, isopropylamine (CAS: 75-31-0) (0.11 g, 1.98 mmol, 1.0 equivalents) was added at the same temperature. The resulting reaction mixture was then stirred at RT for 16 h. The reaction was monitored by TLC (using EtOAc: hexane; 1.0: 1.0 as mobile phase), which confirmed that the reaction was complete after stirring for 16 h at RT. The resulting reaction mixture was extracted with EtOAc (50 mL) and H2O (50 mL), and the organic layer was dried over Na2SO4, filtered, and concentrated under high vacuum to afford a crude product. The crude product was purified by combi-flash using 230-400 mesh size silica, and the product was eluted with 12% EtOAc:hexane to produce 8-bromo-N-isopropylquinoline-3-carboxamide (A23, 0.323 g, 1.101 mmol, yield: 55.59%).

[0626] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[0627] LCMS (Method A): 1.866 min, 99.55%, 254 nm, MS: ES+294 (M+1)

[0628] Step-2:

[0629] A stirred solution of A23 (0.1 g, 0.34 mmol, 1 equivalent) in dioxane: HO (3: 1) was prepared in a 10 mL glass vial at room temperature. At the same temperature, CAS: 1227068-84-9 (0.08 g, 0.33 mmol, 1 equivalent) and NaCO (0.10 g, 1.02 mmol, 3 equivalents) were added to the reaction solution. Pd(dppf)Cl (0.02 g, 0.03 mmol, 0.1 equivalent) was then added and stirred at 110°C for 2 hours. The reaction was then monitored by TLC (50% EtOAc: hexane as mobile phase), which confirmed that the reaction was complete after stirring at 110°C for 2 hours. 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 obtain a crude product. The crude product was purified by combi-flash column chromatography using 230-400 mesh size silica and the product was eluted 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%).

[0630] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[0631] LCMS (Method A): 2.313 min, 96.62%, 254.0 nm, MS: ES+331.2 (M+1)

[0632] HPLC (Method B): 8.486 min, 99.62%, 254.0 nm.

[0633] Example 23 Synthesis of (S)-8-(4,4-difluorocyclohex-1-en-1-yl)-N-(1-(pyridin-2-yl)ethyl)quinoline-3-carboxamide (Compound 27)

[0634]

[0635] Step-1:

[0636] A stirred solution of 8-bromoquinoline-3-carboxylic acid methyl ester (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 at room temperature under N2 atmosphere. The reaction solution was degassed by N2 at room temperature for 15 minutes. PdCl2(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 to 110 ° C for 16 h. By TLC (using EtOAc: hexane; 3.0: 7.0 as mobile phase) monitoring reaction, this confirmed that after 110 ℃ of stirring 16h, the reaction was complete. The resulting reaction mixture was cooled to room temperature, diluted with EtOAc (10mL), filtered through a bed of diatomaceous earth, washed with EtOAc (30mL), and the filtrate was concentrated under reduced pressure to provide 0.7g crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) as stationary phase (10% EtOAc in hexane), producing 8- (4,4- difluorocyclohex-1-ene-1-yl) quinoline-3-methyl formate (A24, 0.3g, 0.98mmol, yield: 65.93%).

[0637] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[0638] LCMS (Method A): 2.613 min, 98.28%, 254 nm, MS: ES+304.1 (M+1)

[0639] Step-2:

[0640] A stirred solution of 8-(4,4-difluorocyclohex-1-ene-1-yl)quinoline-3-formic acid methyl ester (A24, 0.3 g, 0.98 mmol, 1.0 equivalent) 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 equivalent) was added to the reaction solution at the same temperature. The glass vial was sealed with a lid and heated to 50 ° C for 4 h. The reaction was monitored by TLC (using EtOAc: hexane; 3.0: 7.0 as mobile phase), which confirmed that the reaction was 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 solution was added to the reaction mixture until the pH became acidic, to obtain a precipitate. The obtained precipitate was filtered through a Buchner funnel, washed with water (10 mL) and dried under vacuum to give 8-(4,4-difluorocyclohex-1-en-1-yl)quinoline-3-carboxylic acid (A25, 0.24 g, 0.82 mmol, yield: 83.91%).

[0641] 1 H 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 can exchange with DMSO water.

[0642] LCMS (Method A): 2.164 min, 98.32%, 254 nm, MS: ES+290.1 ​​(M+1)

[0643] Step-3:

[0644] A stirred solution of 8-(4,4-difluorocyclohex-1-ene-1-yl)quinoline-3-carboxylic acid (A25, 0.1 g, 0.34 mmol, 1.0 equivalent) 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 equivalents) and HATU (0.19 g, 0.51 mmol, 1.5 equivalents) were added to the reaction solution at 0 ° C under a nitrogen atmosphere. After stirring at 0 ° C for 30 min, (1S) -1- (pyridin-2-yl) second -1-amine hydrochloride (CAS: 40154-78-7) (0.067 g, 0.34 mmol, 1.0 equivalents) was added at the same temperature. The resulting reaction mixture was then stirred for 1 h from 0 ° C to RT. The reaction was monitored by TLC (using pure EtOAc as mobile phase), which confirmed that the reaction was complete after stirring for 1 h from 0 ° C to RT. The resulting reaction mixture is diluted with cold water (5mL) and extracted with EtOAc (3 × 5mL).The organic layer merged is through Na SO Drying, filter and under reduced pressure concentrate, to provide 0.12g crude product.The crude material obtained uses silica (230-400 mesh) as stationary phase purification (elution gradient, 30% EtOAc in hexane) by flash column chromatography, produces (S)-8-(4,4-difluorocyclohex-1-ene-1-yl)-N-(1-(pyridin-2-yl) ethyl) quinoline-3-carboxamide (compound 27, 0.099g, 0.25mmol, yield: 72.79%).

[0645] 1 H NMR (DMSO-d6, 400MHz): δppm, 9.31 (d, J = 2.4Hz, 1H), 9.20 (d, J = 8.0Hz, 1H), 8.90 (d, J = 2.4 Hz,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(brs,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).

[0646] 1H NMR (MeOD, 400MHz): δppm, 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,1H),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=7.2Hz,1H),2.89-2.86(m,2H),2.83-2.74(m,2H),2.32-2.25(m,2H),1.66(d,J=7.2Hz,3H). (Note: -NH protons can be exchanged with deuterium from MeOD)

[0647] LCMS (Method A): 2.027 min, 95.17%, 210 nm, MS: ES+394.2 (M+1)

[0648] HPLC (Method B): 8.283 min, 98.25%, 254 nm

[0649] Chiral HPLC (Method C): 2.59 min, 98.10%, 240 nm

[0650] Example 24: Synthesis of 8-(4,4-difluorocyclohex-1-en-1-yl)-N-(1-hydroxypropyl-2-yl)quinoline-3-carboxamide (Compound 28):

[0651]

[0652] Step-1:

[0653] 8-(4,4-difluorocyclohex-1-ene-1-yl)quinoline-3-carboxylic acid (A25, 0.1g, 0.34mmol, 1.0 equivalent) in DMF (1.0mL) was stirred at room temperature in a 10mL glass vial. DIPEA (0.18mL, 1.03mmol, 3.0 equivalents) and HATU (0.19g, 0.51mmol, 1.5 equivalents) were added to the reaction solution at 0°C under a nitrogen atmosphere. After stirring at 0°C for 30min, (S)-2-aminopropan-1-ol (CAS:2749-11-3) (0.025g, 0.34mmol, 1.0 equivalents) was added at the same temperature. The resulting reaction mixture was then stirred for 1h from 0°C to RT. The reaction was monitored by TLC (using pure EtOAc as mobile phase), which confirmed that the reaction was complete after stirring for 1h from 0°C to RT. The resulting reaction mixture is diluted with cold water (5mL) and extracted with EtOAc (3 × 5mL).The organic layer merged is through Na SO Drying, filter and under reduced pressure concentrate, to provide 0.18g crude product.The crude material obtained uses silica (230-400 mesh) as stationary phase purification (70% EtOAc in hexane) by flash column chromatography, produces (S)-8-(4,4-difluorocyclohex-1-ene-1-yl)-N-(1-hydroxypropyl-2-yl) quinoline-3-carboxamide (compound 28, 0.075g, 0.21mmol, yield: 63.02%).

[0654] 1 H NMR (DMSO-d6, 400MHz): δppm, 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,1 H), 2.89 (brs, 2H), 2.79 (t, J = 14.8Hz, 2H), 2.25-2.18 (m, 2H), 1.18 (d, J = 6.4Hz, 3H).

[0655] 1H 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 can exchange with deuterium from MeOD)

[0656] LCMS (Method A): 1.970 min, 98.04%, 254 nm, MS: ES+347.2 (M+1)

[0657] HPLC (Method B): 7.064 min, 97.63%, 254 nm

[0658] Chiral HPLC (Method C): 2.79 min, 99.18%, 248 nm

[0659] Example 25-Synthesis of 8-(4,4-difluorocyclohex-1-en-1-yl)-N-(oxazol-2-ylmethyl)quinoline-3-carboxamide (Compound 29):

[0660]

[0661] Step-1:

[0662] 8- (4,4- difluorocyclohex-1-ene-1-yl) quinoline -3- carboxylic acid (A25, 0.1g, 0.34mmol, 1.0 equivalent) in DMF (1.0mL) was prepared in room temperature in a 10mL glass vial. DIPEA (0.30mL, 1.72mmol, 5.0 equivalents) and HATU (0.19g, 0.51mmol, 1.5 equivalents) were added to the reaction solution at 0°C under a nitrogen atmosphere. After stirring at 0°C for 30min, oxazol-2-ylmethylamine hydrochloride (0.046g, 0.34mmol, 1.0 equivalents) was added at the same temperature. The resulting reaction mixture was then stirred for 1h from 0°C to RT. The reaction was monitored by TLC (using EtOAc; 10.0 as mobile phase), which confirmed that the reaction was complete after stirring for 1h from 0°C to RT. The resulting reaction mixture is diluted with cold water (5mL) and extracted with EtOAc (3 × 5mL).The organic layer merged is through Na SO Drying, filter and under reduced pressure concentrate, to provide 0.13g crude product.The crude material obtained uses silica (230-400 mesh) as stationary phase purification (50% EtOAc in hexane) by flash column chromatography, produces 8-(4,4-difluorocyclohex-1-ene-1-yl)-N-(oxazol-2-ylmethyl) quinoline-3-carboxamide (compound 29, 0.085g, 0.23mmol, yield: 66.92%).

[0663] 1 H NMR (DMSO-d6, 400MHz): δppm, 9.53 (t, J = 5.2Hz, 1H), 9.28 (d, J = 2.0Hz, 1H), 8.87 (d, J = 2.0H z,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).

[0664] LCMS (Method A): 2.111 min, 97.20%, 254 nm, MS: ES+370.1 (M+1)

[0665] HPLC (method B): 7.544 min, 98.69%, 254 nm

[0666] Example 26-Synthesis of 8-(4,4-dimethylcyclohex-1-en-1-yl)-N-isopropylquinoline-3-carboxamide (Compound 30):

[0667]

[0668] Step-1:

[0669] A stirred solution of A23 (0.1 g, 0.34 mmol, 1 equivalent) in dioxane:H2O (3:1) was prepared in a 10 mL glass vial at room temperature. CAS: 859217-67-7 (0.08 g, 0.33 mmol, 1 equivalent) and Na2CO3 (0.10 g, 1.02 mmol, 3 equivalents) were added to the reaction solution at the same temperature. Pd(dppf)Cl2 (0.02 g, 0.03 mmol, 0.1 equivalent) was then added and stirred at 110°C for 2 hours. The reaction was then monitored by TLC (50% EtOAc: hexane as mobile phase), which confirmed that the reaction was complete after stirring at 110°C for 2 hours. The resulting reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under high vacuum. The crude product was purified by combi-flash column chromatography using 230-400 mesh silica. The product was eluted with 7% EtOAc:hexane to yield 8-(4,4-dimethylcyclohex-1-en-1-yl)-N-isopropylquinoline-3-carboxamide (compound 30, 0.051 g, 0.158 mmol, yield: 46.40%).

[0670] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[0671] 1H 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 can exchange with deuterium from MeOD)

[0672] LCMS (Method A): 2.797 min, 100%, 254 nm, MS: ES+ 323.2 (M+1).

[0673] HPLC (Method B): 10.612 min, 100%, 254 nm.

[0674] Example 27 Synthesis of (S)-8-(4,4-dimethylcyclohex-1-en-1-yl)-N-(1-(pyridin-2-yl)ethyl)quinoline-3-carboxamide (Compound 31):

[0675]

[0676] Step-1:

[0677] Commercially available 8- (4,4- dimethylcyclohex-1-ene-1-yl) quinoline-3-carboxylic acid (A26, 0.1g, 0.35mmol, 1.0 equivalent) stirred solution in DMF (1.0mL) was prepared in a 10mL glass vial at room temperature. DIPEA (0.30mL, 1.03mmol, 5.0 equivalents) and HATU (0.20g, 0.53mmol, 1.5 equivalents) were added to the reaction solution at 0°C under a nitrogen atmosphere. After stirring at 0°C for 30min, (S) -1- (pyridin-2-yl) ethylamine hydrochloride (CAS: 40154-78-7) (0.069g, 0.35mmol, 1.0 equivalents) was added at the same temperature. The resulting reaction mixture was then stirred for 1h from 0°C to RT. The reaction was monitored by TLC (using pure EtOAc as mobile phase), which confirmed that the reaction was complete after stirring for 1h from 0°C to RT. The resulting reaction mixture was diluted with cold water (5 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layer was dried over Na SO , filtered, and concentrated under reduced pressure to provide 0.14 g of crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) as a stationary phase (40% EtOAc in hexane) to produce (S)-8-(4,4-dimethylcyclohex-1-ene-1-yl)-N-(1-(pyridin-2-yl)ethyl)quinoline-3-carboxamide (compound 31, 0.078 g, 0.20 mmol, yield: 56.93%).

[0678] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[0679] LCMS (Method A): 2.560 min, 100%, 254 nm, MS: ES+386.2 (M+1)

[0680] HPLC (Method B): 10.376 min, 100%, 254 nm

[0681] Chiral HPLC (Method C): 9.687 min, 100%, 240 nm

[0682] Example 28 Synthesis of (S)-8-(4,4-dimethylcyclohex-1-en-1-yl)-N-(1-hydroxypropyl-2-yl)quinoline-3-carboxamide (Compound 32):

[0683]

[0684] Step-1:

[0685] A stirring solution of A26 (0.090g, 0.310mmol, 1.0 equivalent) in DMF (1.0mL) was prepared in 10mL glass vials at room temperature. At the same temperature under a nitrogen atmosphere, DIPEA (0.124g, 0.950mmol, 3.0 equivalents) and HATU (0.18g, 0.470mmol, 1.5 equivalents) were added to the reaction solution. After stirring for 10min, (S)-2-aminopropan-1-ol (CAS:2749-11-3) (0.024g, 0.310mmol, 1.0 equivalents) was added at the same temperature. The resulting reaction mixture was then stirred at RT for 16h. The reaction was monitored by TLC (using pure ethyl acetate as mobile phase), which confirmed that the reaction was complete after stirring 16h at RT. The resulting reaction mixture was poured into cold water (40mL) and extracted with ethyl acetate (50mL×2). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product, which was purified by preparative TLC to produce (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%).

[0686] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[0687] LCMS (method A): 2.411 min, 100%, 254.0 nm, MS: ES+339.11 (M+1)

[0688] HPLC (method B): 8.906 min, 100%, 254.0 nm

[0689] Chiral HPLC (Method B): 4.01 min, 100%, 260.0 nm

[0690] Example 29-Synthesis of 8-(4,4-dimethylcyclohex-1-en-1-yl)-N-(oxazol-2-ylmethyl)quinoline-3-carboxamide (Compound 33):

[0691]

[0692] Step-1:

[0693] A stirred solution of A26 (0.1 g, 0.35 mmol, 1 equivalent) in DMF (1 mL) was prepared at room temperature in a 10 mL glass vial. DIPEA (0.19 g, 1.053 mmol, 3 equivalents) and HATU (0.20 g, 0.53 mmol, 1.5 equivalents) were added to the reaction solution at 0 ° C, and stirring continued for 10 min. Oxazol-2-ylmethylamine (0.03 g, 0.30 mmol, 1 equivalent) was then added, and the resulting reaction mixture was stirred at RT for 16 h. The reaction was monitored by TLC (EtOAc: hexane; 7.0: 3.0 as mobile phase), which confirmed that the reaction was complete after stirring 16 h at RT. The resulting reaction mixture was extracted with EtOAc (20 mL) and H o (20 mL). The organic layer was dried over Na sO , filtered, and concentrated under high vacuum to obtain a crude product. The crude product was purified by combi-flash column chromatography using 230-400 mesh size silica and the product was eluted with 50% EtOAc:hexanes to yield 8-(4,4-dimethylcyclohex-1-en-1-yl)-N-(oxazol-2-ylmethyl)quinoline-3-carboxamide (compound 33, 0.026 g, 0.074 mmol, yield: 20.27%).

[0694] 1H NMR (DMSO-d6, 400MHz): δppm, 9.51 (br s, 1H), 9.27 (s, 1H), 8.84 (s, 1H), 8.08 (s, 1H), 7.98 (t, J = 4.4Hz 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).

[0695] 1 H 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 can exchange with deuterium from MeOD)

[0696] LCMS (method A): 2.569 min, 98.86%, 254 nm, MS: ES+362 (M+1)

[0697] HPLC (Method B): 9.413 min, 100%, 254 nm.

[0698] Example 30-Synthesis of 8-(cyclohex-1-en-1-yl)-N-isopropylquinoline-3-carboxamide (Compound 34):

[0699]

[0700] Step-1:

[0701] 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. Na2CO3 (1.19 g, 11.20 mmol, 3.0 equiv) was added to the reaction solution at the same temperature. The resulting reaction mixture was then stirred at RT and purged with nitrogen for 15 min. After purging nitrogen, PdCl2 (dppf) was added at RT, and the reaction was then stirred at 110°C for 16 h. The reaction was monitored by TLC (20% ethyl acetate in hexane as mobile phase), which confirmed that the reaction was complete after stirring at 110°C for 16 h. The resulting reaction mixture was then cooled at RT and poured into cold water (200 mL). Then extract with ethyl acetate (2 × 200mL) again, the organic layer is through Na SO Drying, filter and under reduced pressure concentrate to obtain crude material, this crude material uses hexane and ethyl acetate purification by column chromatography.Product is eluted with 7% ethyl acetate in hexane, to provide 8-(cyclohex-1-ene-1-yl)quinoline-3-formic acid methyl esters (A27, 0.6 g, 2.244 mmol, yield: 59.72%).

[0702] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[0703] LCMS (Method A): 2.821 min, 96.51%, 254.0 nm, MS: ES+268.10 (M+1)

[0704] Step-2:

[0705] At room temperature, in 35mL glass vials, prepare A27 (0.6g, 2.240mmol, 1.0 equivalent) in MeOH:H2O (4.2:1.8mL) stirring solution.To this reaction solution, add NaOH (0.179g, 4.480mmol, 2.0 equivalent) at the same temperature.Then, the resulting reaction mixture is stirred for 3h at 50 ℃.By TLC (using pure ethyl acetate as mobile phase), monitoring reaction, this confirmed that after RT stirring 3h, the reaction is completed.The resulting reaction mixture is directly concentrated under reduced pressure, then adds water (15mL) to obtain white solid after acidifying with citric acid.Precipitate is filtered through Buchner funnel and washed with water (20mL) and dried through high vacuum to produce 8-(cyclohexamethylene-1-ene-1-yl) quinoline-3-carboxylic acid (A28, 0.45g, 1.776mmol, yield: 79.22%).

[0706] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[0707] LCMS (Method A): 2.220 min, 99.73%, 254.0 nm, MS: ES+254.10 (M+1)

[0708] Step-3:

[0709] A stirring solution of A28 (0.1 g, 0.390 mmol, 1.0 equivalent) in DMF (1.0 mL) was prepared in a 10 mL glass vial at room temperature. At the same temperature under a nitrogen atmosphere, DIPEA (0.153 g, 1.180 mmol, 3.0 equivalents) and HATU (0.225 g, 0.590 mmol, 1.5 equivalents) were added to the reaction solution. After stirring for 10 min, propan-2-amine (CAS:75-31-0) (0.023 g, 0.390 mmol, 1.0 equivalents) was added at 0 ° C. The resulting reaction mixture was then stirred at RT for 16 h. The reaction was monitored by TLC (using 50% ethyl acetate in hexane as mobile phase), which confirmed that the reaction was complete after stirring 16 h at RT. The resulting reaction mixture was poured into cold water (40 mL) and extracted with ethyl acetate (2 × 40 mL). The organic layer was dried over Na SO and concentrated under reduced pressure to give a 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 produce 8-(cyclohex-1-ene-1-yl)-N-isopropylquinoline-3-carboxamide (compound 34, 0.065 g, 0.220 mmol, yield: 56.03%).

[0710] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[0711] LCMS (Method A): 2.397 min, 100%, 254.0 nm, MS: ES+ 295.16 (M+1)

[0712] HPLC (Method B): 9.316 min, 99.74%, 254.0 nm

[0713] Example 31-(S)-8-(cyclohex-1-en-1-yl)-N-(1-(pyridin-2-yl)ethyl)quinoline-3-carboxamide (Compound 35)

[0714]

[0715] Step-1:

[0716] In room temperature in 10mL glass vial, prepare a stirring solution of A28 (0.1g, 0.390mmol, 1.0 equivalent) in DMF (1.0mL). At the same temperature under nitrogen atmosphere, to this reaction solution, add DIPEA (0.255g, 1.900mmol, 5.0 equivalents) and HATU (0.225g, 0.590mmol, 1.5 equivalents). After stirring for 10min, CAS:40154-78-7 (0.077g, 0.390mmol, 1.0 equivalents) was added at 0°C. Then the resulting reaction mixture was stirred at RT for 16h. By TLC (using pure ethyl acetate as mobile phase), the reaction was monitored, and this confirmed that after RT stirring for 16h, the reaction was complete. The resulting reaction mixture was poured into cold water (40 mL) and extracted with ethyl acetate (2×40 mL). The organic layer was dried over Na SO and concentrated under reduced pressure to give a crude product, which was purified by conventional column chromatography using hexane and ethyl acetate. The product was eluted with 35% ethyl acetate in hexane and further purified by preparative TLC to produce (S)-8-(cyclohex-1-ene-1-yl)-N-(1-(pyridin-2-yl)ethyl)quinoline-3-carboxamide (compound 35, 0.031 g, 0.086 mmol, yield: 21.98%).

[0717] 1 H NMR (DMSO-d6, 400MHz): δppm, 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) 7.9 8(t,J=4.8Hz,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).

[0718] LCMS (Method A): 2.131 min, 100%, 210 nm, MS: ES+358.12 (M+1)

[0719] HPLC (Method B): 9.162 min, 99.49%, 254.0 nm

[0720] Chiral HPLC (Method C): 2.88 min, 98.97%, 241.0 nm

[0721] Example 32 Synthesis of (S)-8-(cyclohex-1-en-1-yl)-N-(1-hydroxypropyl-2-yl)quinoline-3-carboxamide (Compound 36):

[0722]

[0723] Step-1:

[0724] program:

[0725] In room temperature in 10mL glass bottle, prepare the stirring solution of A28 (0.1g, 0.390mmol, 1.0 equivalent) in DMF (1.0mL).At the same temperature under nitrogen atmosphere, to this reaction soln, add DIPEA (0.153g, 1.110mmol, 3.0 equivalents) and HATU (0.225g, 0.590mmol, 1.5 equivalents).After stirring for 10min, at 0 ℃, add (S)-2-aminopropan-1-ol (CAS:2749-11-3) (0.030g, 0.390mmol, 1.0 equivalents).Then resulting reaction mixture is stirred at RT for 16h.By TLC (using pure ethyl acetate as mobile phase) monitoring reaction, this has confirmed that after RT stirring 16h, reaction is completed. The resulting reaction mixture was poured into cold water (35 mL) and extracted with ethyl acetate (2 × 50 mL). The organic layer was dried over Na SO and concentrated under reduced pressure to give a crude product which was purified by conventional column chromatography using hexane and ethyl acetate. The product was eluted with 50% ethyl acetate in hexane to produce (S)-8-(cyclohex-1-ene-1-yl)-N-(1-hydroxypropyl-2-yl)quinoline-3-carboxamide (compound 36, 0.055 g, 0.177 mmol, yield: 45.08%).

[0726] 1H NMR (DMSO-d6, 400MHz): δppm, 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).

[0727] LCMS (Method A): 2.006 min, 95.61%, 254 nm, MS: ES+311.11 (M+1)

[0728] HPLC (method B): 7.558 min, 97.76%, 254.0 nm

[0729] Chiral HPLC (Method C): 2.85 min, 100%, 241.0 nm

[0730] Example 33-Synthesis of 8-(cyclohex-1-en-1-yl)-N-(oxazol-2-ylmethyl)quinoline-3-carboxamide (Compound 37):

[0731]

[0732] Step-1:

[0733] A stirring solution of A28 (0.1g, 0.39mmol, 1 equivalent) in DMF (1mL) was prepared in 10mL glass vials at room temperature. DIPEA (0.15g, 1.8mmol, 3 equivalents), HATU (0.22g, 0.58mmol, 1.5 equivalents) were added to the reaction solution at 0°C, and stirring continued for 10min. Then oxazol-2-ylmethylamine (0.03g, 0.39mmol, 1 equivalent) was added, and the resulting reaction mixture was stirred at RT for 16h. The reaction was monitored by TLC (MeOH:DCM, 1.0:9.0 as mobile phase), which confirmed that the reaction was complete after stirring 16h at RT. The resulting reaction mixture was extracted with EtOAc (20mL) and H o (20mL). The organic layer was dried at Na sO , filtered, and concentrated under high vacuum to obtain a crude product. The crude product was purified by combi-flash column chromatography using 230-400 mesh size silica and the product was eluted with 12% EtOAc:hexanes 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%).

[0734] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[0735] 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 can exchange with deuterium from MeOD)

[0736] LCMS (Method A): 2.209 min, 95.17%, 254 nm, MS: ES+334.1 (M+1)

[0737] HPLC (Method B): 8.202 min, 96.41%, 254 nm

[0738] Example 34 - Synthesis of N-methyl-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 38):

[0739]

[0740] Step-1:

[0741] To 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) stirred at 0 ° C. under a nitrogen atmosphere for 10 min was added CAS: 74-89-5 (0.021 g, 0.420 mmol, 1.5 equiv). The resulting mixture was stirred at room temperature for 16 h. The reaction was monitored on TLC (using EtOAc: hexane; 8:2 as the mobile phase), which confirmed that the reaction was complete after 16 h. 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 Na2SO4 and concentrated under reduced pressure to provide 0.15 g of crude product. The obtained crude material was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (50% ethyl acetate in hexane) to produce N-methyl-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 38, 0.035 g, 0.104 mmol, yield: 37.38%).

[0742] 1H 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, = 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-CH3 proton is merged with the DMSO solvent peak and is clearly visible in the MeOD NMR)

[0743] 1 H 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 can exchange with deuterium from MeOD)

[0744] LCMS (Method A): 2.327 min, 98.92%, 254.0 nm, MS: ES+429.3 (M+1)

[0745] HPLC (Method A): 8.561 min, 97.93%, 210.0 nm

[0746] Chiral HPLC (Method A): Peak-1 3.73min, 49.03%, 240.0nm; Peak-2 4.02min, 50.02%, 240.0nm

[0747] Example 35 Synthesis of N-(2-hydroxyethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 39):

[0748]

[0749] Step-1:

[0750] To 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) stirred at 0°C under a nitrogen atmosphere for 10 min was added CAS: 141-43-5 (0.025 g, 0.420 mmol, 1.5 equiv). The resulting mixture was stirred at room temperature for 16 h. The reaction was monitored on TLC (using EtOAc: hexane; 8:2 as the mobile phase), which confirmed that the reaction was complete after 16 h. The resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to provide 0.15 g of crude product. The obtained crude material was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (80% ethyl acetate in hexane as the elution gradient) to produce 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%).

[0751] 1 H NMR (DMSO-d6, 400MHz): δppm, 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-CH3 proton merges with the DMSO solvent peak and is clearly visible in the MeOD NMR)

[0752] 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, 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 can exchange with deuterium from MeOD)

[0753] LCMS (Method A): 2.154 min, 100%, 254.0 nm, MS: ES+365 (M+1)

[0754] HPLC (Method A): 7.651 min, 99.49%, 210.0 nm

[0755] Chiral HPLC (Method A): Peak-1 4.25 min, 49.65%, 240.0 nm; 4.69 min, 49.98%, 240.0 nm

[0756] Example 36 Synthesis of N-(2-methoxyethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 40):

[0757]

[0758] Step-1

[0759] To 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) stirred at 0 ° C. under a nitrogen atmosphere for 20 min was added CAS: 109-85-3 (0.0315 g, 0.420 mmol, 1.5 equiv). The resulting mixture was stirred at room temperature for 16 h. The reaction was monitored on TLC (using EtOAc: hexane; 7.0: 3.0 as the mobile phase), which confirmed that the reaction was complete after 16 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 Na2SO4 and concentrated under reduced pressure to provide 0.08 g of crude product. The obtained crude material was purified by flash column chromatography using silica (230-400 mesh size) as the stationary phase (elution gradient, 50% ethyl acetate in hexane) to produce 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%).

[0760] 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-CH3 proton is merged with the DMSO solvent peak and is clearly visible in the MeOD NMR)

[0761] 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 can exchange with deuterium from MeOD)

[0762] LCMS (Method A): 2.393 min, 98.83%, 254.0 nm, MS: ES+379.1 (M+1)

[0763] HPLC (Method A): 8.672 min, 97.52%, 254.0 nm

[0764] Chiral HPLC: Peak-1: 5.14min, 49.67%, 240nm; Peak-2: 5.57min, 50.32%, 240nm

[0765] Example 37: Synthesis of N-isopropyl-N-methyl-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 41):

[0766]

[0767] Step-1:

[0768] Under inert conditions N 2(g)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) was added HATU (0.159 g, 0.42 mmol, 1.5 equiv). The reaction was monitored by TLC (using ethyl acetate (3:7) in hexane as the mobile phase), which confirmed that the reaction was 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 Na 2 SO 4 and concentrated under reduced pressure to provide 0.07 g of crude product. The crude product 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).

[0769] 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-CH3 proton is merged with the DMSO solvent peak and is clearly visible in the MeOD NMR)

[0770] 1 H-NMR (MeOD, 400MHz): δppm, 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)

[0771] 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: due to the observation of broad rotamer peaks)

[0772] LCMS (Method-A): 2.512 min, (100%), 254 nm, m / z=377.17 (M+H) +

[0773] HPLC (Method-A): 9.81 min, (100%), 210 nm

[0774] Example 38 - Synthesis of N-(pyrimidin-2-ylmethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 42):

[0775]

[0776] Step-1:

[0777] Under inert conditions N 2(g)Under 40 ℃, to 8-(4-(trifluoromethyl)cyclohex-1-ene-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) stirring solution was added HATU (0.178 g, 0.46 mmol, 1.5 equiv). The reaction was monitored by TLC (using MeOH (0.5:9.5) in DCM as mobile phase), which confirmed that the reaction was 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 x 50 mL), dried over Na2SO4 and concentrated under reduced pressure to afford 0.06 g of crude product. The crude product was purified by manual column chromatography using silica (230-400 mesh) as the stationary phase (gradient elution, 50% methanol in DCM) to produce compound 42 (0.039 g, 0.094 mmol, yield: 32.88%).

[0778] 1 H-NMR(DMSO-d6,400MHz): δppm 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-CH3 proton merges with the DMSO solvent peak and is clearly visible in the MeOD NMR)

[0779] 1H-NMR (MeOD, 400MHz): δppm, 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 can exchange with deuterium from MeOD; 2H is merged with the MeOD water peak)

[0780] LCMS (Method-A): 2.28 min, (98.45%), 254 nm; MS: ES+413 (M+1)

[0781] HPLC (Method-A): 8.20 min, (97.7%), 210 nm

[0782] Example 39 - Synthesis of N-(pyridazin-3-ylmethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 43):

[0783]

[0784] Step-1:

[0785] To 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 added CAS: 93319-65-4 (0.036 g, 0.336 mmol, 1.2 equiv) at 0 ° C. under a nitrogen atmosphere for 10 min. The resulting mixture was stirred at room temperature for 16 h. The reaction was monitored on TLC (using MDC: MeOH; 9: 1 as the mobile phase), which confirmed that the reaction was complete after 16 h. 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 provide 0.15 g of crude product. The obtained crude material was purified by flash column chromatography using silica (230-400 mesh size) as the stationary phase (5% MeOH in DCM) to produce N-(2-hydroxyethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 43, 0.076 g, 0.184 mmol, yield: 65.79%).

[0786] 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-CH3 proton is merged with the DMSO solvent peak and is clearly visible in the MeOD NMR.)

[0787] 1H NMR (MeOD, 400MHz): δppm, 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(brs,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: -NH protons can be exchanged with deuterium from MeOD)

[0788] LCMS (Method A): 2.243 min, 98.55%, 254.0 nm, MS: ES+413 (M+1)

[0789] HPLC (Method A): 7.95 min, 98.09%, 254.0 nm

[0790] Chiral HPLC (Method A): Peak-1 4.25 min, 49.65%, 240.0 nm; Peak-2 4.69 min, 49.98%, 240.0 nm

[0791] Example 40 - Synthesis of N-(pyrazin-2-ylmethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 44):

[0792]

[0793] Step-1

[0794] To 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) stirred at 0° C. under a nitrogen atmosphere for 20 min was added CAS: 20010-99-5 (0.046 g, 0.420 mmol, 1.5 equiv). The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored on TLC (using 100% EtOAc as the mobile phase), which confirmed that the reaction was complete after 2 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 Na2SO4 and concentrated under reduced pressure to provide 0.072 g of crude product. The obtained crude material was purified by flash column chromatography using silica (230-400 mesh size) as the stationary phase (elution gradient, 95% ethyl acetate in hexane) to produce 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%).

[0795] 1 H NMR (DMSO-d6, 400MHz): δppm, 9.54 (t, J = 5.6Hz, 1H), 9.30 (d, J = 2.0Hz, 1H), 8.88 (d, J = 1.6Hz, 1H) ,8.73(s,1H),8.62(s,1H),8.57(d,J=2.0Hz,1H),8.03-8.01(m,1H),7.66-7.63(m,2H),5.87(br s,1H),4.71(d,J=5.6Hz,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 merges with the DMSO solvent peak and is clearly visible in the MeOD NMR)

[0796] 1H NMR (MeOD, 400MHz): δppm, 9.30 (d, J = 2.0Hz, 1H), 8.83 (d, J = 2.0Hz, 1H), 8.75 (s, 1H), 8.6 2(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: -NH protons can be exchanged with deuterium from MeOD)

[0797] LCMS (Method-A): 2.305 min, 98.22%, 254.0 nm, MS: ES+413.2 (M+1)

[0798] HPLC (Method-A): 8.360 min, 97.65%, 254.0 nm

[0799] Example 41 - Synthesis of N-((5-methyloxazol-2-yl)methyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 45):

[0800]

[0801] Step-1

[0802] To 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) stirred at 0 ° C. under a nitrogen atmosphere for 20 min was added CAS: 2173992-46-4 (0.0457 g, 0.420 mmol, 1.5 equiv). The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored on TLC (using 5% MeOH:DCM as the mobile phase), which confirmed that the reaction was complete after 2 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 Na2SO4 and concentrated under reduced pressure to provide 0.08 g of crude product. The obtained crude material was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (5% MeOH in DCM) to produce N-((5-methyloxazol-2-yl)methyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 45, 0.038 g, 0.0914 mmol, yield: 32.66%).

[0803] 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-CH3 protons merge with the DMSO solvent peak, which is clearly observed in the MeOD NMR)

[0804] 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 can exchange with deuterium from MeOD)

[0805] LCMS (Method-A): 2.433 min, 97.16%, 254.0 nm, MS: ES+416.1 (M+1)

[0806] HPLC (Method-A): 8.81 min, 97.37%, 254.0 nm

[0807] 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):

[0808]

[0809] Step-1

[0810] To 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 added CAS: 1187930-63-7 (0.065 g, 0.308 mmol, 1.1 equiv) at 0 ° C. under a nitrogen atmosphere for 20 min. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored on TLC (using MeOH:DCM; 0.5:9.5 as the mobile phase), which confirmed that the reaction was complete after 2 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 Na2SO4 and concentrated under reduced pressure to provide 0.08 g of crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh size) as the stationary phase (elution gradient, 95% ethyl acetate in hexane) to produce N-(2-hydroxy-1-(pyridin-2-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-ene-1-yl)quinoline-3-carboxamide (compound 46, 0.058 g, 0.131 mmol, yield: 46.90%).

[0811] 1 H NMR (DMSO-d6, 400MHz): δppm, 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 merge with the DMSO solvent peak, which is clearly observed in the MeOD NMR)

[0812] 1H NMR (MeOD, 400MHz): δppm, 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 can exchange with deuterium from MeOD)

[0813] LCMS (Method-A): 2.171 min, 100%, 210.0 nm, MS: ES+442.2 (M+1)

[0814] HPLC (Method-A): 8.19 min, 99.16%, 254.0 nm

[0815] Example 43 - Synthesis of N-((1H-pyrazol-5-yl)methyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 47):

[0816]

[0817] Step-1

[0818] To 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) stirred at 0 ° C. under a nitrogen atmosphere for 20 min was added CAS: 1196153-72-6 (0.041 g, 0.308 mmol, 1.1 equiv). The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored on TLC (using MeOH:DCM; 0.5:9.5 as the mobile phase), which confirmed that the reaction was complete after 2 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 Na2SO4 and concentrated under reduced pressure to provide 0.08 g of crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh size) as the stationary phase (elution gradient, 5% MeOH in DCM) to produce 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%).

[0819] 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-CH3 proton is merged with the DMSO solvent peak and is clearly visible in the MeOD NMR)

[0820] 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 can exchange with deuterium from MeOD)

[0821] LCMS (Method-A): 2.257 min, 98.28%, 254.0 nm, MS: ES+401.2 (M+1)

[0822] HPLC (Method-A): 8.02min, 95.17%, 254.0nm

[0823] 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):

[0824]

[0825] Step-1

[0826] To 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 added CAS: 1197157-75-7 (0.041 g, 0.308 mmol, 1.1 equiv) at 0 ° C. under a nitrogen atmosphere for 20 min. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored on TLC (using MeOH:DCM; 0.5:9.5 as the mobile phase), which confirmed that the reaction was complete after 2 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 Na2SO4 and concentrated under reduced pressure to provide 0.07 g of crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh size) as the stationary phase (elution gradient, 5% MeOH in DCM) to produce 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%).

[0827] 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-CH3 proton is merged with the DMSO solvent peak and is clearly visible in the MeOD NMR)

[0828] 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 can exchange with deuterium from MeOD)

[0829] LCMS (Method-A): 2.069 min, 99.06%, 254.0 nm, MS: ES+402.2 (M+1)

[0830] HPLC (Method-A): 6.22 min, 98.60%, 254.0 nm

[0831] Example 45 - Synthesis of N-(cyanomethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 49):

[0832]

[0833] Step-1:

[0834] To 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 added CAS: 6011-14-9 (0.03168 g, 0.342 mmol, 1.1 equiv) at 0° C. under a nitrogen atmosphere for 20 min. The resulting mixture was stirred at room temperature for 30 min. The reaction was monitored on TLC (using EtOAc: hexane; 1:1 as the mobile phase), which confirmed that the reaction was complete after 30 min. 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 Na2SO4 and concentrated under reduced pressure to provide 0.15 g of crude product. The obtained crude material was purified by flash column chromatography using silica (230-400 mesh size) as the stationary phase (30% ethyl acetate in hexane) to produce N-(cyanomethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (compound 49, 0.1 g, 0.278 mmol, yield: 89.41%).

[0835] 1 H NMR (DMSO d 6 , 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, 1H), 1.75-1.64 (m, 1H) (Note: - One CF3-CH3 proton merged with the DMSO solvent peak and is clearly visible in the MeOD NMR)

[0836] 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 can exchange with deuterium from MeOD)

[0837] LCMS (Method A): 2.438 min, 100%, 254.0 nm, MS: ES+360.07 (M+1)

[0838] HPLC (Method A): 8.764 min, 100%, 254.0 nm

[0839] Chiral HPLC: Peak 1 = 3.87 min, 49.62%, 240.0 nm; Peak 2 = 4.46 min, 50.38%, 240.0 nm

[0840] Example 4 Synthesis of 6-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carbonyl)-D-alanine (Compound 50):

[0841]

[0842] Step-1:

[0843] Under inert conditions N2 (g), 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) was added HATU (0.88 g, 2.3 mmol, 1.5 equiv). The reaction was monitored by TLC (using pure ethyl acetate as the mobile phase), which confirmed that the reaction was 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 provide 0.45 g of crude product. The crude product was purified by manual column chromatography using silica (230-400 mesh) as the stationary phase (gradient elution, 20% ethyl acetate in hexanes) to yield methyl (3R)-3-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamido)butanoate (A29, 0.3 g, 0.738 mmol, 47.44% yield).

[0844] 1 H NMR(DMSO-d6,400MHz): δppm 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)

[0845] LCMS: 2.51 min, 100%, 215 nm

[0846] Step-2:

[0847] At 0 ° C, to a stirred solution of A29 (0.15 g, 0.36 mmol, 1.0 equivalent) in MeOH:H o (8: 2) was added LiOH (0.018 g, 0.44 mmol, 1.2 equivalents) and the reaction was allowed to run at room temperature. The reaction was monitored by TLC (using pure ethyl acetate as mobile phase), which confirmed that the reaction was complete after stirring at room temperature for 2 h. The resulting reaction mixture was concentrated, acidified with 1N HCl, and then filtered using a Buchner funnel to produce (8-(4-(trifluoromethyl)cyclohex-1-ene-1-yl)quinoline-3-carbonyl)-D-alanine (compound 50, 0.056 g, 0.143 mmol, 38.67% yield).

[0848] 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-CH3 proton merged with the DMSO solvent peak and was not detected in MeOD Clearly visible in NMR)

[0849] 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 can exchange with deuterium from MeOD)

[0850] LCMS: 2.28 min, 100%, 210 nm

[0851] HPLC: 4.49 min, 99.17%, 254 nm

[0852] Chiral HPLC: Peak-1 3.58 min, 48.54%, 240 nm; Peak-2: 3.90 min, 49.73%, 240 nm

[0853] Example 47: Synthesis of 7-O-methyl-N-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carbonyl)-D-serine (Compound 51):

[0854]

[0855] Step-1:

[0856] In 250mL three-necked RB flask, 8-(4-(trifluoromethyl) cyclohex-1-ene-1-yl) quinoline-3-carboxylic acid (compound 15, 0.250g, 0.775mmol), O-methyl-D-serine methyl ester hydrochloride CAS1800300-79-1 (0.315g, 0.934mmol, 1.2 equivalents) and DIPEA (1.12ml, 2.35mmol, 3.0 equivalents) and HATU (0.89g, 1.16mmol, 1.5 equivalents) as white amorphous material are stirred in DMF (2mL, 10v) for 16h in room temperature.On TLC (using EtOAc: hexane; 3:7 is as mobile phase), upper monitoring reaction confirms that after stirring at room temperature 16h, the reaction is complete. Obtained reaction mixture is diluted with ice-cold water (10mL) and extracted with DCM. The combined layers were evaporated under vacuum, and the crude residue was purified on silica column chromatography (60-120 mesh; 30% EtOAc and hexanes) to yield O-methyl-N-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carbonyl)-D-serine methyl ester (A30, 0.185 g, 0.424 mmol, yield: 54.48%).

[0857] 1 H NMR(DMSO-d6,400MHz): δppm 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).

[0858] LCMS (Method A): 2.513 min, 100.0%, MS: ES+437.18 [M+H]

[0859] Step-2:

[0860] By O-methyl-N-(8-(4-(trifluoromethyl)cyclohex-1-ene-1-yl)quinoline-3-carbonyl)-D-serine methyl ester (A30, 0.170g, 0.3895mmol, 1.0 equivalents) suspension in THF / water (3mL / 1mL) is cooled to 0 ℃, then with LiOH (0.033g, 0.824mmol 2.0 equivalents) process, and the reaction solution is stirred at this temperature for 12 hours.Solution is acidified with 1N HCl.The resulting reaction mixture is diluted with water (10mL) and extracted with EtOAc (3×20mL). The combined organic layers were extracted with EtOAc (2 x 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 grey solid.

[0861] 1 H NMR (400MHz, DMSO-d6) δppm: 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-CH3 proton merges with the DMSO solvent peak and is clearly visible in the MeOD NMR)

[0862] 1H 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 can be exchanged with deuterium from MeOD)

[0863] LCMS (Method A): 2.31 min, 95.47%, 254 nm

[0864] HPLC (Method A): 4.34 min, 96.33%, 254 nm

[0865] Chiral HPLC: Peak-1 6.26 min, 36.05%, 240 nm; Peak-2 6.71 min, 43.16%, 240 nm

[0866] 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):

[0867]

[0868] Step-1:

[0869] 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 conditions N2(g), followed by the addition of HATU (0.232 g, 0.612 mmol, 1.5 equiv). The reaction was monitored by TLC (using pure ethyl acetate as the mobile phase), which confirmed that the reaction was 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 Na2SO4 and concentrated under reduced pressure to provide 0.45 g of crude product. The crude product was purified by manual column chromatography using silica (230-400 mesh) as the stationary phase (gradient elution, 20% ethyl acetate in hexanes) and then by preparative HPLC (Method-A) to produce 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).

[0870] 1 H NMR (DMSO-d6, 400MHz): δppm 9.28 (d, J = 2.0Hz, 1H), 8.91-8.88 (m, 2H), 8.02-7.80 (m, 2H), 7.95 (m, J = 4.4Hz, 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-CH3 proton merges with the DMSO solvent peak and is clearly visible in the MeOD NMR)

[0871] 1H 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 can exchange with deuterium from MeOD)

[0872] LCMS (Method A): 2.20 min, 100%, 254.0 nm, m / z=406.12 (M+H) +

[0873] HPLC (Method A): 7.75 min, 99.61%, 210 nm

[0874] Chiral HPLC: Peak-1: 3.55 min, 42.28%, 245 nm; Peak-2: 4.07 min, 43.73%, 245 nm

[0875] Example 49 - Synthesis of N-((R)-1-aminopropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 53):

[0876]

[0877] Step-1:

[0878] Under inert conditions N2 (g), 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) was added HATU (0.35 g, 0.93 mmol, 1.5 equiv). The reaction was monitored by TLC (using pure ethyl acetate as the mobile phase), which confirmed that the reaction was 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 provide 0.3 g of crude product. The crude product was purified by manual column chromatography using silica (230-400 mesh) as the stationary phase (gradient elution, 20% ethyl acetate in hexanes) to yield tert-butyl ((2R)-2-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamido)propyl)carbamate (A31, 0.22 g, 0.461 mmol, 67.28% yield).

[0879] 1 H NMR(DMSO-d6,400MHz): δppm 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)

[0880] LCMS (Method-A): RT=2.72 min, 100%, 254 nm, m / z=478.24 (M+H) +

[0881] Step-2:

[0882] 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 allowed to run at room temperature. The reaction was monitored by TLC (using pure ethyl acetate as the mobile phase), which confirmed that the reaction was complete after stirring at room temperature for 16 h. The resulting reaction mixture was concentrated and then triturated with pentane and diethyl ether to produce N-((R)-1-aminopropan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-ene-1-yl)quinoline-3-carboxamide (compound 53, 0.070 g, 0.18 mmol, 88.57% yield).

[0883] 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-CH3 proton is merged with the DMSO solvent peak and is clearly visible in the MeOD NMR.)

[0884] 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 can exchange with deuterium from MeOD)

[0885] LCMS (Method-A): 1.86 min, 100%, 210.0 nm, m / z=378.1

[0886] HPLC (Method-A): 8.34 min, 100%, 210 nm

[0887] Chiral HPLC: Peak-1: 5.27 min, 47.54%, 240 nm; Peak-2: 5.75 min, 52.45%, 240 nm

[0888] Example 50: Synthesis of N-((R)-4-hydroxybutan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 54):

[0889]

[0890] Step-1:

[0891] Under inert conditions N2 (g), 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) was added HATU (0.355 g, 0.934 mmol, 1.5 equiv). The reaction was monitored by TLC (using pure ethyl acetate as the mobile phase), which confirmed that the reaction was 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 provide 0.45 g of crude product. The crude product was purified by manual column chromatography using silica (230-400 mesh size) as the stationary phase (gradient elution, 20% ethyl acetate in hexanes) to produce 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, 25.79% yield).

[0892] 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-CH3 proton is merged with the DMSO solvent peak and is clearly visible in the MeOD NMR)

[0893] 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 can exchange with deuterium from MeOD)

[0894] LCMS (Method-A): 2.27 min, 98.91%, 254.0 nm, m / z=393.17 (m+H) +

[0895] HPLC (Method-A): 8.25 min, 100%, 210 nm

[0896] Chiral HPLC: Peak-1: 4.22 min, 50.06%, 240 nm; Peak-2: 4.53 min, 49.93%, 240 nm

[0897] Example 51 Synthesis of 3-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamido)butanoic acid (Compound 55):

[0898]

[0899] Step-1

[0900] Under inert conditions N2(g) 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) was added HATU (0.798 g, 2.1 mmol, 1.5 equiv). The reaction was monitored by TLC (using neat ethyl acetate as the mobile phase), which confirmed that the reaction was 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 Na 2 SO 4 and concentrated under reduced pressure to provide 0.45 g of crude product. The crude product was purified by manual column chromatography using silica (230-400 mesh) as the stationary phase (gradient elution, 20% ethyl acetate in hexanes) to yield methyl (3R)-3-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamido)butanoate (A32, 0.41 g, 0.975 mmol, 69.72% yield).

[0901] 1 H NMR (MeOD, 400MHz): δppm 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=6.8Hz,3H). (Note: -NH protons may exchange with deuterium from MeOD; traces of EA solvent observed).

[0902] LCMS (Method A): 2.523 min, 100%, 254 nm, (M+H) + =421.12

[0903] Chiral HPLC: Peak-1 3.31min, 49.60%, 240nm Peak-2 3.52min, 50.39%, 240nm

[0904] Step-2

[0905] At 0 ℃, to (A32, 0.38g, 0.90mmol, 1.0 equivalents) in MeOH:HO (8:2) stirred solution is added LiOH.HO (0.094g, 1.80mmol, 2.0 equivalents), then allow the reaction to run at room temperature. Monitor the reaction by TLC (using pure ethyl acetate as mobile phase), which confirms that the reaction is complete after stirring at room temperature for 2h. The resulting reaction mixture is concentrated, then acidified with 1N HCl, then filtered using a Buchner funnel, to produce (3R)-3-(8-(4-(trifluoromethyl)cyclohex-1-ene-1-yl)quinoline-3-formamido)butanoic acid (compound 55, 0.18g, 0.44mmol, yield 49%).

[0906] 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-CH3 proton is merged with the DMSO solvent peak and is clearly visible in the MeOD NMR)

[0907] 1 H 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 can exchange with deuterium from MeOD)

[0908] LCMS (Method A): 2.28 min, 100%, 242.0 nm, (M+H) + =407.12

[0909] HPLC (Method A): 4.51 min, 99.47%, 254 nm

[0910] Chiral HPLC: Peak-1 4.97 min, 47.33%, 240 nm; Peak-2 5.52 min, 44.05%, 240 nm

[0911] 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):

[0912]

[0913] Step-1

[0914] Under inert conditions N 2(g) 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 DCM (2 mL) was added EDCI.HCl (0.0757 g, 0.395 mmol, 1.5 equiv) and HOBt (0.0534 g, 0.39 mmol, 1.5 equiv). The reaction was monitored by TLC (using pure ethyl acetate as the mobile phase), which confirmed that the reaction was 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 Na 2 SO 4 and concentrated under reduced pressure to provide 0.07 g of crude product. The crude product was purified by manual column chromatography using silica (230-400 mesh) as the stationary phase (gradient elution in pure ethyl acetate) to produce 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, 40.75% yield).

[0915] 1H NMR (MeOD, 400MHz): δppm 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)

[0916] 1 H NMR (CD3CN, 400MHz): δppm 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)

[0917] LCMS (Method A): 2.22 min, 99.89%, 254 nm, (M+H) + =420.18

[0918] HPLC (Method A): 7.69 min, 99.53%, 210 nm

[0919] Chiral HPLC: Peak-1 11.21 min, 52.16%, 225 nm; Peak-2 11.81 min, 47.84%, 225 nm

[0920] Example 53-Synthesis of 5-(4,4-difluorocyclohex-1-en-1-yl)-N-isopropyl-2-naphthamide (Compound 57):

[0921]

[0922] Step-1

[0923] To 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) stirred at 0 ° C. under a nitrogen atmosphere for 20 min was added propan-2-amine CAS: 75-31-0 (0.258 g, 4.389 mmol, 1.1 equiv). The resulting mixture was stirred at room temperature for 16 h. The reaction was monitored on TLC (using EtOAc: hexane; 3:7 as mobile phase), which confirmed that the reaction was complete 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 provide 1.3 g of crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) as a stationary phase (0%-20% ethyl acetate in hexane) to produce 5-bromo-N-isopropyl-2-naphthamide (A33) (0.95 g, 3.251 mmol, yield: 81.64%).

[0924] 1 H NMR (DMSO-d 6 , 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: There are some aliphatic impurities related to SM.

[0925] LCMS (Method A): 2.286 min, 97.67%, 254.0 nm, MS: ES+ 292.1 (M), 294.1 (M+2)

[0926] Step-2

[0927] A stirred solution of 5-bromo-N-isopropyl-2-naphthamide (A33) (0.3 g, 1.229 mmol, 1.0 eq), 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 eq) and tripotassium phosphate (0.78 g, 3.687 mmol, 3.0 eq) in 1,4-dioxane (3 mL) was purged with nitrogen for 30 min, then Pd(PPh3)4 (0.143 g, 0.123 mmol, 1.3 eq) was added and the resulting reaction mixture was heated up to 100°C for 16 h. The reaction was monitored by TLC (using EA: hexane; 3:7 as mobile phase), which confirmed the completion of the reaction after stirring at 100° C. for 16 h. The resulting reaction mixture was filtered through a bed of celite, and the filtrate was concentrated under reduced pressure to obtain a crude residue (0.4 g), which was purified by silica gel (60-120 mesh) as a stationary phase (25% EtOAc in hexane) to produce 5-(4,4-difluorocyclohex-1-en-1-yl)-N-isopropyl-2-naphthamide (Compound 57) (0.14 g, 0.425 mmol, yield: 34.65%).

[0928] 1 H NMR (DMSO-d6, 400MHz): δppm 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).

[0929] LCMS (method A): 2.398 min, 98.32%, MS: ES+330.16 [M+H]

[0930] HPLC (method C): 8.357 min, 96.83%, 210 nm

[0931] Example 54 - Synthesis of N-((S)-1-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-2-naphthamide (Compound 58):

[0932]

[0933] Step-1

[0934] 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 on TLC (using EA: hexane; 2.0: 8.0 as mobile phase), which confirmed that the reaction was complete after stirring at 120 ° C for 5 h. The resulting reaction mixture was cooled to RT. The solid obtained was filtered off and washed with AcOH (50 mL) and water (200 mL) to provide 20.0 g of crude product. The crude material was then ground using MeOH (2 × 50 mL) to provide 5-bromo-2-naphthoic acid (A34) (15.0 g, 59.74 mmol, yield: 42.86%).

[0935] 1 H NMR(DMSO-d6,400MHz): δppm,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).

[0936] Step-2

[0937] 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 K3PO4 (1.05 g, 4.980 mmol, 5.0 equiv) in dioxane (2 mL) and water (1 mL) was added Pd(dppf)Cl2 under N2. .The product was stirred at 100 ℃ for 2 hours in DCM (0.081 g, 0.099 mmol, 0.1 equivalent). The resulting mixture was stirred at 100 ℃ for 2 hours. The reaction was monitored by TLC (using EA: hexane; 8.0: 2.0 as mobile phase), which confirmed that the reaction was complete after stirring at 100 ℃ for 2 hours. The resulting reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to provide 0.320 g of crude product. The crude material obtained was purified by flash column chromatography using silica gel (230-400 mesh) as a stationary phase (69% EA in hexane) to provide 5-(4-(trifluoromethyl)cyclohex-1-ene-1-yl)-2-naphthoic acid (A35) (0.30 g, 0.936 mmol, yield: 94.06%).

[0938] 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: A small amount of aliphatic impurity peaks were observed.

[0939] LCMS (Method A): 2.732 min, 92.64%, 280.0 nm, MS: ES-319.4 (M-1)

[0940] Step-3

[0941] To 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) stirred at 0 ° C. under a nitrogen atmosphere for 15 min was added CAS: 40154-78-7 (0.068 g, 0.562 mmol, 1.2 equiv) under an 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 mobile phase), which confirmed that the reaction was 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 Na2SO4 and concentrated under reduced pressure to provide 0.250 g of crude product. The obtained crude material was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (35% ethyl acetate in hexane) to provide 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%).

[0942] 1 H NMR (DMSO, 400MHz): δppm, 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).

[0943] 1H NMR (MeOD, 400MHz): δppm, 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, 2 H),7.85(td,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=7.2Hz,3H). Note: No amide -NH was observed.

[0944] LCMS (Method A): 2.572 min, 97.37%, 210.0 nm, MS: ES+ 425.23 (M+1)

[0945] HPLC (method B): 6.907 min, 95.34%, 210.0 nm

[0946] Chiral HPLC (Method A): 2.51 min, 95.16%, 230.0 nm

[0947] Example 55: Synthesis of N-isopropyl-8-(spiro[2.5]oct-5-en-6-yl)quinoline-3-carboxamide (Compound 59):

[0948]

[0949] Step-1

[0950] To a stirred solution of 1,4-dioxaspiro[4.5]decan-8-one (CAS: 4746-97-8) (25 g, 160.07 mmol, 1.0 eq), CAS: 1779-49-3 (57.1 g, 160.07 mmol, 1.0 eq) in toluene (200 mL) was added KO under N2 atmosphere. tBu (21.5 g, 192.08 mmol, 1.2 equiv). The resulting mixture was then stirred at 110 ° C for 16 h. The reaction was monitored by TLC (using EA: hexane; 1: 9 as mobile phase), which confirmed that the reaction was 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 provide 25 g of crude product. The crude product was purified by manual column chromatography using silica (60-120 mesh) as the stationary phase (gradient elution, 4% EA in hexane) to provide 8-methylene-1,4-dioxaspiro[4.5]decane (A36) (18 g, 116.88 mmol, 72.92% yield).

[0951] 1 H NMR (CDCl3, 400MHz): δppm 4.69 (s, 2H), 3.98 (s, 4H), 2.30 (t, J = 6.4Hz, 4H), 1.72 (t, J = 6.8Hz, 4H).

[0952] Step-2

[0953] At -40 ° C under N2 atmosphere, diethyl zinc (87.9 mL, 87.9 mmol, 2.56 equivalents) was added to a stirred solution of A36 (5.2 g, 34 mmol, 1.0 equivalents) in toluene (52 mL). The resulting mixture was then stirred for 20 min at -40 ° C. CH2I2 (46.06 g, 172 mmol, 5.2 equivalents) was added at -40 ° C, and the reaction mixture was allowed to run overnight. The reaction was monitored by TLC (EA: hexane; 1: 9 as mobile phase), which confirmed that the reaction was complete after stirring at room temperature for 18 h. The resulting reaction mixture was quenched with NH4Cl and extracted with ether (4 × 30 mL). The combined organic layer was washed with sodium thiosulfate (3 × 40 ml) and dried over Na2SO4, then concentrated under reduced pressure to provide 5.3 g of crude product. The crude product was purified by manual column chromatography using silica (230-400 mesh) as the stationary phase (gradient elution, 3% ethyl acetate in hexanes) to give 7,10-dioxadispiro[2.2.4.2]dodecane (A37) (3 g, 17.85 mmol, 52% yield).

[0954] 1 H NMR (CDCl3, 400MHz): δppm 3.98 (s, 4H), 1.71 (t, J = 6.0Hz, 4H), 1.45-1.42 (m, 4H), 0.30 (s, 4H).

[0955] Step 3

[0956] At 0 DEG C under N2 atmosphere, to A37 (1.1g, 6.54mmol, 1.0 equivalent) in THF:HO (8.33mL, 3:2) stirred solution was added TFA (1.67mL, 21.58mmol, 3.3 equivalent). The resulting mixture was stirred at 0 DEG C for 18h. The reaction was monitored by TLC (using ether:pentane; 1:9 as mobile phase), which confirmed that the reaction was complete after stirring at room temperature for 18h. After completion, the reaction mixture was quenched with Na2CO3 aqueous solution and extracted with ether (4×30mL). The combined organic layers were washed with Na2SO3 (3×40ml) and dried over Na2SO4, concentrated under reduced pressure to provide 5.3g crude product. The crude product was purified by manual column chromatography using silica (230-400 mesh) as the stationary phase (2% ethyl acetate in hexanes) to yield spiro[2.5]octan-6-one (A38) (0.2 g, 1.61 mmol, 24.63% yield).

[0957] 1 H NMR (CDCl3, 400MHz): δppm 2.54-2.42 (m, 4H), 1.70 (t, J = 6.8Hz, 4H), 0.51 (s, 4H).

[0958] Step 4

[0959] At -78 ° C under N2 atmosphere, to a stirred solution of A38 (0.2 g, 1.61 mmol, 1.0 equivalent) in THF (4 mL) was added LiHMDS (1.7 mL, 1.77 mmol, 1.1 equivalents, 1.0 M in THF) 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 equivalents) was added to the reaction mixture, and the reaction was allowed to run overnight. The reaction was monitored by TLC (ethyl acetate: hexane, 1: 9 as mobile phase), which confirmed that the reaction was complete after stirring at room temperature for 18 h. The resulting reaction mixture was quenched with H2O and extracted with ethyl acetate (4 × 30 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide 0.25 g of crude product. The crude product was purified by manual column chromatography using silica (230-400 mesh) as the stationary phase (gradient elution, 5% ethyl acetate in hexanes) to provide spiro[2.5]oct-5-en-6-yl trifluoromethanesulfonate (A39) (0.19 g, 0.74 mmol, 46.04% yield).

[0960] 1 H NMR (CDCl3, 400MHz): δppm 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).

[0961] Step 5

[0962] To a stirred solution of A39 (1.4 g, 5.46 mmol, 1.0 eq) in dioxane (14 mL) was added B2Pin2 (CAS: 73183-34-3) (1.52 g, 6.0 mmol, 1.1 eq), followed by KOAc (1.62 g, 16.54 mmol, 3.03 eq), PdCl2(dppf) (0.39 g, 0.54 mmol, 0.1 eq), and the reaction mixture was purged with N2 for 10 min and then stirred at 100 ° C overnight. TLC (ethyl acetate: hexane; 1:9 as mobile phase) confirmed the completion of the reaction. The resulting reaction mixture was filtered using celite and extracted with ethyl acetate (4×30 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to provide 0.41 g of crude product. The crude product was purified by manual column chromatography using silica (230-400 mesh) as the stationary phase (10% ethyl acetate in hexanes) to yield 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).

[0963] 1 H NMR (CDCl3, 400MHz): δppm 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).

[0964] Step 6

[0965] To a stirred solution of A40 (0.07 g, 0.29 mmol, 1.1 eq) and A23 (0.08 g, 0.27 mmol, 1.0 eq) in dioxane:H2O (8:2) was added K3PO4 (0.173 g, 0.81 mmol, 3.0 eq), PdCl2(dppf).DCM (0.11 g, 0.31 mmol, 0.5 eq), and the reaction mixture was allowed to run at 110 °C overnight. The reaction was monitored by TLC (ethyl acetate: hexane; 5:5 as mobile phase), which confirmed that the reaction was complete after stirring at 110 °C for 16 h. The resulting reaction mixture was filtered using celite, and the filtrate was extracted with ethyl acetate (4 × 30 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to provide 0.078 g of crude product. The crude product was purified by manual column chromatography using silica (230-400 mesh) as the stationary phase (gradient elution, 35% ethyl acetate in hexanes) to give N-isopropyl-8-(spiro[2.5]oct-5-en-6-yl)quinoline-3-carboxamide (Compound 59) (0.03 g, 0.09 mmol, 31.32% yield).

[0966] 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, 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), 0.44 (s, 4H). Note: -CONH protons are exchanged in MeOD NMR.

[0967] LCMS (Method A) -2.57 min, 100%, 254.0 nm MS; ES+ 321.2 (M+H)

[0968] HPLC (Method A) - 9.81 min, 95.41%, 210 nm

[0969] Example 56 Synthesis of 6-(S)-N-(1-(pyridin-2-yl)ethyl)-8-(spiro[2.5]oct-5-en-6-yl)quinoline-3-carboxamide (Compound 60):

[0970]

[0971] Step-1

[0972] To a stirred solution of methyl 8-bromoquinoline-3-carboxylate (A13) (1.8 g, 6.76 mmol, 1.0 eq), A40 (1.74 g, 7.44 mmol, 1.1 eq) in dioxane:HO (8:2) was added KPO (4.28 g, 20.2 mmol, 3.0 eq) and purged with N for 15 min. PdCl(dppf) (0.24 g, 0.338 mmol, 0.05 eq) was then added to the reaction mixture, which was then stirred at 110 °C for 16 h. TLC (EA:hexane; 1:1 as mobile phase) indicated that the reaction was complete. The resulting reaction mixture was filtered using celite, and the filtrate was then extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to provide 1.75 g of crude product. The crude product was purified by manual column chromatography using silica (60-120 mesh) as the stationary phase (gradient elution, 30% ethyl acetate in hexanes) to afford methyl 8-(spiro[2.5]oct-5-en-6-yl)quinoline-3-carboxylate (A41) (1.15 g, 3.91 mmol, 57.95% yield).

[0973] 1 H NMR (MeOD, 400MHz): δppm 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).

[0974] LCMS (Method A): 2.982min, 99.11%, 254.0nm, MS: ES+294.2(M+1)

[0975] Step 2

[0976] At RT, to A41 (1.1g, 3.74mmol, 1.0 equivalent) in MeOH:H o (8: 1) (11ml) stirred solution was added NaOH (0.74g, 18.74mmol, 5.0 equivalent). Then the resulting mixture was stirred at room temperature for 16h. The reaction was monitored by TLC (using 100% ethyl acetate as mobile phase), which confirmed that the reaction was complete after stirring at room temperature for 16h. The resulting reaction mixture was concentrated under vacuum, and the residue was then acidified with dilute HCl (PH=3). The solid obtained was filtered and dried under vacuum to provide 8- (spiro [2.5] oct-5-ene-6-yl) quinoline-3-carboxylic acid (A42) (0.73g, 2.61mmol, 69.70% yield).

[0977] 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 are exchangeable in MeOD NMR.

[0978] LCMS (Method A): 2.510 min, 99.38%, 254.0 nm, MS: ES+280.11 (M+1)

[0979] Step 3

[0980] Under N2 atmosphere, 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). Then, 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 RT for 18 h. The reaction was monitored by TLC (100% EA as 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 Na2SO4 and concentrated under reduced pressure to provide a crude product. The crude product was purified by manual column chromatography using silica (100-200 mesh) as the stationary phase (gradient elution, 100% ethyl acetate) to provide (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).

[0981] 1 H NMR (MeOD, 400MHz): δppm 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 protons are exchanged in MeOD NMR.

[0982] LCMS (Method A): 2.273 min, 100%, 254.0 nm, MS: ES+384.2 (M+1)

[0983] HPLC (Method A): 9.67 min, 99.33%, 254.0 nm.

[0984] Chiral HPLC (Method A): 7.82 min, 94.27%, 300 nm.

[0985] Example 57: Synthesis of N-(oxazol-2-ylmethyl)-8-(spiro[2.5]oct-5-en-6-yl)quinoline-3-carboxamide (Compound 61):

[0986]

[0987] Step-1

[0988] At 0 ℃ under nitrogen atmosphere, to a stirred solution of oxazole-2-carboxaldehyde (5.0 g, 51.5 mmol, 1.0 equivalent) in DMF (10 mL) was added 2-methylpropane-2-sulfinamide CAS: 146374-27-8 (7.4 g, 61.8 mmol, 1.2 equivalents) and piperidine-1-carboxaldehyde CAS: 3087-36-3 (25.5 ml, 10.3 mmol, 2.0 equivalents). The reaction mixture was then stirred at RT for 16 h. TLC (50% EtOAc in hexane as mobile phase) showed that the reaction was complete. The resulting reaction mixture was poured into water (100 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were dried over Na SO , filtered and concentrated under reduced pressure to obtain a crude product. The crude product obtained was purified by column chromatography using silica gel 230-400 mesh size, and the desired product was eluted with 40% EtOAc in hexanes to provide (E)-2-methyl-N-(oxazol-2-ylmethylene)propane-2-sulfenamide (A43) (4.9 g, 24.46 mmol, yield: 47.50%).

[0989] 1 H NMR (DMSO, 400MHz): δ ppm 8.45 (s, 1H), 8.28 (s, 1H), 7.62 (s, 1H), 1.27 (s, 9H).

[0990] LCMS (Method A): LCMS did not support the expected mass of the product.

[0991] Step-2

[0992] At 0 ℃, to (E) -2- methyl -N- (oxazol-2-ylmethylene) propane -2- sulfinamide (A43) (4.9g, 29.9mmol, 1.0 equivalent) in MeOH (20mL) stirring solution was added NaBH4 (1.7g, 44.9mmol, 2.0 equivalent). The reaction mixture was stirred at RT for 30min and monitored on TLC (5% DCM: MeOH as mobile phase). The resulting reaction mixture was poured into water (400mL) and extracted with EtOAc (3 × 200mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by column chromatography (desired product was eluted with 2% MeOH in DCM) to afford 2-methyl-N-(oxazol-2-ylmethyl)propane-2-sulfenamide (A44) (4.1 g, 20.26 mmol, yield: 82.84%).

[0993] LCMS (Method A): 1.303 min, 100.0%, 210.0 nm MS: ES+ 203.0 (M+1).

[0994] 1 H NMR (DMSO, 400MHz): δppm 7.64 (s, 1H), 7.09 (s, 1H), 4.49-4.37 (m, 2H), 3.94 (t, J = 8.8Hz 1H), 1.24 (s, 9H).

[0995] Step-3

[0996] At 0 DEG C, to 2-methyl-N-(oxazol-2-ylmethyl)propane-2-sulfinamide (A44) (9.0g, 44.4mmol, 1.0 equivalent) stirred solution in MeOH (90mL) is added 4M HCl (11.68g, 31.1mmol, 7.0v) in dioxane, and reaction mixture is stirred at RT for 1h.Reaction is monitored on TLC (using 5%DCM:MeOH as mobile phase).After completion, resulting reaction mixture is directly concentrated under reduced pressure to obtain crude material, and this crude material is ground using pentane to provide oxazol-2-ylmethylamine hydrochloride (A45) (7.0g, 52.02mmol, yield: 87.88%).

[0997] LCMS (Method A): LCMS did not support the expected mass of the product.

[0998] 1H NMR (DMSO, 400MHz): δ ppm 8.94 (s, 3H), 8.23 ​​(s, 1H), 7.30 (s, 1H), 4.22 (s, 2H).

[0999] Step-4

[1000] 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, followed by addition of (A45) (0.12 g, 0.93 mmol, 1.3 equiv) to the reaction mixture under an N atmosphere after 10 min. The resulting reaction mixture was stirred at room temperature for 16 h. TLC (100% EA as mobile phase) indicated that the reaction was complete. The resulting reaction mixture was poured into ice water (10 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to provide 0.21 g of crude product. The crude product was purified by manual column chromatography using silica (100-200 mesh) as the stationary phase (gradient elution, 100% ethyl acetate) to produce 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).

[1001] 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 are exchanged in MeOD NMR.

[1002] 1H NMR (DMSO, 400MHz): δppm 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(brs,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).

[1003] LCMS (Method A) -2.38 min, 100%, 254.0 nm, MS: ES+360.3 (M+1)

[1004] HPLC (Method A) - 8.76 min, 97.68%, 210 nm

[1005] Example 58: Synthesis of N-((S)-1-hydroxy-3-methoxyprop-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 62):

[1006]

[1007] Step-1

[1008] A solution of benzonitrile CAS100-47-0 (15 g, 145.63 mmol, 1.0 equivalent) and acetyl chloride (83 mL, 1165.04 mmol, 8.0 equivalent) in EtOH (75 mL) was stirred at RT for 16 h. The reaction was monitored on TLC (using EtOAc: hexane; 3: 7 as mobile phase), which confirmed that the reaction was complete after 16 h. The resulting reaction mixture was quenched with saturated NaHCO (30 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over Na SO and concentrated under reduced pressure to provide 20.0 g of crude product. The crude material obtained was purified by manual column chromatography using silica (100-200 mesh) as the stationary phase (gradient elution, 10% EA in hexanes) to afford ethyl benzimidate (A46) (14 g, 93.95 mmol, yield: 64.52%).

[1009] 1H NMR (DMSO-d6, 400MHz): δppm, 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)

[1010] LCMS (Method A): 1.081 min, 91%, 254.0 nm, MS: ES+149 (M+1)

[1011] Step-2

[1012] A solution of ethyl benzimidate (A46) (14 g, 93.95 mmol, 1.0 equiv) and L-serine methyl ester hydrochloride CAS5680-80-8 (16 g, 103.35 mmol, 1.1 equiv) in 1,2DCE (140 mL) was stirred at 80 ° C for 20 h. TLC (EA: hexane; 1: 1 as mobile phase) showed that the reaction was complete, and the resulting reaction mixture was then filtered through a bed of celite, and the filtrate was concentrated under reduced pressure to obtain a residue. The crude residue obtained was purified by manual column chromatography using silica (100-200 mesh) as the stationary phase (gradient elution, 30% EA in hexane) to provide (S) -2-phenyl-4,5-dihydrooxazole-4-carboxylate (A47) (14 g, 68.292 mmol, yield: 72%).

[1013] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[1014] LCMS (Method A): 1.799 min, 99.47%, 254.0 nm, MS: ES+206 (M+1)

[1015] Step-3

[1016] At 0 ° C, to a stirred solution of (S) -2-phenyl -4,5- dihydrooxazole -4- carboxylate (A47) (14g, 68.292mmol, 1.0 equivalent) in THF (1.8mL) was added DIBAL-H (204mL, 204.87mmol, 3.0 equivalents). The resulting reaction mixture was stirred at room temperature for 3h. The reaction was monitored on TLC (EA: hexane; 7: 2 as mobile phase), which confirmed that the reaction was complete after 3h. The resulting reaction mixture was quenched with saturated NH4Cl (50mL) and extracted with EtOAc (3 × 100mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to provide 15g of crude product. The obtained crude material was purified by manual column using silica (100-200 mesh) as the stationary phase (70% EA in hexanes) to afford (R)-(2-phenyl-4,5-dihydrooxazol-4-yl)methanol (A48) (8.0 g, 45.197 mmol, yield: 66%).

[1017] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[1018] LCMS (Method A): 1.006 min, 94%, 254.0 nm, MS: ES+178 (M+1)

[1019] Step-4

[1020] 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. The reaction mixture was then stirred at RT for 16 h. The reaction was monitored by TLC (EA: hexane; 1: 1 as mobile phase), which indicated that the reaction was complete. The resulting reaction mixture was poured into ice-cold water (50 mL) and extracted with EtOAc (3×100 mL), dried over Na2SO4 and concentrated under reduced pressure to provide a crude product. The crude material obtained was purified by manual column using silica (100-200 mesh) as the stationary phase (gradient elution, 50% EA in hexanes) to give (R)-4-(methoxymethyl)-2-phenyl-4,5-dihydrooxazole (A49) (3.5 g, 18.324 mmol, yield: 40%).

[1021] 1 H NMR(DMSO-d6,400MHz): δppm,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).

[1022] LCMS (Method A): 1.345 min, 88%, 254.0 nm, MS: ES+192 (M+1)

[1023] Step-5

[1024] 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 RT for 5 min, and the resulting reaction mixture was then heated at 110 ° C for 20 h. TLC (5% MeOH in DCM as mobile phase) indicated that the reaction was complete. The resulting reaction mixture was cooled to RT and then filtered through a Buchner funnel. The obtained filtrate was extracted with diethyl ether (4×100 mL) to remove impurities, and the combined aqueous layers were then concentrated under reduced pressure to provide 12.0 g of (S)-2-amino-3-methoxypropan-1-ol hydrochloride (A50) (12.0 g, 114.12 mmol, yield: quantitative).

[1025] 1H NMR (DMSO-d 6 ,400MHz): δppm 8.31(br s,3H),3.57-3.47(m,5H),3.27(s,3H),3.21-3.20(m,1H).

[1026] LCMS (Method A): 0.197 min, 70.29%, 210.0 nm, MS: ES+106.0 (M+1)

[1027] Step-6

[1028] To 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) stirred at 0° C. under a nitrogen atmosphere for 20 min was added (S)-2-amino-3-methoxypropan-1-ol (A50) (0.327 g, 3.115 mmol, 2.0 equiv). The resulting mixture was stirred at room temperature for 16 h. TLC indicated the reaction was complete; 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 Na 2 SO 4 and concentrated under reduced pressure to provide the crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (70% ethyl acetate in hexanes) to provide N-((S)-1-hydroxy-3-methoxyprop-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 62) (0.15 g, 0.367 mmol, yield: 23.60%).

[1029] 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 are incorporated into the DMSO solvent peak.

[1030] 1 H 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 are exchangeable in MeOD NMR.

[1031] LCMS (Method A): 2.215 min, 100%, 254.0 nm, MS: ES+409.42 (M+1)

[1032] HPLC (Method A): 7.84 min, 100%, 254.0 nm

[1033] Example 59 - Synthesis of N-((R)-4-aminobutan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 63):

[1034]

[1035] Step-1:

[1036] To 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 added CAS: 1187927-71-4 (0.12 g, 0.68 mmol, 1.1 equiv) at 0 ° C. under a nitrogen atmosphere for 15 min. The resulting mixture was stirred at room temperature for 30 min. The reaction was monitored on TLC (using EtOAc: hexane; 7:3 as the mobile phase), which confirmed that the reaction was complete after 30 min. The resulting reaction mixture was quenched with ice-cold water (50 mL) and extracted with EtOAc (3×15 mL). The organic layers combined are through Na SO Drying and under reduced pressure concentrated, to provide crude product.The crude material obtained uses silica (230-400 mesh) as stationary phase purification (40% ethyl acetate in hexane) by flash column chromatography to produce tert-butyl ((3R)-3-(8-(4-(trifluoromethyl)cyclohex-1-ene-1-yl)quinoline-3-formamido)butyl)carbamate (A51) (0.2 g, 0.40 mmol, yield: 65.38%).

[1037] 1 H NMR (DMSO d 6 ,400MHz): δppm,9.24(d,J=2.0Hz,1H),8.78(d,J=2.0Hz,1H),8.56(d,J=8.4 Hz,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).

[1038] LCMS (Method A): 2.781 min, 100%, 254.0 nm, MS: ES+492.2 (M+1)

[1039] Step-2

[1040] 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 h. The reaction was monitored on TLC (using MeOH:DCM; 0.5:9.5 as mobile phase), which confirmed that the reaction was complete after 4 h. The resulting reaction mixture was evaporated to obtain the crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (15% MeOH:DCM) to produce 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%).

[1041] 1 H NMR (MeOD, 400MHz): δppm, 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).

[1042] 1H NMR (DMSO d 6, 400MHz): δppm, 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).

[1043] LCMS (Method A): 1.886 min, 100%, 254.0 nm, MS: ES+392.2 (M+1)

[1044] HPLC (Method A): RT=5.51 min, 100%, 270 nm.

[1045] Chiral HPLC: Peak 1 RT = 8.56 min, 39.00%, 241 nm; Peak 2 = RT: 9.92 min, 60.09%, 241 nm

[1046] 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)

[1047]

[1048] Step-1

[1049] To a stirred solution of ((benzyloxy)carbonyl)-L-serine (CAS: 1145-80-8) (2.00 g, 8.36 mmol, 1.0 eq) in DCM (20 ml) was added 1.0 M dimethylamine CAS: 124-40-3 (0.843 ml, 12.54 mmol, 1.5 eq), followed by DIPEA (4.36 ml, 25.08 mmol, 3.0 eq) and HATU (4.765 g, 12.54 mmol, 1.5 eq). The resulting mixture was stirred at room temperature for 16 h. TLC indicated the reaction was complete; the resulting reaction mixture was concentrated under reduced pressure to provide the crude product. The crude material obtained was purified by flash column chromatography using silica gel (230-400 mesh) as the stationary phase (the desired product was eluted with 3% MeOH in DCM) to afford benzyl (S)-(1-(dimethylamino)-3-hydroxy-1-oxopropan-2-yl)carbamate (A52) (0.358 g, 1.34 mmol, 16% yield).

[1050] 1 H NMR(DMSO-d6,400MHz): δppm,7.38-7.29(m,6H),5.01(s,2H),4.87(t,J=6.0Hz,1 H),4.54(m,1H),3.57-3.53(m,1H),3.46-3.42(m,1H),3.05(s,3H),2.82(s,3H).

[1051] LCMS (Method A): 1.495 min, 95.91%, 220.0 nm, MS: ES+ 267.15

[1052] Step-2

[1053] At room temperature under nitrogen atmosphere, to a solution of (S)-(1-(dimethylamino)-3-hydroxy-1-oxopropyl-2-yl)benzyl carbamate (A52) (0.15 g, 0.56 mmol, 1.0 equivalent) in MeOH (5 mL) was added Pd / C (0.075 g, 50 wt %) and stirred at room temperature under H2 atmosphere for 5 h. TLC showed that the reaction was complete. The resulting reaction mixture was filtered through a bed of diatomaceous earth and concentrated under reduced pressure to provide the desired product A53 (S)-2-amino-3-hydroxy-N, N-dimethylpropionamide (0.078 g, 0.59 mmol, yield: 7.44%).

[1054] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[1055] LCMS (Method B): 0.70 min, 100%, 220.0 nm, MS: ES+133.1

[1056] Step-3

[1057] 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-dimethylpropionamide (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 that the reaction was complete and the resulting reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 125 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure to provide a crude product. The crude material obtained was purified by preparative HPLC (Method-A) to afford 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%).

[1058] 1 H 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 proton peaks are combined with the DMSO solvent peak)

[1059] 1H NMR (MeOD, 400MHz): δppm, 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).

[1060] HPLC (Method A): 7.419 min, 100%, 254.0 nm.

[1061] LCMS (Method A): 2.164 min, 100%, 254.0 nm, MS: ES+ 436.2

[1062] Chiral HPLC: Peak-1: 3.96, 49.9%; Peak-2: 4.90, 50% 250 nm.

[1063] 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)

[1064]

[1065] Step-1

[1066] At-78 ℃ in 100mL 3 neck RBF, prepare a stirring solution of DMSO (2.1g, 27.21mmol, 2.4 equivalents) in DCM (40mL).Add oxalyl chloride (1.43g, 11.34mmol, 1.0 equivalents) and stir to continue 30min to this solution at the same temperature, add 2-((tert-butyldimethylsilyl) oxygen base) second-1-alcohol (CAS:102229-10-7) (2.0g, 11.34mmol, 1.0 equivalents) subsequently, and stir again at the same temperature and continue other 30min.After 30min, at-78 ℃, add Et3N (5.7g, 56.71mmol, 5.0 equivalents), and the resulting reaction mixture is stirred at room temperature and continues 3h.TLC shows that the reaction is complete, and the resulting reaction mixture is diluted with water (100mL) and extracted with EtOAc (3 × 50mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to afford crude 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (A54) (2.2 g, 0.126 mmol, yield: quantitative). (Due to the volatile nature of the product, the obtained crude product was used directly in the next step without any further purification.)

[1067] Step-2

[1068] A stirred solution of 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (A54) (2.0 g, 11.47 mmol, 1.0 equiv), 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 3-neck RBF at 0°C. To this solution was added Ti(OC2H5)4 (CAS: 3087-36-3) (5.2 g, 22.94 mmol, 2.0 equiv) at 0°C, and the reaction mixture was allowed to stir at room temperature for 16 h. TLC indicated that the reaction was complete. The resulting reaction mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL). The two layers were then filtered through a Buchner funnel and separated. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product obtained was purified by flash column chromatography using silica gel (100-200 mesh) (50% EtOAc in hexanes as mobile phase) to afford N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfenamide (A55) (0.6 g, 2.162 mmol, yield: 18.86%).

[1069] 1H NMR (DMSO-d6, 400MHz): δppm, 7.90 (s, 1H), 4.60 (d, J = 2.8Hz, 2H), 1.12 (s, 9H), 0.89 (s, 9H), 0.07 (s, 6H).

[1070] LCMS (Method A): 2.853 min, 99.01%, 254.0 nm, MS: ES+278.15 (M+1)

[1071] Step-3

[1072] A stirred solution of oxazole (CAS: 288-42-6) (0.024 g, 0.360 mmol, 1.0 equivalent) in THF (2 mL) was prepared in a 30 mL glass vial at -78 ° C. To this solution was added n-BuLi (2.5 M in hexane) (0.14 mL, 0.360 mmol, 1.0 equivalent) and stirred for 1 h. Subsequently, N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide (A55) (0.1 g, 0.360 mmol, 1.0 equivalent) was added and the reaction mixture was stirred at room temperature for 16 h. TLC indicated that the reaction was complete and the resulting reaction mixture was quenched with NH4Cl aqueous solution (1 mL) and diluted with water (10 mL) and further extracted with EtOAc (3 × 10 mL). The organic layer that merges is through anhydrous Na SO Drying, filter and under reduced pressure concentrate, to obtain crude product.The crude product that obtains uses silica gel (100-200 mesh) purifying (60% EtOAc in hexane as mobile phase) by flash column chromatography, to provide N-(2-((tert-butyldimethylsilyl) oxygen base)-1-(oxazole-2-yl) ethyl)-2-methylpropane-2-sulfinamide (A56) (0.03g, 0.086mmol, yield: 24.19%).

[1073] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[1074] LCMS (Method A): 2.550 min, 97.60%, 220.0 nm, MS: ES+347.11 (M+1)

[1075] Step-4

[1076] A stirred solution of N-(2-((tert-butyldimethylsilyl)oxy)-1-(oxazol-2-yl)ethyl)-2-methylpropane-2-sulfinamide (A56) (0.03 g, 0.086 mmol, 1.0 equiv) in MeOH (0.3 mL) was prepared at room temperature in a 5 mL single-necked RBF. To this solution was added 4 M HCl in dioxane (0.3 mL) at room temperature, and the resulting reaction mixture was stirred for 16 h. TLC indicated that the reaction was complete, and the resulting reaction mixture was concentrated directly under reduced pressure to provide 2-amino-2-(oxazol-2-yl)ethan-1-ol hydrochloride (A57) (0.02 g, yield: quantitative). (The crude product obtained was used directly in the next step as is without any further purification).

[1077] LCMS (Method B): 0.70 min, 100.00%, 210.0 nm, MS: ES+129.1 (M+1)

[1078] Step-5

[1079] 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 eq) in DMF (2 mL) was prepared in a 10 mL glass vial at room temperature. To this solution was added HATU (0.311 g, 0.820 mmol, 1.5 eq) and DIPEA (0.212 g, 1.641 mmol, 3.0 eq) at 0°C and the reaction mixture was stirred for 10-15 min, followed by the addition of A57 (0.090 g, 0.547 mmol, 1.0 eq) at room temperature and stirring for 16 h. TLC indicated the reaction was complete, and the resulting reaction mixture was diluted with water (30 mL) and EtOAc (2 x 30 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product obtained was purified by flash column chromatography using silica gel (230-400 mesh) (5% MeOH in DCM as mobile phase) to afford 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%).

[1080] 1H NMR (DMSO-d6, 400MHz): δppm, 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=5.6Hz,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: CF3CH- protons are merged with the DMSO solvent peak)

[1081] 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 are exchanged with MeOD.

[1082] LCMS (Method A): 2.196 min, 97.78%, 254.0 nm, MS: ES+ 432.23 (M+1)

[1083] HPLC (Method A): 7.61 min, 96.07%, 254.0 nm

[1084] Example 62: Synthesis of N-((5-oxopyrrolidin-2-yl)methyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 66)

[1085]

[1086] Step-1

[1087] 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 (0.088 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 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 RT for 4 h. TLC indicated the completion of the reaction, the resulting reaction mixture was poured into cold water (20 mL) and precipitated out, which was filtered and washed with water (50 mL) and dried under reduced pressure to obtain a crude product, which was purified by normal phase column chromatography (the desired product was eluted with 7% MeOH in DCM) to provide 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%).

[1088] 1 H NMR (DMSO-d6, 400MHz): δppm, 9.26 (d, J = 2.0Hz, 1H), 8.87 (t, J = 5.6Hz, 1H), 8.8 2(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,2 H),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-CH protons merge with the DMSO solvent peak, which is clearly observed in MeOD.

[1089] 1H NMR (MeOD, 400MHz): δppm, 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 in MeOD solvent.

[1090] LCMS (Method A): 2.156 min, 99.55%, 254.0 nm, MS: ES+418.2 (M+1)

[1091] HPLC (Method A): 7.39 min, 99.49%, 254.0 nm

[1092] 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

[1093] 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)

[1094]

[1095] Step-1

[1096] 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 eq) in DMF (1.0 mL) at 0° C. was added HATU (0.088 g, 0.233 mmol, 1.5 eq) and stirred for 10 minutes. Subsequently, DIPEA (0.07 mL, 0.466 mmol, 3.0 eq) and 6-(aminomethyl)pyridin-2(1H)-one hydrochloride (CAS: 95878-02-7) (0.027 g, 0.171 mmol, 1.1 eq) were added at 0° C. The resulting reaction mixture was then stirred at RT for 4 h. TLC indicated the reaction was complete; the resulting reaction mixture was poured into cold water (5 mL) to obtain a precipitate. The obtained precipitate was filtered through a Buchner funnel and washed with water (20 mL), then dried under reduced pressure, and the crude product was purified by column chromatography (the desired product was eluted with 0-2% MeOH in DCM) to provide 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%).

[1097] 1 H NMR(DMSO-d6,400MHz): δppm,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).

[1098] 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 are exchanged in MeOD NMR.

[1099] LCMS (Method A): 2.189 min, 100.00%, 254 nm, MS: ES+ 428.23 (M+1)

[1100] HPLC (Method A): 7.37 min, 99.08%, 254 nm

[1101] Chiral HPLC: Peak-1 6.07 min, 49.36%, 242 nm; Peak-2 6.53 min, 49.55%, 242 nm

[1102] 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)

[1103]

[1104] Step-1

[1105] 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)pyridin-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 RT for 3 h. TLC showed that the reaction was completed, and the resulting reaction mixture was poured into cold water (20 mL) and precipitated out, which was filtered and washed with water (50 mL) and dried under reduced pressure to obtain a crude product, and purified by reverse phase column chromatography, the desired product was eluted with 50% water in acetonitrile to provide 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%).

[1106] 1 H NMR (DMSO-d6, 400MHz): δppm, 11.69 (s, 1H), 9.29 (d, J = 1.6Hz, 1H), 9.16 (t, J = 5.6Hz, 1H), 8.87 (d, J = 2.0 Hz,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=5.6Hz,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 CF3CH- protons are merged with the DMSO solvent peak.

[1107] 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 are exchanged in MeOD NMR.

[1108] LCMS (Method A): 2.266 min, 95.77%, 254.0 nm, MS: ES+428.2 (M+1)

[1109] HPLC (Method A): 7.56 min, 100%, 254.0 nm

[1110] Chiral HPLC: Peak-1: 7.75 min, 49.18%, 240.0 nm; Peak-2: 8.57 min, 50.81%, 240.0 nm

[1111] Example 65 - Synthesis of N-(1-(hydroxymethyl)cyclopropyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 69)

[1112]

[1113] Step-1

[1114] 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. To the reaction solution was added DIPEA (0.12 g, 0.93 mmol, 3.0 equiv) at 0° C. under a nitrogen atmosphere, stirred for 5 min, and then HATU (0.17 g, 0.46 mmol, 1.5 equiv) was added. After stirring for 30 min, 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 RT for 3 h. TLC indicated that 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 Na2SO4 and concentrated under reduced pressure to obtain the crude product, which was purified by normal phase flash column chromatography on silica gel (230-400 mesh) (desired product was eluted with 40% ethyl acetate in hexane) to afford 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%).

[1115] 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 are exchangeable in MeOD NMR.

[1116] 1H NMR (DMSO-d6 400MHz): δppm, 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).

[1117] LCMS (Method A): 2.244 min, 100%, 254.0 nm, MS: ES+391.17 (M+1)

[1118] HPLC (Method A): 7.99min, 99.74%, 254.0nm

[1119] Chiral HPLC: Peak-1: 3.06 min, 49.18%, 240.0 nm; Peak-2: 3.50 min, 49.9%, 240.0 nm

[1120] Example 66: Synthesis of N-((R)-1-acetamidoprop-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 70)

[1121]

[1122] Step-1

[1123] Under N2 atmosphere, to a stirred solution of N-((R)-1-aminopropyl-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). TEA (0.08 mL, 0.61 mmol, 2.0 equiv) was subsequently added, and the reaction mixture was stirred at RT for 1 h. TLC indicated that 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 provide the crude product. The crude product was purified by manual column chromatography using silica gel (230-400 mesh) as the stationary phase (gradient elution, 20% ethyl acetate in hexanes) to provide 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).

[1124] 1 H NMR (DMSO-d6, 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: The CF3CH3 protons are combined with the DMSO solvent peak.

[1125] 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 are exchanged in MeOD NMR.

[1126] LCMS (Method A): 2.22 min, 100%, 220 nm, MS: ES+420.13 (M+1)

[1127] HPLC (Method A): 7.75 min, 99.80%, 210 nm

[1128] Chiral HPLC: 6.74 min, 7.06 min, 48.93%, 51.06%, 240 nm

[1129] Example 67 - Chiral Separation of N-((S)-1-(pyridin-2-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 71 and Compound 72)

[1130]

[1131] Column ID: CHIRALCEL ODH (250×4.6mm 5μm)

[1132] Mobile phase A: liquid CO2

[1133] Mobile phase B: M.NH3-MEOH-ACN (50-50)

[1134] Flow rate (ML / MIN): 3

[1135] Instrument ID: SFC INVESTIGATOR

[1136] Method: Time: Flow: %A:%B (0:14:60:40), (7:14:60:40)

[1137] Input amount: 0.060g.

[1138] Output: Compound 71 = 0.015 g (% yield = 33.33%) and Compound 72 = 0.013 g (% yield = 25%)

[1139] Compound 71:

[1140] 1 H NMR (MeOD, 400MHz): δppm, 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= 8 Hz, 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 are exchanged in MeOD NMR.

[1141] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[1142] LCMS (Method A): 2.321 min, 100%, 254.0 nm, MS: ES+426.3 (M+1)

[1143] HPLC (Method A): 9.18 min, 100%, 254.0 nm

[1144] Chiral HPLC: 2.29 min, 100%, 246 nm

[1145] Compound 72:

[1146] 1 H NMR (MeOD, 400MHz): δppm, 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= 8 Hz, 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 are exchanged in MeOD NMR.

[1147] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[1148] LCMS (Method A): 2.321 min, 100%, 254.0 nm, MS: ES+426.3 (M+1)

[1149] HPLC (Method A): 9.20 min, 100%, 254.0 nm

[1150] Chiral HPLC (Method A): 2.32 min, 100%, 246 nm

[1151] Example 68 - Synthesis of N-((R)-1-(oxazol-2-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 73)

[1152]

[1153] Step-1

[1154] 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 was added n-BuLi (90.50 mL, 144.80 mmol, 1.0 equiv) and stirred for 1 h. CAS: 2591-86-8 (16.36 g, 144.80 mmol, 1.0 equiv) was then added under an N2 atmosphere. The resulting reaction mixture was stirred at RT for 16 h. TLC indicated the reaction was complete; the resulting reaction mixture was quenched with 1N HCl (200 mL) and extracted with DCM (3×300 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to provide crude oxazole-2-carbaldehyde (A58) (12.8 g, 131.86 mmol, yield: 91.07%). The crude material obtained 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 at a lower temperature of 25°C and the solvent was not completely removed).

[1155] 1 H NMR (DMSO-d6, 400MHz): δppm, 9.73 (s, 1H), 8.50 (s, 1H), 7.66 (s, 1H).

[1156] Step-2

[1157] To a solution of oxazole-2-carboxaldehyde (A58) (5.0 g, 51.509 mmol, 1.0 equivalent) in THF (50 mL) was added CAS: 343338-28-3 (7.49 g, 61.811 mmol, 1.2 equivalents) and Ti(OC H ) CAS: 3087-36-3 (22.988 g, 103.06 mmol, 2.0 equivalents), and the reaction mixture was allowed to stir at RT for 16 h. TLC indicated that 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 Na SO and concentrated under reduced pressure to provide a crude product. The crude material obtained 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 hexanes) to afford (S,E)-2-methyl-N-(oxazol-2-ylmethylene)propane-2-sulfenamide (A59) (4.0 g, 19.974 mmol, yield: 38.78%).

[1158] 1 H NMR (DMSO-d6, 400MHz): δppm, 8.46 (s, 1H), 8.29 (s, 1H), 7.64 (s, 1H), 1.19 (s, 9H).

[1159] LCMS (Method A): 1.547 min, 100%, 285.0 nm, MS: ES+201.0 (M+1)

[1160] Step-3

[1161] Under N at -78 ℃, to (E) -2- methyl -N- (oxazol-2-ylmethylene) propane -2- sulfinamide (A59) (4.0 g, 19.974 mmol, 1.0 equivalent) in DCM (40 mL) was added CH MgBr (3M in Et O) (7.989 mL, 23.969 mmol, 1.2 equivalents). The resulting mixture was stirred at -78 ℃ for 1.5 h, then allowed to warm to room temperature for 1.5 h. A second portion of CH MgBr (3M in Et O) (7.989 mL, 23.969 mmol, 1.2 equivalents) was added, and the reaction mixture was stirred at -78 ℃ for 1 h again. After 1 h, it was allowed to warm to room temperature for 3 h. At -78 ℃, add the third part of CH MgBr (in Et o 3M) (3.99mL, 11.984mmol, 0.6 equivalent), then allow the reaction mixture to warm to room temperature and continue 16h. TLC shows that the reaction is complete, and the resulting reaction mixture is slowly poured into NH in the Cl aqueous solution (100mL) and extracted with EtOAc (3×100mL). The combined organic layer is dried over Na SO and concentrated under reduced pressure to provide a crude product. The crude material obtained is purified by grinding with pentane, to provide (S) -2- methyl -N- ((R) -1- (oxazol-2-yl) ethyl) propane -2- sulfenamide (A60) (3.0g, 13.868mmol, yield: 69.44%).

[1162] 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).

[1163] LCMS (Method A): 1.404 min, 100%, 220.0 nm, MS: ES+217.1 (M+1).

[1164] Chiral HPLC: 4.14 min, 100%, 216.0 nm.

[1165] Step-4

[1166] To a solution of (S)-2-methyl-N-((R)-1-(oxazol-2-yl)ethyl)propane-2-sulfenamide (A60) (3.0 g, 13.870 mmol, 1.0 eq) in MeOH (30 mL) was added 4 M HCl in dioxane (7.28 mL, 29.126 mmol, 2.1 eq) and stirred at RT for 1 h. TLC indicated the reaction was complete and the mixture was then concentrated under reduced pressure to provide (R)-1-(oxazol-2-yl)ethan-1-amine hydrochloride (A61) (2.77 g, 18.642 mmol, yield: quantitative).

[1167] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[1168] LCMS (Method A): 0.196 min, 94.57%, 210.0 nm, MS: ES+112.9 (M+1)

[1169] Step-5

[1170] To 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 eq), HATU (8.876 g, 23.343 mmol, 1.5 eq) and DIPEA (8.045 ml, 46.685 mmol, 3.0 eq) in DMF (50 mL) stirred at 0° C. under a nitrogen atmosphere for 20 min was added A61 (2.77 g, 18.674 mmol, 1.2 eq) and the reaction mixture was stirred at room temperature for 3 h. TLC indicated the reaction was complete, then water (100 mL) was added and extracted with EtOAc (3×100 mL). The combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure to provide the crude product. The crude material obtained was purified by flash column chromatography using silica gel (230-400 mesh) as the stationary phase (the desired product was eluted with 60% ethyl acetate in hexanes) to provide 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%).

[1171] 1H NMR (DMSO-d6, 400MHz): δppm, 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).

[1172] 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 are exchanged in MeOD NMR.

[1173] LCMS (Method A): 2.460 min, 98.73%, 254.0 nm, MS: ES+416.2 (M+1)

[1174] HPLC (Method A): 8.77 min, 99.01%, 254.0 nm

[1175] Chiral HPLC: Peak-1 (5.02 min, 47.83%, 245.0 nm); Peak-2 (6.08 min, 49.16%, 245.0 nm)

[1176] 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)

[1177]

[1178] Step-1

[1179] To 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), EDCl.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) stirred at 0° C. under nitrogen atmosphere for 15 min was added dimethylamine (2 M in THF) CAS: 124-40-3 (0.067 g, 1.476 mmol, 4.0 equiv) under nitrogen. The resulting mixture was stirred at room temperature for 16 h. 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 provide a crude product. The crude material obtained was purified by grinding with n-pentane to provide N-((R)-4-(dimethylamino)-4-oxobutan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-ene-1-yl)quinoline-3-carboxamide (compound 74) (0.04 g, 0.0922 mmol, yield: 25%).

[1180] 1 H NMR (MeOD, 400MHz) δppm 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 are exchanged in MeOD NMR.

[1181] 1H NMR(DMSO-d6,400MHz)δppm 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).

[1182] LCMS (Method A): 2.290 min, 100%, 210.0 nm, MS: ES+434.3 (M+1)

[1183] HPLC (Method A): 8.26 min, 98.29%, 210.0 nm.

[1184] Chiral HPLC (Method A): Peak 1: 8.12 min, 45.66%, 240 nm; Peak 2: 8.49 min, 53.04%, 240 nm.

[1185] Example 70 - Synthesis of N-(3-(dimethylamino)-3-oxopropyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 75)

[1186]

[1187] Step-1

[1188] 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) at 0°C was added HATU (0.88 g, 2.33 mmol, 1.5 equiv). DIPEA (0.8 mL, 4.67 mmol, 3.0 equiv) was then added and stirred at 0°C. After stirring for 10 min, CAS: 3196-73-4β-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 RT for 4 h. TLC indicated the reaction was complete; 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%).

[1189] 1 H NMR (DMSO-d6, 400MHz): δppm 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).

[1190] LCMS (Method A): 2.418 min, 99.31%, MS: ES+407.22 [M+H].

[1191] Step-2

[1192] At 0 ° C, to a solution of methyl 3-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-formamido)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 equivalents). The reaction mixture was stirred at room temperature for 3 h, and TLC showed that the reaction was complete. The resulting reaction mixture was acidified with 1N HCl and extracted with ethyl acetate (15 mL×3). The combined organic layers were concentrated under reduced pressure to provide 3-(8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-formamido)propanoic acid (A63) (0.32 g, 0.765 mmol, yield: 32.82%) as a white amorphous solid.

[1193] 1 H NMR (DMSO-d6, 400MHz): δppm 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).

[1194] LCMS (method A): 2.191 min, 100%, MS: ES+393.17 [M+H] +

[1195] Step-3

[1196] 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) at 0° C. was added HATU (0.21 g, 0.57 mmol, 1.5 equiv). 10 min later, DIPEA (0.2 ml, 1.14 mmol, 3.0 equiv) was added at the same temperature and stirring was continued 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 RT for 4 h. TLC indicated that the reaction was complete; the resulting reaction mixture was diluted with ice-cold water (10 mL) and extracted with EtOAc (10 mL×2). The combined layers were evaporated under vacuum, and the crude residue was purified by column chromatography using silica gel (60-120 mesh; 50% EtOAc and hexanes) to provide N-(3-(dimethylamino)-3-oxopropyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 75) (0.064 g, 0.155 mmol, yield: 43.13%).

[1197] 1 H NMR (DMSO-d6, 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: The CF3CH3 protons are combined with the DMSO solvent peak.

[1198] 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 are exchanged in MeOD NMR.

[1199] LCMS (Method A): 2.22 min, 99.25%, MS: ES+420.3 [M+H]

[1200] HPLC (Method A): 7.98 min. 99.11%, 254 nm

[1201] Chiral HPLC (Method A): 6.46 + 7.39 min. 49.63 + 49.80%, 242 nm

[1202] Example 71 - Synthesis of N-(3-(methylamino)-3-oxopropyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 76)

[1203]

[1204] Step-1

[1205] 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) at 0° C. was added HATU (0.21 g, 0.57 mmol, 1.5 equiv). DIPEA (0.2 mL, 1.14 mmol, 3.0 equiv) and CAS: 74-89-5 methylamine (2 M in THF) (0.28 mL, 0.57 mmol, 1.5 equiv) were subsequently added. The resulting reaction mixture was stirred at RT for 16 h. TLC indicated the reaction was complete 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 was purified by silica column chromatography (60-120 mesh; 50% EtOAc and hexanes) to provide 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%).

[1206] 1 H NMR(DMSO-d6,400MHz): δppm 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(brs,1H), 3.55(q,J=7.2Hz,2H),2.85-2.75(m,1H),2.74-2.65(m,1H),2.58(d,J =4.8Hz,3H),2.42-2.39(m,3H),2.18-2.07(m,1H),1.74-1.63(m,1H). Note: 3H protons are incorporated into the DMSO solvent peak.

[1207] 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 are exchanged in MeOD NMR.

[1208] LCMS (method A): 2.12 min, 98.87%, MS: ES+406.37 [M+H]

[1209] HPLC (Method A): 7.49 min. 99.45%, 254 nm

[1210] Example 72 - Synthesis of N-((R)-4-acetylaminobutan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 77)

[1211]

[1212] Step-1

[1213] 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) at 0° C. under a nitrogen atmosphere was added HATU (0.355 g, 0.933 mmol, 1.5 equiv) and DIPEA (0.32 mL, 1.867 mmol, 3.0 equiv) followed by stirring for 5 min before the addition of CAS: 1187927-71-4(R)-1-Boc-amino-butyl-3-amine (0.129 g, 0.685 mmol, 1.1 equiv) under nitrogen. The resulting mixture was stirred at room temperature for 4 h. TLC indicated the reaction was complete; the resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with DCM (3×20 mL). The organic layers combined are dried over Na SO and concentrated under reduced pressure to provide a crude product. The crude material obtained is purified by flash column chromatography using silica (230-400 mesh) as a stationary phase (50% EtOAc in hexane) to provide tert-butyl ((3R)-3-(8-(4-(trifluoromethyl)cyclohex-1-ene-1-yl)quinoline-3-formamido)butyl)carbamate (A64) (0.22 g, 0.448 mmol, yield: 71.90%).

[1214] 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).

[1215] LCMS (Method A): 2.725 min, 96.87%, 254.0 nm, MS: ES+ 492.4 (M+1).

[1216] Step-2:

[1217] To a solution of tert-butyl ((3R)-3-(8-(4-(trifluoromethyl)cyclohex-1-ene-1-yl)quinoline-3-formamido)butyl)carbamate (A64) (0.22 g, 0.448 mmol, 1.0 equivalents) in MeOH (2 mL) was added the 4MHCl (0.22 mL, 0.895 mmol, 2.0 equivalents) in dioxane and stirred at RT for 3 h. TLC showed that the reaction was complete, and the reaction mixture was concentrated under reduced pressure, to provide a crude product. The crude material obtained was purified by grinding with ether (5 mL), to provide N-((R)-4-aminobutan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-ene-1-yl)quinoline-3-carboxamide (A65) (0.2 g, 0.511 mmol, quantitative).

[1218] 1 H NMR (DMSO-d6, 400MHz): δppm, 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 an HCl salt.

[1219] LCMS (Method A): 1.853 min, 97.76%, 254.0 nm, MS: ES+392 (M+1)

[1220] Step-3

[1221] To 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) stirred at 0° C. under a nitrogen atmosphere for 10 min was added CH COCl (0.036 mL, 0.460 mmol, 1.0 equiv), and the reaction mixture was stirred at room temperature for another 4 h. TLC indicated 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 Na SO and concentrated under reduced pressure to provide the crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (50% EtOAc in hexanes) to provide N-((R)-4-acetylaminobutan-2-yl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 77) (0.087 g, 0.201 mmol, yield: 43.65%).

[1222] 1 H NMR (DMSO-d6 400MHz): δppm, 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).

[1223] LCMS (Method A): 2.198 min, 98.97%, 242.0 nm, MS: ES+434.3 (M+1)

[1224] HPLC (Method A): 7.87 min, 97.93%, 254.0 nm

[1225] Chiral HPLC: 4.93 min. 98%, 242 nm

[1226] Example 73 - Synthesis of N-(3-acetylaminopropyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 78)

[1227]

[1228] Step-1

[1229] A solution of propane-1,3-diamine (CAS: 109-76-2) (0.1 g, 1.348 mmol, 1.0 eq), CH3COCl (0.105 g, 1.348 mmol, 1.0 eq) and DIPEA (0.704 ml, 4.047 mmol, 3.0 eq) in DCM (1 mL) was stirred at -78°C under a nitrogen atmosphere for 10 min, then allowed to warm to room temperature and stirring was continued at RT for 16 h. TLC indicated the reaction was complete; the resulting reaction mixture was quenched with 5% HCl (2 mL) and basified with saturated NaHCO3 (3×10 mL), then extracted with DCM (10 mL), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to provide the crude product. The crude material obtained was purified by trituration with n-pentane to afford N-(3-aminopropyl)acetamide (A66) (0.1 g, 0.862 mmol, yield: 63.79%).

[1230] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[1231] LCMS (method B): 1.25 min, 78%, 210.0 nm, MS: ES+117 (M+1)

[1232] Step-2

[1233] To 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) stirred at 0° C. under a nitrogen atmosphere for 10 min was added A66 (0.039 g, 0.342 mmol, 1.1 equiv) and allowed to stir at room temperature for 7 h. TLC indicated the reaction was complete; 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 Na 2 SO 4 and concentrated under reduced pressure to provide the crude product. The crude material obtained was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (5% MDC in MeOH) to afford 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%).

[1234] 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 are exchanged in MeOD NMR.

[1235] 1 H NMR (DMSO-d6, 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: The CF3CH protons are incorporated into the DMSO solvent peak.

[1236] LCMS (Method A): 2.150 min, 97.87%, 254.0 nm, MS: ES+420.38 (M+1)

[1237] HPLC (Method A): 7.62 min, 97.0%, 254.0 nm

[1238] Example 74 - Synthesis of N-(2-acetylaminoethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 79)

[1239]

[1240] Step-1

[1241] 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) at 0°C under a nitrogen atmosphere were added HATU (0.17 g, 0.467 mmol, 1.5 equiv) and DIPEA (0.16 mL, 0.934 mmol, 3.0 equiv) and stirred for 10 min. CAS: 1001-53-2N-acetylethylenediamine (0.034 g, 0.342 mmol, 1.1 equiv) was added under nitrogen. The resulting mixture was stirred at room temperature for 7 h. TLC indicated the reaction was complete; the resulting reaction mixture was quenched with ice-cold water (10 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography using silica (230-400 mesh) as the stationary phase (5% MDC in MeOH) to afford N-(2-acetylaminoethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 79) (0.038 g, 0.093 mmol, yield: 30.12%).

[1242] 1H 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 are exchanged in MeOD NMR.

[1243] 1 H NMR (DMSO-d6, 400MHz): δppm, 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).

[1244] LCMS (Method A): 2.122 min, 100%, 242.0 nm, MS: ES+406.22 (M+1)

[1245] HPLC (Method A): 7.45 min, 99.69%, 254.0 nm

[1246] Example 75: Synthesis of N-(1-(1H-pyrazol-5-yl)ethyl)-8-(4-(trifluoromethyl)cyclohex-1-en-1-yl)quinoline-3-carboxamide (Compound 80)

[1247]

[1248] Step-1

[1249] 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 eq) in 7M NH3 in MeOH (2.0 mL) at 0°C was added Ti(Oi To the 4-thiazolyl-1-ylpyrazole-5-yl)-1-amine (A67) was added 1-(1H-pyrazol-5-yl)ethyl)-1-amine (0.22 g, 1.97 mmol, yield: quantitative).

[1250] LCMS (Method B): 1.22 min, 10.93%, 254 nm, MS: ES+112.2 (M+1)

[1251] Step-2

[1252] 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) at 0° C. was added HATU (0.17 g, 0.46 mmol, 1.5 equiv). DIPEA (0.16 mL, 0.934 mmol, 3.0 equiv) was then added and stirring continued for another 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 RT for 4 h. TLC indicated the reaction was complete; the resulting reaction mixture was poured into cold water (5 mL) to obtain a precipitate. The precipitate was filtered through a Buchner funnel and washed with water (20 mL) and dried over high vacuum, then purified by column chromatography (the desired product was eluted with 80% EtOAC in hexanes) to provide 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%).

[1253] 1H NMR(DMSO-d6,400MHz): δppm,12.57(br s,1H),9.27(d,J=2.0,1H),9.04(brs,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).

[1254] LCMS (Method A): 2.293 min, 97.06%, 254 nm, MS: ES+415.2 (M+1)

[1255] HPLC (Method A): 8.25 min, 95.14%, 254 nm

[1256] Example 76 - Chiral Separation of N-((R)-1-hydroxypro...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; R 1 Select from -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 Selected from the group consisting of: -C1-C6 alkyl, -(surrounded by one or two -OR 5 substituted C1-C6 alkyl), -(C1-C6 alkylene)-CN, -(C1-C6 alkylene)-S(O) n -(C1-C6 alkyl), -(optionally substituted by OR 5 Substituted C1-C4 alkylene)-C(O)OR 5 , -(optionally OR 5 Substituted C1-C4 alkylene)-C(O)N(R 6 )2,-(C0-C4 alkylene)-phenyl,-(C1-C6 alkylene)-N(R 6 )2, a 5-6 membered heteroaryl group having one, two or three heteroatoms independently selected from N, O and S, -(optionally replaced by OR 5 substituted C1-C4 alkylene)-(5-6 membered heteroaryl having one, two or three heteroatoms independently selected from N, O and S), -(C0-C4 alkylene)-C3-C 10 Cycloalkyl, and -(C0-C4 alkylene)-(3-10 membered heterocyclyl having one, two, three or four heteroatoms independently selected from N, O and S), wherein any of the aforementioned phenyl, 5-6 membered heteroaryl, C3-C 10 Cycloalkyl and 3-10 membered heterocyclyl are optionally substituted; m is 1 or 2; n is 0, 1, or 2; R 3 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 With R 3 and R 4 The attached carbons together form a 3-7 membered carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more halogens; Each R 5 are independently hydrogen or -C1-C6 alkyl; Each R 6 are independently hydrogen or -C1-C6 alkyl; Each R x Independently selected from -C1-C6 alkyl, halogen, -OR 5 , -CN and -N(R 6 )2; Each R y Independently selected from -C1-C6 alkyl, halogen, -OR 5 , -CN and -N(R 6 )2; s is 0, 1, or 2; and t is 0, 1, 2, or 3.

2. A compound of formula (I'): or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; R 1 Select from -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 Selected from the group consisting of: -C1-C6 alkyl, -(surrounded by one or two -OR 5 substituted C1-C6 alkyl), -(C1-C6 alkylene)-CN, -(C1-C6 alkylene)-S(O) n -(C1-C6 alkyl), -(optionally substituted by OR 5 Substituted C1-C4 alkylene)-C(O)OR 5 ,-(optionally replaced by CN or OR 5 Substituted C1-C4 alkylene)-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, a 5-6 membered heteroaryl group having one, two or three heteroatoms independently selected from N, O and S, -(optionally replaced by OR 5 substituted C1-C4 alkylene)-(5-6 membered heteroaryl having one, two or three heteroatoms independently selected from N, O and S), -(C0-C4 alkylene)-C3-C 10 Cycloalkyl, and -(C0-C4 alkylene)-(3-10 membered heterocyclyl having one, two, three or four heteroatoms independently selected from N, O and S), wherein any of the aforementioned phenyl, 5-6 membered heteroaryl, C3-C 10 Cycloalkyl and 3-10 membered heterocyclic groups are optionally substituted by one or more R w replace; m is 1 or 2; n is 0, 1, or 2; R 3 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 With R 3 and R 4 The attached carbons together form a 3-7 membered carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more halogens; Each R 5 are independently hydrogen or -C1-C6 alkyl; Each R 6 are independently hydrogen or -C1-C6 alkyl; R 7 Selected from the group consisting of: 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); Each R w independently selected from -C1-C6 alkyl, halogen, -N(R 6 )2 and oxo, wherein the -C1-C6 alkyl is optionally substituted by -OH; Each R x Independently selected from -C1-C6 alkyl, halogen, -OR 5 and -CN group; Each R y Independently selected from -C1-C6 alkyl, halogen, -OR 5 and -CN group; s is 0, 1, or 2; and t is 0, 1, 2, or 3.

3. The compound according to claim 1 or 2, wherein X is N.

4. A compound according to any one of claims 1 to 3, wherein R 1 Yes-C(O)-NHR 2 .

5. The compound according to any one of claims 1 to 3, wherein R 1 It is -C(O)OH.

6. A compound according to any one of claims 1 to 3, wherein R 1 It is -S(O)CH3.

7. A compound according to any one of claims 1 to 3, wherein R 1 It is -S(O)2CH3.

8. A compound according to any one of claims 1 to 3, wherein R 1 It is -S(O)2NHCH3.

9. A compound according to any one of claims 1 to 8, wherein R 2 Selected from the group consisting of: -C1-C6 alkyl, -(surrounded by one or two -OR 5 substituted C1-C6 alkyl), -(C1-C6 alkylene)-CN, -(C1-C6 alkylene)-S(O) n -(C1-C6 alkyl), -(optionally replaced by OR 5 Substituted C1-C4 alkylene)-C(O)OR 5 , -(optionally OR 5 Substituted C1-C4 alkylene)-C(O)N(R 6 )2, -(C1-C6 alkylene)-N(R 6 )2 and -(optionally OR 5 substituted C1-C4 alkylene)-(5-6 membered heteroaryl having one, two or three heteroatoms each independently selected from N, O and S).

10. A compound according to any one of claims 1 to 9, wherein R 2 It is -(C1-C4 alkylene)-5-6 membered heteroaryl.

11. A compound according to any one of claims 1 to 10, wherein R 2 It is -CH(CH3)-5-6 membered heteroaryl.

12. A compound according to any one of claims 1 to 10, wherein R 2 It is -CH2-5-6 membered heteroaryl.

13. according to the compound described in any one of claims 1-12, wherein said 5-6 membered heteroaryl is optionally replaced by C1-C6 alkyl or N(R a )2, wherein each R a are independently hydrogen or C1-C6 alkyl.

14. The compound according to any one of claims 1 to 13, wherein the 5-6 membered heteroaryl is pyridinyl.

15. A compound according to any one of claims 1 to 14, wherein the 5-6 membered heteroaryl is 16. The compound of any one of claims 1-13, wherein the 5-6 membered heteroaryl is oxazolyl.

17. A compound according to any one of claims 1-13 and 16, wherein the 5-6 membered heteroaryl is 18. A compound according to any one of claims 1 to 9, wherein R 2 It is a -C1-C6 alkyl group.

19. A compound according to any one of claims 1 to 9 and 18, wherein R 2 It is isopropyl.

20. A compound according to any one of claims 1 to 9, wherein R 2 is -(by one or two -OR 5 substituted C1-C6 alkyl).

21. A compound according to any one of claims 1 to 9, wherein R 2 is-(being-OR 5 substituted C1-C6 alkyl).

22. A compound according to any one of claims 1-9, 20 and 21, wherein R 2 It is -(C1-C6 alkyl substituted by -OH).

23. A compound according to any one of claims 1-9 and 20, wherein R 2 It is -(C1-C6 alkyl substituted by -OH and -OCH3).

24. A compound according to any one of claims 1 to 9, wherein R 2 is -(C1-C6 alkylene)-S(O) n -(C1-C6 alkyl).

25. A compound according to any one of claims 1 to 9, wherein R 2 It is -(C1-C6 alkylene)-CN.

26. A compound according to any one of claims 1 to 9, wherein R 2 Yes - (optionally OR 5 Substituted C1-C4 alkylene)-C(O)OR 5 .

27. A compound according to any one of claims 1 to 9, wherein R 2 Yes - (optionally OR 5 Substituted C1-C4 alkylene)-C(O)N(R 6 )2.

28. A compound according to any one of claims 1 to 9, wherein R 2 is -(C1-C6 alkylene)-N(R 6 )2.

29. A compound according to any one of claims 1 to 28, wherein R 3 It is -(C1-C6 haloalkyl).

30. A compound according to any one of claims 1 to 29, wherein R 3 It is trifluoromethyl.

31. A compound according to any one of claims 1-28, wherein R 3 is a halogen (eg, -F).

32. A compound according to any one of claims 1 to 31, wherein R 4 It's hydrogen.

33. A compound according to any one of claims 1 to 31, wherein R 4 is a halogen (eg, -F).

34. A compound according to any one of claims 1-28, wherein R 3 and R 4 With R 3 and R 4 The attached carbons together form a 3-7 membered carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more halogens (eg, -F).

35. The compound of any one of claims 1-34, wherein s and t are both 0.

36. A compound of formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: R 2 Selected from the group consisting of: -C1-C6 alkyl, -(surrounded by one or two -OR 5 substituted C1-C6 alkyl), -(C1-C6 alkylene)-CN, -(C1-C6 alkylene)-S(O) n -(C1-C6 alkyl), -(optionally replaced by OR 5 Substituted C1-C4 alkylene)-C(O)OR 5 , -(optionally OR 5 Substituted C1-C4 alkylene)-C(O)N(R 6 )2, -(C1-C6 alkylene)-N(R 6 )2 and -(optionally OR 5 substituted C1-C4 alkylene)-(5-6 membered heteroaryl having one, two or three heteroatoms each independently selected from N, O and S), wherein the 5-6 membered heteroaryl is optionally substituted; n is 0, 1, or 2; R 3 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 With R 3 and R 4 The attached carbons together form a 3-7 membered carbocyclic ring, wherein the 3-7 membered carbocyclic ring is optionally substituted with one or more halogens; Each R 5 Each occurrence is independently hydrogen or -C1-C6 alkyl; and Each R 6 Each occurrence is independently hydrogen or -C1-C6 alkyl.

37. A compound of formula (Ia'): or a pharmaceutically acceptable salt thereof, wherein: R 2 Selected from the group consisting of: -C1-C6 alkyl, -(surrounded by one or two -OR 5 substituted C1-C6 alkyl), -(C1-C6 alkylene)-CN, -(C1-C6 alkylene)-S(O) n -(C1-C6 alkyl), -(optionally replaced by CN or OR 5 Substituted C1-C4 alkylene)-C(O)OR 5 , -(optionally OR 5 Substituted C1-C4 alkylene)-C(O)N(R 6 )2, -(C1-C6 alkylene)-N(R 6 R 7 )、-(C1-C6 alkylene)-OP(O)(OR 5 )2 and -(optionally OR 5 substituted C1-C4 alkylene)-(5-6 membered heteroaryl having one, two or three heteroatoms independently selected from N, O and S), wherein the 5-6 membered heteroaryl is optionally substituted by one or more R w replace; n is 0, 1, or 2; R 3 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 With R 3 and R 4 The attached carbons together form a 3-7 membered carbocyclic ring, wherein the 3-7 membered carbocyclic ring is optionally substituted with one or more halogens; Each R 5 Each occurrence is independently hydrogen or -C1-C6 alkyl; and Each R 6 Each occurrence is independently hydrogen or -C1-C6 alkyl; R 7 Selected from the group consisting of: 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); Each R w independently selected from -C1-C6 alkyl, -N(R 6 )2 and oxo, wherein the -C1-C6 alkyl is optionally substituted by -OH.

38. The compound according to claim 36 or 37, wherein the compound is a compound of formula (Ib): or a pharmaceutically acceptable salt thereof.

39. The compound according to claim 36 or 37, wherein the compound is a compound of formula (Ic): or a pharmaceutically acceptable salt thereof.

40. A compound according to any one of claims 36-39, wherein R 2 It is -(C1-C4 alkylene)-5-6 membered heteroaryl.

41. according to the compound described in any one of claims 36-39, wherein R 2 It is -CH(CH3)-5-6 membered heteroaryl.

42. A compound according to any one of claims 36-39, wherein R 2 It is -CH2-5-6 membered heteroaryl.

43. according to the compound described in any one of claims 36-42, wherein said 5-6 membered heteroaryl is optionally replaced by -C1-C6 alkyl or -N(R a )2, wherein each R a are independently hydrogen or C1-C6 alkyl.

44. The compound of any one of claims 36-43, wherein the 5-6 membered heteroaryl is pyridinyl.

45. according to the compound described in any one of claims 36-44, wherein said 5-6 membered heteroaryl is 46. ​​The compound of any one of claims 36-43, wherein the 5-6 membered heteroaryl is oxazolyl.

47. according to the compound described in any one of claims 36-43 and 46, wherein said 5-6 membered heteroaryl is 48. A compound according to any one of claims 37-39, wherein R 2 Selected from the group consisting of: -(one or two -OR 5 Substituted C1-C6 alkyl), -(C1-C6 alkylene)-S(O) n -(C1-C6 alkyl), -(optionally replaced by OR 5 Substituted C1-C4 alkylene)-C(O)OR 5 , -(optionally OR 5 Substituted C1-C4 alkylene)-C(O)N(R 6 )2, -(C1-C6 alkylene)-N(R 6 R 7 )2, -(C1-C6 alkylene)-OP(O)(OR 5 )2, -(optionally OR 5 substituted C1-C4 alkylene)-(5-6 membered heteroaryl having one, two or three heteroatoms each independently selected from N, O and S) and -(C0-C4 alkylene)-(3-10 membered heterocyclyl having one, two, three or four heteroatoms each independently selected from N, O and S), wherein any of the aforementioned 5-6 membered heteroaryl and 3-10 membered heterocyclyl are optionally substituted by 1, 2, 3 or 4 substituents each independently selected from the group consisting of methyl, -NH2 and oxo.

49. A compound according to any one of claims 37-39, wherein R 2 Selected from the group consisting of: -(one or two -OR 5 Substituted C1-C6 alkyl), -(C1-C6 alkylene)-N(R 6 R 7 )2 and -(optionally OR 5 substituted C1-C4 alkylene)-(5-6 membered heteroaryl having one, two or three heteroatoms each independently selected from N, O and S), wherein any of the aforementioned 5-6 membered heteroaryl and 3-10 membered heterocyclyl are optionally substituted by 1, 2, 3 or 4 substituents each independently selected from the group consisting of methyl, -NH2 and oxo.

50. A compound according to any one of claims 36-39, wherein R 2 It is a -C1-C6 alkyl group.

51. according to the compound described in any one of claims 36-39 and 50, wherein R 2 It is isopropyl.

52. according to the compound described in any one of claims 36-39, wherein R 2 is -(by one or two -OR 5 substituted C1-C6 alkyl).

53. according to the compound described in any one of claims 36-39 and 52, wherein R 2 is-(being-OR 5 substituted C1-C6 alkyl).

54. according to the compound described in any one of claims 36-39, 52 and 53, wherein R 2 It is -(C1-C6 alkyl substituted by -OH).

55. according to the compound described in any one of claims 36-39, wherein R 2 It is -(C1-C6 alkyl substituted by -OH and -OCH3).

56. according to the compound described in any one of claims 36-39, wherein R 2 is -(C1-C6 alkylene)-S(O) n -(C1-C6 alkyl).

57. according to the compound described in any one of claims 36-39, wherein R 2 It is -(C1-C6 alkylene)-CN.

58. according to the compound described in any one of claims 36-39, wherein R 2 Yes - (optionally OR 5 Substituted C1-C4 alkylene)-C(O)OR 5 .

59. according to the compound described in any one of claims 36-39, wherein R 2 Yes - (optionally OR 5 Substituted C1-C4 alkylene)-C(O)N(R 6 )2.

60. A compound according to any one of claims 36-39, wherein R 2 is -(C1-C6 alkylene)-N(R 6 )2.

61. according to the compound described in any one of claim 36,37 and 40-60, wherein R 3 It is -C1-C6 haloalkyl.

62. according to the compound described in any one of claim 36,37 and 40-61, wherein R 3 It is trifluoromethyl.

63. according to the compound described in any one of claim 36,37 and 40-60, wherein R 3 It's a halogen.

64. according to the compound described in any one of claims 36, 37, 40-60 and 63, wherein R 3 Yes -F.

65. according to the compound described in any one of claim 36,37 and 40-64, wherein R 4 It's hydrogen.

66. according to the compound described in any one of claim 36,37 and 40-64, wherein R 4 It's a halogen.

67. A compound according to any one of claims 36, 37, 40-64 and 66, wherein R 4 Yes -F.

68. according to the compound described in any one of claim 36,37 and 40-60, wherein R 3 and R 4 With R 3 and R 4 The attached carbons together form a 3-7 membered carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more halogens (eg, -F).

69. A compound according to any one of claims 1-68, wherein the compound is selected from Table 1.

70. A pharmaceutical composition comprising a compound according to any one of claims 1-69 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

71. A method of treating a disease or condition mediated by hyperactivation of a TEAD isoform selected from TEAD1 and TEAD4 in a subject in need thereof, the method comprising administering to the subject a compound or pharmaceutically acceptable salt of any one of claims 1-69 or a pharmaceutical composition of claim 70.

72. The method of claim 71, wherein the disease or condition is cancer characterized by hyperactivation of a TEAD isoform selected from TEAD1 and TEAD4.

73. The method of claim 72, 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.

74. The method of claim 72 or 73, wherein the cancer is selected from the group consisting of hepatocellular carcinoma, breast cancer, pancreatic adenocarcinoma, and malignant mesothelioma.

75. The method of any one of claims 72-74, wherein the cancer is malignant mesothelioma.

76. The method of any one of claims 72-75, wherein the cancer is metastatic.

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