Novel compounds as GLP-1r agonists and uses thereof

Abstract

Described herein are GLP-1R agonists and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for the treatment of a GLP-1 associated disease or disorder, including Type 2 diabetes or obesity.

Description

FIELD OF THE DISCLOSURE

[0001] The present disclosure relates to novel compounds or pharmaceutically acceptable salts thereof, which are useful as glucagon-like peptide-1 receptor (GLP-1R) agonists. The present disclosure further relates to pharmaceutical compositions comprising one or more of such compounds or pharmaceutically acceptable salts thereof as an active ingredient, and use of such compounds or pharmaceutically acceptable salts thereof in the treatment of diseases or disorders, such as cancer. BACKGROUND

[0002] The glucagon-like peptide-1 receptor (GLP-1R) is a validated target for the treatment of diabetes and obesity. Biologies that target this receptor, such as semaglutide and liraglutide have proven clinically successful in regulating blood glucose levels, but they are not without drawbacks that include daily or weekly injections and reports of ADRs ranging from nausea and diarrhea to pancreatitis. In order to produce an orally available GLP-1R agonist, increased efforts have been directed towards the development of small molecules.

[0003] Therefore, there are still unsatisfied needs for novel compounds as GLP-1R agonists. SUMMARY

[0004] In one aspect, the present disclosure provides a compound of Formula (I): z2 Formula (I), or a pharmaceutically acceptable salt thereof, as disclosed herein.

[0005] In one aspect, the present disclosure provides a compound of Formula (I-1) or Formula (I-2): Formula (1-1), Formula (1-2), or a pharmaceutically acceptable salt thereof, as disclosed herein.

[0006] In one aspect, the present disclosure provides a compound of formula selected from: Formula (A-3) or Formula (A-2), or a pharmaceutically acceptable salt thereof, as disclosed herein.

[0007] In one aspect, the present disclosure provides a compound of formula selected from: Formula (B-l), Formula (B-3), Formula (B-4), Formula (B-5), Formula (B-6), Formula (B-7), Formula (B-8) or Formula (B-9), or a pharmaceutically acceptable salt thereof, as disclosed herein.

[0008] In one aspect, the present disclosure provides a compound of Formula (C-l): Formula (C-l), or a pharmaceutically acceptable salt thereof, as disclosed herein.

[0009] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of Formula (I), Formula (1-1), Formula (1-2), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (B-l), Formula (B-2), Formula (B-3), Formula (B-4), Formula (B-5), Formula (B-6), Formula (B-7), Formula (B-8), Formula (B-9) or Formula (C-l), or a compound set forth in Table 1.1, Table 1.2, Table 2.1, Table 2.2, or Table 3), or a pharmaceutically acceptable salt, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0010] Also disclosed herein is a method of activating GLP-1R in a subject, the method comprising administering to the subject the compound disclosed herein (e.g., a compound of Formula (I), Formula (1-1), Formula (1-2), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (B-l), Formula (B-2), Formula (B-3), Formula (B-4), Formula (B-5), Formula (B-6), Formula (B-7), Formula (B-8), Formula (B-9) or Formula (C-l), or a compound set forth in Table 1.1, Table 1.2, Table 2.1, Table 2.2, or Table 3), or a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition disclosed herein.

[0011] Also disclosed herein is use of the compound disclosed herein (e.g., a compound of Formula (I), Formula (1-1), Formula (1-2), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (B-l), Formula (B-2), Formula (B-3), Formula (B-4), Formula (B-5), Formula (B-6), Formula (B-7), Formula (B-8), Formula (B-9) or Formula (C-l), or a compound set forth in Table 1.1, Table 1.2, Table 2.1, Table 2.2, or Table 3), or a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition disclosed herein in the manufacture of a medicament for activating GLP-1R in a subject.

[0012] Also disclosed herein is use of the compound disclosed herein (e.g., a compound of Formula (I), Formula (1-1), Formula (1-2), Formula (A-l), Formula (A-2), Formula (A-3), Formula (A-4), Formula (B-l), Formula (B-2), Formula (B-3), Formula (B-4), Formula (B-5), Formula (B-6), Formula (B-7), Formula (B-8), Formula (B-9) or Formula (C-l), or a compound set forth in Table 1.1, Table 1.2, Table 2.1, Table 2.2, or Table 3), or a pharmaceutically acceptable salt, or stereoisomer thereof, or the pharmaceutical composition disclosed herein in the manufacture of a medicament for treating or preventing a disease or disorder in a subject in need thereof. In some embodiments, the disease or disorder is a GLP-1 associated disease or disorder. INCORPORATION BY REFERENCE

[0013] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION Definitions

[0014] In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0015] Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0016] The terms below, as used herein, have the following meanings, unless indicated otherwise.

[0017] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, 2nd Edition, University Science Books, Sausalito, 2006; Smith and March March’s Advanced Organic Chemistry, 6th Edition, John Wiley & Sons, Inc., New York, 2007; Larock, Comprehensive Organic Transformations, 3rd Edition, VCH Publishers, Inc., New York, 2018; Carruthers, Some Modern Methods of Organic Synthesis, 4th Edition, Cambridge University Press, Cambridge, 2004; the entire contents of each of which are incorporated herein by reference.

[0018] At various places in the present disclosure, linking substituents are described. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl”, then it is understood that the “alkyl” represents a linking alkylene group.

[0019] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0020] When any variable (e.g., R1) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R1 moieties, then the group may optionally be substituted with up to two R1 moieties and R1 at each occurrence is selected independently from the definition of R1. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0021] As used herein, the term “Ci-Cj” indicates a range of the carbon atoms numbers, wherein i and j are integers and the range of the carbon atoms numbers includes the endpoints (i.e. i and j) and each integer point in between, and wherein j is greater than i. For examples, Ci-Ce indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms and six carbon atoms. In some embodiments, the term “C1-12” indicates 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3 or particularly 1 to 2 carbon atoms.

[0022] ‘‘Oxo” refers to =0.

[0023] “Cyano” refers to -CN.

[0024] “Nitro” refers to -NO2.

[0025] ‘‘Amino”, whether as part of another term or used independently, refers to the group - NRaRb, wherein Ra and Rb are independently selected from groups consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or other suitable organic groups and each of which may be optionally substituted.

[0026] “Hydroxy” or “hydroxyl”, whether as part of another term or used independently, refers to -OH.

[0027] “Alkyl”, whether as part of another term or used independently, refers to a straight-chain, or branched-chain saturated hydrocarbon radical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-l-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-l-propyl, 2-methyl-l-pentyl, 3-methyl-1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-l-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “Ci-Ce alkyl” or “Ci-6alkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a Ci-walkyl. In some embodiments, the alkyl is a Ci-ealkyl. In some embodiments, the alkyl is a Ci-salkyl. In some embodiments, the alkyl is a Ci-4alkyl. In some embodiments, the alkyl is a Ci-walkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with one or more substituents, such as oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with one or more substituents, such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0028] “Alkenyl”, whether as part of another term or used independently, refers to a straight-chain, or branched-chain hydrocarbon radical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation, or alternatively, E or Z conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” or “C2-6alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclyl, heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with one or more substituents, such as oxo, halogen, -CN, -C00H, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with one or more substituents, such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0029] “Alkynyl”, whether as part of another term or used independently, refers to a straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6alkynyl” or “C2-6alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with one or more substituents, such as oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with one or more substituents, such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0030] “Alkylidenyl” is alkyl as defined above that is attached via the terminal divalent carbon. Exemplary alkylidenyls include, but are not limited to, methylidenyl (H2C=), ethylidenyl (CH3CH=), propylidenyl (such as =C(CH3)2 and =CHCH2CH3), hexylidenyl (such as CH3(CH2)4CH=), and the like. For example, in the compound below: I , the alkylidenyl group (i.e., ethylidenyl group), is enclosed by the box which is indicated by the arrow.

[0031] “Alkoxy” or “alkoxyl”, whether as part of another term or used independently, refers to a radical of the formula -ORa where Ra is an alkyl radical as defined herein. Whenever it appears herein, a numerical range such as “Ci-Ce alkoxy” or “Ci-6alkoxy”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkoxy” where no numerical range is designated. In some embodiments, the alkoxy is a Ci-walkoxy. In some embodiments, the alkoxy is a Ci-6alkoxy. In some embodiments, the alkoxy is a Ci-salkoxy. In some embodiments, the alkoxy is a Ci-4alkoxy. In some embodiments, the alkyl is a Ci-3alkoxy. In some embodiments, the alkyl is a Ci-2alkoxy. In some embodiments, the alkyl is methoxy. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0032] “Aryl”, whether as part of another term or used independently, refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic or polycyclic (including but not limited to, bicyclic, tricyclic, or tetracyclic) ring system. The polycyclic ring system may include fused (for example, an aromatic ring fused with a cycloalkyl ring) or bridged (for example, an aromatic ring fused with a bridged cycloalkyl ring) ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with one or more substituents, such as halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclyl, heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with one or more substituents, such as halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with one or more substituents, such as halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0033] “Cycloalkyl”, whether as part of another term or used independently, refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (for example, fused with another cycloalkyl ring), spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. In some embodiments, the cycloalkyl is partially saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (Cs-Cs fully saturated cycloalkyl or Cs-Cs cycloalkenyl), from three to six carbon atoms (C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -C00H, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0034] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0035] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0036] “Hydroxylalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyl radicals, as defined above, e.g., hydroxylmethyl, 2-hydroxylethyl, 1,2-dihydroxylethyl, 1,2-dihydroxylpropyl, and the like.

[0037] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amino radicals, as defined above, e.g., aminomethyl, 2-aminoethyl, 1,2-diaminoethyl, 1,2-diaminopropyl, and the like.

[0038] “Alkoxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more alkoxy radicals, as defined above. Examples of alkoxyalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH(OCH3)2, -CH2CH(OCH3)2, -C(OCH3)3, -CH2C(OCH3)3, and the like.

[0039] “Haloalkoxy” refers to an alkoxyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1,2-difluoroethoxy, 3-bromo-2-fluoropropoxy, 1,2-dibromoethoxy, and the like.

[0040] “Heteroalkyl”, whether as part of another term or used independently, refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In some embodiments, a heteroalkyl is a Ci-Ceheteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0041] “Heteroalkenyl”, whether as part of another term or used independently, refers to an alkenyl group in which one or more skeletal atoms of the alkenyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. A heteroalkenyl is attached to the rest of the molecule at a carbon atom of the heteroalkenyl. In some embodiments, a heteroalkenyl is a C2-C6 heteroalkenyl wherein the heteroalkenyl is comprised of 2 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkenyl is attached to the rest of the molecule at a carbon atom of the heteroalkenyl. Examples of such heteroalkenyl are, for example, -CH=CHOCH3, -CH=CHOCH2CH2OCH3, -CH2CH2OCH=CHOCH3, -C(=CH2)OCH3, -CH=NCH3, -CH2N=CH2,-CH=CHNHCH3, or -CH=CHN(CH3)2- Unless stated otherwise specifically in the specification, a heteroalkenyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkenyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkenyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkenyl is optionally substituted with halogen.

[0042] “Heteroalkynyl”, whether as part of another term or used independently, refers to an alkynyl group in which one or more skeletal atoms of the alkynyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. A heteroalkynyl is attached to the rest of the molecule at a carbon atom of the heteroalkynyl. In some embodiments, a heteroalkynyl is a C2-C6 heteroalkynyl wherein the heteroalkynyl is comprised of 2 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkynyl is attached to the rest of the molecule at a carbon atom of the heteroalkynyl. Examples of such heteroalkynyl are, for example, -C=COCH3, -C=COCH2CH2OCH3, -CHzCHzOC^COCHs, -C=C-NHCH3, or -C=C-N(CH3)2- Unless stated otherwise specifically in the specification, a heteroalkynyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkynyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkynyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkynyl is optionally substituted with halogen.

[0043] “Heterocyclyl”, whether as part of another term or used independently, refers to a 3- to 24membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocyclyl is fully saturated. In some embodiments, the heterocyclyl is partially unsaturated. In some embodiments, the heterocyclyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocyclyl comprises one to three nitrogens. In some embodiments, the heterocyclyl comprises one or two nitrogens. In some embodiments, the heterocyclyl comprises one nitrogen. In some embodiments, the heterocyclyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocyclyl radical may be a monocyclic or polycyclic (including but not limited to, bicyclic, tricyclic, or tetracyclic) ring system. The polycyclic ring system may include fused (for example, a heterocyclyl ring fused with a cycloalkyl or another heterocyclyl ring), spiro, or bridged ring systems. The nitrogen, carbon, or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocyclyls include, but are not limited to, heterocyclyls having from two to fifteen carbon atoms (C2-C15 heterocyclyl), from two to ten carbon atoms (C2-C10 heterocyclyl), from two to eight carbon atoms (C2-C8 heterocyclyl), from two to seven carbon atoms (C2-C7 heterocyclyl), from two to six carbon atoms (C2-C6 heterocycly), from two to five carbon atoms (C2-C5 heterocyclyl), or two to four carbon atoms (C2-C4 heterocyclyl). Examples of such heterocyclyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, dihydrofuryl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-l-yl, 3-oxo-l,3-dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocyclyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocyclyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocyclyl, the number of carbon atoms in the heterocyclyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocyclyl (i.e. skeletal atoms of the heterocyclyl ring). In some embodiments, the heterocyclyl is a 3- to 8-membered fully saturated heterocyclyl. In some embodiments, the heterocyclyl is a 3- to 7-membered fully saturated heterocyclyl. In some embodiments, the heterocyclyl is a 3- to 6-membered fully saturated heterocyclyl. In some embodiments, the heterocyclyl is a 4- to 6-membered fully saturated heterocyclyl. In some embodiments, the heterocyclyl is a 5- to 6-membered fully saturated heterocyclyl. Unless stated otherwise specifically in the specification, a heterocyclyl may be optionally substituted as described below, for example, with one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclyl, heteroaryl, and the like. In some embodiments, the heterocyclyl is optionally substituted with one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -C00H, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocyclyl is optionally substituted with one or more substituents, such as halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocyclyl is optionally substituted with halogen.

[0044] “Heteroaryl”, whether as part of another term or used independently, refers to a 5- to 14membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. The heteroaryl radical may be a monocyclic or polycyclic (such as, bicyclic, tricyclic, or tetracyclic) ring system. The polycyclic ring system may include fused (for example, a heteroaryl ring fused with a cycloalkyl, heterocyclyl or aryl ring), bridged (for example, an aryl or heteroaryl ring fused with a bridged cycloalkyl or heterocyclyl ring) or spiro (for example, an aryl ring fused with a spiro heterocyclyl ring, or an heteroaryl ring fused with a spiro cycloalkyl or spiro heterocyclyl ring) ring systems. The nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridyl, pyridyl 1-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl may be optionally substituted, for example, with one or more substituents, such as halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclyl, heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with one or more substituents, such as halogen, methyl, ethyl, -CN, -C00H, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with one or more substituents, such as halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0045] The term “heteroarylalkyl” refers to an alkyl radical, as defined above, that is linked to an aryl radical, as defined above. In some embodiments, a heteroarylalkyl can be attached to the parent molecular moiety through heteroaryl moiety or alkyl moiety. In some embodiments, a heteroarylalkyl can be a linking substituent in the form of -heteroaryl-alkyl- or -alkyl-heteroaryl-.

[0046] The term “heterocyclylalkyl” refers to an alkyl radical, as defined above, that is linked to a heterocycly radical, as defined above. In some embodiments, a heterocyclylalkyl can be attached to the parent molecular moiety through heterocycly moiety or alkyl moiety. In some embodiments, a heterocyclylalkyl can be a linking substituent in the form of -heterocyclyl-alkyl- or -alkyl-heterocyclyl-.

[0047] The term “partially saturated” or “partially unsaturated” refers to a radical that includes at least one double or triple bond and is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.

[0048] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical and / or synthetically non-feasible. Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.

[0049] The term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, four substituents, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.

[0050] An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0051] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition. Compounds

[0052] Described herein are compounds, or pharmaceutically acceptable salts thereof useful as GLP-1R agonists and in the treatment of diseases or disorders, such as cancer.

[0053] In one aspect, provided herein is a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: x2 N is heteroaryl; X1 is N, and X2is C; WO 2025 / 140532 or X1 is C, and X2 is N; Y1 is -C(=O)-, -C(Ra)2-, or -S(=O)2-; Ring A is heteroaryl optionally substituted with one or more RA; each Ra is independently halogen, hydroxy, oxo, SF5, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein the alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with one or more RA1; each RA1 is independently halogen, hydroxy, oxo, alkyl or alkoxy; Y2 is -Y2a-Y2b-Y2c-’ each of Y2a and Y2c is a bond or alkyl; Y2b is alkyl, SF5, haloalkyl or cycloalkyl, wherein the alkyl, haloalkyl and cycloalkyl are optionally substituted with one or more groups independently selected from alkyl, haloalkyl or cycloalkyl; T is -C(=O)O(Rb), -C(=O)N(Rb)-alkyl, -C(=0)N(Rb)C(=0)(Rb), -C(=O)N(Rb)-S(=O)(Rb), -C(=O)N(Rb)-S(=O)2(Rb), heterocyclyl or heteroaryl, wherein the alkyl, heterocyclyl and heteroaryl are optionally substituted with one or more RT; each Rx is independently halogen, hydroxyl, cyano, alkyl, SF5, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy or alkoxy alkyl; or two Rx taken together with the intervening atom(s) form a cycloalkyl, or heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more Rxx; each Rxx is independently halogen, hydroxy, oxo, alkyl, SF5, haloalkyl, hydroxyalkyl, alkoxy or alkoxyalkyl;Q is cycloalkyl, aryl, heterocyclyl or heteroaryl, each optionally substituted with one or more RQ; Z1 is a bond, -N(RC)-, -N(Rc)-alkyl-,-N(Rc)-C(=O)-, -N(RC)-C(=O)-N(RC)-, heterocyclyl, heteroaryl, heterocyclyl-alkyl or heteroaryl-alkyl, wherein the alkyl, heterocyclyl and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxy, cyano, oxo, alkyl, haloalkyl, hydroxyalkyl, or alkoxy; Z2 is alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each optionally substituted with one or more Rz; each Rt is independently halogen, hydroxy, oxo, alkyl, SF5, haloalkyl, hydroxyalkyl, alkoxy or alkoxy alkyl; WO 2025 / 140532                                   PCT / CN2024 / 143124 each Rq is independently halogen, hydroxy, cyano, alkyl, SF5, haloalkyl, hydroxyalkyl, alkoxy or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more groups independently selected from halogen, haloalkyl, or alkyl; each Rz is independently halogen, hydroxyl, cyano, oxo, alkyl, SF5, haloalkyl, alkoxyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(Rd)2, -C(=0)N(Rd)2, -S(=O)(Rd), -S(=O)2(Rd), or -P(=O)(Rd)2, wherein the alkyl, alkoxyl, cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxy, oxo, alkyl, alkoxy, OCF3; or two Rz together with the same atom to which they are both attached form a C2-C6 alkylidenyl optionally substituted with one or more groups independently selected from halogen, hydroxy, oxo, SF5, haloalkyl, alkyl or alkoxy; or one RT together with one RQ form a linking moiety L connecting T and Q; or one Rz together with one RQ form a linking moiety L connecting Z2 and Q; or one RT together with one Rx form a linking moiety L connecting T and Rx; each L is a bond or a linear C1-20 bivalent hydrocarbon chain optionally substituted with one or more Ry, wherein one or more methylene units of the chain are optionally and independently replaced by cycloalkyl, heterocyclyl, -C(RL)=C(RL)-,           , -O-, -S-, -N(RL)-, -C(=O)-, -00(=0)-, - 0(=0)0-, -S(=0)-, -S(=0)2-, -N(Rl)C(=0)-, - C(=O)N(Rl)-, -N(Rl)S(=0)2-, or -S(=0)2N(RL)-; each Rl is independently hydrogen, alkyl, or cycloalkyl; each Ry is independently halogen, oxo, cyano, nitro, -0Ryl, -0C(=0)Ryl, -0C(=0)0Ryl, -OC(=O)N(Ry2)2, -SRyl, -S(=O)Ryl, -S(=O)2Ryl, -S(=O)2N(Ry2)2, -S(=0)(=NRy2)Ryl, -N(Ry2)2, -NRy2C(=O)N(Ry2)2, -NRy2C(=0)Ryl, -NRy2C(=O)ORyl, -NRy2S(=O)2Ryl, -N=S(=0)(Ryl)2, -C(=0)Ryl, -C(=0)0Ry2, -C(=O)N(Ry2)2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, SF5, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl or heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl and heterocyclyl are optionally substituted with one or more Ry3; each Ryl is independently hydrogen, alkyl, SF5, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl, each optionally substituted with one or more Ry3; each Ry2 is independently hydrogen, alkyl, SF5, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -alkyl-cycloalkyl, or -alkyl-heterocyclyl, optionally substituted with one or more Ry3; or two Ry2 on the same atom are taken together with the atom to which they are attached to form a heterocyclyl optionally substituted with one or more Ry3; and each Ry3 is independently halogen, cyano, hydroxy, oxo, -SF5, -SH, -S(=O)-alkyl, -S(=0)2-alkyl, -S(=O)2NH2, -S(=O)2NH-alkyl, -S(=O)2N(alkyl)2, -S(=O)(=N-alkyl)(alkyl), -NH2, -NH-alkyl, -N(alkyl)2, -N=S(=O)(alkyl)2, -C(=O)-alkyl, -C(=O)OH, -C(=O)O-alkyl, -C(=0)NH2, -C(=0)NH-alkyl, -C(=O)N(alkyl)2, -P(=O)(alkyl)2, alkyl, alkoxy, SF5, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, heteroalkyl or cycloalkyl; each of Ra, Rb and Rc is independently hydrogen or alkyl; or two Ra taken together with the same atom to which they are attached form a cycloalkyl or heterocyclyl; each Rd is independently hydrogen, alkyl, or cycloalkyl; n is any integer of 0-6; and q is any integer of 1-3; provided that the compound comprises at least one linking moiety L.

[0054] In some embodiments of Formula (I), the compound is of Formula (1-1): <w N—Q / Formula (1-1).

[0055] In some embodiments of Formula (1-1), the compound is of Formula (1-1-1): Formula (I-1-1), wherein R3 is hydrogen or Rx, n-1 is any integer of 0-5. In some embodiments, R3 is methyl. In some embodiments, n-1 is 0, 1, 2, or 3.

[0056] In some embodiments of Formula (I), the compound is of Formula (1-2): Formula (1-2).

[0057] In some embodiments of Formula (1-2), the compound is of Formula (1-2-1): wherein R3 is hydrogen or Rx, n-1 is any integer of 0-5. In some embodiments, R3 is methyl. In some embodiments, n-1 is 0, 1, 2, or 3.

[0058] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), or (1-2-1), at least one linking moiety L exists. In some embodiments, one linking moiety L exists.

[0059] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), or (1-2-1), one or more Rx is Ci-6 alkyl, Ci-5 alkyl, Ci-4 alkyl, C1-3 alkyl or C1-2 alkyl. In some embodiments, one or more Rx is C& alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl or Ci alkyl.

[0060] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2) or (1-1-2), two Rxtaken together with the same atom to which they are attached form a C3-6 cycloalkyl, C3 5 cycloalkyl or C3 4 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more R^. In some embodiments, two Rx taken together with the same atom to which they are attached form a C& cycloalkyl, C5 cycloalkyl, C4 cycloalkyl or C3 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more R^.

[0061] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2) or (1-2-1), two Rx taken together with the adjacent atoms to which they are attached form a C3-6 cycloalkyl, C3 5 cycloalkyl or C3-4 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more R^. In some embodiments, two Rx taken together with the adjacent atoms to which they are attached form a C& cycloalkyl, C5 cycloalkyl, C4 cycloalkyl or C3 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more R^.

[0062] In some embodiments of Formula (I), (1-1), or (1-2), n is 1 and Rx is C1-6 alkyl, C1-5 alkyl, Ci-4 alkyl, C1-3 alkyl or C1-2 alkyl. In some embodiments, n is 1 and Rx is C& alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl or Ci alkyl.

[0063] In some embodiments of Formula (1-1-1) or (1-2-1), n-1 is 1 and Rx is C1-6 alkyl, C1-5 alkyl, Ci-4 alkyl, C1-3 alkyl or C1-2 alkyl. In some embodiments, n-1 is 1 and Rx is C& alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl or Ci alkyl.

[0064] In some embodiments of Formula (I), (1-1) or (1-2), n is 3, one Rx is C1-6 alkyl and the other two Rx taken together with the same atom to which they are attached form a cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more R^. In some embodiments, n is 3, one Rx is C1-6 (e.g. C1-3, Ci, C2, C3, C4, C5 or C&, etc) alkyl and the other two Rx taken together with the same atom to which they are attached form a C3 6 (e.g. C3 4, C3, C4, C5 or Ce, etc) cycloalkyl, C3 5 cycloalkyl or C3 4 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more R^. In some or embodiments, , X10 is 0, 1, 2, or 3. In some embodiments, X10 is 0, 1, or 2. n some embodiments, X10 is 0, or 1. In some embodiments, X10 is 0. In some embodiments, X10 is 1. In

[0065] In some embodiments of Formula (I), (1-1) or (1-2), each is independently halogen, hydroxy, oxo, Ciealkyl, Ciehaloalkyl, Ci (.hydroxyalkyl, Ciealkoxy or C। (.alkoxyCi (.alkyl. In some embodiments, each Rxx is independently halogen, hydroxy, oxo, or Ci-3alkyl.

[0066] In some embodiments of Formula (I), (1-1) or (1-2), n is 3, one Rx is Ci-6 alkyl and the other two Rx taken together with the adjacent atoms to which they are attached form a cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more R^. In some embodiments, n is 3, one Rx is Ci-6(e.g. Ci-3, Ci, C2, C3, C4, C5 or Ce, etc) alkyl and the other two Rx taken together with the adjacent atoms to which they are attached form a C3 6 (e.g. C3 4, C3, C4, C5 or Ce, etc) cycloalkyl, C3 5 cycloalkyl or C3 4 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more R^.

[0067] In some embodiments of Formula (1-1-1) or (1-2-1), n-1 is 2, two Rxtaken together with the same atom to which they are attached form a cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more R^. In some embodiments, n-1 is 2, two Rx taken together with the same atom to which they are attached form a C3 6 (e.g. C3 4, C3, C4, C5 or Ce, etc) cycloalkyl, C3 5 cycloalkyl or C3 4 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more R^.

[0068] In some embodiments of Formula (1-1-1) or (1-2-1), n-1 is 2, two Rx taken together with the adjacent atoms to which they are attached form a cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more R^. In some embodiments, n-1 is 2, two Rx taken together with the adjacent atoms to which they are attached form a C3-6 (e.g. C3-4, C3, C4, C5 or Ce, etc) cycloalkyl, C3 5 cycloalkyl or C3 4 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more R^.

[0069] In some embodiments of Formula (I), (1-1) or (1-2), n is 0, 1, 2 or 3. In some embodiments, n is 0.

[0070] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), or (1-2-1), one RT and one RQ form a linking moiety L connecting T and Q.

[0071] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), or (1-2-1), Q is aryl optionally substituted with one or more RQ, T is heterocyclyl or heteroaryl optionally substituted with one or more RT, and one RT and one RQ form a linking moiety L connecting T and Q.

[0072] In some embodiments of Formula (I), (1-1) or (1-1-1), the compound is of formula selected from: Formula (A-l), Formula (A-2), 0 Formula (A-4), Formula (A-3) or wherein: each of RQ1, RQ2, RQ3, RQ4 and RQ5 is independently hydrogen or RQ; or RQ1 and RQ2, RQ2 and RQ3, RQ3 and RQ4, or RQ4 and RQ5 together with the intervening atoms form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted with one or more group independently selected from halogen, hydroxy, cyano, alkyl, haloalkyl, hydroxylalkyl, alkoxy or cycloalkyl; each of R1, R2 and R3 is independently hydrogen or Rx.

[0073] In some embodiments of Formula (A-l), (A-2), (A-3) or (A-4), R1 is hydrogen.

[0074] In some embodiments of Formula (A-l), (A-2), (A-3) or (A-4), R2 is hydrogen.

[0075] In some embodiments of Formula (A-l), (A-2), (A-3) or (A-4), R3 is alkyl. In some embodiments, R3 is Ci-6 alkyl, C1-5 alkyl, C1-4 alkyl, C1-3 alkyl or C1-2 alkyl. In some embodiments, R3 is C& alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl or Ci alkyl.

[0076] In some embodiments of Formula (A-l), (A-2), (A-3) or (A-4), each of RQ1, RQ2, RQ3, RQ4 and Rq5 is independently hydrogen, halogen, alkyl or cycloalkyl. In some embodiments, each of RQ1, RQ2, RQ3, RQ4 and RQ5 is independently hydrogen, halogen, C1-6 (e.g. C1-3, Ci, C2, C3, C4, C5 or Ce, etc) alkyl or C3-6 (e.g. C3 5, C3, C4, C5 or Ce, etc) cycloalkyl. In some embodiments, RQ1 and RQ2, RQ2 and RQ3, RQ3 and RQ4, or RQ4 and RQ5 together with the intervening atoms form a C3 6 (e.g. C3 5, C3, C4, C5 or Ce, etc) cycloalkyl, 3- to 6- membered (e.g. 3-, 4-, 5- or 6-membered) heterocyclyl, Ce aryl, or 5- to 6- membered heteroaryl, each optionally substituted with one or more group independently selected from halogen, hydroxy, cyano, alkyl, haloalkyl, hydroxylalkyl, alkoxy or cycloalkyl.

[0077] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), or (1-2-1), one Rz and one RQ form a linking moiety L connecting T and Q.

[0078] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), or (1-2-1), Q is aryl optionally substituted with one or more RQ, Z2 is aryl optionally substituted with one or more Rz, and one Rz and one Rq form a linking moiety L connecting Z2 and Q.

[0079] In some embodiments of Formula (I), (1-1), or (1-1-1), the compound is of formula selected from: Formula (B-l), Formula (B-3), Formula (B-4), Formula (B-5), Formula (B-6), Formula (B-7), Formula (B-8) or Formula (B-9), wherein: each of RQ1, RQ2, RQ3, RQ4 and RQ5 is independently hydrogen or RQ; WO 2025 / 140532                                   PCT / CN2024 / 143124 each of RZ1, RZ2, RZ3, RZ4 and Rz5 is independently hydrogen or Rz; or RQ1 and RQ2, RQ2 and RQ3, RQ3 and RQ4, RQ4 and RQ5, RZ1 and RZ2, RZ2 and RZ3, RZ3 and R24, or RZ4 and Rz5 together with the intervening atoms form a cycloalkyl, aryl, heterocyclyl or heteroaryl, each optionally substituted with one or more group independently selected from halogen, hydroxy, alkyl, haloalkyl, alkoxy or cycloalkyl; and each of R1, R2a, R2b and R3 is independently hydrogen or Rx.

[0080] In some embodiments of Formula (B-l), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B-8) or (B-9), R1 is hydrogen.

[0081] In some embodiments of Formula (B-l), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B-8) or (B-9), R1 and R2a are taken together with the atoms they attached to form a cycloalkyl or heterocyclyl. In some embodiments, R1 and R2a are taken together with the atoms they attached to form a C3 6 cycloalkyl (such as Ce cycloalkyl, C5 cycloalkyl, C4 cycloalkyl, or C3 cycloalkyl) or 3- to 6-membered heterocyclyl (such as 6-membered heterocyclyl, 5-membered heterocyclyl, 4-membered heterocyclyl, or 3-membered heterocyclyl).

[0082] In some embodiments of Formula (B-l), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B-8) or (B-9), R2a and R2b are taken together with the atom they attached to form a cycloalkyl or heterocyclyl. In some embodiments, R2a and R2b are taken together with the atoms they attached to form a C3-6 cycloalkyl (such as Ce cycloalkyl, C5 cycloalkyl, C4 cycloalkyl, or C3 cycloalkyl) or 3- to 6-membered heterocyclyl (such as 6-membered heterocyclyl, 5-membered heterocyclyl, 4-membered heterocyclyl, or 3-membered heterocyclyl).

[0083] In some embodiments of Formula (B-l), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B-8) or (B-9), each of RQ1, RQ2, RQ3, RQ4 and RQ5 is independently hydrogen, halogen, alkyl or cycloalkyl. In some embodiments, each of RQ1, RQ2, RQ3, RQ4 and RQ5 is independently hydrogen, halogen, Ci-e(e.g. C1-3, Ci, C2, C3, C4, C5 or Ce, etc) alkyl or C3 6 (e.g. C3 5, C3, C4, C5 or Ce, etc) cycloalkyl. In some embodiments, RQ1 and RQ2, RQ2 and RQ3, RQ3 and RQ4, or RQ4 and RQ5 together with the intervening atoms form a C3 6(e.g. C3 5, C3, C4, C5 or Ce, etc) cycloalkyl, 3- to 6- membered (e.g. 3-, 4-, 5- or 6membered) heterocyclyl, Ce aryl, or 5- to 6- membered heteroaryl, each optionally substituted with one or more group independently selected from halogen, hydroxy, cyano, alkyl, haloalkyl, hydroxylalkyl, alkoxy or cycloalkyl.

[0084] In some embodiments of Formula (B-l), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B-8) or (B-9), R3 is alkyl. In some embodiments, R3 is Ci e alkyl, C1-5 alkyl, C1-4 alkyl, C1-3 alkyl or C1-2 alkyl. In some embodiments, R3 is Ce alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl or Ci alkyl.

[0085] In some embodiments of Formula (B-l), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B-8) or (B-9), each of RZ1, RZ2, RZ3, RZ4 and Rz5 is independently hydrogen, halogen or alkyl. In some embodiments, each of RZ1, RZ2, RZ3, R24 and Rz ’ is independently hydrogen, -F or methyl.

[0086] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), or (1-2-1), one RT together with one Rx form a linking moiety L connecting T and Rx.

[0087] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), or (1-2-1), n is an integer of 1 to 6, T is heterocyclyl or heteroaryl optionally substituted with one or more RT, and one RT and one Rx form a linking moiety L connecting T and Rx.

[0088] In some embodiments of Formula (I), (1-1), or (1-1-1), the compound is of Formula (C-l): z2 0 Formula (C-l), wherein R3 is hydrogen or Rx.

[0089] In some embodiments of Formula (C-l), R3 is Ci-6 alkyl, C1-5 alkyl, C1-4 alkyl, C1-3 alkyl or C1-2 alkyl. In some embodiments, R3 is C& alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl or Ci alkyl.

[0090] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4), (B-l), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B-8), (B-9) or (C-l), L is H11__|_12__L13__[_14__|_15__I ’, each of L11, L12, L13, L14, and L15 is independently selected from a bond, S, -C(=O)-, O, NH, -S(=O)2-, -S(=O)-, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, or heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, or heterocyclyl are optionally substituted with one or more (e.g. two, or three, etc) Ry. In some embodiments, L11 is attaching to Q or Z2 or Rx. In some embodiments, at least one of L11, L12, L13, L14, and L15 is not a bond. In some embodiments, one of L11, L12, L13, L14, and L15 is a bond. In some embodiments, two of L11, L12, L13, L14, and L15 are bonds. In some embodiments, three of L11, L12, L13, L14, andL15 are bonds. In some embodiments, four of L11, L12, L13, L14, and L15 are bonds. In some embodiments, the linker L1 has a structure of -Ln-L12-, -L11-L12-L13-, -Lu-L12-L13-L14-, -Lu-L12-L13-L14-L15-, -L13-L14-L15-, or -Ln-L15-. In some embodiments, the linker L1 has a structure of -Ln-L12-. In some embodiments, each of L11, L12, L13, L14, and L15 is independently selected from a bond, S, -C(=O)-, O, NH, -S(=O)2-, -S(=O)-, C1-6 (e.g. C1-3, Ci, C2, C3, C4, C5 or C&, etc) alkyl, C2 6 (e.g. C2-3, C2, C3, C4, C5 or Ce, etc) alkenyl, C2 6 (e.g. C2-3, C2, C3, C4, C5 or Ce, etc) alkynyl, C1-6 (e.g. C1-3, Ci, C2, C3, C4, C5 or Ce, etc) heteroalkyl, C2 6 (e.g. C2-3, C2, C3, C4, C5 or Ce, etc) heteroalkenyl, C2 6 (e.g. C2-3, C2, C3, C4, C5 or Ce, etc) heteroalkynyl, C3 6 (e.g. C3 4, C3, C4, C5 or Ce, etc) cycloalkyl, or 3- to 6- membered (e.g. 3-, 4-, 5- or 6-membered) heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, or heterocyclyl are optionally substituted with one or more (e.g. two, or three, etc) Ry. In some embodiments, each of L11, L12, L13, L14, and L15 is independently selected from a bond, S, -C(=O)-, O, NH, -S(=O)2-, -S(=O)-, -CH2-, -CH2CH2-, -CH=CH-, I = I or^V^ , wherein NH, -CH2-, -CH2CH2- , -CH=CH-, or are optionally substituted with one or more Ry.

[0091] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4), (B-l), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B-8), (B-9) or (C-l), L is a bond or a linear C1-20 bivalent hydrocarbon chain optionally substituted with one or more Ry, wherein one or more methylene units of the chain are optionally and independently replaced by C3-6 (e.g. C3 4, C3, C4, C5 or Ce, etc) cycloalkyl, 3- to 6- membered (e.g. 3-, 4-, 5- or 6-membered) heterocyclyl, -C(RL)=C(RL)-, I-O-, -S-, -N(Rl)-, -C(=O)-, -00(=0)-, -0(=0)0-, -S(=O)-, -S(=O)2-, -N(Rl)C(=0)-, -C(=0)N(Rl)-, -N(Rl)S(=O)2-, or -S(=O)2N(RL)-. In some embodiments, each RL is independently hydrogen, Ci-e(e.g. C1-3, Ci,C2, C3, C4, C5 or Ce, etc) alkyl, or C3 6 (e.g. C3 4, C3, C4, Csor Ce, etc) cycloalkyl.

[0092] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4), (B-l), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B-8), (B-9) or (C-l), each Ry is independently halogen, oxo, cyano, nitro, -ORyl, -OC(=O)Ryl, -0C(=0)0Ryl, -OC(=O)N(Ry2)2, -SRyl, -S(=O)Ryl, -S(=O)2Ryl, -S(=O)2N(Ry2)2, -S(=O)(=NRy2)Ryl, -N(Ry2)2, -NRy2C(=O)N(Ry2)2, -NRy2C(=0)Ryl, -NRy2C(=0)0Ryl, -NRy2S(=O)2Ryl, -N=S(=O)(Ryl)2, -C(=O)Ryl, -C(=O)ORy2, -C(=O)N(Ry2)2, Ci-6 (e.g. C1-3, Ci, C2, C3, C4, C5 or Ce, etc) alkyl, C2-6 (e.g. C2-3, C2, C3, C4, C5 or Ce, etc) alkenyl, C2-6 (e.g. C2-3, C2, C3, C4, C5 or Ce, etc) alkynyl, Ci e (e.g. C1-3, Ci, C2, C3, C4, C5 or Ce, etc) heteroalkyl, C2 6 (e.g. C2 3, C2, C3, C4, C5 or Ce, etc) heteroalkenyl, C2 6 (e.g. C2-3, C2, C3, C4, C5 or Ce, etc) heteroalkynyl, Ci e (e.g. C1-3, Ci, C2, C3, C4, C5 or Ce, etc) haloalkyl, hydroxyalkyl, Ci e (e.g. C1-3, Ci, C2, C3, C4, C5 or Ce, etc) aminoalkyl, C3 6 (e.g. C3 4, C3, C4, C5 or Ce, etc) cycloalkyl or 3- to 6- membered (e.g. 3-, 4-, 5- or 6-membered) heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl and heterocyclyl are optionally substituted with one or more Ry3. In some embodiments, each Ryl is independently hydrogen, Ci-e(e.g. C1-3, Ci,C2, C3, C4, C5 or Ce, etc) alkyl, Ci-e(e.g. C1-3, Ci,C2, C3, C4, C5 or Ce, etc) haloalkyl, Ci e (e.g. C1-3, Ci, C2, C3, C4, C5 or Ce, etc) hydroxyalkyl, Ci e (e.g. C1-3, Ci, C2, C3, C4, C5 or Ce, etc) aminoalkyl, Ci e (e.g. C1-3, Ci, C2, C3, C4, C5 or Ce, etc) heteroalkyl, C2 6 (e.g. C2 3, C2, C3, C4, C5 or Ce, etc) alkenyl, C2 6 (e.g. C2 3, C2, C3, C4, C5 or Ce, etc) alkynyl, C3 6 (e.g. C3 4, C3, C4, C5 or Ce, etc) cycloalkyl or 3- to 6- membered (e.g. 3-, 4-, 5- or 6-membered) heterocyclyl, each optionally substituted with one or more Ry3. In some embodiments, each Ry2 is independently hydrogen, Ci e (e.g. C1-3, Ci, C2, C3, C4, C5 or Ce, etc) alkyl, Ci e (e.g. C1-3, Ci, C2, C3, C4, C5 or Ce, etc) haloalkyl, Ci e (e.g. C1-3, Ci, C2, C3, C4, C5 or Ce, etc) hydroxyalkyl, aminoalkyl, Ci e (e.g. C1-3, Ci, C2, C3, C4, C5 or Ce, etc) heteroalkyl, C2 6 (e.g. C2 3, C2, C3, C4, C5 or Ce, etc) alkenyl, C2 6 (e.g. C2-3, C2, C3, C4, C5 or Ce, etc) alkynyl, C3-6 (e.g. C3 4, C3, C4, C5 or Ce, etc) cycloalkyl, 3- to 6- membered (e.g. 3-, 4-, 5- or 6- membered) heterocycloalkyl, C& 12 (e.g. C& 11 orCe, etc) aryl, 5- to 12- membered (e.g. 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 5-to 6-, 7- to 8- or 10- to 12- membered) heteroaryl, -Ci-e(e.g. C1-3, Ci,C2, C3, C4, C5 or C&, etc) alkyl-Cs 6 (e.g. C3 4, C3, C4, C5 or Ce, etc) cycloalkyl, or -Ci-e(e.g. C1-3, Ci,C2, C3, C4, C5 or Ce, etc) alkyl- 3- to 6- membered (e.g. 3-, 4-, 5- or 6-membered) heterocyclyl, optionally substituted with one or more Ry3. In some embodiments, two Ry2 on the same atom are taken together with the atom to which they are attached to form a 3- to 6- membered (e.g. 3-, 4-, 5- or 6-membered) heterocyclyl optionally substituted with one or more Ry3. In some embodiments, each Ry3 is independently halogen, cyano, hydroxy, oxo, -SF5, -SH, -S(=O)-Ci-6 (e.g. C1-3, Ci, C2, C3, C4, C5 or Ce, etc) alkyl, -S(=O)2-Ci-6 (e.g. C1-3, Ci,C2, C3, C4, C5 or Ce, etc) alkyl, -S(=O)2NH2, -S(=O)2NH-Ci-6 (e.g. Ci-3, Ci,C2, C3, C4, C5 or Ce, etc) alkyl, -S(=O)2N(Ci-e(e.g. C1-3, Ci,C2, C3, C4, C5 or Ce, etc) alkyl)2, -S(=O)(=N-Ci-6(e.g. C1-3, Ci,C2, C3, C4, C5 orCe, etc) alkyl)(Ci-e(e.g. C1-3, Ci,C2, C3, C4, C5 or Ce, etc) alkyl), -NH2, -NH-C1-6 (e.g. C1-3, Ci,C2, C3, C4, C5 or Ce, etc) alkyl, -N(Ci-e(e.g. C1-3, Ci, C2, C3, C4, C5 or Ce, etc) alkyl)2, -N=S(=O)(Ci-e (e.g. C1-3, Ci, C2, C3, C4, C5 or Ce, etc) alkyl)2, -C(=O)-Ci-6 (e.g. C1-3, C1,C2, C3, C4, C5 or Ce, etc) alkyl, -C(=O)OH, -C(=O)O-Ci-e(e.g. C1-3, Ci,C2, C3, C4, C5 or Ce, etc) alkyl, -C(=0)NH2, -C(=O)NH-Ci 6 (e.g. C1-3, Ci, C2, C3, C4, C5 or Ce, etc)alkyl, -C(=O)N(Ci-6(e.g. C1-3, Ci,C2, C3, C4, C5 or Ce, etc) alkyl)2, -P(=O)(Ci-e(e.g. C1-3, Ci,C2, C3, C4, C5 or Ce, etc) alkyl)2, Ci e (e.g. C1-3, Ci, C2, C3, C4, C5 or Ce, etc) alkyl, Ci e (e.g. C1-3, Ci, C2, C3, C4, C5 or Ce, etc) alkoxy, Ci e (e.g. C1-3, Ci,C2, C3, C4, C5 or Ce, etc) haloalkyl, Ci e(e.g. C1-3, Ci,C2, C3, C4, C5 or Ce, etc) haloalkoxy, Ci e (e.g. C1-3, Ci, C2, C3, C4, C5 or Ce, etc) hydroxyalkyl, Ci e (e.g. C1-3, Ci, C2, C3, C4, C5 or Ce, etc) aminoalkyl, Ci e (e.g. C1-3, Ci, C2, C3, C4, C5 or Ce, etc) heteroalkyl or C3 6 (e.g. C3 4, C3, C4, C5 or Ce, etc)cycloalkyl.

[0093] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4), (B-l), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B-8), (B-9) or (C-l), L is -CH2CH2-#, -CH2CH2CH2-#, -CH2CH2CH2CH2-#, -CH2CH2C=CH-#,-CH2CH2O-#, -OCH2CH2-#, -NHCH2CH2-# or -CH2CH2NH-#, -CH2CH2CH2O-#, -OCH2CH2CH2-#, -CH2CH2CH2CH2O-#, -OCH2CH2CH2CH2-#, -OCH2CH2O-#, -OCH2CH2CH2O-#, -CH=CHCH2O-#, -OCH2CH=CH-#, -CH2CH2CH2NH-# , -NHCH2CH2CH2-#, -CH2CH2OCH2CH2-#,-CH2CH2OCH2-#, -CH2-cyclobutyl-O-#, or -CH2-cyclopropyl-O-#, wherein# end of L is connected to Q or Z2 or Rx.

[0094] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4), (B-l), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B-8), (B-9) or (C-l), Ring A is a bicyclic heteroaryl optionally substituted with one or more (e.g. two or three, etc) RA. In some embodiments, the bicyclic heteroaryl comprises at least one N atom. In some embodiments, the bicyclic heteroaryl is fused bicyclic heteroaryl. In some embodiments, the bicyclic heteroaryl is fused bicyclic heteroaryl comprising a 5-membered ring fused with a 6-membered ring. In some embodiments, Ring A is selected from the group consisting of: end of Ring A is connected to Y1.

[0095] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4), (B-l), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B-8), (B-9) or (C-l), each RA is independently halogen, hydroxy, oxo, cycloalkyl or heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more (e.g. two or three, etc) RA1. In some embodiments, one or more of RA is oxo. In some embodiments, one or more of RA is independently Cs s cycloalkyl, C4-8 cycloalkyl, Cs s cycloalkyl, Cs 7 cycloalkyl or Cs 6 cycloalkyl, each optionally substituted with one or more (e.g. two or three, etc) RA1. In some embodiments, one or more of RA is independently C3 cycloalkyl, C4 cycloalkyl, Cs cycloalkyl, Cs cycloalkyl, C7 cycloalkyl or Cs cycloalkyl, each optionally substituted with one or more (e.g. two or three, etc) RA1. In some embodiments, one or more of RA is independently 3- to 8-membered heterocyclyl, 4- to 8-membered heterocyclyl, 4- to 7membered heterocyclyl or 4- to 6-membered heterocyclyl, each optionally substituted with one or more RA1. In some embodiments, one or more of RA is independently 3-membered heterocyclyl, 4membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl or 8-membered heterocyclyl, each optionally substituted with one or more(e.g. two or three, etc) RA1.

[0096] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4), (B-l), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B-8), (B-9) or (C-l), each RA1 is independently oxo, alkyl or alkoxy. In some embodiments, each RA1 is independently oxo, Ci-s(e.g. C1-3, Ci,C2, C3, C4, Cs, Cs, etc) alkyl or Ci s (e.g. C1-3, Ci,C2, C3, C4, Cs, Cs, etc) alkoxy. In some embodiments, each RA1 is independently oxo, -CH3, or -OCH3.

[0097] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4), (B-l), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B-8), (B-9) or (C-l), Ring A is a bicyclic heteroaryl o=sO^ \ substituted with one or more RA, and one RA is o or O ; or Ring A is a tricyclic or tetracyclic heteroaryl optionally substituted with one or more RA.

[0098] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4),

[0099] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4), (B-l), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B-8), (B-9) or (C-l), Y1 is -C(=O)-, -C(Ra)2-, or - S(=O)2-. In some embodiments, Y1 is -C(=O)-. In some embodiments, Y1 is -C(Ra)2-, and Ra is hydrogen or Ci-e(e.g. C1-3, Ci,C2, C3, C4, C5, Ce, etc) alkyl. In some embodiments, Y1 is -C(Ra)2-, and two Ra taken together with the same atom to which they are attached form a C3-6 (e.g. C3, C4, C5, or Ce, etc) cycloalkyl or 3- to 6-membered (e.g. 3-, 4-, 5-, 6-, 3- to 4-, 4- to 5-, 5- to 6- membered, etc) heterocyclyl. In some embodiments, Y1 is . In some embodiments, Y1 is -8(=6))2-.

[0100] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4), (B-l), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B-8), (B-9) or (C-l), Y2 is alkyl or cycloalkyl optionally substituted with alkyl. In some embodiments, Y2 is C3 6 cycloalkyl, C3 5 cycloalkyl or C3-4 cycloalkyl, each optionally substituted with alkyl. In some embodiments, Y2 is Ce cycloalkyl, C5 cycloalkyl, C4 cycloalkyl, C3 cycloalkyl, each optionally substituted with alkyl. In some embodiments, Y2 is C1-6 alkyl, C1-5 alkyl, C1-4 alkyl, C1-3 alkyl or C1-2 alkyl. In some embodiments, Y2 is Ce alkyl, C5 alkyl, C4 alkyl, C3 alkyl or C2 alkyl or Ci alkyl. In some embodiments, Y2 is , or .

[0101] In some embodiments of Formula (I), (1-1), (I-1 -1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4), (B-l), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B-8), (B-9) or (C-l), Z1 is a bond, -N(RC)-, -N(RC)-C(=O)-, -N(RC)-C(=O)-N(RC)-, heterocyclyl, heteroaryl, heterocyclylalkyl or heteroarylalkyl, wherein the heterocyclyl or heteroaryl, heterocyclylalkyl or heteroarylalkyl are optionally substituted with one or more groups independently selected from halogen, hydroxy, oxo, alkyl or haloalkyl. In some embodiments, Z1 is a bond. In some embodiments, Z1 is heterocyclyl optionally substituted with one or more groups independently selected from halogen, hydroxy, oxo, alkyl or haloalkyl. In some embodiments, Z1 is a 3- to 8-membered (e.g. 3-, 4-, 5-, 6-, 7-, 8-, 4- to 8-, 4- to 7-, or 4- to 6membered, ect) heterocyclyl, each optionally substituted with one or more groups independently selected from halogen, hydroxy, oxo, alkyl or haloalkyl. In some embodiments, Z1 is heteroaryl optionally substituted with one or more groups independently selected from halogen, hydroxy, oxo, alkyl or haloalkyl. In some embodiments, Z1 is a 5- to 10-membered (e.g.5-, 6-, 7-, 8-, 9-, 10-, 5- to 9-, 5- to 8-, 5- to 7-, or 5- to 6- membered, etc) heteroaryl, each optionally substituted with one or more groups independently selected from halogen, hydroxy, oxo, alkyl or haloalkyl. In some embodiments, Z1 is heterocyclylalkyl optionally substituted with one or more groups independently selected from halogen, hydroxy, oxo, alkyl or haloalkyl. In some embodiments, Z1 is a 3- to 8membered (e.g. 3-, 4-, 5-, 6-, 7-, 8-, 4- to 8-, 4- to 7-, or 4- to 6- membered, etc) heterocyclyl-Ci io (e.g. Ci, C2, C3, C4, C5, or Ce, etc) alkyl, each optionally substituted with one or more groups independently selected from halogen, hydroxy, oxo, alkyl or haloalkyl. In some embodiments, Z1 is heteroarylalkyl optionally substituted with one or more groups independently selected from halogen, hydroxy, oxo, alkyl or haloalkyl. In some embodiments, Z1 is a 5- to 10-membered (e.g. 5-, 6-, 7-, 8-, 9- or 10- membered) heteroaryl-Ciw (e.g. Ci, C2, C3, C4, C5, or Ce, etc) alkyl, each optionally substituted with one or more groups independently selected from halogen, hydroxy, oxo, alkyl or haloalkyl.

[0102] In some embodiments of Formula (I), (1-1), (I-1 -1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4), (B-l), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B-8), (B-9) or (C-l), Z1 is selected from the group consisting of: are optionally substituted with one or more groups independently selected from halogen, hydroxy, oxo, alkyl or haloalkyl, pl is any integer of 1-3; p2 is any integer of 0-10; p3 is any integer of 0-10; Rza is hydrogen, Ci-6 alkyl, or (Ci-6 alkyl)carbonyl; Rzb and Rzc are independently hydrogen or Ci-6 alkyl; and * end of Z1 is connected to X2. In some embodiments, Z1 is selected from the group consisting of: a bond.

[0103] In some embodiments, pl is 1, 2, or 3. In some embodiments, p2 is 0, 1, 2, 3, or 4. In some embodiments, p3 is 0, 1, 2, 3, or 4. In some embodiments, Rza is hydrogen, C1-3 alkyl, or (C1-3 alkyl)carbonyl. In some embodiments, Rzb and Rzc are independently hydrogen or C1-3 alkyl.

[0104] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4) or (C-l), Z2 is aryl or heteroaryl, each optionally substituted with one or more Rz.

[0105] In some embodiments of Formula (I), (1-1), (I-1 -1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4) or (C-l), Z2 is C& 12 (e.g. C12, Cn, Cw, C9, Cs, C7, or Ce) aryl, each optionally substituted with one or more (e.g. two or three, etc) Rz.

[0106] In some embodiments of Formula (I), (1-1), (I-1 -1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4) or (C-l), Z2 is 5- to 14-membered(e.g., 5-, 6-, 7-, 8-, 9-, 10-, 11-,12-, 13-, or 14-membered) heteroaryl, 6- to 14-membered heteroaryl, 7- to 14-membered heteroaryl, 8- to 14-membered heteroaryl, 8- to 13-membered heteroaryl, 8- to 12-membered heteroaryl, each optionally substituted with one or more(e.g. two or three, etc) Rz.

[0107] In some embodiments of Formula (I), (1-1), (I-1 -1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4) or (C-l), Z2 is tricyclic aryl or tricyclic heteroaryl, each optionally substituted with one or more (e.g. two or three, etc) Rz. In some embodiments, Z2 is spiro-system containing tricyclic aryl or spirosystem containing tricyclic heteroaryl, each optionally substituted with one or more (e.g. two or three, etc) Rz.

[0108] In some embodiments of Formula (I), (1-1), (I-1 -1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4) or (C-l), Z2 is aryl or heteroaryl, each optionally substituted with one or more (e.g. two or three, etc) ZN1 ZN2 Rz. In some embodiments, Z2 is ZN^ , wherein ring ZN1 is aryl or heteroaryl, ring ZN2 is cycloalkyl or heterocyclyl, ring ZN3 is cycloalkyl or heterocyclyl, each of ring ZN1, ring ZN2 and ring ZN3 is independently optionally substituted with one or more (e.g. two or three, etc) Rz. In some embodiments, ring ZN1 is phenyl or 5- to 6- membered heteroaryl, ring ZN2 is C4 6 cycloalkyl, or 4-to -6 heterocyclyl, ring ZN3 is C3 6 cycloalkyl, 3- to 6- membered heterocyclyl, each of ring ZN1, ring ZN2 and ring ZN3 is independently optionally substituted with one or more(e.g. two or three, etc) Rz. In some embodiments, each Rz is independently halogen, or Ci-6alkyl(such as methyl, etc), or C1-6

[0109] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4) substituted with one or more (e.g. two or three, etc) Rz.

[0110] In some embodiments of Formula (I), (1-1), (I-1 -1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4) or (C-l), Z2 is cycloalkyl or heterocyclyl, each optionally substituted with one or more (e.g. two or three, etc) Rz.

[0111] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4) or (C-l), Z2 is C6-12 (e.g. C12, Cn, Cio, C9, Cs, C7, or C&) cycloalkyl, C& 11 cycloalkyl, C& 10 cycloalkyl, C& 9 cycloalkyl or Ce-s cycloalkyl, each optionally substituted with one or more (e.g. two or three, etc) Rz

[0112] In some embodiments of Formula (I), (1-1), (I-1 -1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4) or (C-l), Z2 is 5- to 14-membered(e.g., 5-, 6-, 7-, 8-, 9-, 10-, 11-,12-, 13-, or 14-membered) heterocyclyl, 6- to 14-membered heterocyclyl, 7- to 14-membered heterocyclyl, 8- to 14-membered heterocyclyl, 8- to 13-membered heterocyclyl or 8- to 12-membered heterocyclyl, each optionally substituted with one or more (e.g. two or three, etc) Rz. In some embodiments, Z2 is , each optionally substituted with one or more (e.g. two or three, etc) Rz.

[0113] In some embodiments of Formula (I), (1-1), (I-1 -1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4) or (C-l), each Rz is independently halogen, alkyl, oxo, haloalkyl, -N(Rd)2, -C(=O)N(Rd)2, -S(=O)2(Rd), -P(=O)(Rd)2 or heterocyclyl optionally substituted with one or more groups independently selected from halogen, hydroxy, oxo, alkyl or alkoxy. In some embodiments, each Rz is independently halogen, Ci-6 alkyl, Ci-6 haloalkyl, 5- to 6- membered heterocyclyl optionally substituted with one or more groups independently selected from halogen, hydroxy, oxo, alkyl or alkoxy, -N(Rd)2, - X .0 S(=O)2(Rd), or -P(=O)(Rd)2- In some embodiments, each Rz is independently         , methyl, F, oxo, -CHF2, -CH2F, -CF3, -CH2CH2OCH3, -NH(CH3), -C(=O)N(CH3)2, -S(=O)2(cyclopropyl) or -P(=O)(CH2CH3)2. In some embodiments, two Rz together with the same atom to which they are both attached form a C2-C6 alkylidenyl optionally substituted with one or more R. In some embodiments, two Rz together with the same atom to which they are both attached form a C2-C6 alkylidenyl optionally substituted with one or more halogen. In some embodiments, two Rz together with the same atom to which they are both attached form a C2-C4 alkylidenyl optionally substituted with one or more halogen. In some embodiments, two Rz together with the same atom to which they are both attached form a optionally substituted with one or more halogen. In some embodiments, two Rz together with the same atom to which they are both attached form a

[0114] In some embodiments of Formula (I), (1-1), (I-1 -1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4)

[0115] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), (1-2-1), or (C-l), Q is aryl optionally substituted with one or more (e.g. two or three, etc) RQ. In some embodiments, Q is Ce 12 (e.g. C12, Cn, C10, C9, Cs, C7, or Ce) aryl, each optionally substituted with one or more (e.g. two or three, etc) RQ. In some embodiments, Q is phenyl optionally substituted with one or more (e.g. two or three, etc) RQ. In some embodiments, Q is fused bicyclic aryl. In some embodiments, Q is In some embodiments, Q is In some embodiments, Q is RQ3 , each of RQ1, RQ2, RQ3, RQ4 and RQ5 is independently hydrogen or RQ. In some embodiments, each of RQ1, RQ2, RQ3, RQ4 and Rq5 is independently hydrogen, cyano, halogen, C1-6 alkyl, C3 6 cycloalkyl substituted with one or more groups independently selected from halogen or haloalkyl, In some embodiments, each of RQ1, rQ2, RQy rQ4 and rQ5 -s independently hydrogen, cyano, F, Cl, Br, I, -CH3, or RQ4 and RQ5 together with intervening atoms form a cycloalkyl, aryl, heterocyclyl or heteroaryl, each optionally substituted with one or more group independently selected from halogen, hydroxy, alkyl, haloalkyl, alkoxy or cycloalkyl. In some embodiments, RQ1 and RQ2, RQ2 and RQ3, RQ3 and RQ4, or RQ4 and RQ5 together with intervening atoms form a C3 6 (e.g. C3, C4, C5, Ce, or, C5 6, etc) cycloalkyl optionally substituted with one or more group independently selected from halogen, hydroxy, alkyl, haloalkyl, alkoxy or cycloalkyl. In some embodiments, RQ1 and RQ2, RQ2 and RQ3, RQ3 and RQ4, or RQ4 and RQ5 together with intervening atoms form a phenyl optionally substituted with one or more group independently selected from halogen, hydroxy, alkyl, haloalkyl, alkoxy or cycloalkyl. In some embodiments, RQ1 and RQ2, RQ2 and RQ3, RQ3 and RQ4. or RQ4 and RQ5 together with intervening atoms form a 3- to 6- (e.g. 3-, 4-, 5-, 6-, 5- to 6-, etc) membered heterocyclyl optionally substituted with one or more group independently selected from halogen, hydroxy, alkyl, haloalkyl, alkoxy or cycloalkyl. In some embodiments, RQ1 and RQ2, RQ2 and RQ3, RQ3 and RQ4. or RQ4 and RQ5 together with intervening atoms form a 3- to 6- (e.g. 3-, 4-, 5-, 6-, 5- to 6-, etc) membered heteroaryl optionally substituted with one or more group independently selected from halogen, hydroxy, alkyl, haloalkyl, alkoxy or cycloalkyl.

[0116] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), (1-2-1),or (C-l), Q is cycloalkyl or heterocyclyl, each are optionally substituted with one or more (e.g. two or three, etc) RQ. In some embodiments, Q is cycloalkyl optionally substituted with one or more (e.g. two or three, etc) RQ. In some embodiments, Q is C&-12 (e.g. C12, Cn, Cw, C9, Cs, C7, or Ce) cycloalkyl, Ce n cycloalkyl, Ceio cycloalkyl, C& 9 cycloalkyl or Ce-s cycloalkyl, each optionally substituted with one or more RQ.

[0117] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), (1-2-1),or (C-l), Q is heterocyclyl optionally substituted with one or more (e.g. two or three, etc) RQ. In some embodiments, Q is 5- to 14-membered (e.g., 5-, 6-, 7-, 8-, 9-, 10-, 11-,12-, 13-, or 14-membered) heterocyclyl, 6- to 14membered heterocyclyl, 7- to 14-membered heterocyclyl, 8- to 14-membered heterocyclyl, 8- to 13membered heterocyclyl or 8- to 12-membered heterocyclyl, each optionally substituted with one or O-\ more RQ. In some embodiments, Q is   X—'   .

[0118] In some embodiments of Formula ((I), (1-1), (1-1-1), (1-2), (1-2-1),or (C-l), Q is aryl substituted with one or more RQ, and one RQ is cycloalkyl substituted with one or more groups independently selected from halogen or haloalkyl.

[0119] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), (1-2-1),or (C-l), Q is aryl substituted with one or more RQ, and one RQ is C3-6 cycloalkyl, C3 5 cycloalkyl or C3 4 cycloalkyl, each substituted with one or more groups independently selected from halogen or haloalkyl. In some embodiments of, Q is aryl substituted with one or more RQ, and one RQ is Ce cycloalkyl, C5 cycloalkyl, C4 cycloalkyl or C3 cycloalkyl, each substituted with one or more groups independently selected from halogen or haloalkyl.

[0120] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), (1-2-1),or (C-l), Q is aryl V iF’ q \ C substituted with one or more R \ and one R ' is ' ,     ' ,     ' or '

[0121] .In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), (1-2-1), (A-l), (A-2), (A-3), (A-4), (B-l), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B-8), (B-9) or (C-l), each RQ is independently halogen, hydroxy, cyano, alkyl, haloalkyl, hydroxyalkyl, alkoxy or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more (e.g. two or three, etc) groups independently selected from halogen, haloalkyl, or alkyl. In some embodiments, each RQ is independently halogen (e.g. F, Cl, Br, I), alkyl, or cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more groups independently selected from halogen, haloalkyl, or alkyl. In some embodiments, RQ is cycloalkyl substituted with one or more groups independently selected from halogen or haloalkyl. In some embodiments, RQ is C3 6 cycloalkyl, C3 5 cycloalkyl or C3 4 cycloalkyl, each substituted with one or more groups independently selected from halogen or haloalkyl. In some embodiments, RQ is C& cycloalkyl, C5 cycloalkyl, C4 cycloalkyl or C3 cycloalkyl, each substituted with one or more groups independently selected from halogen or haloalkyl. In some embodiments, RQ is In some embodiments, RQ is alkyl optionally substituted with one or more groups independently selected from halogen or haloalkyl. In some embodiments, RQ is C1-6 alkyl (e.g., Ci alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C& alkyl) optionally substituted with one or more groups independently selected from halogen or haloalkyl.

[0122] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), (1-2-1), (B-l), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B-8), (B-9) or (C-l), T is heterocyclyl or heteroaryl, each optionally substituted with one or more RT. In some embodiments, T is heterocyclyl. In some embodiments, T is 5- to 14membered (e.g., 5-, 6-, 7-, 8-, 9-, 10-, 11-,12-, 13-, or 14- membered) heterocyclyl, 6- to 14membered heterocyclyl, 7- to 14-membered heterocyclyl, 8- to 14-membered heterocyclyl, 8- to 13membered heterocyclyl or 8- to 12-membered heterocyclyl, each optionally substituted with one or more RT. In some embodiments, T is heteroaryl. In some embodiments, T is 5- to 14-membered (e.g., 5-, 6-, 7-, 8-, 9-, 10-, 11-,12-, 13-, or 14- membered) heteroaryl, 6- to 14-membered heteroaryl, 7- to 14-membered heteroaryl, 8- to 14-membered heteroaryl, 8- to 13-membered heteroaryl or 8- to 12membered heteroaryl, each optionally substituted with one or more RT. In some embodiments, each Rt is independently oxo, halogen or alkyl.

[0123] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), (1-2-1), (B-l), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B-8), (B-9) or (C-l), T is selected from oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, oxadiazolonyl, thiadiazolonyl, triazolyl, dihydrotriazolyl, or

[0124] In some embodiments of Formula (I), (1-1), (1-1-1), (1-2), (1-2-1), or (C-l), q is 1, 2 or 3. In some embodiments, q is 1. In some embodiments, q is 2 or 3.

[0125] In some embodiments the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is one of the compounds in Table 1.1, Table 1.2, Table 2.1, Table 2.2 and Table 3. TABLE 1.1 Exemplary Compounds Compound No. Structure Compound No. Structure 5 1 N— X? Cl O 1 n^o / rO I O\ y—N / —\ H1 N TABLE 1.2 Exemplary Compounds TABLE 2.1 Exemplary Compounds 19-1 & 21 °K (ft     V C? AO    |3 Jr—         Co      A~ A0    A0 CAT    AJ o=\                   o=\ z—<                      Z—k n.--W    /                                      / A > Ax z A X CzCy    Zi=^ \_ / "r\ 20-1 & 22 Axt « N-N o / & Aa N-N / 24 & 25 0 \ re / AC OxXC p-^ rX = n-w i nX XJ o - Jx % 0 N [>      O^N J Ca \X N-N    n / & \w / O-NH XXT = N-S. I XJ o - J > °^N A>   oA? C a X J N-N / 26 &27 0 \f < A A,nAuc ^-N Jl         ^ / ~F p-N,H rY = n-w i X-J o ■ j " X 0 n^A oA‘ j « N-N    o / & °\ \(RV / =\      / ^*N >5—A 4 A । X>x Ac ^-N   -N^jzX LAF px ri b n-^ x 0 Aa 0 oA / j « N-N / 23 °-\ vh OxX0 p-NH N        i    N-S. ] ' A? S oc N-N / 28 L , oA irAx o Ki J           F n rsA_°     J \\ L h ICsT     o^ N ' A % zN-N 29&30 A XA c-& .A X? / 31 ^0AnQxn^^f O-NH A i N-^ 1 o^nXA °Af J % N-N / 33 ° vO Sr V / ’""z 1 O n 34 O-NHNMf 1 N-X 1 °X^Y> °   0^N? “j Ox !l N-N / 35 O-NH N jf i            1 Q. II N-N / 36 °—\ \—x                / ===y Mx Mx Vf~F O-NH N^Y L=       1 Ok ll N-N / 37 G-V \W O-NH          =    N-& 1 o^k^o ' oM Q 38 °~\ vH nQQoXf O-NH ¢1 Y i N-^x 7 oXXl ' oA\i L /         L VNH Ox N-N / 39 0-\ oo^^cx p-NH y 1 i NA / o N          O^N 4° N-N / 40 viJ <? m 42 0~\ vOmQQOK 0-NH N ]f i N-^ ] J XJ o - J ° N^>    0^N? J Ox N-N / 43 °~\ QxnW v- O-NH N Y = N-x 4 oXXX-0 ’ O^N7 ] 1 44 Q-A / =\         N    / ¾^ Ml ON M O-NH ^ Y = NY L oXXX-0 ' oA' 7 Ox \O N-N / 45 {S' O-NH N^Y I N-X 1 oXXM    0^ N-N / 46 Q-X y=\     z^>^n / ===^7 Vn N if I N-x I 0\ Kl 0 ' X ? > N [>      O^N J N-N / 47 °-x \__       _____N / === / x \__   ( V N~<  \ v / A n^>=< VAf O-NH N'^lf ■.    N-^ 1 O^N7 X Ox N-N / 48&49 0-^ \=\        N 4 )=\ ( XML p-NH         i N% ] nX XJ o - T \> < 0 N |>      O^N   ] N~N & p—\ \=^      / \x-N ( X WX ^-N A. WV X F p-Nn fY i N-K 1 ° » y 0 A / j N-N / 5O&51 xxX; & । v \ 0Kn^T / ° H 52 xx / N—N 53 / ==^            v-T 4 M i DiXc p-N.H rn = n-t. । AH ° ' oK 5 N-N / 54 0-\ \ / sy oT Xnn_^y °W ° = KT H » A / J (X \ II zN~N 55 °-A q X-N 0   \ 56 °'\ \K Xk^nCQtT Vn         = N-A I 6 Cl 57 o-x               _ / Ll          ^n. y^X Qt^znY^nTV ?-TjL 0 " °T oK 58 °A o-Nn N^f ; n 1 u 59 °T / =\ z^rN MX M Vf O-NH U fl =    N-7\ L qAn j T F 73 g7- .....4g Vn / =\ vK U° >x ■n 74&75 o                       o Ko             Ko C? t     X J            22 1     X J s Y                      § Y 1 o=\ 1 73-1 & 73-2 p-\ \ (SV sX- ok;K % zN-N & '<.,. 0 n wK—0 ' „Jl3 % ZN-N 76 O-x O' J  0^ ^Nl>   O^N a N-N / 133 ■ ft 78 & 78-1 Xx^vt, ° • ■ xX ¢: / N~N & Qi °X / < o -- ru l>    o<V S « zN-N 79 & 79-1 4?^ <>^N    / \ H । L N— O-NFTn-^yN-®-^5^ \zAf ’X«H ° ! X ZN~N    & 0 oTM or zN-N 77 O-N 'n^VN          \ F °^nXO ' jn i h         o^N> > « zN-N 109 0^ }|^^nxX 0 £ oXK Of zN-N 110 0^ --A (s) / %-M. o      n-> i N WS>—        J \\ I H ''W      0^N? > HN^ 111 0^ (s) / $ 112 o-y °   ° l / n-n / 113 ..0 \Va      mV IV L     Wf p-N     1T i N-& ] KJ o - J < ° N V    <^N J Y N-N / 114 Ml “V o t A o 115 o—r \ (3) / ovQi ifnn-vY '^-N' N Y<N Y’P o K? S = n-> Y N ®K_° J % 1 h >sr    o*=v 1 A CN 116 - ocf3 117 QvO>\ o-nhiMv --       oJ °AnZ% q ocf3 118 & 118-1 p-\ \ (S) / % / N'N & O-f \ (3) / YV MJ i / N—N 111-1 & 111 2 0^ (3) / "' i: zN-N & 0^ -^\ (3) / feY 134 kXn^nY V o K? S = N-j Y F H ^ST     0 N 7 A zN-n 135 0^ M \ (3) / i-Y' ' '6: zN-n 136 A \ (Ry -Yip 142 tGu mY' Qty / Mny O-NH               ° / ^ 0^nzW^    £A N'N / TABLE 2.2Exemplary Compounds p-\ \ (S) / n • • s 1 o XXN 4 XX X T>>N 0-< XX&<nyx °nKX ■ jXc H l>     0^ / S A ,0-7 0 jXn 0^. 44 Y 4« Yf on3j = jy T h nr 0^ N n X ,0^ 0 iXN X tXn x \m / xx h nr 0^ N 3 ]XN LL == Ya <    1 2- / / W / , , XX „ Y'n Y XF W 0 8 J3Y H L>     O’Y s dX iXN 4 XX X 4 / VXnX^yYf °Y 2 8 43 Y H l> Y / S X XX XAkx ! 1 .Ki 0 N J (X yXN p-\ \ (S) / XxnXXf 0 0 A 8 YY t!Y>—    / 3 k H 1^-    0^ N > (X lXn 4 nY_° ■ 43 4 h         0=%7 M°     J X 0 H Rr oX 4 . 4 °n'X° 1 43X H >   0^4% (X^ jXn 4 .yy / p—K \ (8) / Y ° ' X .. / Xu, -133 4 P“\ \ (8) / X\&(NXf n rak_°    J3 4 h nr °n $ / Xu x..... „y O^J> O'^O V^^Nr^xX XX h nr o^ N > 1 °"7 X fX p^ °3xYXxx °NKy 0 8 nY X N^ 4 .X'X' x N7 p \ \ X XxXx ° ^> ° 43T H l> oX S A x N^ / / nYncn ^> *1 i ,0-7 (X N^ O—4 vx 0 X ^x XVX XX %X ' JX H HsT     0 n / A zO"7 (X N' °-\ *\ (3) / oxXi Xk^rY Yn-vY vXp 0, V? A      N-J T X 0^? 4 x N^ Xy XyX ' OX dX N SxAxt, ^■X" ' XX z °Yf F H p —V \ ($) / VCX^xQXXf n X—  „x3 d H               ° 'N I ■ c h 1^"     ° n / zO-^ ri If ^^0 F vYi eC'N-dY O-NH Ndf     X, XF o i Xk l>     o^N X X P-\ \ ($) / H                                    '1 CI If \^-O F A \ w / Cfx 0 F X; h i^r cXN d A zO-7 OC If ^^0 F d CtYf - o -> d N             j "A I H       0^ / Y X Xdl X; VVy nQCn-<I °'N x 0 ' JV C H l>     0XN' X 6fiF Yx^o^F d O=, Y z-z oYVIYxYXf °X, 0 ' Ilk >> °x S Crv 0 F p —V \ ($) / ^dfC'-XX x °1 ~XCd<X ^ “X» ‘ XX X P“\ \ (S) / dddvdQXXF °n'X-° e xd C H            N Z di d N X- ‘ jX 1 H HT   cZ N X 6y ^^0 F VCd XI..... 0^ °'nMx xl o h l>     oXN>X dUcF d dllF ^^0 F P“\ \ ($) / xYYzX °«x •' xC dliF F SX^xX 11 xi dlip ^^O^F P“\ \ ($) / ^WxNdeN~<XF o. X? A a n-r Y nx _0 jI I H       °N J dliF O F °—v VXXXdxX °nX_° £ jxY H I^T    O^N / c: N-N 0 XJ A £ N-S Y «X  X k H       o»V k ¢: ^N-N °-"\         --1       — / ~7d®.       / X" "d' XF rn^'^N'X vi o oV oj °'nV      / X X'     V-N" <J ° Qx'dV\ vv' X d xX X VX'N ° C \ ($) / ^1¾1 " c: ZN-N °—\ / Cj^ /         v 7 N        0^N? J '■ & N-N / o—\ x\ JS) / °nH 0 ‘ dC N-N / IdX'' ' ’6; / N—N rvN    / o \__(7 II I I N—Z^V xXnYnYV\\ VF °n'Y ° H ddX H l-w      ° N > c: N-N TABLE 3 Exemplary Compounds Further Forms of Compounds Disclosed Herein Isomers / Stereoisomers

[0126] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some embodiments, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. Tautomers

[0127] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. . / 0 . / 0H

[0128] For example, HN^y ’ and Nv « are tautomers, and can be used interchangeably , o herein. A compound disclosed herein with group        ' include the corresponding compound with , OH ’SVi group Isotopic form

[0129] Unless otherwise stated, compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, denoted 'H (protium), 2H (deuterium), and 3H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford some therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism.

[0130] For example, the compounds described herein may be artificially enriched in one or more particular isotopes. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes that are not predominantly found in nature. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes selected from deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). In some embodiments, the compounds described herein are artificially enriched in one or more isotopes selected from 2H, nC, 13c, 14c, 15c, 12n, 13n, 15n, 16n, 16o, 17o, 14f, 15f, 16f, 17e 18F, 33S, 34S, 35S, 36S, 35C1,37C1,79Br, 81Br, 131I, and 125I. In some embodiments, the abundance of the enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% by molar.

[0131] In some embodiments, the compound is deuterated in at least one position. In some embodiments, the compounds disclosed herein have some or all of the 'H atoms replaced with 2H atoms.

[0132] The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997, and the following synthetic methods. For example, deuterium substituted compounds may be synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chern., 1981, 64(1-2), 9-32.

[0133] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co. Pharmaceutically acceptable salts

[0134] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0135] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of several inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0136] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, y-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1 -napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0137] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l -carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, and their pharmaceutically acceptable acid addition salts.

[0138] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(Ci-4 alkyl)4, and the like.

[0139] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Method of Treatment

[0140] Disclosed herein are methods of modulating glucagon-like peptide-1 receptor (GLP-1R) in a subject in need thereof, comprising administering to the subject a therapeutically affective amount of a compound, or a pharmaceutically acceptable salt thereof, disclosed herein.

[0141] Disclosed herein are methods of activating GLP-1R in a subject in need thereof, comprising administering to the subject a therapeutically affective amount of a compound, or a pharmaceutically acceptable salt thereof, disclosed herein.

[0142] Disclosed herein are methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically affective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein. In some embodiments, the disease or disorder is a GLP-1 associated disease or disorder.

[0143] In some embodiments, the GLP-1 associated disease or disorder is non-insulin-dependent diabetes mellitus (Type 2 diabetes), hyperglycemia, impaired glucose tolerance, insulin dependent diabetes mellitus (Type 1 diabetes), diabetic complication, obesity, hypertension, hyperlipidemia, arteriosclerosis, coronary heart disease, brain infarction, non-alcoholic steatohepatitis, Parkinson’s disease or dementia. In some embodiments, the GLP-1 associated disease or disorder is non-insulindependent diabetes mellitus (Type 2 diabetes) or obesity.

[0144] Also disclosed herein is use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein in the manufacture of a medicament for modulating GLP-1 R, in a subject in need thereof.

[0145] Also disclosed herein is use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein in the manufacture of a medicament for activating GLP-1 R, in a subject in need thereof.

[0146] Also disclosed herein is use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein in the manufacture of a medicament for treating a disease or disorder, in a subject in need thereof. In some embodiments, the disease or disorder is a GLP-1 associated disease or disorder.

[0147] In some embodiments, the GLP-1 associated disease or disorder is non-insulin-dependent diabetes mellitus (Type 2 diabetes), hyperglycemia, impaired glucose tolerance, insulin dependent diabetes mellitus (Type 1 diabetes), diabetic complication, obesity, hypertension, hyperlipidemia, arteriosclerosis, coronary heart disease, brain infarction, non-alcoholic steatohepatitis, Parkinson’s disease or dementia. In some embodiments, the GLP-1 associated disease or disorder is non-insulindependent diabetes mellitus (Type 2 diabetes) or obesity. Dosing

[0148] In some embodiments, the compositions containing the compound(s) described herein are administered for therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[0149] In some embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition. Routes of Administration

[0150] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections. Pharmaceutical Compositions / F ormulations

[0151] The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[0152] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure. Examples

[0153] For the purpose of illustration, the following examples are included. The Examples provided herein describe the synthesis of compounds disclosed herein as well as intermediates used to prepare the compounds. However, it is to be understood that these examples do not limit the present disclosure and are only meant to suggest a method of practicing the present disclosure. Persons skilled in the art will recognize that the chemical reactions described may be readily adapted to prepare a number of other compounds of the present disclosure, and alternative methods for preparing the compounds of the present disclosure are deemed to be within the scope of the present disclosure. For example, the synthesis of non-exemplified compounds according to the present disclosure may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents and building blocks known in the art other than those described, and / or by making routine modifications of reaction conditions. Besides, persons skilled in the art will also understand that individual steps described herein or in the separate batches of a compound may be combined. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the present disclosure. The following description is, therefore, not intended to limit the scope of the present disclosure, but rather is specified by the claims appended hereto.

[0154] Step 1: int-1-1

[0155] A mixture of ethyl 5-bromo-1 / / -indole-2-carboxylate (25.0 g, 93.0 mmol), 2-(3,6-dihydro-2 / / -pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (29.4 g, 140.0 mmol), K2CO3 (25.8 g, 186.0 mmol) and PdC12(dppf) (3.41 g, 4.66 mmol) in 1,4-dioxane (200 mL) and water (67 mL) was degassed and purged with N2 for 3 times, the resulting mixture was stirred at 90 °C for 2 hrs under N2 atmosphere. After cooling to r.t., the reaction was concentrated. After being diluted with water (200 mL), the residue was extracted with EtOAc (200 mL x 3), washed with brine (50 mL x 3), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-1-1 (22.2 g, 81.67 mmol, 87.8 % yield). LCMS: 272.2 [M+ H]+. ’HNMR (400 MHz, DMSO-t / 6) <5 11.77 (s, 1H), 7.48 (s, 1H), 7.39 (d, J= 8.0 Hz, 1H), 7.19 (d, J= 8.0 Hz, 1H), 7.09 (s, 1H), 4.33 (q, J= 8.0 Hz, 2H), 4.03 - 3.88 (m, 2H), 3.48 - 3.41 (m, 2H), 2.86 - 2.74 (m, 1H), 1.78 - 1.63 (m, 4H), 1.34 (t, J= 8.0 Hz, 3H).

[0156] Step 2: int-1-2

[0157] To a solution of int-1-1 (11.0 g, 40.5 mmol) in MeOH (330 mL) was added Pd(OH)2 / C (1.1 g, 10%). The resluting mixture was degassed and purged with H2 for 3 times and stirred at 25 °C for 12 hrs under H2 (15 Psi). The mixture was filtered and the cake was washed with MeOH and DCM (10:1, 330 mL x 3). The filtrate was concentrated and triturated with PE:EA (1:1, 100 mL) to afford int-1-2 (7.65 g, 28.0 mmol, 69.0% yield). LCMS: 274.2 [M+ H]+.

[0158] Step 3: int-1-3

[0159] To a solution of int-1-2 (12.60 g, 46.10 mmol) in Toluene (100 mL) was added N-methylaniline (12.5 mL, 115.0 mmol) and Trimethylaluminium (69.0 mL, 138.0 mmol, 2 M in Toluene) at 0 °C. The mixture was degassed and purged with N2 for 3 times and stirred at 90 °C for 2 hrs. After pouring into cold water (200 mL), the mixture was stirred for 10 mins, filtered, the cake was washed with EtOAc (150 mL x 3). The filtrate was washed with brine (500 mL), dried over Na2SO4, filtered, concentrated, triturated with MeOH (50 mL) to afford int-1-3 (9.00 g, 26.90 mmol, 58.4% yield). LCMS: 335.2 [M+ H]+.

[0160] Step 4: int-1-4

[0161] To a solution of int-1-3 (8.00 g, 23.92 mmol) in DMF (80 mL) was added NaH (2.39 g, 59.80 mmol, 60%) at 0 °C under N2 atomsphere protionwise and the mixture was stirred at 20 °C for 1 hr, 2-bromoacetonitrile (3.30 mL, 47.8 mmol) was added afterward and the mixture was stirred for another hr. The reaction was poured into water (200 mL), extracted with EtOAc (200 mL x 3). Combined organic layers were wahsed with water (200 mL x 3) and brine (200 mL), dried over Na2SO4, filtered, concentrated and triturated with PE: EtOAc (1:1, 30 mL) to afford int-1-4 (7.00 g, 18.74 mmol, 78.4% yield). LCMS: 374.2 [M+ H]+.

[0162] Step 5: int-1-5

[0163] To a solution of int-1-4 (4.40 g, 11.78 mmol) and 1,3,2-dioxathiolane 2,2-dioxide (3.66 g, 29.5 mmol) in THF (45 mL) was added LiHMDS (47.0 ml, 47.0 mmol, 1 M in THF) at 5 °C. Resulting mixture was stirred at 5 °C for 1 hr, was poured into water (100 mL), extracted with EtOAc (100 mL x 4). Combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-1-5 (2.60 g, 6.51 mmol, 55.2% yield). LCMS: 400.2 [M+ H]+. ’HNMR (400 MHz, DMSO-t / 6) 3 7.55 (d, J = 8.0 Hz, 1H), 7.40 - 7.31 (m, 4H), 7.30 - 7.23 (m, 3H), 5.97 (s, 1H), 3.98 - 3.86 (m, 2H), 3.44 (s, 3H), 3.43 - 3.37 (m, 2H), 2.78 (p, J= 8.0 Hz, 1H), 2.08 - 1.92 (m, 2H), 1.77 - 1.69 (m, 2H), 1.69 - 1.61 (m, 4H).

[0164] Step 6: int-1-6

[0165] To a solution of int-1-5 (2.10 g, 5.26 mmol) and hydroxylamine hydrochloride (1.83 g, 26.3 mmol) in EtOH (33.6 mL) was added K2CO3 (3.63 g, 26.3 mmol). Resulting mixture was stirred at 90 °C for 2 hrs. After cooling to r.t., the reaction was poured into water (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, concentrated and triturated with Pe and EA (5:1, 20 mL) to afford int-1-6 (1.84 g, 4.25 mmol, 81% yield). LCMS: 433.3 [M+ H]+. ’HNMR (400 MHz, DMSO-t / 6) S 9.27 (s, 1H), 7.64 (d, J= 8.0 Hz, 1H), 7.42 (t, J= 8.0 Hz, 2H), 7.37 - 7.27 (m, 4H), 7.21 (dd, J= 8.0, 4.0 Hz, 1H), 6.13 (brs, 2H), 4.01 - 3.95 (m, 2H), 3.52 (s, 3H), 3.49 - 3.45 (m, 2H), 2.84 - 2.73 (m, 1H), 1.99 - 1.88 (m, 1H), 1.74 - 1.67 (m, 4H), 1.59 - 1.44 (m, 1H), 1.36 - 1.29 (m, 1H), 1.07 - 0.93 (m, 1H).

[0166] Step 7: int-1-7

[0167] To a solution of int-1-6 (2.00 g, 4.62 mmol) in DMSO (20 mL) were added CDI (1.50 g, 9.25 mmol) and DBU (1.8 mL, 11.56 mmol). Resulting mixture was degassed and purged with N2 for 3 times and stirred at 80 °C for 2 hrs under N2 atmosphere. After cooling to r.t., the mixture was poured into water (30 mL), extracted with EtOAc (50 mL x 3). The aqueous phase was adjusted pH to 5~6 with HC1 (1 N) and extracted with EtOAc (40 mL x 2). Combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, concentrated to afford int-1-7 (2.30 g, 4.51 mmol, 98% yield). LCMS: 459.2 [M+ H]+. ’HNMR (400 MHz, DMSO-A) 3 12.07 (brs, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.39 - 7.34 (m, 2H), 7.33 - 7.25 (m, 3H), 7.25 - 7.21 (m, 1H), 7.17 (dd, J= 8.0, 4.0 Hz, 1H), 5.93 (s, 1H), 3.95 - 3.86 (m, 2H), 3.45 - 3.39 (m, 2H), 3.39 (s, 3H), 2.80 - 2.69 (m, 1H), 1.91 - 1.85 (m, 2H), 1.70 - 1.61 (m, 6H).

[0168] Step 8: int-1

[0169] To a solution of int-1-7 (2.00 g, 4.36 mmol) in THF (120 mL) was added potassium tert-butoxide (4.89 g, 43.6 mmol) and water (0.3 mL). The mixture was stirred at 25 °C for 1 hr and was poured into water (60 mL), extracted with EtOAc (100 mL x 3). The aqueous phase was adjusted pH to 4~5 with HC1 (IN) and extracted with EtOAc (80 mL x 4). Combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered, concentrated to afford int-1 (1.43 g, 3.87 mmol, 89 % yield). LCMS: 370.1 [M+ H]+. Example b: Synthesis of int-2

[0170] Step 1: int-2-1

[0171] To a solution of (5-bromo-2-fluoro-3-methylphenyl)boronic acid (78.0 g, 0.34 mol) in THF (780 mL) was added H2O2 (68 mL, 670 mmol, 30%) at 5 °C. The resulting mixture was stirred at 25 °C for 3 hrs and was poured into H2O (1 L), extracted with EtOAc (500 mL x 3). Combined organic layers were washed with brine (IL), dried over Na2SO4, filtered and concentrated to afford int-2-1 (84.0 g, 287 mmol, 86% yield). ’HNMR (400 MHz, DMSO-76) 3 10.28 (s, 1H), 6.93 (dd, J = 8.0, 4.0 Hz, 1H), 6.87 (dd, 7=8.0, 4.0 Hz, 1H), 2.18 (s, 3H).

[0172] Step 2: int-2-2

[0173] To a solution of int-2-1 (84.0 g, 0.29 mol) in DMF (840 mL) was added K2CO3 (59.5 g, 0.43 mol) and (bromomethyl)benzene (27.3 mL, 0.23 mol). The resulting mixture was stirred at 15 °C for 16 hrs, and was poured into 4 L of water, extracted with EtOAc (500 mL x 3). Combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated to afford int-2-2 (85.0 g, 0.23 mol, 80% yield). ’HNMR (400 MHz, Chloroform-7) 7 7.51 - 7.29 (m, 5H), 6.97 (dd, J = 8.0, 4.0 Hz, 1H), 6.92 (dd, J = 8.0, 4.0 Hz, 1H), 5.08 (s, 2H), 2.25 (s, 3H).

[0174] Step 3: int-2-3

[0175] To a solution of int-2-2 (65.0 g, 220 mmol) in THF (900 mL) was added n-BuLi (106 mL, 0.26 mol) at -65 °C, the mixture was stirred for 0.5 hrs, then a solution of di-tert-butyl azodicarboxylate (65.9 g, 286 mmol) in THF (80 mL) was added dropwised. After stirring at -65 °C under N2 for 1 hr, the reaction mixture was poured into ice-water (1 L), extracted with EtOAc (500 mL x 3). Combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-2-3 (36.0 g, 81 mmol, 36.6% yield). LCMS: 469.3 [M+ Na]+. 1HNMR (400 MHz, DMSO-76) 3 9.58 (s, 1H), 7.47 - 7.33 (m, 7H), 2.20 (s, 3H), 1.43 (s, 9H), 1.41 (s, 9H).

[0176] Step 4: int-2-4

[0177] To a solution of int-2-3 (36.0 g, 81.0 mmol) in a soliution of HC1 (4 M in dioxane) (360 mL) was stirred at 20 °C for 7 hrs. The reaction mixture was concentrated to afford int-2-4 (21 g, HC1 salt, crude). LCMS: 247.3 [M+ H]+.

[0178] Step 5: int-2-5

[0179] To a solution of int-2-4 (21.0 g, 85.00 mmol) in EtOH (210 mL) was added tert-butyl (25)-3-cyano-2-methyl-4-oxopiperidine-l-carboxylate (16.3 g, 68.2 mmol) andPy*HCl (0.98 g, 8.53 mmol), the mixture was stirred at 85 °C for 2 hrs, poured into H2O (600 mL), extracted with EtOAc (500 mL x 2). Combined organic layers were washed with brine (800 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-2-5 (9.0 g, 19.29 mmol, 22.62% yield). LCMS: 467.3 [M+ H]+. ’HNMR (400 MHz, DMSO-76) 3 7.58 - 7.26 (m, 7H), 7.17 (dd, J= 8.0, 4.0 Hz, 1H), 6.99 (dd, J= 8.0, 4.0 Hz, 1H), 5.19 (s, 2H), 5.17 - 5.06 (m, 1H), 4.11 - 3.89 (m, 1H), 3.12 - 2.88 (m, 2H), 2.49 - 2.38 (m, 2H), 2.26 (d, 7 = 4.0 Hz, 3H), 1.43 (s, 9H), 1.28 - 1.21 (m, 3H).

[0180] Step 6: int-2-6

[0181] To a solution of int-2-5 (5 g, 10.72 mmol) in DMA (120 mL) was added NaH (1.72 g, 42.9 mmol, 60%) at 0 °C for 30 mins, then A-(2,2-dimethoxyethyl)-l / 7-imidazole-l-carboxamide (4.27 g, 21.43 mmol) was added in portions. The mixture was stirred at 20 °C for 2 hrs and was poured into H2O (600mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-2-6 (1.70 g, 2.84 mmol, 26.5% yield). LCMS: 598.4 [M+ H]+.

[0182] Step 7: int-2-7

[0183] To a solution of int-2-6 (7.0 g, 11.71 mmol) in THF (210 mL) was added pTSA (6.68 g, 35.1 mmol). The mixture was stirred at 60 °C for 2 hrs. After cooling to r.t., the mixture was poured into water (600 mL) and extracted with EtOAc (400 mL x 3). Combined organic layers were washed with brine (400 mL x 2), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-2-7 (4.50 g, 8.43 mmol, 72.0% yield). LCMS: 534.4 [M+ H]+.

[0184] Step 8: int-2-8

[0185] A mixture of int-2-7 (1.00 g, 1.87 mmol), l-bromo-4-(cyclopropylsulfonyl)-2-fluorobenzene (0.628 g, 2.249 mmol), (I.S'.2.S')- / VL / V2-dimcthylcyclohcxanc-L2-diaminc (0.14 g, 0.94 mmol), copper(I) iodide (0.18 g, 0.94 mmol) and K2CO3 (0.52 g, 3.73 mmol) in NMP (20 mL) was degassed and purged with N2. The mixture was stirred at 110 °C for 2 hrs under N2 atmosphere. After cooling to r.t., the mixture was poured into H2O (120 mL) and extracted with EtOAc (50 mL x 3). Combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-2-8 (1.40 g, 1.91 mmol, 90% yield). LCMS: 732.3 [M+ H]+. ’HNMR (400 MHz, DMSO-t / 6) 3 8.01 (d, J = 8.0 Hz, 1H), 7.92 - 7.78 (m, 2H), 7.41 -7.32 (m, 5H), 7.22 - 1.17 (m, 1H), 7.14 - 6.99 (m, 2H), 6.91 - 6.84 (m, 1H), 5.15 (brs, 1H), 5.05 (s, 2H), 4.22 (brs, 1H), 3.23 - 3.07 (m, 1H), 3.02 - 2.92 (m, 1H), 2.78 - 2.72 (m, 1H), 2.68 - 2.57 (m, 1H), 2.23 (d, J= 4.0 Hz, 3H), 1.44 (s, 9H), 1.24 - 1.19 (m, 3H), 1.18 - 1.15 (m, 2H), 1.11 - 1.04 (m, 2H).

[0186] Step 9: int-2-9

[0187] To a mixture of int-2-8 (1.20 g, 1.64 mmol) in THF (35 mL) was added Pd / C (120 mg, 10% purity), the mixture was degassed and purged with H2 for 3 times, was stirred at 15 °C for 3 hrs under H2 atmosphere (15 Psi). The mixture was filtered and the cake was washed with MeOH (15 mL x 2). Combined organic layers were concentrated and purified by column chromatography to afford int-2-9 (630.0 mg, 0.98 mmol, 59.9% yield). LCMS: 642.3 [M+ H]+.

[0188] Step 10: int-2-10

[0189] To a solution of int-2-9 (100 mg, 0.09 mmol) in DMF (2 mL) were added 3-bromopropan-l-ol (78 mg, 0.56 mmol) and K2CO3 (78 mg, 0.56 mmol). Resulting mixture was stirred at 15 °C for 6 hrs and was poured into water (5 mL). After being filtered, the cake was rinsed with MeOH (1 mL x 2) and concentrated to afford int-2-10 (50 mg, 0.06 mmol, 61.1% yield). LCMS: 700.5 [M+ H]+. ’HNMR (400 MHz, DMSO-t / 6) 3 8.06 - 7.98 (m, 1H), 7.89 - 7.81 (m, 2H), 7.20 - 7.15 (m, 1H), 7.06 (brs, 1H), 6.96 (dd, J= 8.0, 4.0 Hz, 1H), 6.85 (dd, J= 8.0, 4.0 Hz, 1H), 5.14 (brs, 1H), 4.58 (t, J= 4.0 Hz, 1H), 4.30 - 4.12 (m, 1H), 4.06 - 3.96 (m, 2H), 3.53 - 3.48 (m, 2H), 3.21 - 3.07 (m, 1H), 3.01 -2.95 (m, 1H), 2.70 - 2.62 (m, 1H), 2.22 (s, 3H), 1.83 (p, J= 8.0 Hz, 2H), 1.44 (s, 9H), 1.23- 1.17 (m, 5H), 1.13-1.05 (m, 2H).

[0190] Step 11: int-2-11

[0191] To a solution of int-2-10 (42 mg, 0.06 mmol) in DMA (4 ml) was added t-BuOK (39 mg, 0.34 mmol) and was stirred at 80 °C for 3 hrs. After cooling to r.t., the mixture was poured into water (10 mL), extracted with EtOAc (10 mL x 3). Combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered, concentrated, and purified by pre-TLC to afford int-2-11 (20 mg, 0.03 mmol, 50.7% yield). LCMS: 680.4 [M+ H]+. ’HNMR (400 MHz, DMSO-t / 6) 3 7.83 - 7.64 (m, 2H), 7.58 (td, J= 8.0, 4.0 Hz, 1H), 7.20 - 7.03 (m, 2H), 7.03 - 6.90 (m, 1H), 6.89 - 6.65 (m, 1H), 5.16 (brs, 1H), 4.41 - 4.05 (m, 5H), 3.18 (brs, 1H), 3.04 - 2.96 (m, 1H), 2.80 - 2.60 (m, 2H), 2.26 (brd, J= 4.0 Hz, 3H), 2.23 - 1.99 (m, 2H), 1.45 (s, 9H), 1.30 - 1.14 (m, 5H), 1.13 - 1.05 (m, 2H).

[0192] Step 11: int-2

[0193] To a solution of int-2-11 (20 mg, 0.03 mmol) in EtOAc (5 mL) was added HC1 in dioxane (4M, 2 ml) and stirred at r.t. for 2 hrs. Resulting mixture was filtered and concentrated to give crude int-2 (22mg, crude). LCMS: 580.4 [M+ H]+. Example c: Synthesis of int-3

[0194] Step 1: int-3-1

[0195] To a solution of int-2-9 (200 mg, 0.31 mmol) in DMA (2 mL) were added 2-((tert-butyldimethylsilyl)oxy)ethan-l-ol (165 mg, 0.94 mmol), t-BuOK (84 mg, 0.75 mmol). The resulting mixture was stirred at 50 °C for 16 hrs. After being quenched by water (100 mL), the mixture was extracted with EtOAc (100 mL x 2). Combined organic layers were washed with water (200 mL) and brine (200 mL), dried over Na2SO4, filtered, concentrated, and purified by column chromatography to afford int-3-1 (130 mg, 0.19 mmol, 61.0% yield). LCMS: 684.3 [M+H]+. ’HNMR (400 MHz, DMSO-dd 3 10.19 (s, 1H), 7.65 (s, 1H), 7.64 - 7.61 (s, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.10 (s, 1H), 6.89 (brs, 1H), 6.83 (d, J= 8.0 Hz, 1H), 6.64 (brs, 1H), 5.11 (brs, 1H), 4.84 (d, J= 4.0 Hz, 1H), 4.29 - 4.13 (m, 3H), 3.68 (d, J= 4.0 Hz, 2H), 3.16 - 3.08 (m, 1H), 2.98 - 2.94 (m, 1H), 2.73 - 2.64 (m, 2H), 2.18 (s, 3H), 1.43 (s, 9H), 1.25 - 1.19 (m, 3H), 1.16 - 1.14 (m, 2H), 1.08 - 1.04 (m, 2H).

[0196] Step 2: int-3-2 To a solution of int-3-1 (100 mg, 0.15 mmol) in THF (2 mL) was added PPhs (58 mg, 0.22 mmol), followed by DIAD (0.05 ml, 0.22 mmol). The mixture was stirred at 40 °C for 2 hrs under N2. After cooling to room temperature, the reaction was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, concentrated, and purified by column chromatography to afford int-3-2 (170 mg, 0.11 mmol, 71.9% yield). LCMS: 666.3 [M+H]+.

[0197] Step 3: int-3 A mixture of int-3-2 (170 mg, 0.11 mmol) in HC1 solution (4 M in dioxane, 2 mL) was stirred at 10 °C for 1 hr. The reaction was concentrated to afford int-3 (100 mg, crude), and was used for next step directly. LCMS: 566.3 [M+H]+. Example d: Synthesis of int-4

[0198] Step 1: int-4-1

[0199] To a solution of int-2-9 (600 mg, 0.94 mmol) in DCM (12 mL) was added TEA (0.37 ml, 2.62 mmol) dropwise and then 2,2,2-trifluoro-A-phenyl-A-((2,2,2-trifluoroethyl)sulfonyl)ethane-l-sulfonamide (396 mg, 1.03 mmol) was added dropwise at 0 °C. After addition, the resulting mixture was stirred at 15 °C for 3 hrs. Then the reaction mixture was quenched by water (50 mL) and extracted with DCM (100 mL x 2). The combined organic layers were washed with water (50 mL), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-4-1 (630 mg, 0.81 mmol, 87.0% yield). LCMS: 774.3 [M+H]+. ’H NMR (400 MHz, DMSO-de) 3 8.01 (dd, J= 8.0, 4.0 Hz, 1H), 7.87 (dd, J= 8.0, 4.0 Hz, 1H), 7.82 (t, J= 8.0 Hz, 1H), 7.58-7.51 (m, 1H), 7.47 - 7.41 (m, 1H), 7.26 - 7.21 (m, 1H), 7.11 (brs, 1H), 5.28 - 4.98 (m, 1H), 4.41 - 4.14 (m, 1H), 3.23 - 3.10 (m, 1H), 3.03 - 2.93 (m, 1H), 2.81 - 2.74 (m, 1H), 2.72 - 2.63 (m, 1H), 2.36 (s, 3H), 1.44 (s, 9H), 1.20 - 1.18 (m, 3H), 1.17 - 1.15 (m, 2H), 1.12 - 1.06 (m, 2H).

[0200] Step 2: int-4-2

[0201] A mixture of int-4-1 (630 mg, 0.81 mmol), (E)-tert-butyldimethyl((3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)allyl)oxy)silane (486 mg, 1.63 mmol), K2CO3 (338 mg, 2.44 mmol), PdCh(dppf)*CH2C12 (66 mg, 0.08 mmol) in dioxane (12 mL) and water (1.2 mL) was degassed and purged with N2 for 3 times and the mixture was stirred at 100 °C for 2 hrs under N2 atmosphere. After cooling to room temperature, the mixture was poured into water (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with (100 mL), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-4-2 (500 mg, 0.63 mmol, 77.0% yield). LCMS: 796.4 [M+H]+. 1HNMR (400 MHz, DMSO-t / 6) 3 7.94 (dd, J = 8.0, 4.0 Hz, 1H), 7.85 - 7.70 (m, 2H), 7.29 (dd, J= 8.0, 4.0 Hz, 1H), 7.15 (dd, J= 8.0, 4.0 Hz, 1H), 7.12 - 7.08 (m, 1H), 7.02 (brs, 1H), 6.67 - 6.58 (m, 1H), 6.33 - 6.21 (m, 1H), 5.16 - 5.00 (m, 1H), 4.26 - 4.24 (m, 2H), 4.22 - 4.08 (m, 1H), 3.15 - 3.05 (m, 1H), 2.95 - 2.88 (m, 1H), 2.72 - 2.58 (m, 2H), 2.19 (s, 3H), 1.39 (s, 9H), 1.18 - 1.14 (m, 3H), 1.13 - 1.09 (m, 2H), 1.06 - 1.02 (m, 2H), 0.83 (s, 9H), 0.00 (s, 6H).

[0202] Step 3: int-4-3

[0203] To a solution of int-4-2 (490 mg, 0.62 mmol) in THF (15 mL) was added Pd / C (50 mg, 10% w / w). The reaction mixture was degassed and purged with H2 for 3 times and stirred at 25 °C for 3 hrs under H2 atmosphere (15 psi). The reaction mixture was filtered through a silica gel pad and the cake was rinsed with MeOH (50 mL x 3). The combined organic layers were concentrated to afford int-4-3 (500 mg, 0.56 mmol, 92.0% yield). LCMS: 798.4 [M+H]+. ’HNMR (400 MHz, DMSO-t / 6) S 8.05 - 8.00 (m, 1H), 7.92 - 7.84 (m, 2H), 7.21 - 7.15 (m, 2H), 7.14 - 7.00 (m, 2H), 5.33 - 5.04 (m, 1H), 4.29 - 4.20 (m, 1H), 3.59 (t, J= 8.0 Hz, 2H), 3.20 (s, 1H), 3.02 - 2.98 (m, 1H), 2.81 - 2.68 (m, 2H), 2.66 (t, J= 8.0 Hz, 2H), 2.25 (s, 3H), 1.71 - 1.68 (m, 2H), 1.47 (s, 9H), 1.27 - 1.20 (m, 5H), 1.14 - 1.08 (m, 2H), 0.86 (s, 9H), 0.02 (s, 6H).

[0204] Step 4: int-4-4

[0205] To a solution of int-4-3 (500 mg, 0.63 mmol) in THF (15 mL) was added TBAF (1.25 ml, 1.25 mmol, 1 M in THF). The resulting mixture was stirred at 15 °C for 2 hrs. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with water (50 mL), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-4-4 (350 mg, 0.51 mmol, 82.0% yield). LCMS: 684.3 [M+H]+.

[0206] Step 5: int-4-5

[0207] To a solution of int-4-4 (200 mg, 0.29 mmol) in DMA (8 mL) was added potassium tert-butoxide (39 mg, 0.35 mmol). The resulting mixture was stirred at 10 °C for 1 hr. After completion, the mixture was poured into 20 mL of water and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with water (10 mL), followed by brine (10 mL), dried over Na2SO4, filtered, concentrated and purified by prep-TLC to afford int-4-5. LCMS: 664.3 [M+H]+.

[0208] Step 6: int-4 A mixture of int-4-5 (25 mg, 0.04 mmol) and HC1 (4 M in Dioxane, 2 mL, 8.0 mmol) was stirred at 15 °C for 1 hr. The mixture was concentrated, diluted with DCM (10 mL), and concentrated again. This was repeated 3 times to afford int-4 (15 mg, 0.03 mmol, 70.7% yield). LCMS: 564.2 [M+H]+. ’HNMR (400 MHz, DMSO-< / 6) 3 7.80 - 7.26 (m, 4H), 7.15 - 6.96 (m, 1H), 6.86 - 6.71 (m, 1H), 6.70 - 6.57 (m, 1H), 4.66 - 4.52 (d, J= 6.7 Hz, 1H), 4.20 - 4.02 (m, 2H), 3.70 - 3.58 (m, 1H), 3.53 - 3.37 (m, 2H), 3.36 - 3.24 (s, 1H), 3.04 - 2.89 (m, 3H), 2.87 - 2.75 (m, 1H), 2.30 - 2.16 (m, 3H), 2.07 - 1.88 (m, 2H), 1.60 -1.40 (m, 3H), 1.22 - 1.13 (m, 2H), 1.12 - 1.06 (m, 2H). Example e: Synthesis of int-5a and int-5b int-2-7

[0209] Step 1: int-5-9

[0210] A mixture of int-2-7 (1.0 g, 1.87 mmol), l-bromo-4-(cyclopropylsulfonyl)-2-fluorobenzene (0.63 g, 2.25 mmol), (IS,25)-^1,A2-dimethylcyclohexane-l,2-diamine (0.14 g, 0.94 mmol), copper(I) iodide (0.18 g, 0.94 mmol) and K2CO3 (0.52 g, 3.73 mmol) in NMP (20 mL) was degassed and purged with N2 for 3 times. The resulting mixture was stirred at 110 °C for 2 hrs under N2 atmosphere. After cooling to room temperature, the reaction mixture was poured into H2O (120 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (100 mL), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-5-9 (1.40 g, 1.91 mmol, 90% yield). LCMS: 732.3 [M+H]+. ’HNMR (400 MHz, DMSO-dd 3 8.01 (d, J= 8.0 Hz, 1H), 7.92 - 7.78 (m, 2H), 7.41 - 7.32 (m, 5H), 7.22 - 1.17 (m, 1H), 7.14 -6.99 (m, 2H), 6.91 - 6.84 (m, 1H), 5.15 (brs, 1H), 5.05 (s, 2H), 4.22 (brs, 1H), 3.23 - 3.07 (m, 1H), 3.02 - 2.92 (m, 1H), 2.78 - 2.72 (m, 1H), 2.68 - 2.57 (m, 1H), 2.23 (d, J= 4.0 Hz, 3H), 1.44 (s, 9H), 1.24- 1.19 (m, 3H), 1.18 - 1.15 (m, 2H), 1.11 - 1.04 (m, 2H).

[0211] Step 2: int-5a

[0212] To a mixture of int-5-9 (1.20 g, 1.64 mmol) in THF (35 mL) was added Pd / C (120 mg, 10% purity, 50% wet), the mixture was degassed and purged with H2 for 3 times. The resulting mixture was stirred at 15 °C for 3 hrs under H2 atmosphere (15 psi). The reaction mixture was filtered, concentrated and washed with MeOH (15 mL x 2). The combined organic layers were concentrated and purified by column chromatography to afford int-5a (630 mg, 0.98 mmol, 59.9% yield). LCMS: 642.3 [M+H]+.

[0213] Step 3: int-5b

[0214] To a solution of int-5a (600 mg, 0.94 mmol) in DCM (12 mL) was added TEA (0.3 ml, 2.6 mmol) dropwise and 2,2,2-trifluoro-A-phenyl-A-((2,2,2-trifluoroethyl)sulfonyl)ethane-1 -sulfonamide (396 mg, 1.03 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 15 °C for 3 hrs. The reaction mixture was quenched by water (50 mL) and extracted with DCM (100 mL x 2). The combined organic layers were washed with water (50 mL), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-5b (630 mg, 0.81 mmol, 87.0% yield). LCMS: 774.3 [M+H]+. Example f: Synthesis of int-6

[0215] Step 1: int-6-1

[0216] A mixture of int-5b (900 mg, 1.16 mmol), (E)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)but-3-en-l-yl)oxy)silane (727 mg, 2.32 mmol), PdC12(dppf)*CH2C12 (95 mg, 0.11 mmol) and K2CO3 (482 mg, 3.49 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was degassed and purged with N2 for 3 times, the mixture was stirred at 100 °C for 2 hrs under N2 atmosphere. After cooling to room temperature, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with water (50 mL x 2), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-6-1 (560 mg, 0.69 mmol, 59.4% yield). LCMS: 810.3 (M+H)+. ’HNMR (400 MHz, DMSO-dd 3 7.99 (d, J= 8.0 Hz, 1H), 7.88 - 7.79 (m, 2H), 7.31 (dd, J= 8.0, 4.0 Hz, 1H), 7.20 - 7.13 (m, 2H), 7.05 (brs, 1H), 6.53 (d, J= 16.0 Hz, 1H), 6.23 (dt, J= 16.0, 8.0 Hz, 1H), 5.14 (brs, 1H), 4.22 (brs, 1H), 3.65 (t, J= 8.0 Hz, 2H), 3.22 - 3.05 (m, 1H), 3.02 - 2.92 (m, 1H), 2.78 - 2.61 (m, 2H), 2.36 (q, J = 8.0 Hz, 2H), 2.23 (s, 3H), 1.44 (s, 9H), 1.24 - 1.16 (m, 5H), 1.12 - 1.07 (m, 2H), 0.83 (s, 9H), 0.00 (s, 6H).

[0217] Step 2: int-6-2

[0218] To a solution of int-6-1 (300 mg, 0.37 mmol) in NMP (4.5 mL) was added CS2CO3 (241 mg, 0.74 mmol). The mixture was stirred at 100 °C for 2 hrs. After cooling to room temperature, the mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (50 mL x 2), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-6-2 (260 mg, 0.30 mmol, 81.0% yield). LCMS: 696.3 (M+H)+.

[0219] Step 3: int-6-3

[0220] To a solution of int-6-2 (230 mg, 0.33 mmol) in THF (7 mL) was added Pd / C (23 mg, 10% w / w). The reaction mixture was degassed and purged with FL for 3 times, then stirred at 15 °C under FL atmosphere (15 Psi) for 2 hrs. After being filtered through Celite, the filter cake was rinsed with MeOH (20 mL x 3). The combined organic layers were concentrated and purified by column chromatography to afford int-6-3 (130 mg, 0.18 mmol, 56.4% yield). LCMS: 698.3 (M+H)+. 'HNMR (400 MHz, DMSO-dg) 3 8.01 (dd, J= 12.0 Hz, 1H), 7.90-7.83 (m, 2H), 7.18-7.14 (m, 2H), 7.10-6.99 (m, 2H), 5.14 (s, 1H), 4.22 (s, 1H), 3.32 (s, 1H), 3.20-3.08 (m, 1H), 3.02-2.95 (m, 1H), 2.79-2.54 (m, 5H), 2.24 (s, 3H), 1.55-1.48 (m, 2H), 1.44 (s, 9H), 1.42-1.36 (m, 2H), 1.25-1.15 (m, 6H), 1.12-1.07 (m, 2H).

[0221] Step 4: int-6-4

[0222] To a solution of int-6-3 (120 mg, 0.17 mmol) in NMP (3.6 mL) was added potassium tert-butoxide (29 mg, 0.26 mmol). The resulting mixture was stirred at 50 °C for 1 hr. After cooling to room temperature, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (50 mL x 2), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-6-4 (65 mg, 0.1 mmol, 55.8% yield). LCMS: 678.4 (M+H)+. ’HNMR (400 MHz, DMSO-tL) 3 7.767.48 (m, 3H), 7.38 (dd, J= 20.0, 4.0 Hz, 1H), 7.11-6.67 (m, 3H), 5.18-5.08 (m, 1H), 4.35-4.01 (m, 3H), 3.20 (s, 1H), 2.97-2.86 (m, 1H), 2.74-2.55 (m, 4H), 2.28 (s, 3H), 1.80-1.65 (m, 2H), 1.64-1.49 (m, 2H), 1.45 (d, J= 4.0 Hz, 9H), 1.29-1.21 (m, 3H), 1.19-1.12 (m, 2H), 1.12 -1.04 (m, 2H).

[0223] Step 5: int-6

[0224] A mixture of int-6-4 (65 mg, 0.09 mmol) in HC1 solution (4 M in dioxane, 2 mL) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated to afford int-6 (60 mg, 0.09 mmol, 97% yield), which was used directly for the next step. LCMS: 578.4 (M+H)+. Example g: Int-7, Int-7-Pl and Int-7-P2 int-7                                         int-7-P1                      int-7-P2

[0225] The synthesis of int-7 was referred to intermediate 31 of WO-2022017338.

[0226] Int-7 (100 mg) was separated by chiral SFC to afford int-7-Pl (9 mg) and int-7-P2 (9 mg). Preparative separation method: Instrument: WATERS 150 preparative SFC (SFC-26). Column: ChiralCel OJ, 250x30mm I.D., 10pm. mobile phase: A for CO2 and B for Methanol (0.1%NH3H2O), Gradient: B 35%, flow rate: 120 mL / min, back pressure: 100 bar. Retention time: int-7-Pl 1.090min, int-7-P2 1.277min. LCMS: 398.3 [M+H]+. ’HNMR (400 MHz, DMSO-A) <5 12.20 (brs, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.30 (s, 1H), 6.71 (dd, J= 8.0, 4.0 Hz, 1H), 6.67 (s, 1H), 3.74 - 3.66 (m, 2H), 2.96 -2.83 (m, 1H), 1.83 - 1.76 (m, 2H), 1.72 - 1.65 (m, 2H), 1.57 - 1.41 (m, 3H), 1.34 - 1.12 (m, 8H). Example h: Synthesis of int-8

[0227] The synthesis of int-8-1 was referred to WO-2021155841.

[0228] Step 1: int-8-2

[0229] To a solution of int-8-1 (10.0 g, 36.60 mmol) in DMF (100 mL) was added NaH (2.20 g, 54.9 mmol, 60% purity) in portions at 0 °C. After being stirred at 20 °C for 0.5 hr, tert-butyl 2-bromoacetate (7.85 g, 40.2 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 20 °C for 1 hr. The reaction mixture was quenched by H2O (500 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-8-2 (12.0 g, 31.0 mmol, 85.0% yield). LCMS: 388.2 [M+H]+.

[0230] Step 2: int-8-3

[0231] To a solution of int-8-2 (12.0 g, 31.0 mmol) in DCM (40 ml) was added TFA (120 mL) at 0 °C. The resulting mixture was stirred at 50 °C for 0.5 hr. The reaction mixture was concentratedand triturated with MTBE (20 mL) at 20 °C for 0.5 hrs to afford int-8-3 (10.0 g, 30.20 mmol, 97% yield). LCMS: 332.3 [M+H]+. ’HNMR (400 MHz, DMSO-A) 5 12.89 (brs, 1H), 7.58 - 7.51 (m, 2H), 7.30 -7.21 (m, 2H), 5.27 (s, 2H), 4.28 (q, J = 8.0 Hz, 2H), 4.01 - 3.88 (m, 2H), 3.49 - 3.43 (m, 2H), 2.91 -2.78 (m, 1H), 1.81 - 1.64 (m, 4H), 1.31 (t, J = 8.0 Hz, 3H).

[0232] Step 3: int-8-4

[0233] To a solution of int-8-3 (10.0 g, 30.20 mmol) in THF (100 mL) was added CDI (5.87 g, 36.20 mmol). After being stirred at 20 °C for 2 hrs, hydrazine hydrate (33 ml, 604 mmol, 80% purity) was added. The resulting mixture was stirred at 20 °C for 1 hr. The reaction was filtered and triturated with H2O (10 mL) at 20 °C for 0.5 hrs. After being filtered, the cake was dried to afford int-8-4 (9.50 g, 27.50 mmol, 91.0% yield). LCMS: 346.2 [M+H]+.

[0234] Step 4: int-8-5

[0235] To a solution of int-8-4 (10.0 g, 29.00 mmol) in DCM (100 mL) was added 1-(isocyanatomethyl)-4-methoxybenzene (5.20 g, 31.80 mmol). The mixture was stirred at 10 °C for 5 hrs. The reaction was concentrated and triturated with MTBE (20 mL) at 10 °C for 0.5 hr to afford int-8-5 (10.0 g, 19.66 mmol, 67.9% yield). LCMS: 509.2 [M+H]+.

[0236] Step 5: int-8-6

[0237] A mixture of int-8-5 (6.0 g, 11.80 mmol) in NaOH (2 M in water, 40.0 mL) and EtOH (40 mL) was stirred at 110 °C for 48 hrs. After cooling to room temperature, the mixture was concentrated, neutralized with diluted HC1, filtered and washed with water (20 mL x 2). The cake was dried to afford int-8-6 (4.50 g, crude). LCMS: 463.3 [M+H]+.

[0238] Step 6: int-8-7

[0239] To a solution of int-8-6 (200 mg, 0.43 mmol, crude) in MeOH (2 mL) was added thionyl chloride (6 mg, 0.04 mmol). The mixture was stirred at 80 °C for 2 hrs. After cooling to room temperature, the mixture was concentrated and purified by column chromatography to afford int-8-7 (70 mg, 0.15 mmol, 34.0% yield). LCMS: 477.3 [M+H]+.

[0240] Step 7: int-8-8

[0241] To a solution of int-8-7 (500 mg, 1.05 mmol) in DMF (10 mL) was added NaH (126 mg, 3.15 mmol, 60% purity) in portions at 0 °C and stirred for 0.5 hr. Then 2-bromoethan-l-ol (0.22 ml, 3.15 mmol) was added dropwise. The mixture was stirred at 10 °C for 12 hrs. The reaction was quenched by H2O (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (20 mL x 3), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-8-8 (260 mg, 0.50 mmol, 47.6% yield). LCMS: 521.3 [M+H]+. ’HNMR (400 MHz, DMSO-A) 3 7.50 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.15 (d, J= 8.0 Hz, 2H), 6.92 ((d, J= 8.0 Hz, 2H), 6.70 (s, 1H), 5.25 (s, 2H), 4.98 (s, 2H), 4.89 (t, J= 8.0 Hz, 1H), 3.98 - 3.93 (m, 2H), 3.87 - 3.81 (m, 2H), 3.76 - 3.71 (m, 5H), 3.64 (s, 3H), 3.48 - 3.41 (m, 2H), 2.86 - 2.78 (m, 1H), 1.74 - 1.69 (m, 4H).

[0242] Step 8: int-8

[0243] To a solution of int-8-8 (250 mg, 0.48 mmol) in MeOH (3 mL) and water (3 mL) was added NaOH (57 mg, 1.44 mmol). The resulting mixture was stirred at 10 °C for 2 hrs. The reaction mixture was diluted with H2O (20 mL), acidified with 2 M HC1, extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (30mL), dried over Na2SO4, filtered and concentrated to afford int-8 (260 mg, crude). LCMS: 507.2 [M+H]+. 'HNMR (400 MHz, DMSO-A) d 7.45 - 7.38 (m, 2H), 7.17 - 7.12 (m, 3H), 6.94 - 6.89 (m, 2H), 6.59 (s, 1H), 5.04 (s, 2H), 4.92 (s, 2H), 3.97 - 3.93 (m, 2H), 3.86 - 3.81 (m, 2H), 3.75 - 3.71 (m, 5H), 3.47 - 3.41 (m, 2H), 2.83 - 2.79 (m, 1H), 1.73 - 1.67 (m, 4H). Example j: Synthesis of int-11 int-11-9 int-11-10 int-11

[0244] Step 1: int-11-2

[0245] To a solution of int-11-1 (35.0 g, 251.0 mmol) in DMF (400 mL) was added NBS (49.2 g, 277.0 mmol) in portions at 0 °C and the mixture was stirred at 20 °C for 0.5 hrs. The reaction was poured into water (2 L) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with water (300 mL x 2), followed by brine (300 mL x 2), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-11-2 (40.0 g, 183.0 mmol, 72.9% yield). LCMS: 218.0 [M+H]+. ’HNMR (400 MHz, DMSO-t / 6) 3 6.56 (d, J = 8.0 Hz, 1H), 5.03 (s, 2H), 2.20 (d, J= 4.0 Hz, 3H), 2.09 (d, J= 4.0 Hz, 3H).

[0246] Step 2: int-11-3

[0247] To a solution of int-11-2 (35.0 g, 160.0 mmol) in conc.HCl (6.6 mL) was added a solution of sodium nitrite (12.18 g, 177 mmol) in H2O (26.5 mL) dropwise at 0 °C and the mixture was stirred at 0 °C for 1 hr. Then a solution of tin(II) chloride dihydrate (145.0 g, 642.0 mmol) in conc.HCl (39.8 mL) was added drop wise at 0 °C and the mixture was stirred at 0 °C for 2 hrs. The reaction was diluted with H2O (300 mL) and filtered, washed with water (20 mL x 2). After dring, the cake was triturated with MTBE (100 mL) at 20 °C for 30 mins to afford int-11-3 (30.0 g, 129.00 mmol, 80.0% yield). LCMS: 233.0 [M+H]+. ’HNMR (400 MHz, DMSO-t / 6) 3 6.96 (d, J = 8.0 Hz, 1H), 6.04 (s, 1H), 4.13 (s, 2H), 2.21 (s, 3H), 2.17 (s, 3H).

[0248] Step 3: int-11-4

[0249] To a solution of int-11-3 (30.0 g, 195.00 mmol) in EtOH (450 mL) were added tert-butyl (2>S')-3-cyano-2-methyl-4-oxopiperidine-l-carboxylate (37.1 g, 156.0 mmol) and pyridine hydrochloride (2.25 g, 19.46 mmol). The mixture was stirred at 85 °C for 2 hrs. After cooling to room temperature, the reaction was concentrated, dissolved in EtOAc (500 mL), and washed with saturated NazCOs solution (1 L), followed by brine (500 mL). After being dried over Na2SO4 and filtered, the organic layer was concentrated and purified by column chromatography to afford int-11-4 (45.0 g, 120.0 mmol, 61.8% yield). LCMS: 453.0 [M+H]+. ’HNMR (400 MHz, DMSO-A) 5 7.22 (s, 1H), 5.13 - 4.91 (m, 3H), 4.23 - 4.03 (m, 1H), 3.10 - 2.93 (m, 1H), 2.44 (s, 2H), 2.34 (s, 3H), 2.23 (s, 3H), 1.44 (s, 9H), 1.23 (s, 3H).

[0250] Step 4: int-11-5

[0251] To a solution of int-11-4 (5.0 g, 11.03 mmol) in DMA (60 mL) were added A-(2,2-dimethoxyethyl)-l / 7-imidazole-l-carboxamide (2.20 g, 11.0 mmol) and potassium tert-butoxide (3.71 g, 33.1 mmol). The resulting mixture was stirred at 80 °C for 2 hrs. After cooling to room temperature, the mixture was poured into water (300 mL) and extracted with EtOAc (100 mL x 3). The combined organic layeres were washed with brine (200 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-11-5 (4.20 g, 7.19 mmol, 65.2% yield). LCMS: 584.1 [M+H]+.

[0252] Step 5: int-11-6

[0253] To a solution of int-11-5 (4.50 g, 7.70 mmol) in THF (225 mL) was added p-TsOH*H2O (4.39 g, 23.10 mmol). The resulting mixture was stirred at 60 °C for 2 hrs. After cooling to room temperature, the mixture was poured into water (500 mL), extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-11-6 (2.80 g, 5.38 mmol, 69.8% yield). LCMS: 520.0 [M+H]+. ’HNMR (400 MHz, DMSO-A) 3 10.22 (s, 1H), 7.43 (brs, 1H), 6.47 (t, J = 4.0 Hz, 1H), 6.33 (s, 1H), 5.17 (brs, 1H), 4.40 - 4.10 (m, 1H), 3.15 - 2.98 (s, 1H), 2.74 - 2.55 (m, 2H), 2.30 (s, 3H), 2.21 (s, 3H), 1.44 (s, 9H), 1.15 - 1.02 (m, 3H).

[0254] Step 6: int-11-7

[0255] To a solution of int-11-6 (5.00 g, 9.61 mmol) in THF (100 mL) was added nBuLi (12.6 mL, 31.70 mmol) dropwise at -65 °C under N2 atomsphere. The mixture was stired for 0.5 hrs at -65 °C, trimethyl borate (1.6 mL, 14.41 mmol) was added dropwise below -60 °C. The mixture was stirred at -65 °C for 1 hr. The mixture was quenched by H2O (300 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, concentrated to afford int-11-7 (5.10 g, crude). LCMS: 486.3 [M+H]+.

[0256] Step 7: int-11-8

[0257] To a solution int-11-7 (5.00 g, 8.81 mmol, crude) in THF (50 mL) was added acetic acid (0.5 mL, 8.81 mmol) and hydrogen peroxide (1.8 mL, 17.62 mmol, 30% purity).The resulting mixture was stirred at 30 °C for 9 hrs. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-11-8 (3.60 g, 7.87 mmol, 89.0% yield). LCMS: 458.2 [M+H]+

[0258] Step 8: int-11-9

[0259] To a solution of int-11-8 (3.60 g, 7.87 mmol) in DMF (36 mL) were added K2CO3 (1.31 g, 9.44 mmol) and (bromomethyl)benzene (808 mg, 4.72 mmol). The resulting mixture was stirred at 20 °C for 1 hr. The reaction mixture was poured into water (300 mL) and extracted with EtOAc (100 mL x 3). The combined organic layeres were washed with brine (200 mL), dried over Na2SO4, filtered, concentrated and purified by HPLC to afford int-11-9 (LOO g, 1.83 mmol, 23.2% yield). LCMS: 548.2 [M+H]+. ’HNMR (400 MHz, DMSO-A) 3 10.20 (s, 1H), 7.35 - 7.27 (m, 3H), 7.22 (d, J = 8.0 Hz, 1H), 7.18-7.10 (m, 2H), 6.44 (s, 1H), 6.17 (s, 1H), 5.14 (brs, 1H), 4.59 (d, J= 8.0 Hz, 1H), 4.51 (d, J= 8.0 Hz, 1H), 4.39 - 4.11 (m, 1H), 3.21 - 2.91 (m, 1H), 2.75 - 2.56 (m, 2H), 2.20 (s, 3H), 2.08 (s, 3H), 1.45 (s, 9H), 1.09 (d, J= 8.0 Hz, 3H).

[0260] Step 9: int-11-10

[0261] To a solution of int-11-9 (850 mg, 1.55 mmol) in NMP (1.5 mL) were added 5-bromo-4-fluoro-1 -methyl- IH-indazole (711 mg, 3.10 mmol, synthesized according to WO2022017338), copper(I) iodide (296 mg, 1.55 mmol), K2CO3 (644 mg, 4.66 mmol) and (1R,2R)-A1,A2-dimethylcyclohexane-l,2-diamine (110 mg, 0.78 mmol). The resulting mixture was degassed and purged with N2 for 3 times and stirred at 130 °C for 5 hrs under N2. After cooling to room temperature, the reaction was poured into water (100 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-11-10 (800 mg, 1.15 mmol, 74.1% yield). LCMS: 696.3 [M+H]+

[0262] Step 10: int-11

[0263] To a solution of int-11-10 (150 mg, 0.22 mmol) in DCM (3 mL) was added boron tribromide (0.4 mL, 4.3 mmol) dropwise at -65 °C. The resulting mixture was warmed up to 0 °C and stirred for 2 hrs. The reaction was quenched by 5 mL of water, and basified with saturated NaHCO ; solution. After extraction with DCM (10 mL x 3), the combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, concentrated and purified by prep-TLC to afford int-11 (90 mg, 0.18 mmol, 82.6% yield). LCMS: 506.2 [M+H]+. ’HNMR (400 MHz, DMSO-t / 6) 8 8.33 (s, 1H), 7.66 (d, J= 8.0 Hz, 1H), 7.42 (dd, J = 8.0, 4.0 Hz, 1H), 6.99 - 6.91 (m, 2H), 6.67 (d, J= 4.0 Hz, 1H), 4.16 (s, 3H), 3.99 (q, J= 8.0 Hz, 1H), 3.30 - 3.20 (m, 3H), 2.98 - 2.88 (m, 1H), 2.76 - 2.61 (m, 2H), 2.17 (s, 6H), 1.19 (d, J= 6.5 Hz, 3H). Example p: Synthesis of int-17, int-18 The synthesis of int-17 was referred to intermediates 31k of WO-2018056453. The synthesis of int-18 was referred to intermediates 8b of WO-2018056453. Example q: Synthesis of int-19 Step 1: int-19-2 To a solution of int-19-1 (4.25 g, 13.10 mmol, WO2023169456) in EtOH (50 mL) was added hydroxylamine hydrochloride (2.73 g, 39.3 mmol) and triethylamine (7.95 g, 79.00 mmol). The resulting mixture was stirred at 90 °C for 1 hr. After cooling to room temperature, the reaction mixture was poured into water (150 mL), and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by column chromatography to afford int-19-2 (4.68 g, 11.78 mmol, 90.0% yield). LC-MS (ESI+): m / z 358.1 (M+H)+. ’H NMR (400 MHz, DMSO-dd) 5 9.09 (s, 1H), 8.26 (d, J= 8.0 Hz, 1H), 7.29 (s, 1H), 6.78 (d, J= 8.0 Hz, 1H), 6.66 (s, 1H), 5.34 (s, 2H), 4.04 - 3.92 (m, 2H), 3.85 (s, 3H), 3.52 - 3.39 (m, 2H), 2.80 - 2.64 (m, 1H), 1.80 - 1.39 (m, 6H), 0.92 (s, 2H). Step 2: int-19-3 To a solution of int-19-2 (4.38 g, 12.25 mmol) and CDI (3.97 g, 24.51 mmol) in 1,4-Dioxane (50 mL) was added DBU (5.60 mL, 36.90 mmol). The resulting mixture was stirred at 80 °C for 2 hrs. After cooling to room temperature, the reaction mixture was poured into water (150 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with water (100 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-19-3 (4.30 g, 10.65 mmol, 87.0% yield). LC-MS (ESI+): m / z 384.2 (M+H)+. 1H NMR (400 MHz, DMSO-cL) 5 12.06 (s, 1H), 8.24 (d, J= 8.0 Hz, 1H), 7.34 (s, 1H), 6.77 (d, J= 8.0 Hz, 1H), 6.74 (s, 1H), 4.03 - 3.93 (m, 2H), 3.80 (s, 3H), 3.46 (t, J = 8.0 Hz, 2H), 2.80 - 2.70 (m, 1H), 1.89 -1.82 (m, 2H), 1.80 - 1.76 (m, 1H), 1.75 - 1.73 (m, 1H), 1.72 - 1.62 (m, 2H), 1.59 - 1.43 (m, 1H), 1.42- 1.29 (m, 1H). Step 3: int-19 To a solution of int-19-3 (4.20 g, 10.95 mmol) in THF (10 mL) were added a solutio of lithium hydroxide (2.62 g, 110 mmol) in water (0.75 mL) dropwise. The resulting mixture was stirred at 50 °C for 2 hrs. The reaction mixture was poured into 50 mL of water and extracted with MTBE (100 mL). After being separated, the aqueous phase was acidified with diluted HC1 (aq., 1 M) to pH~3 and extracted with ethyl acetate (100 mL x 3). The combined oragnic layers were washed with brine (100 mL), dried Na2SO4, filtered and concentrated to afford int-19 (3.90 g, 9.50 mmol, 87 % yield). LC-MS (ESI+): m / z 370.1 (M+H)+. ’H NMR (400 MHz, DMSO-t / 6) 5 12.32 (brs, 1H), 12.06 (brs, 1H), 8.21 (d, J= 8.0 Hz, 1H), 7.32 (s, 1H), 6.74 (dd, J= 8.0, 4.0 Hz, 1H), 6.71 (s, 1H), 4.03 - 3.92 (m, 2H), 3.45 (t, J= 8.0 Hz, 2H), 2.81 - 2.67 (m, 1H), 1.89 - 1.79 (m, 2H), 1.78 - 1.61 (m, 4H), 1.59 -1.47 (m, 1H), 1.39 - 1.26 (m, 1H). Example r: Synthesis of int-20 Br zn-n lnt-20-1 BnO

[0264] Step 1: int-20-2 To a solution of int-20-1 (500 mg, 2.18 mmol) and 2-(benzyloxy)ethan-l-ol (399 mg, 2.62 mmol) in DMA (5 mL) was added potassium tert-butoxide (367.0 mg, 3.27 mmol) in portions. The resulting mixture was stirred at 25 °C for 1 hr, the reaction mixture was quenched by H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated, purified by column chromatography to afford int-20-2 (700 mg, 1.94 mmol, 89.0% yield). LCMS: 361.1 [M+H]+.

[0265] Step 2: int-20-3 To a solution of int-11-8 (300 mg, 0.56 mmol) in NMP (6 mL) were added int-20-2 (609 mg, 1.69 mmol), copper(I) iodide (107 mg, 0.56 mmol), K2CO3 (233 mg, 1.69 mmol) and (1R,2R)-N} ,N2-dimethylcyclohexane-l,2-diamine (40 mg, 0.28 mmol). The resulting mixture was degassed and purged with N2 for 3 times, and then stirred at 130 °C under N2 for 4 hrs. After cooling to room temperature, the mixture was diluted with H2O (50 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (30 mL x 2), dried over Na2SO4, filtered and concentrated, purified by column chromatography to afford int-20-3 (440 mg, 0.54 mmol, 96.0% yield). LCMS: 814.4 [M+H]+.

[0266] Step 3: int-20-4 To a solution of int-20-3 (440 mg, 0.54 mmol) in THF (20 mL) was added Pd / C (88 mg, 20% w / w, 10% purity). The resulting mixture was degassed and purged with H2 for 3 times, and then stirred at 40 °C for 12 hrs under H2 atmosphere. The reaction mixture was filtered. The cake was washed with THF (5 mL x 3) and the filtrate was concentrated and purified by column chromatography to afford int-20-4 (300 mg, 0.47 mmol, 88.0% yield). LCMS: 634.3 [M+H]+.

[0267] Step 4: int-20-5 To a solution of int-20-4 (150 mg, 0.24 mmol) in THF (3 mL) was added PPhs (93 mg, 0.355 mmol). The mixture was degassed and purged with N2 for 3 times, then DIAD (0.069 mL, 0.355 mmol) was added dropwise at 0 °C. After addition, the reaction was stirred at 20 °C under N2 for 1 hr and quenched by H2O (20 mL). The mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-20-5 (100 mg, 0.16 mmol, 68.6% yield). LCMS: 616.3 [M+H]+.

[0268] Step 5: int-20 A mixture of int-20-5 (50.0 mg, 0.081 mmol) in HC1 solution (4 M in dioxane, 1 mL) was stirred at 20 °C for 1 hr. After completion, the reaction mixture was concentrated to afford int-20 (260 mg, 0.41 mmol, 86.0% yield). LCMS: 516.2 [M+H]+. Example o: Synthesis of int-21 The synthesis of int-21 was referred to int-20, the starting material int-2-1 was replaced by 5-bromo-2-fluorophenol. Example s: Synthesis of int-22

[0269] Step 1: int-22-2 To a solution of int-22-1 (100.0 g, 429.09 mmol) in DMF (1 L) were added NBS (76.4 g, 429.09 mmol) in portions at 0 °C. The resulting mixture was stirred at 25 °C for 1 h. The mixture was poured into H2O (3 L) and extracted with EtOAc (2 L x 3). The combined organic layers were washed with brine (1 L), dried over Na2SO4, filtered, concentrated, and triturated with H2O (300 mL) at 20 °C for 1 hr. After filtration, the cake was dried to afford int-22-2 (118.0 g, 378.0 mmol, 88% yield). LCMS: 312.0 [M+H]+.

[0270] Step 2: int-22-3 To a solution of int-22-2 (85.0 g, 272.0 mmol) in AcOH (850 mL)) was added a solution of sodium nitrite (22.56 g, 327 mmol) in water (136 mL) dropwise at 0 °C. The resulting reaction was stirred at 20 °C for 2 hrs. The reaction mixture was concentrated, diluted with water (1.5 L) and adjusted pH to 8 with Na2COs. The mixture was extracted with EtOAc (1 L x 3). The combined organic layers were washed with brine (1 L), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-22-3 (59.0 g, 183.0 mmol, 67.1% yield). LCMS: 323.0 [M+H]+.

[0271] Step 3: int-22-4 To a solution of int-22-3 (60.0 g, 185.80 mmol) in DMF (900 mL) was added NaH (11.15 g, 278.70 mmol, 60% purity) at 0 °C in portions under N2. The mixture was stirred at 20 °C for 0.5 hr, then Mel (11.6 mL, 185.80 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 20 °C for 1.5 hrs. The reaction mixture was poured into H2O (3 L), extracted with EtOAc (1 L x 3). The combined organic layers were washed with brine (1 L x 2), dried over Na2SO4, filtered, concentrated, purified by column chromatography to afford int-22-4 (30 g, 89.03 mmol, 47.92% yield). LCMS: 336.9 [M+H]+. ’HNMR (500 MHz, DMSO-t / 6) 5 7.83 (d, J= 0.9 Hz, 1H), 7.67 (dd, J= 8.8, 0.9 Hz, 1H), 7.63 (d, J= 8.8 Hz, 1H), 4.04 (s, 3H).

[0272] Step 4: int-22-5 To a solution of int-22-4 (500 mg, 1.48 mmol) in 1,4-dioxane (5 mL) and water (1 mL) were added (E)-tert-butyldimethyl((3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)allyl)oxy)silane (575 mg, 1.93 mmol), PdC12(dppf) (109 mg, 0.15 mmol) and K2CO3 (410 mg, 2.97 mmol). The resulting mixture was purged with N2 for 2 mins and then stirred at 100 °C for 2 hrs under N2. After cooling to room temperature, the reaction mixture was poured into 20 mL of water and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-22-5 (250 mg, 0.66 mmol, 44.2% yield). LCMS: 381.0 [M+H]+.

[0273] Step 5: int-22-6 To a solution of int-2-7 (150 mg, 0.28 mmol) in NMP (1.5 mL) were added int-22-5 (214.0 mg, 0.56 mmol), (IR^^-A'^-dimethylcyclohexane-l^-diamine (20 mg, 0.14 mmol), copper(I) iodide (54 mg, 0.28 mmol) and K2CO3 (117 mg, 0.84 mmol). The resulting mixture was purged with N2 for 2 mins and stirred at 130 °C for 5 hrs under N2. After cooling to room temperature, the reaction mixture was poured into water (10 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with water (10 mL), followed by brine (10 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-22-6 (150 mg, 0.18 mmol, 64.0% yield). LCMS: 834.6 [M+H]+.

[0274] Step 6: int-22-7 To a solution of int-22-6 (130 mg, 0.16 mmol) in THF (3 mL) were added Pd / C (13 mg, 10%w / w, 10% purity) andPd(OH)2(13 mg, 10% w / w, 10% purity).The reaction mixture was degassed and purged with H2 for 3 times and stirred at 30 °C under H2 (15 Psi) for 6 hrs. The mixture was filtered. The cake was rinsed with THF (3 mL x 3), the combined filtrate was concentrated to afford int-22-7 (100 mg, 0.13 mmol, 86.0% yield). LCMS: 746.5 [M+H]+.

[0275] Step 7: int-22-8 To a solution of int-22-7 (90 mg, 0.12 mmol) in THF (0.9 mL) were added a solution of TBAF (0.422 ml, 1 M in THF) dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 30 mins. After completion, the residue was diluted with H2O (2 mL) and extracted with solvent EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, concentrated and purified by pre-TLC to afford int-22-8 (60 mg, 0.095 mmol, 79.0% yield). LCMS: 632.4 [M+H]+.

[0276] Step 8: int-22-9 To a solution of int-22-8 (50 mg, 0.079 mmol) in THF (1 mL) were added triphenylphosphine (42 mg, 0.16 mmol), the mixture was degassed and purged with N2 for 3 times, and then DIAD (32 mg, 0.158 mmol) was added dropwise at 0 °C under N2. The resulting mixture was stirred at 25 °C for 1 h under N2. After completion, the residue was quenched by H2O (2 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, concentrated and purified by pre-TLC to afford int-22-9 (70 mg, 0.057 mmol, 72.1% yield). LCMS: 614.4 [M+H]+. ’HNMR (400 MHz, DMSO-t / 6) 5 8.39 - 8.33 (m, 1H), 7.41 (d, J= 8.0 Hz, 1H), 7.34 (d, J= 8.0 Hz, 1H), 7.29 - 7.24 (m, 1H), 7.08 - 7.03 (m, 1H), 6.95 - 6.78 (m, 1H), 6.72 - 6.58 (m, 1H), 5.33 - 5.08 (m, 1H), 4.33 (t, J= 8.0 Hz, 2H), 4.28 - 4.20 (m, 1H), 4.12 - 4.09 (m, 3H), 3.41 - 3.40 (m, 1H), 3.02 - 2.92 (m, 2H), 2.82 - 2.74 (m, 2H), 2.33 - 2.29 (m, 3H), 1.79 - 1.64 (m, 2H), 1.52 - 1.45 (m, 12H)

[0277] Step 9: int-22 A mixture of int-22-9 (70 mg, 0.08 mmol) in HC1 solution (0.7 mL, 4 M in dioxane) was stirred at 25 °C for 1 h. The reaction mixture was concentrated and diluted with DCM (2 mL). The process was repeated for 3 times to afford int-22 (50 mg, 0.049 mmol, 61.0% yield), which was used for next step directly without purification. LCMS: 514.4 [M+H]+. Example t: Synthesis of int-23

[0278] Step 1: int-23-8 To a solution of int-20-1 (3.00 g, 13.10 mmol) in DMA (30 mL) were added phenylmethanol (1.70 g, 15.72 mmol) and tBuOK (2.21 g, 19.65 mmol), the mixture was stirred at 25 °C for 1 hr. The reaction mixture was poured into H2O (150 mL) and extracted with EtOAc (150 mL x 2). The combined organic layers were washed with water (100 mL x 2), followed by brine (150 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-23-8 (3.10 g, 9.77 mmol, 74.6% yield). LCMS: 317.2 [M+H]+.

[0279] Step 2: int-23-1 To a solution of int-2-7 (960.0 mg, 1.80 mmol) in THF (20 ml) and MeOH (20 mL) was added Pd / C (96 mg, 10% w / w, 10% purity). The reaction mixture was degassed and purged with H2 for 3 times and stirred at 30 °C under H2 (15 Psi) for 7 hrs. The mixture was filtered through a celite pad and the cake was rinsed with MeOH (10 mL x 3). The combined filtrate was concentrated and purified by column chromatography to afford int-23-1 (420 mg, 0.95 mmol, 52.6% yield). LCMS: 444.3 [M+H]+.

[0280] Step 3: int-23-2 To a solution of int-23-1 (370.0 mg, 0.83 mmol) in DCM (4 mL) was added TEA (0.35 mL, 2.50 mmol), A-phenyl-bis(trifluoromethanesulfonimide) (283 mg, 0.79 mmol). The reaction mixture was stirred at 25 °C for 1 hr. The reaction mixture was diluted with DCM (20 mL) and washed with water (10 mL), followed by brine (10 mL), dried over Na2SO4, filtered and concentrated and purified by column chromatography to afford int-23-2 (380 mg, 0.66 mmol, 79.0% yield). LCMS: 576.3 [M+H]+.

[0281] Step 4: int-23-3 To a solution of int-23-2 (380 mg, 0.66 mmol), (E)-tert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane (394 mg, 1.32 mmol) in dioxane (7.6 mL) were added PdCh(dppf)*CH2C12 adduct (108 mg, 0.13 mmol), K2CO3 (274 mg, 1.98 mmol) and water (0.76 mL). The resulting mixture was degassed and purged with N2 for 3 times and then stirred at 100 °C for 1 hr under N2 atmosphere. After cooling to room temperature, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-23-3 (290 mg, 0.49 mmol, 73.5% yield). LCMS: 598.4 [M+H]+.

[0282] Step 5: int-23-4 To a solution of int-23-3 (290 mg, 0.49 mmol), int-23-8 (308 mg, 0.97 mmol) in NMP (3 mL) were added (IS,25)^,A2-dimethylcyclohexane-l,2-diamine (35 mg, 0.24 mmol), cuprous iodide (92 mg, 0.49 mmol), K2CO3 (201 mg, 1.46 mmol). The resulting mixture was purged with N2 for 2 mins and stirred at 130 °C for 3 hrs under N2. After cooling to room temperature, the reaction mixture was poured into water (15 mL) and extracted with EtOAc (10 mL x 3), washed with water (10 mL), followed by brine (10 mL), dried over Na2SO4, filtered and concentrated, purified by column chromatography to afford int-23-4 (180 mg, 0.22 mmol, 44.5% yield). LCMS: 834.5 [M+H]+.

[0283] Step 6: int-23-5 To a solution of int-23-4 (180.0 mg, 0.22 mmol) in THF (6 mL) was added Pd / C (36 mg, 20% w / w, 10% purity). The mixture was degassed and purged with H2 for 3 times and stirred at 30 °C for 12 hrs under H2 (15 Psi) atmosphere. The mixture was filtered. The cake was washed with THF (3 mL x 3), the combined filtrate was concentrated and purified by column chromatography to afford int-23-5 (120 mg, 0.16 mmol, 74.5% yield). LCMS: 746.5 [M+H]+.

[0284] Step 7: int-23-6 Int-23-5 (120 mg, 0.17 mmol) in THF (1 mL) was added TBAF (228 mg, 0.87 mmol) in portions. The mixture was stirred at 20 °C for 2 hrs under N2. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with water (10 mL), followed by brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by column chromatography to afford int-23-6 (70 mg, 0.11 mmol, 63.6% yield). LCMS: 632.3 [M+H]+.

[0285] Step 8: int-23-7 To a solution of int-23-6 (60 mg, 0.095 mmol) in anhydrous toluene (3 mL) was added CMBP (92 mg, 0.38 mmol). The mixture was purged with N2 for 2 mins and then stirred at 90 °C for 2 hrs under N2. After cooling to room temperature, the reaction mixture was quenched by water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with water (10 mL), followed by brine (10 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-23-7 (30 mg, 0.049 mmol, 51.5% yield). LCMS: 614.4 [M+H]+.

[0286] Step 9: int-23 A mixture of int-23-7 (40 mg, 0.065 mmol) in HC1 solution (3 mL, 4 M in dioxane) was stirred at 20 °C for 0.5 hr. The reaction mixture was concentrated and diluted with DCM (10 mL). This process was repeated for three times to afford the title compound (40 mg, 0.062 mmol, 96.0% yield). LCMS: 514.4 [M+H]+. ’HNMR (400 MHz, DMSO-A, 80 °C) 5 9.71 (brs, 1H), 9.07 (brs, 1H), 8.27 (s, 1H), 7.50 - 7.42 (m, 2H), 7.41 - 7.28 (m, 1H), 7.07 - 6.98 (m, 1H), 6.96 - 6.74 (m, 2H), 4.77 - 4.58 (m, 1H), 4.16 - 3.96 (m, 4H), 3.82 - 3.73 (m, 1H), 3.59 (s, 3H), 3.53 - 3.43 (m, 1H), 2.98 - 2.79 (m, 2H), 2.30 (s, 3H), 2.23 - 1.88 (m, 2H), 1.58 - 1.39 (m, 3H). Example u: Synthesis of int-24 Step 1: int-24-2 To a solution of int-24-1 (16.60 g, 61.70 mmol) in dioxane (200 mL) was added di-tert-butyl dicarbonate (21.5 mL, 93.0 mmol). The mixture resulting was stirred at 80 °C for 6 hrs and then heated to 95 °C for 6 hrs. After cooling to room temperature, the reaction mixture was poured into water (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with water (500 mL x 2), followed by brine (500 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography with further purification by trituration with petroleum ether at 0 °C for 30 mins to afford int-24-2 (18.60 g, 50.40 mmol, 82.0% yield). LC-MS (ESI+): m / z 368.1 (M-H). ’H NMR (400 MHz, DMSO-t / 6) 5 9.71 (s, 1H), 7.76 (d, J= 8.0 Hz, 2H), 1.47 (s, 9H). Step 2: int-24-3 A mixture of int-24-2 (9.00 g, 24.39 mmol), Pd2(dba)3 (1.12 g, 1.22 mmol), di-tert-butyl(2',4',6'-triisopropyl-3,4,5,6-tetramethyl-[l,l'-biphenyl]-2-yl)phosphane (2.34 g, 4.88 mmol), and KOH (4.10 g, 73.2 mmol) in dioxane (90 mL) and water (90 mL) was degassed and purged with N2 for 3 times, and the resulting mixture was stirred at 105 °C for 3 hrs under N2 atmosphere. After cooling to room temperature, the reaction mixture was poured into water (500 mL) and acidified by diluted HC1 (2 N) to pH ~ 6, extracted with DCM (500 mL x 3). The combined organic layers were washed with water (400 mL x 2), followed by brine (500 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-24-3 (14.20 g, 23.19 mmol, 95.0% yield). LC-MS (ESI+): m / z 303.9 (M-H). ’H NMR (400 MHz, DMSO-t / 6) 5 10.26 (brs, 1H), 9.39 (s, 1H), 7.22 - 7.10 (m, 2H), 1.45 (s, 9H). Step 3: int-24-4 To a solution of int-24-3 (14.20 g, 46.40 mmol) in DMF (200 mL) was added K2CO3 (7.69 g, 55.70 mmol) and benzyl bromide (6.6 mL, 55.70 mmol). The resulting mixture was stirred at 20 °C for 2 hrs. After completion, the reaction mixture was poured into water (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with water (500 mL x 2), followed by brine (500 mL), dried over Na2SO4, filtered, concentrated under reduced pressure to give a residue, which was purified by column chromatography and further purified by trituration with petroleum ether at 20 °C for 1 hr to afford int-24-4 (9.20 g, 23.22 mmol, 50.1% yield). LC-MS (ESI+): m / z 340.0 (M-56)+. 'H NMR (400 MHz, DMSO-t / 6) 5 9.50 (s, 1H), 7.47 - 7.35 (m, 7H), 5.12 (s, 2H), 1.46 (s, 9H). Step 4: int-24-5 To a solution of int-24-4 (9.20 g, 23.22 mmol) in dioxane (140 mL) was added HC1 (92 mL, 4 M in dioxane). The resulting mixture was stirred at 20 °C for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure to afford int-24-5 (7.60 g, crude) as a pale yellow solid, which was used directly in the next step without purification. LC-MS (ESI+): m / z 296.0 (M+H)+. 'H NMR (400 MHz, DMSO-76) 5 7.49 - 7.35 (m, 5H), 6.98 (dd, J= 16.0, 4.0 Hz, 2H), 5.16 (s, 2H). Step 5: int-24-6 To a solution of int-24-5 (5.10 g, 17.22 mmol) in cone. HC1 (50 mL) and 1,4-dioxane (50 mL) was added sodium nitrite (1.78 g, 25.80 mmol) in water (20 mL) dropwise at 0 °C. After addition, the mixture was stirred at 0 °C for 1 hr, then a solution of tin(II) chloride (6531 mg, 34.4 mmol) in HC1 (50 mL) was added dropwise. The resulting mixture was stirred at 20 °C for 3 hrs. After completion, the reaction mixture was poured into ice-water (50 mL) and the prepicitate was collected, rinsed with ice-water (10 mL x 3) and dried on vacuum to give a residue that was purified by trituration with MTBE (5 mL) at 20 °C for 30 mins to afford int-24-6 (1.79 g, 5.75 mmol, 33.4% yield). LC-MS (ESI+): m / z 311.0 (M+H)+. ’H NMR (400 MHz, DMSO-76) 5 7.49 - 7.33 (m, 5H), 6.84 (s, 1H), 6.63 (dd, J = 8.0, 4.0 Hz, 1H), 6.60 - 6.53 (m, 1H), 5.10 (s, 2H), 4.05 (s, 2H). Step 6: int-24-7 A mixture of int-24-6 (1.46 g, 4.69 mmol) and Na2CO; (497.0 mg, 4.69 mmol) in EtOH (30 mL) was stirred at 20 °C for 0.2 hr, then tert-butyl (2>S')-3-cyano-2-methyl-4-oxopiperidine-l-carboxylate (1.12 g, 4.69 mmol) was added. The resulting mixture was stirred at 80 °C for 2 hrs. After cooling to room temperature, the reaction mixture was filtered and was purified by column chromatography to afford int-24-7 (2.30 g, 4.33 mmol, 92.0% yield). LC-MS (ESI+): m / z 531.1 (M+H)+. ’H NMR (400 MHz, DMSO-A) 5 7.51 - 7.32 (m, 7H), 5.38 (s, 2H), 5.25 (s, 2H), 5.18 - 4.98 (m, 1H), 4.25 - 4.00 (m, 1H), 3.16-2.89 (m, 1H), 2.55-2.51 (m, 1H), 2.49-2.39 (m, 1H), 1.42 (s, 9H), 1.25 (d, 7=4.0 Hz, 3H). Step 7: int-24-8 To a solution of int-24-7 (2.30 g, 4.33 mmol) in DMA (46 mL) was added A-(2,2-dimethoxyethyl)-1 / 7-imidazole-l-carboxamide (1.72 g, 6.92 mmol) and potassium tert-butoxide (1.46 mg, 12.98 mmol). The resulting mixture was stirred at 80 °C for 2 hrs. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 3), the combined organic layers were washed with water (100 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-24-8 (2.00 g, 3.02 mmol, 69.7% yield). LC-MS (ESI+): m / z 662.2 (M+H)+. 1H NMR (400 MHz, DMSO-76) 5 8.17 (s, 1H), 7.49-7.34 (m, 7H), 6.60-6.49 (m, 1H), 5.20 (s, 2H), 5.18-4.93 (m, 1H), 4.31 (t, J = 4.0 Hz, 1H), 4.28 - 4.07 (m, 1H), 3.24 (d, J= 4.0 Hz, 6H), 3.19-3.11 (m, 2H), 3.10 - 2.97 (m, 1H), 2.65-2.51 (m, 2H), 1.43 (s, 9H), 1.22 (d, J= 8.0 Hz, 3H). Step 8: int-24-9 To a solution of int-24-8 (2.00 g, 3.02 mmol) in THF (20 mL) was p-toluenesulfonic acid monohydrate (287.0 mg, 1.51 mmol), the resulting mixture was stirred at 60 °C for 2 hrs. After cooling to room temperature, the reaction mixture was poured into water (50 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with water (50 mL x 2), brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-24-9 (1.30 g, 2.17 mmol, 72.0% yield). LC-MS (ESI+): m / z 598.1 (M+H)+. ’H NMR (400 MHz, DMSO-A) 5 10.49 (s, 1H), 7.46 - 7.35 (m, 5H), 7.28 (d, J = 8.0 Hz, 1H), 7.20 - 7.15 (m, 1H), 6.68 (t, J = 4.0 Hz„ 1H), 6.63 (brs, 1H), 5.13 (s, 2H), 5.10 - 4.96 (m, 1H), 4.37-4.10 (m, 1H), 3.21 - 2.99 (m, 1H), 2.79 - 2.58 (m, 2H), 1.43 (s, 9H), 1.14 (d, J= 4.0 Hz, 3H). Step 9: int-24-10 To a solution of int-24-9 (460.0 mg, 0.77 mmol) in 1,4-dioxane (9 mL) and water (2.3 mL) were added potassium cyclopropyltrifluoroborate (227.0 mg, 1.54 mmol), PdC12(dppf) (112.0 mg, 0.15 mmol) and K2CO3 (212.0 mg, 1.54 mmol). The resulting mixture was degassed and purged with N2 for 3 times and then stirred at 120 °C for 5 hrs under N2 atmosphere. After cooling to room temperature, the reaction mixture was concentrated and purified by column chromatography to afford int-24-10 (290.0 mg, 0.52 mmol, 67.4% yield). LC-MS (ESI+): m / z 560.2 (M+H)+. 1H NMR (400 MHz, DMSO-*) 5 10.45 (s, 1H), 7.47 - 7.37 (m, 5H), 7.07 (d, J= 8.0 Hz, 1H), 6.64 - 6.61 (m, 1H), 6.55 (brs, 1H), 6.40 (d, J= 8.0 Hz, 1H), 5.10 (s, 2H), 5.08 - 4.95 (m, 1H), 4.35 - 4.10 (m, 1H), 3.21 -2.99 (m, 1H), 2.76 - 2.56 (m, 2H), 2.12 - 2.02 (m, 1H), 1.42 (s, 9H), 1.14 (d, J= 4.0 Hz, 3H), 1.02 -0.96 (m, 2H), 0.64 - 0.52 (m, 2H). Step 10: int-24-11 To a solution of int-24-10 (320.0 mg, 0.57 mmol) in NMP (4.8 mL) were added int-22-5 (436.0 mg, 1.14 mmol), (1R,2R)-Nl,A2-dimethylcyclohexane-l,2-diamine (81.0 mg, 0.57 mmol), copper(I) iodide (218.0 mg, 1.14 mmol) and K2CO3 (237.0 mg, 1.71 mmol). The resulting mixture was degassed and purged with N2 for 2 mins and then stirred at 140 °C for 5 hrs under N2 atmosphere. After cooling to room temperature, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3), the combined organic layers were washed with water (50 mL x 2), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by prep-TLC to afford int-24-11 (120.0 mg, 0.14 mmol, 24.4% yield). LC-MS (ESI+): m / z 860.4 (M+H)+. 'H NMR (400 MHz, Chloroform-d) 5 8.17 (s, 1H), 7.34 - 7.27 (m, 6H), 7.25 - 7.22 (m, 1H), 7.16 - 7.09 (m, 1H), 6.70 - 6.56 (m, 2H), 6.49 - 6.40 (m, 2H), 6.27 - 6.19 (m, 1H), 5.45 - 5.15 (m, 1H), 5.01 (s, 2H), 4.40 - 4.26 (m, 3H), 4.09 (s, 3H), 3.23 - 3.06 (m, 1H), 2.84 - 2.75 (m, 2H), 2.19 - 2.09 (m, 1H), 1.50 (s, 9H), 1.36 (d, J= 8.0 Hz, 3H), 0.96 (dd, J= 8.0, 4.0 Hz, 2H), 0.89 (s, 9H), 0.75 - 0.66 (m, 2H), 0.07 (s, 6H). Step 11: int-24-12 To a solution of int-24-11 (120.0 mg, 0.14 mmol) in MeOH (4 mL) was added Pd / C (24.0 mg, 20%w / w) and Pd(OH)2 (24.0 mg, 20%w / w). The resulting reaction mixture was degassed and purged with H2 for 3 times and stirred at 30 °C for 2 hrs. The reaction mixture was filtered through a pad of Celite and the cake was rinsed with MeOH (10 mL x 3). The filtrate was concentrated under reduced pressure to afford int-24-12 (115.0 mg, crude, which was used for next step directly without purification. LC-MS (ESI+): m / z 772.2 (M+H)+. Step 12: int-24-13 To a solution of int-24-12 (115.0 mg, 0.15 mmol) in THF (0.6 mL) was added TBAF (0.8 mL, 0.80 mmol). The resulting mixture was stirred at 20 °C for 2 hrs. After completion, the reaction mixture was quenched by water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with water (20 mL x 2), followed by brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by pre-TLC to afford int-24-13 (70.0 mg, 0.11 mmol, 71.4% yield). LC-MS (ESI+): m / z 658.3 (M+H)+. ’H NMR (400 MHz, DMSO-t / 6) 5 10.23 (brs, 1H), 8.21 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.13 (d, J =8.0 Hz, 1H), 7.00-6.81 (m, 3H), 6.32 (d, 7 = 4.0 Hz, 1H), 5.23 - 5.04 (m, 1H), 4.55 - 4.44 (m, 1H), 4.35 - 4.14 (m, 1H), 4.06 (s, 3H), 3.21 - 3.03 (m, 1H), 2.85 - 2.73 (m, 2H), 2.72 - 2.69 (m, 1H), 2.65 - 2.59 (m, 1H), 2.13 - 2.03 (m, 1H), 1.71 - 1.60 (m, 2H), 1.43 (s, 9H), 1.23 (s, 3H), 1.21 (d, J= 8.0 Hz, 2H), 0.99 (d, J= 8.0 Hz, 2H), 0.65 - 0.55 (m, 2H). Step 13: int-24-14 To a solution of int-24-13 (80.0 mg, 0.12 mmol) in anhydrous toluene (2.4 mL) was added 2-(tributylphosphoranylidene)acetonitrile (117.0 mg, 0.49 mmol). The resulting mixture was degassed and purged with N2 for 2 mins and then stirred at 90 °C for 2 hrs under N2 atmosphere. After cooling to room temperature, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water (20 mL x 2), brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by pre-TLC to afford int-24-14 (50.0 mg, 0.08 mmol, 64.3% yield). LC-MS (ESI+): m / z 640.3 (M+H)+. 1H NMR (400 MHz, DMSO-76) 5 8.32 (s, 1H), 7.62 - 7.54 (m, 1H), 7.40 - 7.26 (m, 1H), 7.12 - 6.85 (m, 2H), 6.84 - 6.74 (m, 1H), 6.67 - 6.57 (m, 1H), 5.24 - 5.08 (m, 1H), 4.33 - 4.14 (m, 3H), 4.06 (s, 3H), 3.15 - 3.07 (m, 1H), 2.97 - 2.88 (m, 1H), 2.83 - 2.69 (m, 2H), 2.65 - 2.59 (m, 1H), 2.13 - 2.03 (m, 1H), 1.77 - 1.56 (m, 2H), 1.43 (s, 9H), 1.27 -1.22 (m,3H), 1.05 - 0.99 (m, 2H), 0.78 - 0.67 (m, 2H). Step 14: int-24 A mixture of int-24-14 (50.0 mg, 0.08 mmol) in HC1 solution (4 M in dioxane, 2 mL) was stirred at 20 °C for 1 hr. After completion, the reaction mixture was concentrated to give a residue that was basified by NaHCOs (aq) to pH~7 and extracted with DCM (20 mL x 3). The combined organic layers were washed with water (20 mL x 2), brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by pre-TLC to afford int-24 (30.0 mg, 0.06 mmol, 71.1% yield). LC-MS (ESI+): m / z 540.3 (M+H)+. Example v: Synthesis of int-25 Step 1: int-25-2 To a solution of int-25-1 (2.0 g, 6.19 mmol) in DMF (30 mL) was added NaH (372 mg, 9.29 mmol, 60% purity) at 0 °C. The reaction mixture was stirred at 20 °C for 0.5 hr and then Mel (0.46 mL, 7.43 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 20 °C for 1.5 hr. After completion, the reaction mixture was quenched by cold water (150 mL), and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with water (150 mL x 2), followed by brine (150mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-25-2 (1.00 g, 2.97 mmol, 47.9 % yield). LCMS: 336.7 [M+H]+. Step 2: int-25-3 A mixture of int-25-2 (870 mg, 2.29 mmol), (£)-tert-butyldimethyl((3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) allyl) oxy) silane (886 mg, 2.97 mmol), Pd2(dba)3 (210 mg, 0.23 mmol) and potassium carbonate (632 mg, 4.57 mmol) in dioxane (14 mL) and water (2.8 mL) was degassed and purged with N2 for 3 times and then the mixture was stirred at 100 °C for 2 hrs under N2 atmosphere. After cooling, the reaction mixture was poured into H2O (50 mL), and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (90 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-25-3 (810 mg, 1.10 mmol, 99.0% yield). LCMS: 381.1 [M+H]+. Step 3: int-25-4 To a solution of int-25-3 (1.33 g, 2.09 mmol) in NMP (16 ml) was added int-33-3 (560.0 mg, 1.05 mmol), copper(I) iodide (200.0 mg, 1.05 mmol), K2CO3 (290.0 mg, 2.10 mmol) and (iR^Ry-N1 ,N2-dimethylcyclohexane-l,2-diamine (75.0 mg, 0.52 mmol). The resulting mixture was degassed and purged with N2 for 3 times and stirred at 130 °C under N2 atomsphere for 2 hrs. After cooling to room temperature, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (50 mL x 3), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-25-4 (540.0 mg, 0.39 mmol, 74.0% yield). LC-MS(ESI+): m / z 834.4 [M+Hr.’H NMR (400 MHz, DMSO-A) 5 8.26 (s, 1H), 7.56 (d, J= 8.0 Hz, 1H ), 7.51 (d, J= 8.0 Hz, 1H), 7.01 (dt, J= 16.0, 4.0 Hz, 1H), 6.64 (dt, J = 16.0, 4.0 Hz, 1H), 4.47 - 4.42 (m, 2H), 4.05 (s, 3H), 0.94 (s, 9H), 0.12 (s, 6H). Step 4: int-25-5 To a solution int-25-4 (510.0 mg, 0.61 mmol) in MeOH (15.0 mL) was added Pd / C (102.0 mg, 20% w / w.). The resulting mixture was degassed and purged with H2 for 3 times and stirred at 30 °C under H2 atomsphere (15 psi) for 4 hrs. After completion, the reaction mixture was filtered, concentrated and purified by column chromatography to afford int-25-5 (440.0 mg, 0.41 mmol, 67.5% yield). LC-MS(ESI+): m / z 746.5 [M+H]+ Step 5: int-25-6 To a solution of int-25-5 ( 440.0 mg, 0.59 mmol) in THF (4.5 mL) was added TBAF (3.0 ml, 3.00 mmol). The resulting mixture was stirred at 20 °C for 1 hr. After completion, the reaction mixture was diluted with H2O (10 mL), and extracted with EtOAc (10 mL x 4). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography to afford int-25-6 (300.0 mg, 0.46 mmol, 78.0% yield). LC-MS(ESI+): m / z 632.3 [M+H]+ Step 6: int-25-7 To a solution of int-25-6 (300 mg, 0.475 mmol) in Toluene (12.4 ml) was added 2-(tributylphosphoranylidene)acetonitrile (573.0 mg, 2.37 mmol). The resulting mixture was stirred at 90 °C under N2 for 1 hr. After cooling to room temperature, the reaction mixture was poured into H2O (30mL), and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-25-7 (50.0 mg, 81.5 pmol, 17.7 % yield). LC-MS(ESI+): m / z 614.4 [M+H]+ Step 7: int-25 A mixture of int-25-7 (45 mg, 0.073 mmol) in HC1 solution (4 M in dioxane, 2 mL) was stirred at 20 °C for 1 hr. After completion, the reaction mixture was concentrated under reduced pressure to afford int-25 (41.0 mg, crude), which was used directly in the next step without purification. LC-MS(ESI+): m / z 514.2 [M+H]+ Example w: Synthesis of int-26 Step 1: int-26-2 To a solution of int-26-1 (3.00 g, 13.95 mmol) in DCM (30 mL) was added imidazole (1.42 g, 20.92 mmol) and TBS-C1 (2.52 g, 16.74 mmol). The resulting mixture was stirred at 25 °C for 1 hr. After completion, the reaction mixture was diluted with DCM (30 mL) and washed with brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-26-2 (3.20 g, 9.72 mmol, 69.7% yield). ’H NMR (400 MHz, DMSO-t / 6) 5 7.53 (dt, J= 7.9, 0.8 Hz, 1H), 7.30 - 7.23 (m, 2H), 7.10 (dt, J= 8.0, 4.5 Hz, 1H), 3.59 (t, J= 6.2 Hz, 2H), 2.75 - 2.65 (m, 2H), 1.77 - 1.64 (m, 2H), 0.84 (s, 10H), -0.00 (s, 6H). Step 2: int-26-3 To a solution of int-33-3 (500.0 mg, 0.94 mmol) in NMP (5 mL) was added int-26-2 (926.0 mg, 2.81 mmol), (17?,27?)-A1,A2-dimethylcyclohexane-l,2-diamine (67.0 mg, 0.47 mmol), copper(I) iodide (178.0 mg, 0.94 mmol) and K2CO3 (259.0 mg, 1.87 mmol). The resulting mixture was degassed and purged with N2 for three times, and stirred at 150 °C under N2 atomsphere for 3 hrs. After cooling to room temperature, the residue was poured into H2O (25 mL) and extracted with EtOAc (25 mL x 3). The combined organic layers were washed with water (25 mL x 3), followed by brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-26-3 (300.0 mg, 0.38 mmol, 40.9% yield). LC-MS(ESI+): m / z 782.5 [M+HJL’H NMR (400 MHz, DMSO-A) 5 7.45 - 7.41 (m, 4H), 7.40 - 7.37 (m, 2H), 7.367 - 7.30 (m, 2H), 7.19 - 7.13 (m, 2H), 7.00 - 6.93 (m, 2H), 6.92 - 6.88 (m, 1H), 5.22 - 5.11 (m, 1H), 5.09 (s, 2H), 4.39 - 4.10 (m, 1H), 3.46 (t, J= 8.0 Hz, 2H), 3.38 - 3.36 (m, 1H), 3.22 - 3.08 (m, 1H), 2.80 - 2.60 (m, 2H), 2.27 (s, 3H), 1.67 - 1.54 (m, 2H), 1.46 (s, 9H), 1.26 - 1.21 (m, 3H), 0.85 (s, 9H), 0.00 (s, 6H). Step 3: int-26-4 To a solution of int-26-3 (280.0 mg, 0.36 mmol) in MeOH (10 mL) was added Pd / C (60 mg, 20% w / w.). The resulting mixture was degassed and purged with H2 for 3 times and stirred at 40 °C under H2 atomsphere (15 psi) for 2 hrs. After completion, the reaction mixture was filtered through a celite pad and rinsed with MeOH (5 mL x 2). The filtrate was concentrated and purified by prep-TLC to afford int-26-4 (100.0 mg, 0.17 mmol, 48.4% yield). LC-MS(ESI+): m / z 578.4 [M+H]+1H NMR (400 MHz, DMSO-cL) 5 10.18 (brs, 1H), 7.47 - 7.39 (m, 2H), 7.38 - 7.33 (m, 1H), 7.37 (d, J= 8.0 Hz, 1H), 7.20 (d, J= 8.0 Hz, 1H), 6.93 (d, J= 4.0 Hz, 1H), 6.92 - 6.82 (m, 2H), 6.73 - 6.67 (m, 1H), 5.23 - 5.06 (m, 1H), 4.62 - 4.15 (m, 2H), 3.48 - 3.42 (m, 1H), 3.41 - 3.39 (m, 1H), 3.17 - 3.03 (m, 1H), 2.77 - 2.63 (m, 2H), 2.23 (s, 3H), 1.66 - 1.54 (m, 3H), 1.46 (s, 9H), 1.21 (d, J= 8.0 Hz, 3H). Step 4: int-26-5 To a solution of int-26-4 (90.0 mg, 0.16 mmol) in anhydrous toluene (3.6 mL) were added 2-(tributylphosphoranylidene)acetonitrile (0.12 mL, 0.47 mmol). The resulting mixture was degassed and purged with N2 for 3 times and stirred at 90 °C for 1 hr. After cooling to room temperature, the reaction mixture was poured into 10 mL of water and extrated with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, concentrated and purified by prep-TLC (SiO2, DCM: MeOH=20:l, v / v) to afford int-26-5 (50.0 mg, 0.089 mmol, 57.3% yield). LC-MS(ESI+): m / z 560.4 [M+H]+.1HNMR (400 MHz,) 5 7.50 - 7.37 (m, 3H), 7.36 -7.10 (m, 3H), 7.05 - 6.94 (m, 1H), 6.70 - 6.51 (m, 1H), 5.36 - 4.99 (m, 1H), 4.45 - 4.04 (m, 3H), 3.49 _ 3.44 (m, 1H), 3.21 - 2.84 (m, 2H), 2.77 - 2.63 (m, 2H), 2.31 - 2.26 (m, 3H), 1.67 - 1.54 (m, 2H), 1.46 (s, 9H), 1.26 (d, J= 8.0 Hz, 3H). Step 5: int-26 A mixture of int-26-5 (50 mg, 0.089 mmol) in HC1 solution (4M in dioxane, 0.5 mL) was stirred at 25 °C for 1 hr. After completion, the reaction mixture was concentrated to give a residue, which was diluted with DCM (10 mL) and washed with saturated NaHCOs solution (10 mL), followed by brine (10 mL), dried over Na2SO4, filtered, concentrated and purified by prep-TLC to afford int-26 (30.0 mg, 0.065 mmol, 73.1% yield). LC-MS(ESI+): m / z 460.4 [M+H]+ Example x: Synthesis of int-27 int-27-1 Step 1: int-27-2 To a solution of int-27-1 (1.08 g, 4.76 mmol) in DMF (10 mL) was added benzyl bromide (0.60 mL, 5.00 mmol) and K2CO3 (0.99 g, 7.13 mmol). The resulting mixture was stirred at 25 °C for 2 hrs. After completion, the reaction mixture was poured into water (50 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (50 mL x 2), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-27-2 (1.50 g, 4.73 mmol, 99.0% yield). LC-MS(ESI+): m / z 317.2 [M+H]+. ’H NMR (400 MHz, DMSO-t / 6) 5 8.02 (s, 1H), 7.92 (s, 1H), 7.59 - 7.53 (m, 2H), 7.48 - 7.40 (m, 3H), 7.39 - 7.34 (m, 1H), 5.29 (s, 2H), 4.01 (s, 3H). Step 2: int-27-3 To a solution of int-23-3 (450.0 mg, 0.75 mmol) in NMP (5 mL) were added int-27-2 (478.0 mg, 1.51 mmol), (IR^^-A'^-dimethylcyclohexane-l^-diamine (54.0 mg, 0.38 mmol), copper(I) iodide (143.0 mg, 0.75 mmol) and potassium carbonate (208.0 mg, 1.51 mmol). The resulting mixture was degassed and purged with N2 for 3 times, and stirred at 140 °C for 3 hrs under N2 atomsphere. After cooling to room temperature, the reaction was filtered through a Celite pad and rinsed with EtOAc (10 mL x 3). The filtrate was washed with water (50 mL x 3), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-27-3 (1.10 g, 1.32 mmol, 73.0% yield). LC-MS(ESI+): m / z 834.4 [M+H]+. ’H NMR (400 MHz, DMSO-t / 6) 5 7.95 (s, 1H), 7.61 - 7.48 (m, 4H), 7.39 (s, 1H), 7.38 - 7.35 (m, 1H), 7.34 - 7.32 (m, 1H), 7.27 - 7.24 (m, 2H), 7.20-7.13 (m, 1H), 6.86- 6.83 (m, 1H), 6.65 (dt, J= 16.0, 4.0 Hz, 1H), 6.31 (dt, J= 16.0, 4.0 Hz, 1H), 5.18 (s, 2H), 5.15 - 4.99 (m, 1H), 4.32 - 4.11 (m, 3H), 3.99 (s, 3H), 3.15 - 2.98 (m, 1H), 2.74 - 2.67 (m, 1H), 2.65 - 2.56 (m, 1H), 2.14 (s, 3H), 1.40 (s, 9H), 1.08 (d, J= 4.0 Hz, 3H), 0.83 (s, 9H), 0.00 (s, 6H). Step 3: int-27-4 To a solution of int-27-3 (700.0 mg, 0.84 mmol) in MeOH (14 mL) was added Pd / C (140.0 mg, 20% w / w.). The resulting mixture was degassed and purged with H2 for 3 times and stirred at 50 °C for 4 hrs under H2 atomsphere. After completion, the reaction was filtered through a Celite pad and rinsed with MeOH (10 mL x 3). The filtrate was concentrated to afford int-27-4 (720.0 mg, crude), which was used directly for the next step. 'H NMR (400 MHz, DMSO-t / e) 5 10.31 (brs, 1H), 7.92 (s, 1H), 7.65 - 7.63 (m, 1H), 7.21 - 7.12 (m, 2H), 6.98 (s, 1H), 6.83 (d, J= 4.0 Hz, 1H), 6.80 - 6.68 (m, 1H), 5.23 - 5.06 (m, 1H), 4.41 - 4.15 (m, 1H), 3.94 (s, 3H), 3.60 (t, J= 8.0 Hz, 2H), 3.21 - 3.08 (m, 1H), 2.74 - 2.64 (m, 4H), 2.26 (s, 3H), 1.79 - 1.65 (m, 2H), 1.45 (s, 9H), 1.24 (d, J= 8.0 Hz, 3H), 0.85 (s, 9H), 0.00 (s, 6H). Step 4: int-27-5 To a solution of int-27-4 (700.0 mg, 0.94 mmol) in THF (5 mL) was added TBAF (4.7 ml, 4.70 mmol). The resulting mixture was stirred at 25 °C for 2 hrs. After completion, the reaction was poured into water (10 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-27-5 (350.0 mg, 0.55 mmol, 59.0% yield). LC-MS(ESI+): m / z 632.4 [M+H]+. 'H NMR (400 MHz, DMSO-cL) 5 10.34 (s, 1H), 7.95 (s, 1H), 7.65 (s, 1H), 7.26 - 7.12 (m, 2H), 6.98 (s, 1H), 6.85 (d, J= 4.0 Hz, 1H), 6.78 (brs, 1H), 5.24 - 5.03 (m, 1H), 4.69 - 4.53 (m, 1H), 4.25 (s, 1H), 3.95 (s, 3H), 3.46 - 3.42 (m, 2H), 3.25 - 3.02(m, 1H), 2.76 - 2.64 (m, 4H), 2.27 (s, 3H), 1.76 - 1.65 (m, 2H), 1.46 (s, 9H), 1.24 (d, J= 8.0 Hz, 3H). Step 5: int-27-6 To a solution of int-27-5 (330.0 mg, 0.52 mmol) in anhydrous toluene (3.5 mL) was added 2-(tributylphosphoranylidene)acetonitrile (504.0 mg, 2.09 mmol). The resulting mixture was stirred at 90 °C for 2 hrs. After cooling to room temperature, the reaction was diluted with EtOAc (10 mL), washed with brine (10 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-27-6 (170.0 mg, 0.28 mmol, 53.0% yield). LC-MS(ESI+): m / z 614.4 [M+H]+. ’H NMR (400 MHz, DMSO-t / 6) 5 7.99 (s, 1H), 7.83 (s, 1H), 7.43 - 7.30 (m, 2H), 7.17 - 6.91 (m, 1H), 6.81 - 6.51 (m, 2H), 5.28 - 5.01 (m, 1H), 4.34 - 4.00 (m, 6H), 3.24 - 3.03 (m, 1H), 2.94 -2.82 (m, 1H), 2.77 - 2.62 (m, 3H), 2.28 (s, 3H), 2.26 - 2.18 (m, 1H), 2.05 - 1.84 (m, 1H), 1.45 (s, 9H), 1.30-1.21 (m, 3H). Step 6: int-27 A mixture of int-27-6 (150.0 mg, 0.24 mmol) in HC1 solution (4 mL, 4 M in dioxane) was stirred at 25 °C for 2 hrs. After completion, the reaciton mixture was concentrated to give a residue, which was diluted with DCM (10 mL) and washed with saturated NaHCOs solution (10 mL), followed by brine (10 mL), dried over Na2SO4, filtered, concentrated and purified by prep-TLC to afford int-27 (80.0 mg, 0.16 mmol, 63.7% yield). LC-MS(ESI+): m / z 514.4 [M+H]+ Example y: Synthesis of int-28, int-79 Step 1: int-28-1 To a solution of int-2-7 (200.0 mg, 0.38 mmol) in NMP (3.0 mL) was added int-79 (277.0 mg, 0.75 mmol), (IR^^-A'^-dimethylcyclohexane-l^-diamine (48.0 mg, 0.37 mmol), copper(I) iodide (143.0 mg, 0.75 mmol) and K2CO3 (155.0 mg, 1.12 mmol). The resulting mixture was degassed and purged with N2 for 3 times and stirred at 140 °C for 4 hrs under N2 atomsphere. After cooling to room temperature, the reaction mixture was poured into cold water (20 mL), extracted by EtOAc (20 mL x 3). The combined organic layers were washed with water (20 mL x 2), followed by brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-28-1 (370.0 mg, 0.45 mmol, 80.0 % yield). LC-MS(ESI+): m / z 822.4 [M+H]+ Step 2: int-28-2 To a solution of int-28-1 (360.0 mg, 0.44 mmol) in MeOH (5.0 mL) and THF (5.0 mL) was added Pd / C (72.0 mg, 20% w / w.).The resulting mixture was degassed and purged with H2 for 3 times and stirred at 40 °C for 2 hrs under H2 (15 psi) atomsphere. After completion, the reaction was filtered through a pad of Celite and rinsed with MeOH (10 mL x 3). The filtrate was concentrated to afford int-28-2 (240.0 mg, crude). LC-MS(ESI+): m / z 732.4 [M+H]+ Step 3: int-28-3 To a solution of int-28-2 (220.0 mg, 0.30 mmol) in THF (2.0 mL) was added tetrabutylammonium fluoride (1.5 mL, 1.50 mmol). The resulting mixture was stirred at 25 °C for 2 hrs. After completion, the reaction mixture was poured into water (10 mL), extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-28-3 (100.0 mg, 0.16 mmol, 53.9% yield). LC-MS(ESI+): m / z 618.3 [M+H]+. ’H NMR (400 MHz, DMSO-t / 6) 5 10.20 (s, 1H), 8.20 (s, 1H), 7.59 (d, J= 8.0 Hz, 1H), 7.17 (d, J= 8.0 Hz, 1H), 6.91 (d, J= 4.0 Hz, 1H), 6.89 - 6.77 (m, 2H), 6.74-6.67 (m, 1H), 5.15 (brs, 1H), 4.70 (brs, 1H), 4.34 - 4.17 (m, 1H), 4.06 (s, 3H), 3.80 - 3.57 (m, 3H), 3.21 - 3.06 (m, 1H), 2.96 - 2.87 (m, 2H), 2.72 - 2.66 (m, 1H), 2.23 (s, 3H), 1.44 (s, 9H), 1.23 - 1.19 (m, 3H). Step 4: int-28-4 To a solution of int-28-3 (40.0 mg, 0.065 mmol) in anhydrous toluene (2.0 mL) was added 2-(tributylphosphoranylidene)acetonitrile (24.0 mg, 0.10 mmol). The resulting mixture was purged with N2 for 3 mins and stirred at 120 °C for 2 hrs. After cooling to room temperature, the reaction mixture was poured into water (10 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, concentrated and purified by Prep-TLC to afford int-28-4 (20.0 mg, 0.03 mmol, 51.5% yield). LC-MS(ESI+): m / z 600.4 [M+H]+ Step 5: int-28 A mixture of int-28-4 (20.0 mg, 0.03 mmol) in HC1 solution (1 mL, 4 M in dioxane) was stirred at 25 °C for 2 hrs. After completion, the reaction mixture was concentrated and diluted with DCM (10 mL). The organic layer was washed with saturated NaHCOs solution (10 mL), followed by brine (10 mL), dried over Na2SO4, filtered and concentrated to afford int-28 (20.0 mg, crude), which was used directly for the next step without purification. LC-MS(ESI+): m / z 500.4 [M+H]+ int-22-4 int-79-2 int-79-3 Int-79-4 lnt-79 Step 1: int-79-2 To a solution of int-22-4 (4.00 g, 11.87 mmol) in 1,4-dioxane (67 mL) and water (13 mL) were added (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (4.00 g, 20.18 mmol), Pd2(dba)3 (1.09 g, 1.19 mmol) and potassium carbonate (3.28 g, 23.74 mmol). The resulting mixture was degassed and purged with N2 for 2 mins and then stirred at 100 °C under N2 for 2 hrs. After cooling to room temperature, the reaction mixture was concentrated and purified by column chromatography to afford int-79-2 (2.30 g, 8.18 mmol, 68.9% yield). LC-MS (ESI+): m / z 281.0 (M+H)+. ’H NMR (400 MHz, DMSO-A) 5 8.25 (s, 1H), 7.51 (d, J= 8.0 Hz, 1H), 7.42 (d, J= 12.0 Hz, 1H), 7.38 (d, J= 8.0 Hz, 1H), 6.15 (d, J= 12.0 Hz, 1H), 4.05 (q, J = 8.0 Hz, 2H), 4.02 (s, 3H), 1.31 (t, J= 8.0 Hz, 3H). Step 2: int-79-3 To a solution of int-79-2 (2.30 g, 8.18 mmol) in DCM (50 mL) was added TFA (10 mL, 130.00 mmol) at 0 °C. The reaction was stirred at 20 °C for 2 hrs. After completion, the reaction mixture was quenched by H2O (100 mL), basified with NaHCO? (aq) to pH~7, and extracted with DCM (100 mL x 3). The combined organic layers were washed with water (100 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-79-3 (1.50 g, 5.93 mmol, 72.4% yield). LC-MS (ESH): m / z 253.0 (M+H)+. ’H NMR (400 MHz, DMSO-t / 6) 5 9.74 (s, 1H), 8.16 (s, 1H), 7.57 (s, 2H), 4.26 (s, 2H), 4.05 (s, 3H). Step 3: int-79-4 To a solution of int-79-3 (1.50 g, 5.93 mmol) in MeOH (45 mL) was added NaBH4 (448.0 mg, 11.85 mmol) in portions at 0 °C. The resulting mixture was stirred at 20 °C for 0.5 hr. After completion, the reaction mixture was poured into water (100 mL), extracted with DCM (100 mL x 3). The combined organic layers were washed with water (100 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-79-4 (1.20 g, 4.70 mmol, 79.0% yield). LC-MS (ESI+): m / z 255.0 (M+H)+. ’H NMR (400 MHz, DMSO-A) 5 8.12 (s, 1H), 7.51(d, J= 8.0 Hz, 1H), 7.45 (d, J= 8.0 Hz, 1H), 4.79 (t, J= 8.0 Hz, 1H), 4.02 (s, 3H), 3.69-3.61 (m, 2H), 3.17 (t, J= 8.0 Hz, 2H). Step 4: int-79 To a solution of int-79-4 (1.20 g, 4.70 mmol) in DCM (24 mL) were added 1 / / -imidazole (640.0 mg, 9.41 mmol) and tert-butylchlorodimethylsilane (1.42 g, 9.41 mmol). The resulting mixture was stirred at 20 °C for 1 hr. After completion, the reaction mixture was poured into water (100 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with water (100 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-79 (1.60 g, 4.33 mmol, 92.0% yield). LC-MS (ESI+): m / z 369.1 (M+H)+. ’H NMR (400 MHz, DMSO-t / 6) 5 8.10 (s, 1H), 7.50 (d, J= 8.0 Hz, 1H), 7.45 (d, J= 8.0 Hz, 1H), 4.01 (s, 3H), 3.85 (t, J= 8.0 Hz, 2H), 3.20 (t, J= 8.0 Hz, 2H), 0.74 (s, 9H), 0.15 (s, 6H). Example z: Synthesis of int-29 Step 1: int-29-1 A mixture of int-22-4 (500 mg, 1.48 mmol), (E)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)but-3-en-l-yl)oxy)silane (695 mg, 2.23 mmol), Pd(Ph3P)4 (171 mg, 0.15 mmol) and K2CO3 (410 mg, 2.97 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was degassed and purged with N2 for 3 times, the mixture was stirred at 100 °C for 2 hrs under N2 atmosphere. After cooling to room temperature, the reaction mixture was poured into 10 mL of water and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-29-1 (450 mg, 1.14 mmol, 77.0% yield). LC-MS(ESI+): m / z 395.3 [M+H]+. Step 2: int-29-2 To a solution of int-2-7 (200 mg, 0.38 mmol) in NMP (1 mL) were added int-29-1 (267 mg, 0.68 mmol), (l / ?,2 / ?)-(-)-l,2-diaminocyclohexane (22 mg, 0.19 mmol), copper(I) iodide (36 mg, 0.19 mmol) and K2CO3 (155 mg, 1.12 mmol). The resulting mixture was stirred at 130 °C for 3 hrs. After cooling to room temperature, the reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with water (10 mL x 2), followed by brine (10 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-29-2 (300 mg, 0.35 mmol, 94.0% yield). LC-MS(ESI+): m / z 848.5 [M+H]+. Step 3: int-29-3 To a solution of int-29-2 (250 mg, 0.30 mmol) in MeOH (10 mL) was added Pd / C (25 mg, 50% purity, 10% w / w). The reaction mixture was degassed and purged with H2 for 3 times, and then stirred at 40 °C for 8 hrs. The reaction mixture was filtered, after rinsing the cake with MeOH (5 mL x 3), the filtrate was concentrated to afford int-29-3 (210 mg, 0.276 mmol, 94 % yield). LC-MS(ESI+): m / z 760.5 [M+H]+. Step 4: int-29-4 To a solution of int-29-3 (210 mg, 0.28 mmol) in THF (2.0 mL) was added TBAF (1.4 mL, 1 M in THF) at 0 °C. The resulting mixture was stirred at 25 °C for 1 h. The residue was diluted with H2O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, concentrated and purified by prep-TLC to afford int-29-4 (43 mg, 0.067 mmol, 24.1% yield). LC-MS (ESI+): m / z 646.4 [M+H]+. Step 5: int-29-5 To a solution of int-29-4 (43 mg, 0.067 mmol) in anhydrous toluene (1.72 mL) was added CMBP (0.06 mL, 0.24 mmol). The resulting mixture was degassed and purged with N2 for 3 times and stirred at 90 °C for 2 h under N2. After cooling to room temperature, the reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, concentrated and purified by prep-TLC to afford int-29-5 (30 mg, 0.048 mmol, 71.8% yield). LC-MS(ESI+): m / z 628.3 [M+H]+.’HNMR (400 MHz,) 5 8.31 (s, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.26 (d, J= 8.0 Hz, 1H), 7.19 (s, 1H), 7.06 (d, J= 8.0 Hz, 1H), 6.99 (d, J= 4.0 Hz, 1H), 6.96 (d, J= 4.0 Hz, 1H), 5.16 (s, 1H), 4.12 (s, 2H), 4.10 (d, J= 4.0 Hz, 3H), 2.75 (s, 2H), 2.69 (s, 2H), 2.31 (s, 3H), 2.02 (q, J= 8.0 Hz, 2H), 1.64 (s, 2H), 1.57 (s, 3H), 1.46 (s, 9H). Step 6: int-29 A mixture of int-29-5 (30.0 mg, 0.048 mmol) in HC1 solution (0.5 mL, 4 M in dioxane) was stirred at 20 °C for 1 h. The mixture was concentrated and diluted with DCM (10 mL). The process was repeated for 3 times to afford int-29 (20 mg, 0.038 mmol, 79.0% yield). LC-MS(ESI+): m / z 528.4 [M+H]+. Example aa: Synthesis of int-30 Step 1: int-30-2 To a solution of int-30-1 (2.00 g, 6.30 mmol) and (£)-tert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane (2.44 g, 8.19 mmol) in dioxane (20.0 mL) and water (4.0 mL) were added tris(dibenzylideneaeetone)dipalladium(0) (0.58 g, 0.63 mmol) and K2CO3 (1.74 g, 12.60 mmol). The resulting mixture degassed and purged with nitrogen three times and stirred at 100 °C for 2 hrs under nitrogen atomsphere. After cooling to room temperature, the reaction mixture was poured into water (50 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (100 mL), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-30-2 (1.69 g, 4.44 mmol, 70.4% yield. 'H NMR (400 MHz, DMSO-A) 5 7.75 (d, J= 4.0 Hz, 1H), 7.65 (d, J= 8.0 Hz, 1H), 7.27 (dd, J= 8.0, 4.0 Hz, 1H), 6.85 (dt, J = 16.0, 4.0 Hz, 1H), 6.57 (dt, J = 16.0, 4.0 Hz, 1H), 4.40 - 4.35 (m, 2H), 0.94 (s, 9H), 0.11 (s, 6H). Step 2: int-30-3 To a solution of int-30-2 (1.26 g, 3.49 mmol) and int-33-3 (930.0 mg, 1.74 mmol) in NMP (10 mL) were added (l / ?,2 / ?)- / Vl, / V2-dimcthylcyclohcxanc-l ,2-diaminc (248.0 mg, 1.74 mmol) and copper(I) iodide (664.0 mg, 3.49 mmol) and K2CO3 (723.0 mg, 5.23 mmol). The resulting mixture was degassed and purged with N2 for three times and stirred at 140 °C for 6 hr under N2 atomsphere. After cooling to room temperature, the mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (100 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-30-3 (700.0 mg, 0.82 mmol, 46.8% yield). LC-MS (ESI+): m / z 814.4 (M+H)+. Step 3: int-30-4 To a solution of int-30-3 (1.02 g, 1.25 mmol) in THF (50.0 mL) and MeOH (50.0 mL) was added platinum(IV) oxide (102.0 mg, 10% w / w.). The resulting mixture was degassed and purged with H2 for 3 times stirred under H2 (15 Psi) at 25 °C for 16 hrs. After completion, the reaction mixture was filtered through a Celite pad and rinsed with MeOH (5 mL x 3). The filtrate was concentrated and purified by column to afford int-30-4 (800.0 mg, 1.05 mmol, 84.0% yield). LC-MS (ESI+): m / z 726.4 (M+H)+. Step 4: int-30-5 To a solution of int-30-4 (807.0 mg, 1.11 mmol) in THF (8 mL) was added TBAF (2.91 g, 11.11 mmol) in portions. The resulting mixture was stirred at 25 °C for 4 hrs. After completion, the reaction mixture was poured into water (50 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (50 mL x 2), followed by brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford int-30-5 (430.0 mg, crude), which was used directly in the next step without purification. LC-MS (ESI+): m / z 612.3 (M+H)+. Step 5: int-30-6 To a solution of int-30-5 (400.0 mg, 0.65 mmol) in anhydrous toluene (1.2 mL) was added 2-(tributylphosphoranylidene)acetonitrile (945.0 mg, 3.92 mmol). The mixture was purged with N2 for 3 mins and stirred at 90 °C for 1 hr under N2 atomsphere. After cooling to room temperature, the reaction mixture was diluted with EtOAc (10 mL) and washed with water (10 mL), followed by brine (10 mL), dried over Na2SO4, filtered and concentrated and purified by column chromatography to afford int-30-6 (170.0 mg, 0.26 mmol, 39.4% yield). LC-MS (ESI+): m / z 594.2 (M+H)+. Step 6: int-30 A mixture of int-30-6 (170.0 mg, 0.29 mmol) in HC1 solution (4 M in Dioxane, 3 mL) was stirred at 25 °C for 2 hrs. After completion, the reaction mixture was concentrated to give a residue, which was diluted with DCM (20 mL), washed with saturated NaHCOs (20 mL), followed by brine (20 mL). The organic layer was dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-30 (70.0 mg, 0.14 mmol, 47.0% yield). LC-MS (ESI+): m / z 494.1 (M+H)+. Example ab: Synthesis of int-31 int-31-1 int-31-2 int-31-7                                                   int-31-8                                    int-31 Step 1: int-31-2 To a solution of int-31-1 (3.10 g, 9.09 mmol) and (£)-tert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane (2.85 g, 9.55 mmol) in THF (75 mL) and water (7.5 mL) wereadded 1, T-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.74 g, 0.91 mmol) and K2CO3 (2.51 g, 18.18 mmol). The resulting mixture was degassed and purged with N2 for 3 times and stirred at 60 °C under N2 for 16 hrs. After cooling to room temperature, the mixture was concentrated and purified by column chromatography to afford int-31-2 (1.98 g, 5.14 mmol, 56.5% yield). ’H NMR (400 MHz, DMSO-t / 6) 5 8.01 (s, 1H), 7.68 (d, J= 8.0 Hz, 1H), 7.61 (dd, J= 8.0, 4.0 Hz, 1H), 6.81 (d, J = 16.0 Hz, 1H), 6.39 (dt, J = 16.0, 4.0 Hz, 1H), 4.37 - 4.21 (m, 2H), 0.83 (s, 9H), 0.00 (s, 6H). Step 2: int-31-3 To a solution of int-33-3 (2.00 g, 3.75 mmol) and int-31-2 (1.98 g, 5.14 mmol) in NMP (20 mL) were added copper(I) iodide (0.71 g, 3.75 mmol), K2CO3 (1.04 g, 7.50 mmol) and (1R,2R)-N} ,N2-dimethylcyclohexane-l,2-diamine (0.27 g, 1.87 mmol). The resulting mixture was degassed and purged with N2 for 3 times and stirred at 140 °C under N2 for 3 hrs. After cooling to room temperature, the reaction mixture was poured into 100 mL of water and extratecd with EtOAc (50 mL x 3). The combined organic layers were washed with water (100 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-31-3 (1.80 g, 2.15 mmol, 57.3% yield). LC-MS (ESI+): m / z 838.4 (M+H)+. Step 3: int-31-4 To a solution of int-31-3 (1.30 g, 1.55 mmol) in MeOH (30 mL) was added Pd / C (300.0 mg, 20%w / w.). The resulting mixture was degassed and purged with H2 for three times and stirred at 25 °C for 16 hrs under H2 (15 psi). After completion, the reaction mixture was filtered through a celite pad and resined with MeOH (5 mL x 3). The filtrate was concentrated under reduced pressure to afford int-31-4 (1.60 g, crude), which was used directly in the next step without purification. LC-MS (ESI+): m / z 750.4 (M+H)+. Step 4: int-31-5 To a solution of int-31-4 (1.60 g, 2.13 mmol) in THF (10 mL) were added TBAF (5 mL, 1 M in THF). The resulting mixture was stirred at 25 °C for 3 hrs. After completion, the reaction mixture was poured into water (150 mL). and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-31-5 (950.0 mg, 1.49 mmol, 70.0% yield). LC-MS (ESI+): m / z 636.4 (M+H)+. Step 5: int-31-6 To a solution of int-31-5 (140.0 mg, 0.22 mmol) in anhyrdous toluene (5 mL) was added 2-(tributyl-15-phosphaneylidene)acetonitrile (159.0 mg, 0.66 mmol). The resulting mixture was stirred at 90 °C for 2 hrs under N2 atomsphere. After cooling to room tremperature, the mixture was dilutred with EtOAc (30 mL) and washed with brine (10 mL x 2), dried over Na2SO4, filtered, concentrated and purified by prep-TLC to afford int-31-6 (30.0 mg, 0.05 mmol, 22.1% yield). LC-MS (ESI+): m / z 618.2 (M+H)+. Step 6: int-31-7 To a solution of int-31-6 (30.0 mg, 0.05 mmol) inTHF (0.3 mL) and water (0.3 mL) was added LiOH (6.0 mg, 0.25 mmol). The resulting mixture was stirred at 25 °C for 2 hrs. After completion, the reaction mixture was acidifed by HC1 (aq., 1 M) to pH~l and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water (20 mL x 2), followed by brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford int-31-7 (29.0 mg, crude). LC-MS (ESI+): m / z 604.2 (M+H)+. Step 6: int-31-8 To a solution of int-31-7 (400.0 mg, 0.66 mmol) in DMF (4 mL) were added dimethylamine hydrogen chloride (107.0 mg, 1.33 mmol), DIEA (0.4 mL, 2.00 mmol) and HATU (378.0 mg, 1.00 mmol). The resulting mixture was stirred at 25 °C for 16 hrs. After completion, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (30 mL x 2), followed by brine (30 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-31-8 (311.0 mg, 0.49 mmol, 74.0% yield). LC-MS (ESI+): m / z 631.2 (M+H)+. ’H NMR (400 MHz, DMSO-d6) 5 7.47 (s, 1H), 7.43 - 7.33 (m, 2H), 7.23 - 7.16 (m, 1H), 7.09 - 7.02 (m, 1H), 6.99 - 6.70 (m, 1H), 6.69 - 52 (m, 1H), 5.54 - 5.04 (m, 1H), 4.33 - 4.17 (m, 3H), 3.20 - 3.08 (m, 1H), 3.06 - 2.92 (m, 6H), 2.77 - 2.63 (m, 4H), 2.32 - 2.26 (m, 3H), 1.68 -1.57 (m, 2H), 1.49 - 1.44 (m, 9H), 1.29 - 1.24(m, 3H). Step 7: int-31 A solution of int-31-8 (320.0 mg, 0.51 mmol) in HC1 solution (2mL, 4 M in dioxane) was stirred at 25 °C for 0.5 hr. After completion, the reaction was concentrated under reduced pressure to give a residue, which was diluted with DCM (30 mL) and washed with saturated NaHCOs (aq., 50 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-31 (140.0 mg, 0.26 mmol, 52.0% yield). LC-MS (ESI+): m / z 531.5 (M+H)+. Example ac: Synthesis of int-32 Step 1: int-32-2 int-32 To a solution of int-23-3 (450.0 mg, 0.75 mmol) in NMP (4.5 mL) were added int-32-1 (450.0 mg, 1.51 mmol), copper(I) iodide (143.0 mg, 0.75 mmol), (1 7?,2 / ?)-A1,A2-dimethylcyclohexane-1,2-diamine (107.0 mg, 0.75 mmol) and K2CO3 (312.0 mg, 2.26 mmol). After addition, the resulting mixture was degassed and purged with N2 for 2 mins and then stirred at 130 °C for 1 hr under N2. After cooling to room temperature, the mixture was poured into water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (50 mL x 2), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-32-2 (500.0 mg, 0.61 mmol, 81.0% yield). LC-MS(ESI+): m / z 816.4 [M+H]+ Step 2: int-32-3 To a solution of int-32-2 (450.0 mg, 0.55 mmol) in MeOH (15 mL) was added Pd / C (50.0 mg, 10% w / w.). The resulting mixture was degassed and purged with H2 for 3 times and stirred at 20 °C for 4 hrs under H2 (15 psi). After completion, the mixture was filtered through a celite pad and rinsed with MeOH (5 mL x 3). The filtrate was concentrated under reduced pressure to afford int-32-3 (220.0 mg, 0.30 mmol, 54.8% yield). LC-MS(ESI+): m / z 728.4 [M+H]+ Step 3: int-32-4 To a solution of int-32-3 (200.0 mg, 0.28 mmol) in THF (2 mL) was added TBAF (1.4 mL, 1 M in THF). The resulting mixture was stirred at 30 °C for 0.5 hr. After completion, the mixture was poured into 10 mL of water and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-32-4 (120.0 mg, 0.20 mmol, 71.2% yield). LC-MS(ESI+): m / z 614.3 [M+H]+ Step 4: int-32-5 To a solution of int-32-4 (100.0 mg, 0.16 mmol) in anhydrous toluene (2.0 mL) was added 2-(tributylphosphoranylidene)acetonitrile (236.0 mg, 0.98 mmol). The resulting mixture was degassed and purged with N2 for 3 times and stirred at 90 °C for 2 hrs under N2 atomsphere. After cooling to room temperature, the mixture was poured into 10 mL of water and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by prep-TLC (SiO2, DCM: MeOH=15:l, v / v) to afford int-32-5 (80.0 mg, 0.13 mmol, 82.0% yield). LC-MS(ESI+): m / z 596.4 [M+H]+. ’H NMR (400 MHz, DMSO-A) 5 7.80 - 7.70 (m, 1H), 7.49 - 7.42 (m, 1H), 7.37 - 7.32 (m, 1H), 7.05 - 6.98 (m, 1H), 6.80 - 6.76 (m, 1H), 6.75 - 6.61 (m, 1H), 6.78 (d, J= 4.0 Hz, 1H), 5.17 - 5.07 (m, 1H), 4.38 - 4.23 (m, 1H), 4.02 - 3.92 (m, 2H), 3.16 - 3.08 (m, 1H), 2.78 - 2.65 (m, 4H), 2.26 (s, 3H), 2.18 - 2.10 (m, 2H), 1.95 - 1.87 (m, 1H), 1.44 (s, 9H), 1.25 -1.23 (m, 3H). Step 5: int-32 A mixture of int-32-5 (60.0 mg, 0.10 mmol) in HC1 (1 mL, 4 M in dioxane) was stirred at 25 °C for 1 hr. After completion, the mixture was concentrated under reduced pressure to afford int-32 (50.0 mg, crude), which was used directly in the next step without purification. LC-MS(ESI+): m / z 496.2 [M+H]+ Example ad: Synthesis of int-33 Step 1: int-33-1 To a solution of int-16-3 (5.00 g, 18.92 mmol) and int-2-4 (5.59 g, 22.70 mmol) in EtOH (50 mL) was added pyridine (3.06 mL, 37.8 mmol). The resulting mixture was stirred at 90 °C for 2 hrs. After cooling to room temperature, the mixture was concentrated and purified by column chromatography to afford int-33-1 (10.00 g, 20.30 mmol, 89.4% yield). LC-MS(ESI+): m / z 493.4 [M+H]+ Step 2: int-33-2 To a solution of int-33-1 (10.00 g, 20.30 mmol) in DMAc (200 mL) was added NaH (3.25 g, 81.00 mmol) at 0 °C. After being stirred at 0 °C for 30 mins, A-(2,2-dimethoxyethyl)-lZ7-imidazole-l-carboxamide (8.08 g, 40.6 mmol) was added portion-wise at 0 °C. The resulting mixture was stirred at 20 °C for 1 hr. After completion, the reaction mixture was added poured into water (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with water (200 mL x 2), followed by brine (200 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-33-2 (9.00 g, 14.43 mmol, 71.1% yield). LC-MS(ESI+): m / z 624.4 [M+H]+ Step 3: int-33-3 To a solution of int-33-2 (9.00 g, 14.43 mmol) in THF (90 mL) was added TsOH*H2O (1.37 g, 7.21 mmol). The resulting mixture was stirred at 60 °C for 1 hr. After cooling to room temperature, the mixture was poured into water (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-33-3 (6.70 g, 11.97 mmol, 83.0% yield). LC-MS(ESI+): m / z 560.4 [M+H]+ Step 4: int-33-4 To a solution of int-33-3 (1.00 g, 1.79 mmol) in NMP (13 mL) was added int-22-5 (1.36 g, 3.57 mmol), (l / ^^^-A'^-dimethylcyclohexane-l^-diamine (254.0 mg, 1.79 mmol), copper(I) iodide (681.0 mg, 3.57 mmol) and potassium carbonate (741.0 mg, 5.36 mmol). The resulting mixture was degassed and purged with N2 for 3 times and stirred at 140 °C for 4 hrs under N2 atmosphere. After cooling to room temperature, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with water (100 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-33-4 (830.0 mg, 0.96 mmol, 54.0% yield). LC-MS (ESI+): m / z 860.5 (M+H)+. 1H NMR (400 MHz, DMSO-db) 5 8.31 (s, 1H), 7.64 (d, J= 8.0 Hz, 1H), 7.43 - 7.29 (m, 5H), 7.18 - 7.04 (m, 2H), 7.01 - 6.9 (m, 1H), 6.91 - 6.84 (m, 2H), 6.65 - 6.49 (m, 2H), 5.40 - 5.17 (m, 1H), 5.01 (s, 2H), 4.33 - 4.25 (m, 2H), 4.07 (s, 3H), 3.62 - 3.48 (m, 2H), 2.25 (s, 3H), 1.43 (s, 9H), 1.37 - 1.32 (m, 1H), 1.29 (d, J= 8.0 Hz, 3H), 1.26 - 1.20 (m, 1H), 1.01 - 0.95 (m, 2H), 0.85 (s, 9H), 0.03 (s, 6H). Step 5: int-33-5 To a solution of int-33-4 (830.0 mg, 0.96 mmol) in MeOH (25 mL) was added Pd / C (166.0 mg, 20% w / w). The resulting mixture was degassed and purged with H2 for 3 times and stirred at 30 °C for 2 hrs under H2 atomsphere (15 psi). After completion, the reaction mixture was filtered through a celite pad and rinsed with MeOH (20 mL x 3). The filtrate was concentrated under reduced pressure to afford int-33-5 (720.0 mg, crude), which was used for next step directly without purification. LC-MS (ESI+): m / z 772.4 (M+H)+. Step 6: int-33-6 To a solution of int-33-5 (720.0 mg, 0.93 mmol) in THF (3.6 mL) was added TBAF (4.66 mL, 1 M in THF). The resulting mixture was stirred at 20 °C for 2 hrs. After completion, the mixture was poured into water (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with water (50 mL x 2), brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-33-6 (520.0 mg, 0.79 mmol, 85.0% yield). LC-MS (ESI+): m / z 658.3 (M+H)+. ’H NMR (400 MHz, DMSO-t / 6) 5 10.15 (brs, 1H), 8.21 (s, 1H), 7.58 (d, J= 8.0 Hz, 1H), 7.16 (d, J= 8.0 Hz, 1H), 6.96 - 6.86 (m, 2H), 6.83 (dd, J= 8.0, 4.0 Hz, 1H), 6.71 - 6.64 (m, 1H), 5.42 - 5.13 (m, 1H), 4.47 (brs, 1H), 4.06 (s, 3H), 3.67 - 3.41 (m, 2H), 3.37 - 3.31 (m, 2H), 2.86 - 2.73 (m, 2H), 2.21 (s, 3H), 1.67 (p, J= 8.0 Hz, 2H), 1.43 (s, 9H), 1.37 - 1.31 (m, 1H), 1.27 (d, J= 8.0 Hz, 3H), 1.02 - 0.94 (m, 2H), 0.87 - 0.77 (m, 1H). Step 7: int-33-7 To a solution of int-33-6 (520.0 mg, 0.79 mmol) in anhydrous toluene (13 mL) was added 2-(tributylphosphoranylidene)acetonitrile (1.15 g, 4.74 mmol). The resulting mixture was degassed and purged with N2 for 3 times and stirred at 90 °C for 4 hrs under N2 atmosphere. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with water (100 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-33-7 (430.0 mg, 0.67 mmol, 85.0% yield). LC-MS (ESI+): m / z 640.3 (M+H)+. Step 8: int-33 A mixture of int-33-7 (430.0 mg, 0.67 mmol) in HC1 solution (3 mL, 4 M in dioxane) was stirred at 25 °C for 1 hr. After completion, the mixture was concentrated to give a residue that was diluted with DCM (50 mL). The organic layer was washed with saturated NaHCOs (aq., 100 mL), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-33 (230.0 mg, 0.43 mmol, 63.4% yield). LC-MS (ESI+): m / z 540.3 (M+H)+. 1H NMR (400 MHz, DMSO4) 5 8.34 - 8.29 (m, 1H), 7.61 - 7.54 (m, 1H), 7.34 - 7.20 (m, 1H), 7.16 - 7.07 (m, 1H), 7.02 - 6.68 (m, 2H), 6.67 - 6.54 (m, 1H), 4.41 - 4.09 (m, 3H), 4.08 - 4.04 (m, 3H), 3.23 - 2.85 (m, 4H), 2.82 - 2.70 (m, 1H), 2.29 - 2.21 (m, 3H), 1.78 - 1.54 (m, 2H), 1.30 - 1.22 (m, 3H), 1.21 - 1.15 (m, 1H), 1.07 - 0.98 (m, 1H), 0.96-0.89 (m, 1H), 0.88 - 0.79 (m, 1H). Example ae: Synthesis of int-34 Br Step 1: int-34-1 To a solution of int-33-3 (4.00 g, 7.15 mmol) in MeOH (60 mL) and THF (60 ml) was added Pd / C (800 mg, 20% w / w). The resulting reaction mixture was degassed and purged with H2 for 3 times and stirred at 20 °C for 1 hr. After completion, the mixture was filtered through a celite pad and rinsed with MeOH (10 mL x 2). The filtrate was concentrated under reduced pressure to afford int-34-1 (3.20 g, crude), which was used for next step directly without purification. LC-MS(ESI+): m / z 470.2 [M+H]+. 'H NMR (400 MHz, DMSO-cL) 5 10.31 (s, 1H), 10.09 (s, 1H), 6.74 (dd, J= 8.0, 4.0 Hz, 1H), 6.62 - 6.59 (m, 1H), 6.58 - 6.56 (m, 1H), 6.55 - 6.51 (m, 1H), 5.25 - 5.08 (m, 1H), 3.61 - 3.41 (m, 2H), 2.16 (s, 3H), 1.42 (s, 9H), 1.34 - 1.29 (m, 1H), 1.19 - 1.14 (m, 3H), 0.98 - 0.90 (m, 2H), 0.84 - 0.74 (m, 1H). Step 2: int-34-2 To a solution of int-34-1 (3.20 g, 6.82 mmol) in DCM (60 mL) was added 1,1,1 -trifluoro-A-phenyl-A-((trifluoromethyl)sulfonyl)methanesulfonamide (1.83 g, 6.13 mmol) and TEA (2.85 mL, 20.45 mmol). The resulting mixture was stirred at 20 °C for 1 hr. After completion, the mixture was poured into water (500 mL) and extracted with DCM (200 mL x 3). The combined organic layers were washed with water (200 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-34-2 (2.40 g, 3.99 mmol, 58.5 % yield). LC-MS(ESI+): m / z 602.2 [M-i-HjVH NMR (400 MHz, DMSO-t / 6) 5 10.44 (s, 1H), 7.51 - 7.44 (m, 1H), 7.36 - 7.31 (m, 1H), 6.69 - 6.62 (m, 2H), 5.27 - 5.07 (m, 1H), 3.62 - 3.44 (m, 2H), 2.34 (s, 3H), 1.42 (s, 9H), 1.39 - 1.33 (m, 1H), 1.17 (d, J = 8.0 Hz, 3H), 1.01 - 0.95 (m, 2H), 0.89 - 0.82 (m, 1H). Step 3: int-34-3 To a mixture of int-34-2 (1.00 g, 1.66 mmol)) in dioxane (10 mL) and water (1 mL) was added (E)-tert-butyldimethyl((3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)allyl)oxy)silane (744.0 mg, 2.49 mmol), NaHCOs (279.0 mg, 3.32 mmol) and Pd(Ph3P)4 (192.0 mg, 0.166 mmol). The resulting mixture was degassed and purged with N2 for 3 times and stirred at 100 °C for 2 hrs. After cooling to room temperature, the mixture was poured into water (250 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with water (100 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-34-3 (650.0 mg, 1.04 mmol, 62.7% yield). LC-MS(ESI+): m / z 624.3 [M-i-HjVH NMR (400 MHz, DMSO-t / 6) 5 10.36 (s, 1H), 7.31 - 7.24 (m, 1H), 7.17-7.11 (m, 1H), 6.72 - 6.60 (m, 2H), 6.60 - 6.55 (m, 1H), 6.32 (dt, J = 16.0, 8.0 Hz, 1H), 5.27 - 5.08 (m, 1H), 4.38 - 4.30 (m, 2H), 3.61 - 3.44 (m, 2H), 2.21 (s, 3H), 1.42 (s, 9H), 1.37 - 1.31 (m, 1H), 1.18 (d, J= 8.0 Hz, 3H), 0.98 - 0.92 (m, 2H), 0.90 (s, 9H), 0.85 - 0.83 (m, 1H), 0.08 (s, 6H). Step 4: int-34-4 To a solution of int-34-3 (650.0 mg, 1.04 mmol) in NMP (6 mL) were added int-23-8 (661.0 mg, 2.08 mmol), copper(I) iodide (198.0 mg, 1.04 mmol), K2CO3 (432.0 mg, 3.13 mmol) and (1R, 2R)-N'.N'-dimethylcyclohexane-l,2-diamine (148.0 mg, 1.04 mmol). The resulting mixture was degassed and purged with N2 for 3 times and stirred at 140 °C for 2 hrs under N2. After cooling to room temperature, the reaction mixture was poured into water (300 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with water (200 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-34-4 (500 mg, 0.581 mmol, 55.8 % yield). LC-MS(ESI+): m / z 860.4 [M+H]+ Step 5: int-34-5 To a solution of int-34-4 (1.25 g, 1.45 mmol) in MeOH (40 mL) was added Pd / C (250 mg, 20% w / w). The resulting mixture was degassed and purged with H2 for 3 times and then stirred at 30 °C for 2 hrs under H2 (15 psi). After completion, the reaction mixture was filtered and resined with MeOH (10 mL x 2). The filtrate was concentrated under reduced pressure to afford int-34-5 (LOO g, crude), which was used for next step directly. LC-MS(ESI+): m / z 772.4 [M+H]+ Step 6: int-34-6 To a solution of int-34-5 (LOO g, 1.29 mmol) in THF (10 mL) was added TBAF (1.69 mg, 6.48 mmol). The resulting mixture was stirred at 30 °C for 1 hr. After completion, the reaction mixture was poured into water (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with water (100 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-34-6 (570.0 mg, 0.87 mmol, 66.9% yield). LC-MS(ESI+): m / z 658.4 [M+H]+. ’H NMR (400 MHz, DMSO-t / 6) 5 10.60 (brs, 1H), 8.21 (s, 1H), 7.16 -7.06 (m, 4H), 6.87 - 6.77 (m, 2H), 5.38 - 5.19 (m, 1H), 4.64 - 4.48 (m, 1H), 4.01 (s, 3H), 3.62 - 3.48 (m, 2H), 3.43 - 3.40 (m, 2H), 2.66 - 2.59 (m, 2H), 2.24 (s, 3H), 1.70 - 1.62 (m, 2H), 1.43 (s, 9H), 1.39 - 1.34 (m, 1H), 1.28 (d, J= 8.0 Hz, 3H), 1.01 - 0.92 (m, 2H), 0.89 - 0.82 (m, 1H). Step 7: int-34-7 To a solution of int-34-6 (470.0 mg, 0.72 mmol) in anhydrous toluene (15 mL) was added 2-(tributylphosphoranylidene)acetonitrile (689.0 mg, 2.86 mmol). The resulting mixture was degassed and purged with N2 for 2 mins and stirred at 90 °C for 1 hr. After cooling to room temperature, the reaction mixture was diluted with EtOAc (200 mL) and washed with water (100 mL x 2), followed by brine (100 mL). The organic layer was dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-34-7 (450.0 mg, 0.70 mmol, 98.0% yield). LC-MS(ESI+): m / z 640.4 [M+H]+. ’H NMR (400 MHz, DMSO-t / 6) 5 8.25 - 8.22 (m, 1H), 7.45 - 7.31 (m, 3H), 7.06 - 6.73 (m, 3H), 5.38 - 5.17 (m, 1H), 4.06 (s, 3H), 4.02 - 3.98 (m, 1H), 3.81 - 3.70 (m, 1H), 3.67 - 3.50 (m, 2H), 2.91 - 2.75 (m, 2H), 2.26 (s, 3H), 2.23 - 2.14 (m, 1H), 2.10 - 1.99 (m, 1H), 1.44 (s, 9H), 1.38 - 1.27 (m, 4H), 1.02 - 0.95 (m, 2H), 0.89 - 0.81 (m, 1H). Step 8: int-34 A mixture of int-34-7 (450.0 mg, 0.70 mmol) in HC1 solution (4 mL, 4 M in dioxane) was stirred at 30 °C for 1 hr. After completion, the reaction mixture was concentrated under reduced pressure to afford int-34 (350.0 mg, 0.65 mmol, 92.0% yield). LC-MS(ESI+): m / z 540.3 [M+H]+ Example ah: Synthesis of int-39, int-40, int-41, int-42, int-43 Int-39-5 was synthesized following the procedure for int-27-6 and int-23-7 using int-39-1 instead of int-23-8 and int-27-2. The conversion of int-39-5 to int-39 was carried out following the procedure for the synthesis of int-31 from int-31-6. Int-39: (280.0 mg, 0.53 mmol, 83.0% yield). LC-MS (ESI+): m / z 531.3 (M+H)+. ’H NMR (400 MHz, DMSO-t / 6) 5 7.50 - 7.40 (m, 1H), 7.38 - 7.32 (m, 1H), 7.28 - 7.21 (m, 1H), 7.15 - 6.98 (m, 2H), 6.84 - 6.74 (m, 1H), 6.74 - 6.57 (m, 1H), 4.06 - 3.97 (m, 2H), 3.94 - 3.86 (m, 1H), 3.31 - 3.17 (m, 2H), 3.05 - 2.92 (m, 6H), 2.91 - 2.76 (m, 2H), 2.70 -2.63 (m, 2H), 2.28 (s, 3H), 2.24-2.11 (m, 1H), 2.04-1.85 (m, 1H), 1.28- 1.16 (m, 3H). Step 1: int-40-1 To a solution of int-2-7 (960.0 mg, 1.80 mmol) in THF (20 ml) and MeOH (20 mL) was added Pd / C (96.0 mg, 10% w / w, 10% purity). The reaction mixture was degassed and purged with H2 for 3 times and stirred at 30 °C under H2 (15 Psi) for 7 hrs. After completion, the mixture was filtered through a celite pad and the cake was rinsed with MeOH (10 mL x 3). The combined filtrate was concentrated and purified by column chromatography to afford int-40-1 (420.0 mg, 0.95 mmol, 52.6% yield). LC-MS(ESI+): m / z 444.3 [M+H]+. ’H NMR (400 MHz, DMSO-t / 6) 5 10.32 (s, 1H), 10.16 (brs, 1H), 6.77 (d, J = 4.0 Hz, 1H), 6.65 (d, J = 4.0 Hz, 1H), 6.58 (s, 1H), 6.50 (s, 1H), 5.11 - 4.97 (m, 1H), 4.35 -4.14 (m, 1H), 3.12-2.97 (m, 1H), 2.69-2.60 (m, 2H), 2.17 (s, 3H), 1.42 (s, 9H), 1.11 (d, J = 8.0 Hz, 3H). Step 2: int-40-2 To a solution of int-40-1 (1.00 g, 2.26 mmol) in DMF (10 mL) were added K2CO3 (374.0 mg, 2.71 mmol), followed by 4-(chloromethyl)-l, 2-dimethoxybenzene (461.0 mg, 2.48 mmol) dropwised at 0°C. The mixture was stirred at 25 °C for 16 hrs. After completion, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (50 mL x 2), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-40-2 (700.0 mg, 1.18 mmol, 52.3% yield). LC-MS (ESI+): m / z 594.4 (M+H)+. Step 3: int-40-3 A mixture of int-22-5 (549.0 mg, 1.44 mmol), K2CO3 (298.0 mg, 2.16 mmol), int-40-2 (427.0 mg, 0.72 mmol), Cui (137.0 mg, 0.72 mmol) and (lR,2R)-A,M-Dimethyl-l,2-cyclohexanediamine (51.0 mg, 0.36 mmol) in NMP (5 mL) was degassed and purged with N2 for 3 mins and stirred at 140°C for 3 hrs under N2 atomsphere. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 mL) and washed with H2O (50 mL x 3), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-40-3 (370.0 mg, 0.36 mmol, 50.1% yield). LC-MS (ESI+): m / z 894.3 (M+H)+ Step 4: int-40-4 To a solution of int-40-3 (300.0 mg, 0.34 mmol) in DCM (6 mL) was added TFA (1.2 mL) dropwised and the mixture was stirred at 25 °C for 1 hr. After completion, the reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated NaHCOs (aq., 20 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford int-40-4 (250.0 mg, crude), which was used directly in the next step without purification. LC-MS (ESI+): m / z 530.2 (M+H)+. Step 5: int-40-5 To a solution int-40-4 (250.0 mg, 0.47 mmol) in DCM (5 mL) were added TEA (0.13 mL, 0.94 mmol) and (Boc)2O (0.16 mL, 0.70 mmol). The mixture was stirred at 25 °C for 1 hr. After completion, the mixture was diluted with DCM (20 mL) and washed with water (20 mL x 2). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was dissolved in MeOH (6 mL) and K2CO3 (284.0 mg, 2.06 mmol) was added. After being stirred at 25 °C for 2 hrs, the mixture was filtered and rinsed with dichloromethane (5 mL x 3). The combined organic layers were concentrated and purified by prep-TLC to afford int-40-5 (70.0 mg, 0.11 mmol, 27.0% yield). LC-MS (ESI+): m / z 630.2(M+H)+. Step 6: int-40-6 To a solution of int-40-5 (60 mg, 0.095 mmol) in anhydrous toluene (1.8 mL) was added 2-(tributylphosphoranylidene)acetonitrile (92.0 mg, 0.38 mmol). The resulting mixture was stirred at 100 °C for 2 hrs under N2 atomsphere. After cooling to room temperature, the mixture was diluted with EtOAc (10 mL) and washed with brine (10 mL x 2), dried over Na2SO4, filtered, concentrated and purified by prep-TLC to afford int-40-6 (40.0 mg, 0.07 mmol, 68.6% yield). LC-MS (ESI+): m / z 612.2 (M+H)+. Step 7: int-40 A mixture of int-40-6 (40.0 mg, 0.07 mmol) in HC1 solution (4 M in dioxane, 0.6 mL) was stirred at 25 °C for 1 hr. After completion, the mixture was concentrated to afford int-40 (20.0 mg, 0.04 mmol, 59.8% yield). LC-MS (ESI+): m / z 512.1 (M+H)+. Step 1: int-41-2 To a solution of int-41-1 (1.60 g, 6.45 mmol) in DMF (9.0 mL) was added NaH (0.568 g, 14.19 mmol) in portions under N2 atomsphere at 0 °C. After being stirred at 0°C for 0.5 hr, 1,2-dibromoethane (2.67 g, 14.19 mmol) was added dropwise at 0°C. The resulting mixture was stirred at 0 °C for 2 hrs. After coompletion, the mixture was poured into cold water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with water (100 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-41-2 (1.50 g, 4.93 mmol, 76.0% yield). LC-MS (ESI+): m / z 288.0 (M+H)+. ’H NMR (400 MHz, DMSO-t / 6) 5 8.29 - 8.19 (m, 1H), 7.53 (d, J= 8.0 Hz, 1H), 4.10 (q, J= 8.0 Hz, 2H), 1.59 - 1.51 (m, 2H), 1.51 - 1.39 (m, 2H), 1.15 (t, J= 8.0 Hz, 3H). Step 2: int-41-3 To a mixture of int-34-3 (1.00 g, 1.60 mmol) and int-41-2 (924.0 mg, 3.21 mmol) in NMP (10.0 mL) wass added K2CO3 (665.0 mg, 4.81 mmol), Cui (305 mg, 1.60 mmol) and (H?,2 / ?)-A,M-Dimethyl-l, 2-cyclohexanediamine (114.0 mg, 0.80 mmol). The resulting mixture was degassed and purged with N2 for 3 times and stirred at 130 °C for 3 hrs under N2 atomsphere. After cooling to room temperature, the mixture was was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 4). The combined organic layers were washed with water (100 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-41-3 (900.0 mg, 1.13 mmol, 70.5% yield). LC-MS (ESI+): m / z 717.1 (M+H)+. Step 3: int-41-4 To a solution of int-41-3 (800.0 mg, 1.12 mmol) in MeOH (24.0 mL) was added Pd / C (160 mg, 20%w / w.). The resulting mixture was degassed and purged with H2 for 3 times and stirred at 25 °C for 2 hrs under H2 (15 psi). After completion, the reaction mixture was filtered through a Celite pad and resined with MeOH (30 mL x 3). The filtrate was concentrated under reduced pressure to afford int- 41-4 (600.0 mg, 0.75 mmol, 67.3% yield). LC-MS (ESI+): m / z 719.2 (M+H)+. ’H NMR (400 MHz, DMSO-A) 5 8.07 (t, J= 8.0 Hz, 1H), 7.68 (d, J= 8.0 Hz, 1H), 7.15 - 7.06 (m, 2 H), 7.05 - 6.94 (m, 2H), 5.34 - 5.13 (m, 1H), 4.55 - 4.45 (m, 1H), 4.13 - 4.08 (m, 2H), 3.66 - 3.48 (m, 2H), 3.44 - 3.38 (m, 2H), 2.65 - 2.56 (m, 2H), 2.22 (s, 3H), 1.65 - 1.59 (m, 2H), 1.58 - 1.54 (m, 2H), 1.46 - 1.44 (m ,1H), 1.43 (s, 9H), 1.37 - 1.34 (m, 1H), 1.25 (d, J= 8.0 Hz, 3H), 1.18 - 1.10 (m, 4H), 1.03 - 0.96 (m, 2H), 0.89-0.82 (m, 1H). Step 4: int-41-5 To a solution of int-41-4 (640.0 mg, 0.89 mmol) in DMA (25.0 mL) was added NaH (43.0 mg, 1.781 mmol, 60% purity) in portions at 0 °C under N2 atomsphere. The resulting mixture was stirred at 25 °C for 1 hr. After completion, the mixture was poured into cold water (100 mL) and extracted with EtOAc (100 mL x 3). The combined aqueous layers were washed with brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-41-5 (200.0 mg, 0.15 mmol, 16.7% yield). LC-MS (ESI+): m / z 671.1(M+H)+. Step 5: int-41-6 To a mixture of int-41-5 (100.0 mg, 0.15 mmol) and methylamine hydrochloride (10.0 mg, 0.15 mmol) in DMF (1.5 mL) were added HATU (85.0 mg, 0.22 mmol) and DIEA (0.08 mL, 0.45 mmol). The resulting mixture was stirred at 25 °C for 16 hrs. After completion, the mixture was diluted with EtOAc (20 mL) and washed with water (15 mL x 2). The organic layer was washed with brine (15 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography on silica gel to afford int-41-6 (25.0 mg, 0.029 mmol, 19.6% yield). LC-MS (ESI+): m / z 684.3 (M+H)+. Step 6: int-41 A mixture of int-41-6 (50 mg, 0.073 mmol) in HC1 solution (4 M in dioxane, 1 mL) was stirred at 25 °C for 1 hr. After completion, the reaction mixture was concentrated under reduced pressure to afford int-41 (40.0 mg, 0.06 mmol, 84.0% yield), which was used directly in the next step without purification. LC-MS (ESI+): m / z 584.2 (M+H)+. Step 1: int-42-2 To a solution of int-42-1 (3.00 g, 7.71 mmol) in DMF (60 mL) were added I H-pyiazolc (0.709 g, 10.41 mmol), copper(I) iodide (0.147 g, 0.771 mmol), CS2CO3 (7.54 g, 23.13 mmol) and 2-(pyridin-2-yl)-l / 7-benzo[t / ]imidazole (151.0 mg, 0.77 mmol). The resulting mixture was degassed and purged with N2 for 3 times and then stirred at 100 °C for 12 hrs under N2. After cooling to room temperature, the mixture was poured into water (300 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with water (100 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-42-2 (1.10 g, 3.34 mmol, 43.3% yield). LC-MS(ESI+): m / z 329.0 [M+H]+ Step 2: int-42-3 To a solution of int-23-3 (500.0 mg, 0.80 mmol) in NMP (5 mL) was added int-42-2 (528.0 mg, 1.60 mmol), (IR^^-A'^-dimethylcyclohexane-l^-diamine (57.0 mg, 0.40 mmol), K2CO3 (332.0 mg, 2.40 mmol) and copper(I) iodide (153.0 mg, 0.80 mmol). The resulting mixture was degassed and purged with N2 for 3 times and stirred at 130 °C for 3 hrs under N2. After cooling to room temperature, the mixture was poured into water (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with water (100 mL x 2), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-42-3 (420.0 mg, 0.48 mmol, 60.1% yield). LC-MS(ESI+): m / z 872.5 [M+H]+. ’H NMR (400 MHz, DMSO-t / 6) 5 8.53 (d, J= 4.0 Hz, 1H), 7.74 (d, J= 4.0 Hz, 1H), 7.68 (d, J = 4.0 Hz, 1H), 7.49 (dd, J= 8.0, 4.0 Hz, 1H), 7.36 - 7.23 (m, 7H), 7.14 - 7.10 (m, 1H), 6.89 (s, 2H), 6.63 (d, J = 16.0 Hz, 1H), 6.57 - 6.53 (m, 1H), 6.29 (dt, J= 16.0, 4.0 Hz, 1H), 5.32 - 5.13 (m, 3H), 4.28 - 4.21 (m, 2H), 3.60 - 3.42 (m, 2H), 2.12 (s, 3H), 1.39 (s, 9H), 1.36 - 1.31 (m, 1H), 1.18 - 1.14 (m, 3H), 0.98 - 0.90 (m, 2H), 0.86 - 0.81 (m, 10H), 0.00 (s, 6H). Step 3: int-42-4 To a solution of int-42-3 (320.0 mg, 0.37 mmol) in MeOH (9 mL) was added Pd / C (60 mg, 20% w / w).The resulting mixture was degassed and purged with H2 for 3 times and stirred at 30 °C for 5 hrs under H2 (15 psi). After completion, the reaction mixture was filtered and resined with MeOH (3 mL x 3). The filtrate was concentrated under reduced pressure to afford int-42-4 (360.0 mg, crude), which was used directly in the next step. LC-MS (ESI+): m / z 784.4 [M+H]+ Step 4: int-42-5 To a solution of int-42-4 (360.0 mg, 0.46 mmol) in THF (4 mL) was added TBAF (2.3 mL, 2.30 mmol). The resulting mixture was stirred at 30 °C for 1 hr. After completion, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with water (50 mL), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-42-5 (220.0 mg, 0.33 mmol, 71.4% yield). LC-MS(ESI+): m / z 670.2 [M+H]+ Step 5: int-42-6 To a solution of int-42-5 (210.0 mg, 0.31 mmol) in anhydrous toluene (6 mL) was added 2-(tributylphosphoranylidene)acetonitrile (303.0 mg, 1.25 mmol). The resulting mixture was degassed and purged with N2 for 3 times and then stirred at 90 °C for 1 hr under N2. After cooling to room temperature, the mixture was poured into water (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with water (50 mL x 2), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-42-6 (170.0 mg, 0.26 mmol, 83.0% yield). LC-MS(ESI+): m / z 652.3 [M+HJL’H NMR (400 MHz, DMSO-t / 6) 5 8.63 -8.59 (m, 1H), 7.81 - 7.74 (m, 1H), 7.69 - 7.65 (m, 1H), 7.60 - 7.53 (m, 2H), 7.28 - 7.18 (m, 1H), 7.09 - 6.95 (m, 1H), 6.90 - 6.80 (m, 1H), 6.79 - 6.61 (m, 1H), 6.60 - 6.56 (m, 1H), 5.37 - 5.14 (m, 1H), 4.10 - 3.98 (m, 2H), 3.66 - 3.48 (m, 2H), 2.88 - 2.79 (m, 1H), 2.74 - 2.66 (m, 1H), 2.26 (s, 3H), 2.22 - 2.16 (m, 1H), 1.97 - 1.88 (m, 1H), 1.45 - 1.41 (m, 10H), 1.33 - 1.30 (m, 3H), 0.99 - 0.95 (m, 2H), 0.88 - 0.86 (m, 1H). Step 6: int-42 A mixture of int-42-6 (170.0 mg, 0.26 mmol) in HC1 solution (4 M in dioxane, 2 mL) was stirred at 30 °C for 1 hr. After completion, the mixture was filtered and concentrated under reduced pressure to afford int-42 (150.0 mg, crude). LC-MS(ESI+): m / z 552.3 [M+H]+ Step 1: int-43-2 To a mixture of int-23-3 (300.0 mg, 0.48 mmol) and int-43-1 (334.0 mg, 0.96 mmol) in NMP (4.5 mL) wass added (17?,27?)-A1,A2-dimethylcyclohexane-l,2-diamine (68.0 mg, 0.48 mmol), copper(I) iodide (183.0 mg, 0.96 mmol) and K2CO3 (199.0 mg, 1.44 mmol). The resulting mixture was degassed and purged with N2 for 3 times and then stirred at 130 °C for 3 hrs under N2 atmosphere. After cooling to room temperature, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with H2O (50 mL x 2), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-43-2 (300 .Omg, 0.34 mmol, 70.1% yield). LC-MS (ESI+): m / z 890.3 (M+H)+. ’H NMR (400 MHz, DMSO-<76) 5 7.43 - 7.24 (m, 8H), 7.15 (d, J= 8.0 Hz, 1H), 7.06 (d, J= 8.0 Hz, 1H), 6.99 -6.89 (m, 2H), 6.65 (d, J= 16.0 Hz, 1H), 6.30 (dt, J= 16.0, 4.0 Hz, 1H), 5.39 - 5.20 (m, 1H), 5.19 (s, 2H), 4.33 - 4.19 (m, 2H), 3.65 - 3.43 (m, 2H), 2.15 (s, 3H), 1.42 (s, 9H), 1.38 - 1.34 (m, 1H), 1.26 -1.22 (m, 1H), 1.17 (d, J= 8.0 Hz, 3H), 1.00 - 0.92 (m, 2H), 0.87 (s, 9H), 0.04 (s, 6H). Step 2: int-43-3 To a solution of int-43-2 (300.0 mg, 0.34 mmol) in MeOH (9 mL) was added Pd / C (60 mg, 20% w / w). The resulting mixture was degassed and purged with H2 for 3 times and stirred at 30 °C for 2 hrs under H2 atmosphere (15 psi). After completion, the reaction mixture was filtered through a celite pad and rinsed with MeOH (30 mL x 3). The filtrate was concentrated under reduced pressure to afford int-43-3 (260.0 mg, crude) , which was used directly for the next step. LC-MS (ESI+): m / z 802.2 (M+H)+. ’H NMR (400 MHz, DMSO-^) 5 7.33 - 7.23 (m, 1H), 7.14 - 7.09 (m, 1H), 7.08 - 7.03 (m, 1H), 6.91 (d, J= 4.0 Hz, 1H), 6.87 - 6.75 (m, 2H), 6.74 - 6.63 (m, 1H), 5.43 - 5.07 (m, 1H), 3.62 -3.53 (m, 4H), 2.67 - 2.59 (m, 2H), 2.23 (s, 3H), 1.76 - 1.64 (m, 2H), 1.44 (s, 9H), 1.40 - 1.34 (m, 1H), 1.32 - 1.20 (m, 4H), 1.03 - 0.96 (m, 2H), 0.86 (s, 9H), 0.00 (s, 6H). Step 3: int-43-4 To a solution of int-43-3 (260.0 mg, 0.32 mmol) in THF (1.5 mL) was added TBAF (1.6 mL, 1.60 mmol). The resulting mixture was stirred at 30 °C for 2 hrs. After completion, the mixture was poured into water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (30 mL), followed by brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue that was purified by pre-TLC to afford int-43-4 (190.0 mg, 0.28 mmol, 85.0% yield). LC-MS (ESI+): m / z 688.2 (M+H)+. ’H NMR (400 MHz, DMSO-t / 6) 5 10.70 (brs, 1H), 7.35 (d, J= 8.0 Hz, 1H), 7.13 - 7.02 (m, 2H), 6.96 - 6.92 (m, 1H), 6.92 - 6.86 (m, 2H), 6.85 - 6.77 (m, 1H), 5.35 - 5.06 (m, 1H), 4.51 (brs, 1H), 3.64 - 3.44 (m, 2H), 3.40 - 3.37 (m, 2H), 2.60 (t, J = 8.0 Hz, 2H), 2.22 (s, 3H), 1.68 - 1.60 (m, 2H), 1.43 (s, 9H), 1.38 - 1.32 (m, 1H), 1.26 - 1.23 (m, 3H), 1.01 - 0.94 (m, 2H), 0.88 - 0.81 (m, 1H). Step 4: int-43-5 To a solution of int-43-4 (190.0 mg, 0.28 mmol) in anhydrous toluene (5.8 mL) was added 2-(tributylphosphoranylidene)acetonitrile (267.0 mg, 1.11 mmol). The resulting mixture was degassed and purged with N2 for 3 times and then stirred at 90 °C for 2 hrs under N2 atmosphere. After cooling to room temperature, the mixture was poured into water (30 mL) and extracted with EtOAc (30 mL x 3), the combined organic layers were washed with water (30 mL x 2), followed by brine (30 mL), dried over Na2SO4, filtered, concentrated and purified by pre-TLC to afford int-43-5 (135.0 mg, 0.20 mmol, 73.0% yield). LC-MS (ESI+): m / z 670.2 (M+H)+. 1H NMR (400 MHz, DMSO-t / 6) 5 7.67 -7.56 (m, 1H), 7.29 - 7.21 (m, 2H), 7.15 - 6.97 (m, 2H), 6.96 - 6.80 (m, 1H), 6.80 - 6.58 (m, 1H), 5.55 -5.00 (m, 1H), 4.10 - 3.93 (m, 2H), 3.70 - 3.44 (m, 2H), 2.84 - 2.62 (m, 2H), 2.25 (s, 3H), 2.23 - 2.14 (m, 1H), 1.96 - 1.84 (m, 1H), 1.43 (s, 9H), 1.36 - 1.28 (m, 4H), 1.01 - 0.95 (m, 2H), 0.89 - 0.82 (m, 1H). Step 5: int-43 A mixture of int-43-5 (135.0 mg, 0.20 mmol) in HC1 solution (1 mL, 4 M in dioxane) was stirred at 30 °C for 1 hr. After completion, the reaction mixture was concentrated to give a residue, which was diluted with DCM (10 mL) and washed with saturated NaHCOs (aq., 10 mL). The organic layer was washed with water (30 mL), followed by brine (30 mL), dried over Na2SO4, filtered, concentrated and purified by pre-TLC to afford int-43 (110.0 mg, 0.19 mmol, 96.0% yield). LC-MS (ESI+): m / z 570.1 (M+H)+.’H NMR (400 MHz, DMSO-< / 6) 5 7.61 - 7.44 (m, 1H), 7.32 - 7.17 (m, 2H), 7.13 - 6.92 (m, 2H), 6.83 - 6.53 (m, 2H), 4.14 - 3.92 (m, 3H), 3.08 - 3.02 (m, 1H), 2.86 - 2.68 (m, 3H), 2.25 (s, 3H), 2.20 - 2.13 (m, 1H), 1.95 - 1.84 (m, 1H), 1.25 - 1.21 (m, 3H), 1.20 - 1.14 (m, 1H), 1.02 - 0.96 (m, 1H), 0.93 - 0.79 (m, 2H). Example aj: Synthesis of int-50 Step 1: int-50-2 To a mixture of NaH (38.1 g, 952 mmol) in DMF (1 L) was added a solution of int-50-1 (100g, 476 mmol) in DMF (500 mL) at 0 °C and the mixture was stirred at 25 °C for 30 min. The mixture reaction was added a solution of 1-bromo-2-(2-bromoethoxy)ethane (221 g, 952 mmol) in DMF (500 mL) and the mixture was stirred at 25 °C for 16 hrs. The reaction was quenched with saturated NH4CI (2 L) and extracted with EA (500 mL x 3). The combined organic layers were wash with H2O (500 mL x 2), dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography to give int-50-2 (80.0 g, 60% yield).1H NMR (400 MHz, DMSO-dr,) 5 7.54 (d, J = 2.1 Hz, 1H), 7.47 - 7.40 (m, 1H), 7.30 (d, J = 8.6 Hz, 1H), 4.01 - 3.90 (m, 2H), 3.72 - 3.65 (m, 2H), 2.57 (s, 3H), 2.26 - 2.20 (m, 2H), 1.99- 1.90 (m, 2H). Step 2: int-50-3 To a mixture of int-50-2 (60.0 g, 214 mmol) in THF (1.2 L) was added LDA (214 mL, 428 mmol, 2M THF) at -78 °C under nitrogen, the mixture was stirred at -78 °C for 3 hrs. The reaction was quenched with saturated hydrochloric acid aqueous solution (2N, 500 mL) and extracted with EA (500 mL x 3). The combined organic layers wash with H2O (500 mL x 2), the organic layers were dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography to give int-50-3 (30.0 g, 50% yield). LCMS: 283.0 [M+ H]+. Step 3: int-50-4 To a mixture of int-50-3 (45.0 g, 160 mmol) in MeOH (450 ml) was added NaBH4 (18.2 g, 480 mmol) at 0 °C under nitrogen, the mixture was stirred at 25 °C for 18 hrs. The solvent was concentrated. The residue was partitioned between DCM (500 mL) and water (500 mL). The aqueous layer was extracted with DCM (250 mL x 2), wash with brine (300 mL), dried over sodium sulfate, filtered and concentrated to afford int-50-4 (35.0 g, 77% yield). LCMS: 283.4 [M+ H]+. Step 4: int-50-5 To a mixture of int-50-4 (52.0 g, 184 mmol) in THF (1 L) was added pyridine (21.8 g, 275 mmol), TsCl (43.8 g, 230 mmol) and t-BuOK (72.1 g, 643 mmol) at 25 °C, the mixture was stirred at 25 °C for 18 hrs. The reaction was quenched with H2O (1 L) and extracted with EA (500 mL x 3). The combined organic layers were wash with H2O (500 mL x 2), dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography to give int-50-5 (48.0 g, 99% yield). LCMS: 265.0 [M+ H]+. Step 5: int-50-6 To a mixture of int-50-5 (38.0 g, 143 mmol) in toluene (380 ml) was added tert-butyl carbamate (33.6 g, 287 mmol), K2CO3 (39.6 g, 287 mmol), XPhos (13.7 g, 28.7 mmol) and Pd(OAc)2 (1.6 g, 7.17 mmol) under nitrogen, the mixture was stirred at 100 °C for 18 hrs. The mixture was filtered and concentrated and purified by column chromatography to give int-50-6 (30.0 g, 70% yield). LCMS: 324.2 [M+ H]+. Step 6: int-50-7

[0331] To a mixture of int-50-6 (30.0 g, 100 mmol) in MeOH (300 mL) was added Pd / C (3.0 g, 10% wt, 55% H2O) at 25 °C under hydrogen, the mixture was stirred at 25°C for 18 hrs. The mixture was filtered and concentrate to give int-50-7 (28.0 g, 93% yield). LCMS: 326.2 [M+ Na]+. Step 7: int-50-8 To a mixture of int-50-7 (28.0 g, 92.0 mmol) in DCM (280 mL) was added HCI / dioxanc (115 mL, 461 mmol, 4 M) at 25 °C under nitrogen, the mixture was stirred at 25 °C for 18 hrs. The reaction was quenched with saturated sodium bicarbonate aqueous solution (500 mL) and extracted with DCM (300 mL x 3). The combined organic layers wash with H2O (200 mL x 2), the organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give int-50-9 (11.0 g, 59% yield). LCMS: 204.0 [M+ H]+. Step 8: int-50-9 & int-50-9a To a mixture of int-50-8 (11.0 g, 54.1 mmol) inDMSO(110 mL) was added HOAc (6.50 g, 108 mmol), ethyl 2-oxopropanoate (25.1 g, 216 mmol), 4A molecular sieve (5.0 g) and Pd(OAc)2 (1.20 g, 5.41 mmol) under oxygen, the mixture was stirred at 70 °C for 18 hrs. The reaction was partitioned between EA (200 mL) and water (200 mL). The aqueous layer was extracted with EA (200 mL x 2), The combined organic extracts were wash with brine (100 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography to afford int-50-9 and int-50-9a (7.00g, 43% yield). LCMS: 300.2 [M+ H]+. Step 9: int-50-10 & int-50-10a To a mixture of int-50-9 andint-50-9a (10.0 g, 33.4 mmol) in MeOH (100 mL) was added a solution of LiOH (4.0 g, 167 mmol) in H2O (50 ml) at 25 °C, the mixture was stirred at 40 °C for 18 hrs. The mixture reaction was adjusted pH to 3 ~ 4 with 2N HC1. The aqueous layer was extracted with EA (200 mL x 2), The combined organic extracts were wash with brine (100 mL) and dried over sodium sulfate, dried over anhydrous Na2SO4, filtered and concentrated to give int-50-10 and int-50-10a (6.00 g, 66% yield). LCMS: 272.2 [M+ H]+. Step 10: int-50-11 & int-50-lla To a mixture of int-50-10 and int-50-10a (6.00 g, 22.1 mmol) and HATU (12.6 g, 33.2 mmol) in DMF (60 ml) was added DIEA (8.6 g, 66.3 mmol) and N-methylaniline (2.40 g, 22.1 mmol), the mixture was stirred at 40 °C for 18 hrs. The reaction was partitioned between EA (200 mL) and water (100 mL). The aqueous layer was extracted with EA (100 mL x 2), the combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered, concentrated and purified by column chromatography to afford int-50-11 and int-50-lla (5.60 g, 70% yield). LCMS: 361.2 [M+ H]+. Step 11: int-50-12 & int-50-12a To a mixture of NaH (1.3 g, 53.3 mmol) in DMF (80 mL) was added a solution of int-50-11 and int-50-lla (6.40 g, 17.76 mmol) in DMF (10 mL) at 0 °C, the mixture was stirred at 25 °C for 30 min, then added a solution of 2-bromoacetonitrile (4.30 g, 35.5 mmol) in DMF (20 mL) and the mixture was stirred at 25 °C for 18 hrs. The reaction was quenched with saturated ammonium chloride aqueous solution (100 mL) and extracted with EA (100 mL x 3). The combined organic layers were wash with H2O (50 mL x 2), dried over anhydrous Na2SO4, filtered, concentrated and purified by SFC to give int-50-12. (2.80 g, 39% yield). LCMS: 400.2 [M+ H]+, tR =1.81 min. 1HNMR (400 MHz, DMSO-t / 6) 5 7.47 - 7.42 (m, 1H), 7.38 - 7.30 (m, 4H), 7.29 - 7.23 (m, 1H), 7.19 (s, 1H), 5.95 (s, 1H), 5.59 (s, 2H), 3.79 - 3.70 (m, 2H), 3.49 - 3.40 (m, 2H), 3.42 (s, 3H), 2.95 (t, J = 7.1 Hz, 2H), 2.11 - 2.02 (m, 2H), 1.79 -1.70 (m, 2H), 1.43 - 1.30 (m, 2H). Step 12: int-50-13 To a solution of int-50-12 (1.90 g, 4.76 mmol) and 1,3,2-dioxathiolane 2,2-dioxide (1.48 g, 11.89 mmol) in THF (5 ml) was added KHMDS (38 mL, 38.0 mmol, IM THF) slowly at 0 °C. The mixture was further stirred at 25 °C under N2 for 2 hrs. The mixture reaction was quenched with NH4CI (100 mL) and extracted with EA (200 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered, concentrated to give int-50-13 (1.90 g, 80% yield). LCMS: 425.7 [M+ H]+. Step 13: int-50-14 To a solution of int-50-13 (2.00 g, 4.70 mmol) in DMSO (20 ml) was added sodium bicarbonate (1.97 g, 23.50 mmol) and hydroxylamine hydrochloride (1.63 g, 23.5 mmol). The mixture was stirred at 50 °C for 12 hrs. The suspension was quenched with NH4CI (100 mL) and extracted with EA (200 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated to give int-50-14 (2.00 g, 93% yield). LCMS: 458.7 [M+ H]+. Step 14: int-50-15 To a solution of int-50-14 (1.50 g, 3.27 mmol) in DMSO (15 ml) was added CDI (1.59 g, 9.81 mmol) and DBU (1.48 ml, 9.81 mmol). The mixture was stirred at 25 °C for 12 hrs. The mixture reaction was quenched with H2O (100 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (25 mL x 2), dried over Na2SO4, filtered and concentrated to give int-50-15 (1.00 g, 63% yield). LCMS: 485.2 [M+ H]+.

[0348] Step 15: int-50

[0349] To a solution of int-50-15 (500 mg, 1.03 mmol) in n-PrOH was added KOH (579 mg, 10.32 mmol). The mixture was stirred at 90 °C for 5 hrs. The reaction was adjusted pH = 2 with 2 N HC1 aq. The mixture extracted with EA (50 mL x 3). The combined organic layers were washed with brine (25 mL x 2), dried over Na2SO4, filtered and concentrated to afford int-50 (186.9 mg, 42% yield). LCMS: 394.1 [M+H]+. Example ak: Synthesis of int-51, int-52, int-53 and int-53-P2 int-51 int-52 int-53 int-53-P2 The synthesis of int-51 was referred to intermediate 46-P1 of WO2022017338. The synthesis of int-52 was referred to intermediate 46-P2 of WO2022017338. Step 1: int-53-2 To a solution of int-53-1 (20.00 g, 63.50 mmol) in 1,4-dioxane (300 mL) and water (30 mL) was added 2,2-dimethyl-3,6-dihydro-2Z7-pyran-4-yl trifluoromethanesulfonate (19.82 g, 76.00 mmol), Pd(dppf)C12 (2.32 g, 3.17 mmol) and potassium carbonate (17.54 g, 127.00 mmol). The resulting mixture was degassed and purged with N2 for 3 times and stirred at 100 °C for 2 hrs under N2. After cooling to room temperature, the mixture was poured into 500 mL of water and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-53-2 (11.45 g, 38.20 mmol, 60.3% yield). LC-MS (ESI+): m / z 300.1 (M+H)+. ’H NMR (400 MHz, Chloroform-d) 5 9.05 (s, 1H), 7.68 (s, 1H), 7.46 (d, J =8.0 Hz, 1H), 7.41 (d, J =8.0 Hz, 1H), 7.26-7.15 (m, 1H), 6.12 (s, 1H), 4.44 (q, J = 8.0 Hz, 2H), 4.41 - 4.37 (m, 2H), 2.58 - 2.43 (m, 2H), 1.45 (t, J = 8.0 Hz, 3H), 1.40- 1.35 (m, 6H). Step 2: int-53-3 To a solution of int-53-2 (4.10 g, 13.70 mmol) and / V-mcthylanilinc (3.70 mL, 34.20 mmol) in toluene (80 mL) was added trimethylaluminium (20.54 mL, 2 M in toluene) dropwise at 0 °C. The resulting mixture was stirred at 90 °C for 2 hrs under N2 atmosphere. After cooling to room temperature, the reaction mixture was quenched by cold H2O (100 mL) at 0 °C and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with H2O (100 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-53-3 (3.60 g, 9.99 mmol, 72.9% yield). LC-MS (ESI+): m / z 361.1 (M+H)+. ’H NMR (400 MHz, DMSO-db) 5 11.58 (s, 1H), 7.51 - 7.44 (m, 3H), 7.41 - 7.36 (m, 2H), 7.35 - 7.26 (m, 3H), 6.09 - 6.03 (m, 1H), 5.33 - 5.16 (m, 1H), 4.20 - 4.14 (m, 2H), 3.38 (s, 3H), 2.31 - 2.25 (m, 2H), 1.17 (s, 6H). Step 3: int-53-4 To a solution of int-53-3 (1.80 g, 4.99 mmol) in DMF (36 mL) was added NaH (499.0 mg, 12.48 mmol, 60% purity) in portions at 0 °C. After being stirred at 25 °C for 1 hr, 2-bromoacetonitrile (0.70 mL, 9.99 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 1 hr. After completion, the mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase was separated, washed with H2O (50 mL x 2), brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-53-4 (1.70 g, 4.26 mmol, 85% yield). LC-MS (ESI+): m / z 400.2 (M+H)+. ’H NMR (400 MHz, DMSO-t / 6) 5 7.62 (d, J= 8.0 Hz, 1H), 7.52 - 7.40 (m, 3H), 7.37 - 7.35 (m, 3H), 7.31 - 7.26 (m, 1H), 6.19 - 6.06 (m, 1H), 5.99 (s, 1H), 5.65 (s, 2H), 4.24 - 4.15 (m, 2H), 3.44 (s, 3H), 2.34 - 2.28 (m, 2H), 1.19 (s, 6H). Step 4: int-53-5 To a solution of int-53-4 (1.70 g, 4.26 mmol) and (R)-4-methyl-l,3,2-dioxathiolane 2,2-dioxide (1.47 g, 10.64 mmol) in THF (34 mL) was added LiHMDS (17.02 mL, 1 M in THF) dropwise at 0 °C under N2 atomsphere. The resulting mixture was stirred at 0 °C for 1 hr. After completion, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with water (100 mL), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-53-5 (1.45 g, 3.30 mmol, 78% yield). LC-MS (ESI+): m / z 440.1 (M+H)+. Step 5: int-53-6 To a solution of int-53-5 (1.45 g, 3.30 mmol) and hydroxylamine hydrochloride (688.0 mg, 9.90 mmol) in EtOH (29 mL) was added K2CO3 (912 mg, 6.60 mmol). The resulting mixture was stirred at 90 °C for 1 hr. After cooling to room temperature, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (50 mL), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-53-6 (1.10 g, 2.33 mmol, 70.6% yield). LC-MS (ESI+): m / z 473.1 (M+H)+. ’H NMR (400 MHz, DMSO-t / 6) 5 9.24 (s, 1H), 7.59 (d, J= 8.0 Hz, 1H), 7.43 - 7.32 (m, 4H), 7.31 - 7.22 (m, 3H), 6.39 - 5.88 (m, 4H), 4.34 - 4.07 (m, 2H), 3.47 (s, 3H), 2.35 - 2.25 (m, 2H), 1.75 -1.65 (m, 1H), 1.63 - 1.58 (m, 1H), 1.21 - 1.13 (m, 9H), 1.03 - 0.95 (m, 1H). Step 6: int-53-7 To a solution of int-53-6 (1.070 g, 2.26 mmol) and DBU (1.03 mL, 6.79 mmol) in Dioxane (10 mL) was added CDI (1.10 g, 6.79 mmol). The resulting mixture was stirred at 80 °C for 2 hrs. After cooling to room temperature, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (50 mL x 2), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-53-7 (1.05 g, 2.11 mmol, 93.0% yield). LC-MS (ESI+): m / z 499.2 (M+H)+. Step 7: int-53 and int-53-P2 To a solution of int-53-7 (1.00 g, 2.01 mmol) in t-BuOK in THF (20.06 mL, 1 M in THF) was added H2O (0.04 mL, 2.01 mmol). The resulting mixture was stirred at 25 °C for 12 hrs. After completion, the reaction mixture was poured into water (50 mL), acidifed by HC1 (2 N) to adjusted pH ~1 and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, concentrated and purified by SFC (ChiralCel OJ, 250*30 mm I.D., 10 pm; Mobile Phase [A%: CO2; B%: 25 % MeOH; Flow rate: 120 mL / min; Back pressure: 100 bar; Column temperature: 38 °C) to afford two isomers (int-53, int-53-P2). LC-MS (ESI+): m / z 410.1 (M+H)+. Int-53: (186.0 mg, 0.45 mmol, 22.65% yield). ’H NMR (400 MHz, DMSO-t / 6) 5 12.32 (brs, 1H), 7.72 - 7.68 (m, 1H), 7.53 - 7.46 (m, 1H), 7.38 (t, J= 8.0 Hz, 1H), 7.24 - 7.21 (m, 1H), 6.09 (d, J = 8.0 Hz, 1H), 3.88 - 3.79 (m, 2H), 2.44 - 2.37 (m, 2H), 2.03 - 1.89 (m, 1H), 1.84 - 1.73 (m, 1H), 1.69 - 1.51 (m, 1H), 1.43 - 1.25 (m, 9H). Int-53-P2: (454 mg, 1.11 mmol, 55.3% yield). 'H NMR (400 MHz, DMSO-cL) 5 12.28 (brs, 1H), 7.71 - 7.67 (m, 1H), 7.56 - 7.47 (m, 1H), 7.39 (t, J= 8.0 Hz, 1H), 7.21 (d, J= 4.0 Hz, 1H), 6.25 - 6.08 (m, 1H), 4.29 - 4.19 (m, 2H), 2.40 - 2.34 (m, 2H), 2.02 - 1.88 (m, 1H), 1.83 - 1.74 (m, 1H), 1.69 - 1.52 (m, 1H), 1.42 - 1.25 (m, 3H), 1.23 (d, J= 4.0 Hz, 6H). Example am: Synthesis of int-70-2 lnt-70-1 Int-70-2 To a solution of int-70-1 (1.07 g, 4.18 mmol) in DMF (5 mL) were added CS2CO3 (2.04 g, 6.27 mmol) and Mel (0.34 mL, 5.43 mmol). The resulting mixture was stirred at 50 °C for 1 hr. After cooling to room temperature, the reaction mixture was poured into 20 mL of water and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water (20 mL x 2), followed by brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-70-2 (850.0 mg, 3.15 mmol, 75.0% yield). ’H NMR (400 MHz, DMSO-t / 6) 8 7.31 - 7.23 (m, 1H), 6.85 (d, J= 8.0 Hz, 1H), 3.38 (d, J= 4.0 Hz, 3H), 1.73 - 1.66 (m, 2H), 1.60 - 1.54 (m, 2H). Example an: Synthesis of int-70 Step 1: int-70-3 To a solution of int-70-2 (5.00 g, 18.51 mmol) and phenylmethanol (2.40 g, 22.21 mmol) in DMAc (50 mL) was added tBuOK (3.12 g, 27.80 mmol) at 0 °C in portions. The resulting mixture was stirred at 25 °C for 3.5 hrs. After completion, the reaction mixture was poured into water (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with water (200 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-70-3 (3.80 g, 10.61 mmol, 57.3% yield). LC-MS (ESI+): m / z 358.1 (M+H)+. 1H NMR (500 MHz, DMSO-t / 6) Step 2: int-70-4 To a solution of int-34-3 (450.0 mg, 0.72 mmol) in NMP (5 mL) were added int-70-3 (517 mg, 1.443 mmol), Cui (137.0 mg, 0.72 mmol), (I / ?,2 / ?)- / Vl, / V2-dimcthylcyclohcxanc-l,2-diaminc (51.0 mg, 0.36 mmol) and K2CO3 (299.0 mg, 2.16 mmol). The resulting mixture was degassed and purged with N2 for 3 times and stirred at 130 °C for 6 hrs under N2. After cooling to room temperature, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (50 mL x 2), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-70-4 (170.0 mg, 0.19 mmol, 26.2% yield). LC-MS (ESI+): m / z 923.4 (M+Na)+ Step 3: int-70-5 To a solution of int-70-4 (170.0 mg, 0.19 mmol) in MeOH (3 mL) was added Pd / C (34.0 mg, 20% w / w). The resulting mixture was degassed and purged with H2 for 3 times and stirred at 40 °C for 2 hrs under H2 atomsphere (15 psi). After completion, the reaction mixture was filtered through a Celite pad and resined with MeOH (5 mL x 4). The filtrate was concentrated under reduced pressure to afford int-70-5 (110.0 mg, 0.14 mmol, 71.7% yield). LC-MS (ESI+): m / z 813.4 (M+H)+ Step 4: int-70-6 To a solution of int-70-5 (110.0 mg, 0.14 mmol) in THF (1 mL) was added TBAF (177.0 mg, 0.68 mmol). The resulting mixture was stirred at 30 °C for 1 hr. After completion, the mixture was poured into water (20 mL) and extracted with EtOAc (20 x 3 mL). The combined organic layers were washed with water (20 mL x 2), followed by brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-70-6 (50.0 mg, 0.07 mmol, 52.9% yield). LC-MS (ESI+): m / z 699.4 (M+H)+ Step 5.- int-70-7 To a solution of int-70-6 (40.0 mg, 0.06 mmol) in anhydrous toluene (1.5 mL) was added 2-(tributylphosphoranylidene)acetonitrile (55.0 mg, 0.23 mmol). The resulting mixture was degassed and purged with N2 for 3 times and stirred at 90 °C for 2 hrs. After cooling to room temperature, the mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water (30 mL), followed by brine (30 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-70-7 (30.0 mg, 0.044 mmol, 77.0% yield). LC-MS (ESI+): m / z 681.2 (M+H)+ Step 6: int-70 To a solution of int-70-7 (30 mg, 0.04 mmol) in DCM (1 mL) was added TFA (0.2 mL). The resulting mixture was stirred at 25 °C for 1 hr. After completion, the mixture was concentrated under reduced pressure to afford int-70 (30.0 mg, crude), which was used directly for the next step without purification. LC-MS (ESI+): m / z 581.3 (M+H)+ Example aq: Synthesis of int-56 Step 1: int-56-2 To a solution of int-56-1 (1.00 g, 3.94 mmol) in dioxane (10 ml) were added oxetan-3-ol (1.46 g, 19.68 mmol), CS2CO3 (3.85 g, 11.81 mmol), Cui (0.15 g, 0.79 mmol) and (1R,2R)-Na,N2-dimethylcyclohexane-l,2-diamine (0.22 g, 1.57 mmol). The resulting mixture was degassed and purged with N2 for 3 times and stirred at 110°C for 18 hrs. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (100 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-56-2 (200.0 mg, 6.30 mmol, 20.0% yield). LC-MS (ESI+): m / z 248.1 (M+H)+. Step 2: int-56-3 To a solution of int-56-2 (250.0 mg, 1.01 mmol) and 2-bromoacetonitrile (133.0 mg, 1.11 mmol) in DMSO (3 mL) and water (0.6 mL) were added sodium iodide (152.0 mg, 1.01 mmol) and iron(II) sulfate heptahydrate (141.0 mg, 0.51 mmol), followed by hydrogen peroxide (0.124 ml, 1.213 mmol) dropwise below 10 °C. The resulting mixture was stirred at 5 °C for 1 hr. After completion, the reaction mixture was poured into 30 mL of cold water and stirred for 10 mins. After being filtered, the cake was risned with water (3 mL x 3) and dissolved in 20 mL DCM. The organic layer was dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-56-3 (370.0 mg, 1.29 mmol, 49.2% yield). LC-MS (ESI+): m / z 287.1 (M+H)+. Step 3: int-56-4 To a solution of int-56-3 (370.0 mg, 1.29 mmol) in DMSO (7 mL) was added DBU (0.40 mL, 2.58 mmol) and diphenyl(vinyl)sulfonium trifluoromethanesulfonate (703.0 mg, 1.94 mmol). The resulting mixture was stirred at 15 °C for 1 hr. After completion, the reaction mixture was poured into 50 mL of water and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-56-4 (350.0 mg, 1.12 mmol, 87.0% yield). LC-MS (ESI+): m / z 313.0 (M+H)+. ’H NMR (400 MHz, DMSO-A) 5 8.36 (d, J= 8.0 Hz, 1H), 6.76 - 6.62 (m, 2H), 6.57 (s, 1H), 5.39 - 5.24 (m, 1H), 4.96 (t, J = 8.0 Hz, 2H), 4.62 - 4.49 (m, 2H), 3.84 (s, 3H), 1.98 - 1.92 (m, 2H), 1.50 - 1.37 (m, 2H). Step 4: int-56-5 To a solution of int-56-4 (350.0 mg, 1.12 mmol) in ethanol (7 mL) was added TEA (0.24 mL, 1.68 mmol) and hydroxylamine hydrochloride (93.0 mg, 1.35 mmol). The resulting mixture was stirred at 90 °C for 4 hrs. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, diluted with 10 mL water, acidified with HCOOH to pH~4 and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-56-5 (270.0 mg, 0.78 mmol, 69.8% yield). LC-MS (ESI+): m / z 346.1 (M+H)+. ’H NMR (400 MHz, DMSO-A) 5 9.06 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 6.59 (d, J= 8.0 Hz, 1H), 6.54 (s, 1H), 6.46 (s, 1H), 5.32 (s, 2H), 5.30 - 5.23 (m, 1H), 4.98 - 4.89 (m, 2H), 4.58 - 4.49 (m, 2H), 3.82 (s, 3H), 1.69 - 1.32 (m, 2H), 1.10 - 0.63 (m, 2H). Step 5: int-56-6 To a solution of int-56-5 (250.0 mg, 0.72 mmol) in DMSO (5 mL) was added DBU (0.22 mL, 1.45 mmol) and 1,1'-carbonyldiimidazole (235.0 mg, 1.45 mmol). The resulting mixture was stirred at 20 °C for 1 hr. After completion, the reaction mixture was poured into 50 mL of water and acidified with diluted HC1 (2 M aqueous) to pH~4 and extracted with EtOAc (10 mL x 4). The combined organic layers were washed with water (20 mL x 2), followed by brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford int-56-6 (270.0 mg, crude), which was used directly for the next step without purification. LC-MS (ESI+): m / z 372.2 (M+H)+. Step 6: int-56 To a solution of int-56-6 (250.0 mg, 0.67 mmol) in MeOH (3 mL) and water (0.6 mL) was added LiOH (81.0 mg, 3.37 mmol). The resulting mixture was stirred at 50 °C for 8 hrs. After cooling to room temperature, the reaction mixture was poured into 10 ml of water, acidified by diluted HC1 (2 M aqueous) to pH~3 and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with water (10 mL x 2), followed by brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford int-56 (200.0 mg, crude), which was used directly for the next step without purification. LC-MS (ESI+): m / z 358.1 (M+H)+. ’H NMR (400 MHz, DMSO-t / 6) 5 12.11 (brs, 1H), 8.23 (d, J= 8.0 Hz, 1H), 6.59 (s, 1H), 6.57 - 6.51 (m, 2H), 5.29 (p, J= 4.0 Hz, 1H), 4.97 (t, J= 8.0 Hz, 2H), 4.61 - 4.52 (m, 2H), 1.86 - 1.76 (m, 2H), 1.60 - 1.43 (m, 1H), 1.39 - 1.26 (m, 1H). Example as: Synthesis of int-71 Step 1: int-71-2 To a solution of int-71-1 (3.00 g, 11.19 mmol) in 1,4-dioxane (60 mL) and water (6 mL) were added 2-(4,4-difluorocyclohex-l-en-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (4.10 g, 16.78 mmol), PdCL(dppf) (819.0 mg, 1.12 mmol) and K2CO3 (4.64 g, 33.60 mmol). The resulting mixture was degassed and purged with N2 for 3 times and then stirred at 90 °C for 2 hrs under N2 atmosphere. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with H2O (100 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-71-2 (2.40 g, 7.86 mmol, 70.2% yield). LC-MS (ESI+): m / z 306.1 (M+H)+. ’H NMR (400 MHz, DMSO-A) 5 11.87 (s, 1H), 7.68 (s, 1H), 7.44 - 7.38 (m, 2H), 7.13 (s, 1H), 6.07 - 5.78 (m, 1H), 4.33 (q, J= 8.0 Hz, 2H), 2.79 - 2.66 (m, 4H), 2.27 - 2.13 (m, 2H), 1.34 (t, J= 8.0 Hz, 3H). Step 2: int-71-3 To a solution of int-71-2 (2.40 g, 7.86 mmol) in MeOH (72 mL) was added Pd / C (240 mg, 10% w / w.). The resulting mixture was degassed and purged with H2 for 3 times and stirred at 25 °C for 2 hrs under H2 atmosphere (15 psi). After completion, the reaction mixture was filtered through a celite and resined with MeOH (10 mL x 3). the filtrate was concentrated under reduced pressure to afford int-71-3 (2.5 g, crude), which was used directly for the next step without purification. LC-MS (ESI+): m / z 306.0 (MH) . Step 3: int-71-4 To a solution of int-71-3 (2.50 g, 8.13 mmol) in toluene (50 mL) was added A-methylaniline (2.20 mL, 20.34 mmol) and trimethylaluminium (12.20 mL, 24.40 mmol) dropwised at 0 °C under N2 atomsphere and stirred at 90 °C for 2 hrs under N2 atmosphere. After cooling to room temperature, the reaction mixture was poured into ice-water (50 mL), The mixture was filtered through a Celite pad and rinsed with EtOAc (10 mL x 2). The filtrate was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with water (100 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-71-4 (2.70 g, 7.3 mmol, 90% yield). LC-MS (ESI+): m / z 369.2 (M+H)+. ’H NMR (400 MHz, DMSO-t / 6) 5 11.47 (s, 1H), 7.52 - 7.41 (m, 3H), 7.40 - 7.34 (m, 2H), 7.33 - 7.28 (m, 1H), 7.14 - 7.09 (m, 1H), 7.03 (dd, J= 8.0, 4.0 Hz, 1H), 5.22 (s, 1H), 3.38 (s, 3H), 2.71 - 2.57 (m, 1H), 2.14 - 2.00 (m, 2H), 1.98 - 1.75 (m, 4H), 1.70 - 1.53 (m, 2H). Step 4: int-71-5 To a solution of int-71-4 (2.70 g, 7.33 mmol) in DMF (68 mL) were added NaH (733.0 mg, 18.32 mmol) in portions at 0°C under N2 atomsphere. The mixture was stirred at 25 °C for 1 hr and then 2-bromoacetonitrile (1.02 mL, 14.66 mmol) was added dropwise at 0°C. The resulting mixture was stirred at 25 °C for 1 hr. After completion, the mixture was poured into ice-water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with H2O (50 mL x 2), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-71-5 (2.82 g, 6.92 mmol, 94.0% yield). LC-MS (ESI+): m / z 408.2 (M+H)+. Step 5: int-71-6 To a solution of int-71-5 (2.72 g, 6.68 mmol) and ( / ?)-4-mcthyl-L3.2-dioxathiolanc 2,2-dioxide (2.31 g, 16.69 mmol) in THF (54.0 mL) was dded LiHMDS (27.0 mL, 1 M in THF) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 hr under N2 atmosphere. After completion, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (50 mL x 2), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-71-6 (1.73 g, 3.87 mmol, 57.9% yield). LC-MS (ESI+): m / z 448.2 (M+H)+. Step 6: int-71-7 To a solution of int-71-6 (1.7.0 g, 3.80 mmol) and hydroxylamine hydrochloride (792.0 mg, 11.40 mmol) in EtOH (34 mL) were added K2CO3 (1.05 g, 7.60 mmol). The resulting mixture was stirred at 90 °C for 3 hrs under N2 atmosphere. After cooling to room temperature, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (50 mL x 2), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-71-7 (960.0 mg, 2.00 mmol, 52.6% yield). LC-MS (ESI+): m / z 481.4 (M+H)+. ’H NMR (400 MHz, DMSO-t / 6) 5 9.22 (s, 1H), 7.56 (d, J= 8.0 Hz, 1H), 7.41 - 7.32 (m, 2H), 7.30 - 7.17 (m, 4H), 7.10 (d, J = 8.0 Hz, 1H), 6.63 - 5.63 (m, 3H), 3.46 (s, 3H), 2.73 - 2.61 (m, 1H), 2.12 - 2.00 (m, 2H), 1.97 - 1.76 (m, 4H), 1.72 - 1.55 (m, 4H), 1.17 - 1.14 (m, 3H), 1.01 -0.96 (m, 1H). Step 7: int-71-8 To a solution of int-71-7 (930.0 mg, 1.94 mmol) and DBU (0.88 mL, 5.81 mmol) in dioxane (9.3 mL) were added CDI (941.0 mg, 5.81 mmol). The resulting mixture was stirred at 80 °C for 2 hrs. After cooling to room temperature, the reaction mixture was poured into water (50 mL), acidified by diluted HC1 solution (2 M aqueous) to pH~3 and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (50 mL x 2), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-71-8 (760.0 mg, 1.50 mmol, 78% yield). LC-MS (ESI+): m / z 507.2 (M+H)+. Step 8: int-71 To a solution in int-71-8 ( 730mg, 1.44 mmol) in rBuOK in THF (14.44 mL, 1 M in THF) was added water (26.0 mg, 1.44 mmol). The resulting mixture was stirred at 25 °C for 12 hrs. After completion, the reaction mixture was poured into cold water (40 mL) and extracted with EtOAc (20 mL x 2). The aqueous layer was acidifed by diluted HC1 (3 M aqueous) to pH=2 and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford int-71 (560.0 mg, 1.34 mmol, 93.0% yield). LC-MS (ESI+): m / z 416.0 (M-H). ’H NMR (400 MHz, DMSO-t / 6) 5 12.38 (brs, 1H), 7.57 - 7.51 (m, 1H), 7.38 - 7.32 (m, 1H), 7.31 - 7.23 (m, 1H), 7.20 - 7.14 (m, 1H), 2.85 - 2.72 (m, 1H), 2.17 - 2.00 (m, 3H), 1.98 - 1.84 (m, 4H), 1.82 - 1.52 (m, 4H), 1.41 - 1.38 (m, 1H), 1.29 - 1.22 (m, 2H). Example at: Synthesis of int-72 Step 1: int-72-2 To a solution of potassium trifluoro({3-oxabicyclo[4.1.0]heptan-6-yl})boranuide (1.98 g, 9.70 mmol, WO2022238335) and int-72-1 (2.60 g, 9.70 mmol) in toluene (26 mL) were added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.19 g, 1.46 mmol), CS2CO3 (9.48 g, 29.1 mmol) and water (2.60 mL). The resulting mixture was degassed and purged with N2 for three times and stirred at 90 °C for 16 hrs. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with water (100 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-72-2 (1.38 g, 4.35 mmol, 44.9% yield). LC-MS (ESI+): m / z 284.0 (M-H). ’H NMR (400 MHz, DMSO-76) 5 11.76 (s, 1H), 7.51 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.23 (d, J =8.0 Hz, 1H), 7.08 (s, 1H), 4.33 (q, 7=8.0 Hz, 2H), 4.02 (dd, J= 12.0, 4.0 Hz, 1H), 3.82 (d, J= 12.0 Hz, 1H), 3.53 - 3.42 (m, 1H), 3.42 - 3.38 (m, 1H), 2.12 - 2.02 (m, 1H), 1.98 - 1.90 (m, 1H), 1.38 - 1.30 (m, 4H), 1.04 - 0.97 (m, 1H), 0.86 - 0.81 (m, 1H). Step 2: int-72-3 To a solution int-72-2 (1.28 g, 4.49 mmol) and / V-mcthylanilinc (1.2 mL 11.21 mmol) in toluene (26 mL) was added trimethylaluminium (6.73 mL, 2 M in toluene) dropwise at 0°C under N2 atomsphere and stirred at 90 °C for 2 hrs. After cooling to room temperature, the reaction mixture was poured into ice-water (50 mL) and extracted with EtOAc (50mL x 3). The combined organic layers were washed with water (50 mL), followed by brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-72-3 (1.38 g, 3.78 mmol, 84.0% yield). LC-MS (ESI+): m / z 347.1 (M+H)+. Step 3: int-72-4 To a solution of int-72-3 (1.30 g, 3.75 mmol) in DMF (25 mL) was added NaH (375.0 mg, 9.38 mmol, 60% purity) in portions at 0 °C under N2 atmosphere. The mixture was stirred at 0 °C for 1 hr and then 2-bromoacetonitrile (900.0 mg, 7.51 mmol) was added dropwised at 0 °C. The resulting mixture was stirred at 25 °C for 1 hr. After completion, the mixture was poured into cold water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (100 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-72-4 (890.0 mg, 2.19 mmol, 58.5% yield). LC-MS (ESI+): m / z 386.1 (M+H)+. Step 4: int-72-5 To a solution of int-72-4 (350.0 mg, 0.91 mmol) and (7?)-4-methyl-l,3,2-dioxathiolane 2,2-dioxide (314.0 mg, 2.27 mmol) in THF (10 mL) was added LiHMDS (3.63 mL, 1 M in THF) dropwised at 0 °C under N2 atomsphere. The resulting mixture was stirred at 25 °C for 1 hr under N2 atmosphere. After completion, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (100 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-72-5 (250.0 mg, 0.56 mmol, 61.5% yield). LC-MS (ESI+): m / z 426.2 (M+H)+. Step 5: int-72-6 To a solution of int-72-5 (240.0 mg, 0.56 mmol) in MeOH (3 mL) was added hydroxylamine hydrochloride (118.0 mg, 1.69 mmol) and triethylamine (342.0 mg, 3.38 mmol). The resulting mixture was stirred at 90 °C for 4 hrs. After cooling to room temperature, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (100 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-72-6 (200.0 mg, 0.41 mmol, 73.5% yield). LC-MS (ESI+): m / z 459.2 (M+H)+. ’H NMR (400 MHz, DMSO-A) 5 9.22 (s, 1H), 7.56 (d, J= 8.0 Hz, 1H), 7.43 - 7.08 (m, 8H), 6.35 - 5.88 (m, 2H), 4.00 - 3.90 (m, 1H), 3.82 - 3.74 (m, 1H), 3.46 (s, 3H), 3.44 - 3.39 (m, 1H), 2.08 - 1.94 (m, 1H), 1.90 - 1.80 (m, 1H), 1.73 - 1.64 (m, 1H), 1.63 - 1.55 (m, 1H), 1.29 - 1.21 (m, 2H), 1.17 (d, J= 8.0 Hz, 3H), 1.03 - 0.89 (m, 2H), 0.80 - 0.73 (q, J= 4.5 Hz, 1H). Step 6: int-72-7 To a solution of int-72-6 (180.0 mg, 0.39 mmol) in 1,4-dioxane (1.8 mL) was added CDI (191.0 mg, 1.18 mmol) and DBU (0.18 ml, 1.18 mmol). The resulting mixture was stirred at 80 °C for 4 hrs. After cooling to room temperature, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (100 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-72-7 (160.0 mg, 0.31 mmol, 80.0% yield). LC-MS (ESI+): m / z 485.2 (M+H)+. Step 7: int-72 To a solution of int-72-7 (150 mg, 0.310 mmol) t-BuOKin THF (3.1 mL, 1 M in THF) was added water (6.0 mg, 0.33 mmol). The resulting mixture was stirred at 25 °C for 12 hrs. After completion, the reaction mixture was poured into cold-water (50 mL) and extracted with EtOAc (30 mL x 2). The aqueous phase was acidified by diluted HC1 solution (IM aqueous) to pH=4, extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (50 mL x 2), followed by brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford int-72 (120.0 mg, 0.30 mmol, 98.0% yield). LC-MS (ESI+): m / z 394.0 (M-H). ’H NMR (400 MHz, DMSO-t / 6) 5 12.51 (brs, 1H), 7.56 (s, 1H), 7.39 - 7.27 (m, 2H), 7.19 - 7.08 (m, 1H), 4.06 - 3.98 (m, 1H), 3.88 - 3.78 (m, 1H), 3.50 - 3.44 (m, 2H), 2.13-2 .03 (m, 1H), 1.98 - 1.86 (m, 2H), 1.82 - 1.71 (m, 1H), 1.65 - 1.49 (m, 1H), 1.41 - 1.37 (m, 1H), 1.35 - 1.29 (m, 1H), 1.25 - 1.22 (m, 2H), 1.03 - 0.97 (m, 1H), 0.87 - 0.82 (m, 1H). Example av: Synthesis of int-76 & int-77 ^s^MgCI Int-76 Int-76-3 lnt-77-1 Step 1: int-76-2 To a solution of int-76-1 (1.00 g, 3.72 mmol) in EtOH (10 mL) was added NaBH4 (422.0 mg, 11.15 mmol). The resulting mixture was stirred at 60 °C for 4 hrs. After cooling to room temperature, the mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (100 mL), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-76-2 (550.0 mg, 2.28 mmol, 61.4% yield). LC-MS (ESI+): m / z 241.2 (M+H)+. Step 2: int-76-3 To a solution of int-76-2 (500.0 mg, 2.07 mmol) in DCM (10 mL) was added carbon tetrabromide (894.0 mg, 2.70 mmol) and triphenylphosphane (707.0 mg, 2.70 mmol). The resulting mixture was degassed and purged with N2 for 3 times and stirred at 25 °C for 2 hrs. After completion, the reaction mixture concentrated and purified by column to afford int-76-3 (400.0 mg, 2.07 mmol, 63.4% yield). LC-MS (ESI+): m / z 303.0 (M+H)+. 1H NMR (400 MHz, DMSO-t / 6) 5 8.33 (s, 1H), 7.70 - 7.56 (m, 2H), 5.07 (s, 2H), 4.08 (s, 3H). Step 3: int-76 To a solution of int-76-3 (400.0 mg, 1.32 mmol) in THF (8 mL) was added allylmagnesium bromide (1.97 mL, 1 M in THF) dropwise at -60 °C under N2. The resulting mixture was stirred at -60 °C for 1 hr. After completion, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (100 mL), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-76 (200.0 mg, 0.75 mmol, 57.3% yield). LC-MS (ESI+): m / z 265.0 (M+H)+. ’H NMR (400 MHz, DMSO-A) 5 8.17 (s, 1H), 7.56 - 7.40 (m, 2H), 5.98 - 5.83 (m, 1H), 5.08 - 4.99 (m, 1H), 4.99 - 4.91 (m, 1H), 4.03 (s, 3H), 3.09 (t, J= 8.0 Hz, 2H), 2.42 - 2.30 (m, 2H). Step 1: int-77-1 To a solution of int-34-2 (2.00 g, 3.32 mmol) in dioxane (30 mL) and water (6 mL) were added potassium trifluoro(vinyl)borate (1.34 g, 9.97 mmol), CS2CO3 (3.25 g, 9.97 mmol) and l,l'-Bis (di-t-butylphosphino)ferrocene palladium dichloride (227.0 mg, 0.33 mmol). The resulting mixture was degassed and purged with N2 for 3 times and stirred at 100 °C for 2 hrs. After cooling to room temperature, the mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with water (100 mL), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-77-1 (1.2.0 g, 1.25 mmol, 37.6% yield). LC-MS (ESI+): m / z 480.2 (M+H)+. ’H NMR (400 MHz, DMSO-t / 6) 5 10.38 (s, 1H), 7.37 - 7.29 (m, 1H), 7.24 - 7.17 (m, 1H), 6.87 - 6.74 (m, 1H), 6.68 - 6.54 (m, 2H), 5.81 - 5.71 (m, 1H), 5.44 (d, J= 12.0 Hz, 1H), 5.28 - 5.05 (m, 1H), 3.63 - 3.42 (m, 2H), 2.23 (s, 3H), 1.42 (s, 9H), 1.37 - 1.30 (m, 1H), 1.23 - 1.15 (m, 3H), 1.04 - 0.91 (m, 2H), 0.90 - 0.76 (m, 1H). Step 2: int-77-2 To a mixture of int-77-1 (300.0 mg, 0.63 mmol) and int-76 (199.0 mg, 0.75 mmol) in NMP (3 mL) was added (IR^^-A'^-dimethylcyclohexane-l^-diamine (89.0 mg, 0.63 mmol), copper(I) iodide (119.0 mg, 0.63 mmol) and K2CO3 (259.0 mg, 1.88 mmol). The resulting mixture was degassed and purged with N2 for 3 times and stirred at 130 °C for 4 hrs. After cooling to room temperature, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (100 mL x 2), followed by brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography to afford int-77-2 (90.0 mg, 0.14 mmol, 21.7% yield). LC-MS (ESI+): m / z 664.3 (M+H)+. ’H NMR (400 MHz, DMSO-A) 5 8.22 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.48 - 7.38 (m, 1H), 7.30 - 7.20 (m, 1H), 7.14 - 6.96 (m, 2H), 6.95 - 6.89 (m, 1H), 6.88 - 6.77 (m, 1H), 5.83 (d, J= 16.0 Hz, 1H), 5.75 - 5.55 (m, 1H), 5.47 (d, J = 12.0 Hz, 1H), 5.40-5.10 (m, 1H), 5.00 - 4.72 (t, J = 13.1 Hz, 2H), 4.05 (s, 3H), 3.70 - 3.46 (m, 2H), 2.87 - 2.72 (m, 2H), 2.29 -2.13 (m, 5H), 1.43 (s, 9H), 1.38 - 1.33 (m, 1H), 1.28 (d, J = 8.0 Hz, 3H), 1.09 - 0.91 (m, 2H), 0.90 -0.80 (m, 1H). Step 3: int-77-3 To a solution of int-77-2 (140.0 mg, 0.211 mmol) in DCE (280 mL) was added Hoveyda-Grubbs 2nd reagent (52.0 mg, 0.084 mmol). The resulting mixture was degassed and purged with N2 for 3 times and stirred at 80 °C for 12 hrs. After cooling to room temperature, the reaction was concentrated and purified by pre-TLC to afford int-77-3 (120.0 mg, 0.19 mmol, 89.0% yield). LC-MS (ESI+): m / z 636.2 (M+H)+. ’H NMR (400 MHz, DMSO-t / 6) 5 8.44 - 8.37 (m, 1H), 7.67 - 7.57 (m, 1H), 7.50 - 7.31 (m, 2H), 7.01 - 6.69 (m, 3H), 6.49 (d, J= 12.0 Hz, 1H), 6.18 - 6.02 (m, 1H), 5.38 - 5.13 (m, 1H), 4.12 - 4.03 (m, 3H), 3.69 - 3.45 (m, 2H), 3.21 - 3.13 (m, 1H), 3.11 - 2.90 (m, 1H), 2.60 - 2.56 (m, 1H), 2.32 - 2.21 (m, 3H), 2.10 - 1.91 (m, 1H), 1.46 - 1.41 (m, 9H), 1.32 - 1.28 (m, 3H), 1.01 - 0.95 (m, 2H), 0.91 -0.85 (m, 2H). Step 4: int-77-4 To a solution of int-77-3 (120.0 mg, 0.19 mmol) in MeOH (5 mL) was added Pd / C (12.0 mg, 10% w / w). The resulting mixture was degassed and purged with H2 for 3 times and stirred at 20 °C for 2 hrs under H2 atomsphere (15 psi). After completion, the reaction mixture was filtered through a Celite pad and rinsed with MeOH (10 mL x 3). The filtrate was concentrated under reduced pressure to afford int-77-4 (120 mg, crude), which was used directly for the next step without purification. LC-MS (ESI+): m / z 638.3 (M+H)+. 1H NMR (400 MHz, DMSO-t / 6) 5 8.36 - 8.32 (m, 1H), 7.64 - 7.58 (m, 1H), 7.45 - 7.30 (m, 2H), 7.17 - 6.96 (m, 1H), 6.95 - 6.79 (m, 2H), 5.55 - 5.19 (m, 1H), 4.14 - 4.10 (m, 3H), 3.74 -3.55 (m, 2H), 3.10 - 2.94 (m, 2H), 2.93 - 2.81 (m, 2H), 2.33 - 2.29 (m, 3H), 1.95 - 1.80 (m, 2H), 1.53 - 1.49 (m, 9H), 1.46 - 1.42 (m, 2H), 1.39 - 1.32 (m, 3H), 1.11 - 1.02 (m, 2H), 1.00 - 0.83 (m, 2H). Step 5: int-77 A mixture of int-77-4 (100.0 mg, 0.157 mmol) in HC1 solution (2 mL, 4 M in dioxane) was stirred at 20 °C for 1 hr. After completion, the reaction solution was concentrated to give a residue, which was diluted with DCM (20 mL) and washed with saturated NaHCOs (aq., 20 mL). The organic layer was washed with brine 10 mL, dried over Na2SO4, filtered, concentrated and purified by pre-TLC (SiO2, DCM / MeOH=10 / l, v / v) to afford int-77 (80.0 mg, 0.15 mmol, 95.0% yield). LC-MS (ESI+): m / z 538.2 (M+H)+. ’H NMR (400 MHz, DMSO-t / 6) 5 8.31 - 8.24 (m, 1H), 7.59 - 7.49 (m, 1H), 7.34 - 7.15 (m, 2H), 6.93 (s, 1H), 6.85 - 6.69 (m, 2H), 4.12 - 4.00 (m, 4H), 3.13 - 2.91 (m, 2H), 2.89 - 2.74 (m, 2H), 2.74 - 2.67 (m, 2H), 2.28 - 2.20 (m, 3H), 1.89 - 1.68 (m, 2H), 1.30 - 1.19 (m, 6H), 0.89 - 0.79 (m, 3H). Example 1.1: Synthesis of Compound 1

[0287] To a suspension of int-l(l 1 mg, 0.03 mmol) and int-2 (22mg, crude) in THF (5 ml) was added T3P (13mg, 0.04 mmol, 50%) and TEA (12mg, 0.12mmol). The mixture was stirred at r.t. for Ihr. The mixture was diluted with water (2 ml), extracted with EtOAc (10 mL x 3). Combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by prep-HPLC to afford Compound 1(6 mg, 6.4 umol, 21.5% yield). LCMS: 931.5 [M+ H]+. ’HNMR (400 MHz, DMSO-< / 6, 80 °C) 3 11.92 (brs, 1H), 7.81 - 7.62 (m, 2H), 7.56 (td, J= 8.0, 4.0 Hz, 1H), 7.43 (d, J= 8.0 Hz, 1H), 7.38 - 7.36 (m, 1H),7.33 - 7.01 (m, 4H), 7.00 - 6.89 (m, 1H), 6.89 - 6.65 (m, 1H), 5.89 (s, 1H), 5.20 (brs, 1H), 4.39 - 4.01 (m, 5H), 3.92 - 3.88 (m, 2H), 3.42 - 3.38 (m, 2H), 3.15 (brs, 1H), 3.03 - 2.97 (m, 1H), 2.80 - 2.60 (m, 3H), 2.28- 2.25 (m, 3H), 2.21 - 1.97 (m, 2H), 1.92 - 1.83 (m, 2H), 1.74 - 1.60 (m, 6H), 1.31 - 1.16 (m, 5H), 1.11 - 1.04 (m, 2H).

[0288] The Compounds in Table a below were prepared in accordance with the synthetic sequence in Compound 1 using the corresponding starting materials. TABLE a Comp ound No. Starting material MW [M+H]+ & 'll NMR 2 int-1 & int-3 LCMS: 917.3 [M+H]+. ’HNMR (400 MHz, DMSO-A, 80 °C) <57.73 (d, J= 8.0 Hz, 1H), 7.61 (s, 2H), 7.49 (d, J= 8.0 Hz, 2H), 7.31 - 7.13 (m, 2H), 7.08 (dd, J= 4.0, 2.5 Hz, 1H), 6.83 - 6.51 (m, 3H), 5.57 (s, 1H), 4.67 - 4.14 (m, 5H), 3.98 (ddt, J= 12.0, 8.4, 4.1 Hz, 2H), 3.49 (td, J= 12.0, 4.7 Hz, 2H), 2.99 - 2.79 (m, 5H), 2.28 (d, J= 4.0 Hz, 3H), 1.84 - 1.68 (m, 6H), 1.45 (d, J= 8.0 Hz, 3H), 1.19 (dh, J= 12.0, 4.8 Hz, 2H), 1.13 - 1.05 (m, 2H). 3 int-1 & int-4 LCMS: 915.3 [M+H]+. 1HNMR (400 MHz, DMSO-< / 6, 80 °C) 5 7.72 - 7.37 (m, 6H), 7.21 - 7.06 (m, 3H), 6.92 - 6.84 (m, 1H), 6.55 (s, 1H), 5.71 - 5.53 (m, 1H), 5.39 - 5.19 (m, 1H), 4.44 - 4.20 (m, 1H), 4.14 1 4.03 (m, 2H), 4.02 - 3.94 (m, 2H), 3.82 - 3.58 (m, 1H), 3.55 - 3.43 (m, 2H), 2.97 - 2.92 (m, 1H), 2.88 - 2.81 (m, 2H), 2.77 - 2.70 (m, 2H), 2.31 - 2.18 (s, 4H), 2.08 - 1.92 (d, J= 16.9 Hz, 2H), 1.84 - 1.66 (m, 5H), 1.63 - 1.54 (m, 2H), 1.38 (d, J= 8.0 Hz, 3H), 1.22 -1.66 (s, 2H), 1.12- 1.08 (m, 2H). 4 int-1 & int-6 LCMS: 929.4 (M+H)+. ’HNMR (400 MHz, DMSO-< / 6, 80 °C) 5 11.91 (brs, 1H), 7.82 - 7.47 (m, 5H), 7.45 - 7.36 (m, 1H), 7.26 - 7.18 (m, 1H), 7.14 - 6.91 (m, 1H), 6.89 - 6.84 (m, 1H), 6.82 - 6.68 (m, 2H), 5.75 - 5.13 (m, 1H), 4.78 -4.27 (s, 1H), 4.22 - 3.94 (m, 5H), 3.53 - 3.44 (m, 3H), 2.94 - 2.91 (m, 1H), 2.90 - 2.78 (m, 3H), 2.68 - 2.57 (m, 2H), 2.30 (d, J = 8.0 Hz, 3H), 1.80 - 1.70 (m, 9H), 1.58 - 1.50 (m, 2H), 1.45 - 1.35 (m, 3H), 1.19 - 1.15 (m, 2H), 1.10 - 1.06 (m, 2H). 19-1 &21 int-7-P2 & int-20 Prep-HPLC(Column: YMC Triart Cl8, 20 *250mm, 5pm; Mobile Phase A: 0.1% FA, B: ACN; 15mL / min; gradient: 55-75%) was used to separate the two isomers. 19-1: retention time: 17 min. LCMS: 895.3 (M+H)+. ’HNMR (400 MHz, DMSO-A, 80 °C) 5 8.42 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.38 (s, 1H), 7.29 -7.10 (m, 4H), 6.69 (d, J= 8.0 Hz, 2H), 6.40 (s, 2H), 5.70 (s, 1H), 4.89 (d, J = 12.0 Hz, 1H), 4.76 (d, J = 8.0 Hz, 1H), 4.59 (t, J= 16.0 Hz, 1H), 4.43 (d, J= 12.0 Hz, 1H), 4.04 (s, 4H), 3.79 - 3.66 (m, 2H), 3.41 (s, 1H), 2.96 - 2.89 (m, 1H), 2.71 (s, 2H), 2.27 (s, 3H), 1.77 - 1.68 (m, 2H), 1.63 (s, 2H), 1.58 - 1.52 (m, 1H), 1.51 - 1.48 (m, 1H), 1.40 (s, 2H), 1.28 - 1.24 (m, 6H), 1.20 (s, 3H). 21: retention time: 20 min. LCMS: 895.4 (M+H)+.1HNMR (400 MHz, DMSO-db, 80 °C) 58.43 (s, 1H), 8.07 (d, J= 8.0 Hz, 1H), 7.50 - 7.37 (m, 1H), 7.35 -7.21 (m, 2H), 7.12 ((d, J = 4.0 Hz, 1H), 7.06 (d, J = 4.0 Hz, 1H), 6.77 - 6.57 (m, 2H), 6.56 - 6.46 (m, 1H), 6.39 (s, 1H), 5.87 - 5.52 (m, 1H), 4.95 - 4.89 (m, 1H), 4.77 (t, J= 8.0 Hz, 1H), 4.62 - 4.55 (m, 1H), 4.46 - 4.40 (m, 1H), 4.17 -3.97 (m, 4H), 3.70 (d, J = 8.0 Hz, 2H), 3.39 - 3.32 (m, 1H), 2.93 - 2.87 (m, Comp ound No. Starting material MW [M+H]+ & 'll NMR 1H), 2.75 - 2.61 (m, 2H), 2.28 (s, 3H), 1.75 - 1.66 (m, 1H), 1.65 - 1.56 (m, 4H), 1.47 - 1.37 (m, 4H), 1.30 - 1.22 (m, 6H), 1.19 (s, 3H). 20 -1&22 int-7-P2 & int-21 Prep-HPLC(Column: YMC Triart Cl8, 20 *250mm, 5pm; Mobile Phase A: 0.1% FA, B: ACN; 15mL / min; gradient: 50-70%) was used to separate the two isomers. 20-1: retention time: 15 min. LCMS: 881.4 (M+H)+. ’HNMR (400 MHz, DMSO4, 60 °C) 8 11.88 (brs, 1H), 8.42 (s, 1H), 8.12 (d, J= 4.0 Hz, 1H), 7.49 - 7.12 (m, 6H), 6.70 (d, J = 4.0 Hz, 2H), 6.62 - 6.20 (m, 2H), 5.82 - 4.96 (m, 1H), 4.93 - 4.73 (m, 2H), 4.69 - 4.57 (m, 1H), 4.52 - 4.38 (m, 1H), 4.25 - 3.92 (m, 4H), 3.79 - 3.62 (m, 2H), 3.50 - 3.35 (m, 1H), 2.97 - 2.88 (m, 1H), 2.87 -2.64 (m, 2H), 1.79 - 1.59 (m, 4H), 1.58 - 1.51 (m, 1H), 1.50 - 1.44 (m, 1H), 1.43 - 1.34 (m, 3H), 1.33 - 1.21 (m, 5H), 1.20 (s, 3H). 22: retention time: 18 min. LCMS: 881.3 (M+H)+.1HNMR (400 MHz, DMSO-db, 60 °C) 5 11.82 (brs, 1H), 8.43 (s, 1H), 8.08 (d, J= 8.0 Hz, 1H), 7.53 - 7.08 (m, 7H), 6.67 (d, J= 8.0 Hz, 1H), 6.64 - 6.50 (m, 1H), 6.40 (s, 1H), 5.81 - 5.57 (m, 1H), 4.99 - 4.89 (m, 1H), 4.80 (t, J= 8.0 Hz, 1H), 4.67 - 4.58 (m, 1H), 4.50 - 4.41 (m, 1H), 4.15 - 3.98 (m, 4H), 3.78 - 3.64 (m, 2H), 3.40 - 3.32 (m, 1H), 2.97 - 2.67 (m, 3H), 1.77 - 1.56 (m, 4H), 1.56 - 0.99 (m, 13H). 23 int-18 & int-24 LCMS: 905.0 (M+H)+. ’HNMR (400 MHz, DMSO-t / 6, 60 °C) 5 11.65 (brs, 1H), 8.29 (s, 1H), 7.63 - 7.48 (m, 2H), 7.45 - 7.36 (m, 1H), 7.34 - 7.19 (m, 2H), 6.98 - 6.80 (m, 3H), 6.76 - 6.54 (m, 2H), 5.77 - 5.56 (m 1H), 4.48 - 4.17 (m, 3H), 4.06 (s, 3H), 4.02 - 3.91 (m, 2H), 3.68 - 3.58 (m, 1H), 3.51 - 3.45 (m, 2H), 2.99 - 2.82 (m, 3H), 2.55 - 2.51 (m, 2H), 2.16 - 2.06 (m, 1H), 1.87 - 1.59 (m, 9H), 1.57 - 1.38 (m, 3H), 1.25 - 1.12 (m, 3H), 1.08 - 0.99 (m, 2H), 0.82 -0.70 (m, 2H). 24 &25 int-7-P2 & int-22 Prep-HPLC (Column: Welch Triart C18 250 *21.2 mm *10 pm; mobile phase: [water (0.1% FA) - ACN]; B%: 65%-85%) was used to separate the two isomers. 24: retention time: 18 min. LCMS: 893.4 (M+H)+. ’HNMR (500 MHz, DMSO-db, 60 °C) 8 11.87 (brs, 1H), 8.27 (s, 1H), 8.09 (d, J= 4.0 Hz,lH), 7.60 - 7.43 (m, 1H), 7.36 - 7.12 (m, 3H), 7.05 - 6.57 (m, 4H), 6.39 (s, 1H), 5.82 - 4.75 (m, 1H), 4.28 (s, 2H), 4.20 - 43.92 (m, 4H), 3.77 - 3.66 (m, 2H), 3.50 - 3.28 (s, 1H), 2.92 (t, J= 8.0 Hz, 2H), 2.75 - 2.68 (m, 1H), 2.26 (s, 3H), 2.07 - 1.94 (m, 1H), 1.80 - 1.66 (m, 4H), 1.65 - 1.59 (m, 2H), 1.58 - 1.52 (m, 1H), 1.51 - 1.43 (m, 2H), 1.41 -11.36 (m, 2H), 1.28 - 1.22 (m, 6H), 1.19 (s, 3H). 25: retention time: 21 min. LCMS: 893.4 (M+H)+. ’HNMR (400 MHz, DMSO-db, 60 °C) 5 8.30 (s, 1H), 8.10 (d, J= 8.0 Hz, 1H), 7.65 - 7.50 (m, 1H), 7.46 -7.09 (m, 3H), 6.94 - 6.53 (m, 4H), 6.41 (s, 1H), 5.80 - 5.60 (m, 1H), 4.44 - 4.31 (m, 1H), 4.30 - 4.20 (m, 1H), 4.17 - 4.00 (m, 4H), 3.79 - 3.60 (m, 3H), 3.42 -3.37 (m, 1H), 3.02 - 2.91 (m, 2H), 2.81 - 2.65 (m, 2H), 2.30 (s, 3H), 1.83 - 1.58 (m, 6H), 1.57 - 1.49 (m, 1H), 1.48 - 1.41 (m, 3H), 1.40 - 1.33 (m, 1H), 1.32 -1.23 (m, 5H), 1.20 (s, 3H). 26 &27 int-7-P2 & int-23 Prep-HPLC (column: Welch Triart C18 250*2.12 mm *10pm; mobile phase: [water (0.1% FA) - ACN]; B%: 60%-80%) was used to separate the two isomers. 26: retention time: 17 min. LCMS: 893.4 (M+H)+. ’HNMR (400 MHz, DMSO-db, 60 °C) 5 11.86 (brs, 1H), 8.18 (s, 1H), 8.12 (d, J= 8.0 Hz, 1H), 7.55-7.19 (m, 4H), 7.11 - 6.80 (m, 2H), 6.79 - 6.46 (m, 2H), 6.41 (s, 1H), 5.79 - 4.93 (m, 1H), 4.16 - 3.95 (m, 4H), 3.86 - 3.77 (m, 1H), 3.76 - 3.66 (m, 2H), 3.51 - 3.27 (m, 1H), 2.98 - 2.89 (m, 1H), 2.87 - 2.67 (m, 4H), 2.27 (s, 3H), 2.24 - 2.14 (m, 1H), 2.12 - 1.98 (m, 1H), 1.78 - 1.61 (m, 4H), 1.60 - 1.53 (m, 1H), 1.52 - 1.43 (m, 2H), 1.41 - 1.32 (m, 3H), 1.30 - 1.22 (m, 5H), 1.19 (s, 3H). Comp ound No. Starting material MW [M+H]+ & 'll NMR 27: retention time: 19 min. LCMS: 893.4 (M+H)+.1HNMR (400 MHz, DMSO-d6, 60 °C) 5 11.92 (brs, 1H), 8.20 (s, 1H), 8.07 (d, J= 8.0 Hz, 1H), 7.51 - 7.14 (m, 4H), 6.98 (dd, J= 8.0, 4.0 Hz, 1H), 6.85 - 6.56 (m, 3H), 6.38 (s, 1H), 5.67 (brs, 1H), 4.11 - 4.01 (m, 4H), 3.91 - 3.80 m, 1H), 3.76 - 3.63 (m, 2H), 3.41 -3.29 (m, 1H), 2.97 - 2.61 (m, 5H), 2.30 - 2.17 (m, 4H), 2.07 - 1.94 (m, 1H), 1.77 - 1.66 (m, 2H), 1.65 - 1.57 (m, 2H), 1.56 - 1.51 (m, 1H), 1.49 - 1.41 (m, 4H), 1.27 - 1.24 (m,6H), 1.18 (s, 3H). 28 Int-17 & int-77 LCMS: 931.3 (M+H)+. ’HNMR (500 MHz, DMSO-A, 60 °C) 5 11.79 (brs, 1H), 8.23 (s, 1H), 7.67 - 7.45 (m, 2H), 7.44 - 7.19 (m, 4H), 7.06 - 6.54 (m, 4H), 6.26 - 5.09 (m, 1H), 4.17 - 3.92 (m, 4H), 3.85 - 3.58 (m, 3H), 3.08 - 2.93 (m, 2H), 2.92 - 2.65 (m, 3H), 2.29 - 2.23 (m, 3H), 1.94 - 1.84 (m, 1H), 1.82 -1.67 (m, 5H), 1.66 - 1.46 (m, 6H), 1.45 - 1.33 (m, 3H), 1.30 - 1.22 (m, 6H), 1.21 - 1.14 (m, 5H), 0.99 - 0.88 (m, 1H). 29 &30 int-7-P2 & int-25 Prep-HPLC (column: Welch Triart C18 250*21.2 mm*10 pm; mobile phase: [water (0.1% FA) - ACN]; B%: 65%-85%) was used to separate the two isomers. 29: retention time: 17 min. LCMS: 893.4 (M+H)+. ’HNMR (500 MHz, DMSO-db, 60 °C) 5 11.94 (brs, 1H), 8.17 - 8.01 (m, 2H), 7.88 - 7.63 (m, 1H), 7.33 -7.25 (m, 1H), 7.12 - 6.87 (m, 2H), 6.87 - 6.50 (m, 3H), 6.47 - 6.29 (m, 2H), 5.83 - 4.74 (m, 1H), 4.29 (s, 3H), 4.21 - 3.87 (m, 2H), 3.85 - 3.76 (m, 1H), 3.73 (d, J= 8.0 Hz, 2H), 3.61 - 3.50 (m, 1H), 3.45 - 3.34 (m, 1H), 3.02 - 2.93 (m, 2H), 2.80 - 2.66 (m, 2H), 2.35 - 2.25 (m, 4H), 1.88 - 1.77 (m, 1H), 1.76 -1.70 (m, 2H), 1.64 (d, J= 9.2 Hz, 2H), 1.60 - 1.53 (m, 1H), 1.52 - 1.48 (m, 1H), 1.47 - 1.42 (m, 2H), 1.30 - 1.24 (m, 6H), 1.21 (s, 3H). 30: retention time: 20 min. LCMS: 893.4 (M+H)+. ’HNMR (500 MHz, DMSO-d6, 60 °C) 511.92 (brs, 1H), 8.17 - 8.02 (m, 2H), 7.88 - 7.62 (m, 1H), 7.32 -7.24 (m, 1H), 7.10 - 6.87 (m, 2H), 6.87 - 6.50 (m, 3H), 6.48 - 6.29 (m, 2H), 5.79 - 4.76 (m, 1H), 4.29 (s, 3H), 4.21 - 3.90 (m, 2H), 3.84 - 3.76 (m, 1H), 3.73 (d, J= 8.0 Hz, 2H), 3.62 - 3.48 (m, 1H), 3.45 - 3.32 (m, 1H), 3.03 - 2.92 (m, 2H), 2.80 - 2.65 (m, 2H), 2.35 - 2.22 (m, 4H), 1.88 - 1.78 (m, 1H), 1.77 -1.61 (m, 4H), 1.60 - 1.54 (m, 1H), 1.52 - 1.48 (m, 1H), 1.47 - 1.42 (m, 2H), 1.31 - 1.23 (m, 6H), 1.21 (s, 3H). 31 int-18 & int-22 LCMS: 879.3 (M+H)+. ’HNMR (500 MHz, DMSO-t / 6, 60 °C) 5 11.64 (brs, 1H), 8.29 (s, 1H), 7.63 - 7.47 (m, 2H), 7.46 - 7.36 (m, 1H), 7.35 - 7.18 (m, 3H), 7.06 - 6.59 (m, 4H), 5.80 - 5.46 (m, 1H), 4.53 - 4.19 (m, 3H), 4.06 (s, 3H), 4.01 - 3.92 (m, 2H), 3.77 - 3.55 (m, 1H), 3.51 - 3.43 (m, 2H), 3.01 - 2.80 (m, 3H), 2.31 - 2.25 (m, 3H), 1.87 - 1.40 (m, 13H), 1.31 - 1.10 (m, 4H). 33 int-17 & int-22 LCMS: 907.4 (M+H)+. ’HNMR (400 MHz, DMSO-t / 6, 60 °C) 5 11.65 (brs, 1H), 8.29 (s, 1H), 7.66 - 7.48 (m, 2H), 7.45 - 7.37 (m, 1H), 7.35 - 7.18 (m, 3H), 7.05 - 6.60 (m, 4H), 5.80 - 5.45 (m, 1H), 4.57 - 4.15 (m, 3H), 4.06 (s, 3H), 3.80 - 3.37 (m, 3H), 3.11 - 2.97 (m, 3H), 2.96 - 2.85 (m, 2H), 2.32 - 2.27 (m, 3H), 1.80 - 1.65 (m, 6H), 1.64 - 1.59 (m, 1H), 1.58 - 1.46 (m, 4H), 1.33 - 1.23 (m, 6H), 1.20 (s, 3H), 1.19 - 1.18 (m, 1H). 34 int-1 & int-22 LCMS: 865.4 (M+H)+. ’HNMR (400 MHz, DMSO-t / 6, 60 °C) 5 12.09 (brs, 1H), 8.33 (s, 1H), 7.65 - 7.44 (m, 3H), 7.38 - 7.17 (m, 3H), 7.02 (s, 1H), 6.92 - 6.48 (m, 3H), 5.68 - 4.71 (m, 1H), 4.39 - 4.24 (m, 2H), 4.07 (s, 3H), 3.98 (d, J= 8.0 Hz, 2H), 3.67 - 3.53 (m, 1H), 3.52 - 3.44 (m, 3H), 3.21 - 3.07 (m, 2H), 2.94 - 2.78 (m, 3H), 2.28 (s, 3H), 1.91 - 1.54 (m, 10H), 1.41 (s, 3H). 37 int-17 & int-26 LCMS: 853.4 (M+H)+. ’HNMR (400 MHz, DMSO-t / 6, 60 °C) 5 11.62 (s, 1H), 7.56 - 1 Al (m, 1H), 7.46 - 7.28 (m, 5H), 7.27 - 7.18 (m, 2H), 6.99 - 6.55 (m, 4H), 5.77 - 5.49 (m, 1H), 4.51 - 4.29 (m, 1H), 4.29 - 4.07 (m, 2H), 3.77 - 3.68 (m, 2H), 3.67 - 3.47 (m, 1H), 3.08 - 2.96 (m, 2H), 2.96 - 2.82 (m, 2H), 2.65 - Comp ound No. Starting material MW [M+H]+ & 'll NMR 2.54 (m, 1H), 2.30 - 2.26 (m, 3H), 1.89 - 1.75 (m, 1H), 1.73 - 1.64 (m, 4H), 1.63 - 1.58 (m, 2H), 1.57 - 1.54 (m, 1H), 1.53 - 1.44 (m, 3H), 1.33 - 1.22 (m, 5H), 1.20-1.10 (m, 5H). 42 Int-1 & int-40 LCMS: 863.2 (M+H)+. ’HNMR (400 MHz, DMSO-t / 6, 60 °C) 5 11.86 (brs, 1H), 8.17 (s, 1H), 7.69 - 7.59 (m, 1H), 7.51 - 7.44 (m, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.12 - 7.06 (m, 1H), 6.93 - 6.67 (m, 4H), 6.57 - 6.45 (m, 1H), 6.21 - 6.05(m, 1H), 5.83 - 5.18 (m, 1H), 5.02 (d, J= 16.0 Hz, 1H), 4.86 (d, J = 16.0 Hz, 1H), 4.52 - 4.21 (m, 1H), 4.07 (s, 3H), 3.97 (d, J = 8.0 Hz, 2H), 3.52 - 3.44 (m, 3H), 2.88 - 2.79 (m, 3H), 2.27 (s, 3H), 1.78 -1.72 (m, 6H), 1.51 - 1.45 (m, 1H), 1.41 - 1.35 (m, 3H), 1.20 - 1.17 (m, 1H). 43 int-18 & int-27 LCMS: 879.3 (M+H)+. ’HNMR (400 MHz, DMSO-t / 6, 60 °C) 5 11.52 (brs, 1H), 7.84 (brs, 1H), 7.66 (brs, 1H), 7.41 (s, 1H), 7.34 - 7.23 (m, 2H), 7.20 -7.10 (m, 2H), 7.05 - 6.86 (m, 1H), 6.85 - 6.71 (s, 1H), 6.66 - 6.24 (m, 2H), 5.65 - 5.28 (m, 1H), 4.40 - 4.12 (m, 1H), 3.98 - 3.91 (m, 2H), 3.89 (s, 3H), 3.84 (d, J= 8.0 Hz, 2H), 3.61 - 3.43 (m, 1H), 3.38 - 3.31 (m, 2H), 2.77 - 2.71 (m, 2H), 2.64 - 2.53 (m, 1H), 2.16 (s, 3H), 2.14 - 2.06 (m, 1H), 1.88 - 1.80 (m, 1H), 1.67- 1.55 (m, 6H), 1.54- 1.25 (m, 5H), 1.22- 1.14 (m, 1H), 1.100.90 (m, 3H). 44 int-18 & int-23 LCMS: 879.4 (M+H)+. ’HNMR (400 MHz, DMSO-t / 6, 60 °C) 511.50 (brs, 1H), 8.22 - 8.16 (m, 1H), 7.53 (brs, 1H), 7.47 - 7.36 (m, 3H), 7.35 - 7.29 (m, 1H), 7.28 - 7.20 (m, 1H), 7.08 - 6.97 (m, 1H), 6.94 - 6.62 (m, 3H), 5.73 - 5.56 (m, 1H), 4.47 - 4.23 (m, 1H), 4.10 - 4.03 (m, 4H), 3.97 (d, J= 8.0 Hz, 2H), 3.86 -3.79 (m, 1H), 3.64 - 3.59 (m, 1H), 3.51 - 3.44 (m, 2H), 2.90 - 2.78 (m, 4H), 2.53 - 2.51 (m, 1H), 2.28 (s, 3H), 2.24 - 2.15 (m, 1H), 2.08 - 1.95 (m, 1H), 1.81 - 1.58 (m, 7H), 1.55 - 1.39 (m, 3H), 1.23 - 1.08 (m, 3H). 45 int-17 & int-23 LCMS: 907.4 (M+H)+. ’HNMR (400 MHz, DMSO-t / 6, 60 °C) 5 8.20 (d, J = 4.0 Hz, 1H), 7.52 (brs, 1H), 7.47 - 7.37 (m, 3H), 7.36 - 7.28 (m, 1H), 7.27 -7.21 (m, 1H), 7.08 - 6.96 (m, 1H), 6.96 - 6.64 (m, 3H), 5.72 - 5.57 (m, 1H), 4.43 - 4.30 (m, 1H), 4.10 - 4.02 (m, 4H), 3.87 - 3.82 (m, 1H), 3.74 - 3.71 (m, 2H), 3.06 - 3.02 (m, 1H), 2.93 - 2.78 (m, 4H), 2.54 - 2.52 (m, 1H), 2.29 (s, 3H), 2.26 - 2.17 (m, 1H), 2.10 - 1.97 (m, 1H), 1.88 - 1.77 (m, 1H), 1.76 - 1.60 (m, 5H), 1.58 - 1.43 (m, 4H), 1.29 - 1.16 (m, 9H). 46 int-1 & int-23 LCMS: 865.3 (M+H)+. ’HNMR (400 MHz, DMSO-A, 60 °C) 58.19 (s, 1H), 7.53 - 7.47 (m, 2H), 7.45 - 7.35 (m, 2H), 7.34 - 7.28 (m, 1H), 7.25 - 7.20 (m, 1H), 7.08 - 6.98 (m, 1H), 6.92 - 6.57 (m, 3H), 5.75 - 5.40 (m, 1H), 4.59 - 4.28 (m, 1H), 4.10 - 4.01 (m, 4H), 4.01 - 3.95 (m, 2H), 3.86 - 3.77 (m, 1H), 3.52 -3.45 (m, 3H), 2.92 - .279 (m, 5H), 2.28 (s, 3H), 2.25 - 2.17 (m, 1H), 2.08 -1.99 (m, 1H), 1.81 - 1.71 (m, 6H), 1.69 - 1.45 (m, 2H), 1.44 - 1.36 (m, 3H). 48&49 int-19 & int-23 Prep-HPLC (column: Welch Triart C18 250*21.2 mm*10 pm; mobile phase: [water (0.1% FA) - ACN]; B%: 50%-70%) was used to separate the two isomers. 48: retention time: 17 min. LCMS: 865.3 (M+H)+.1HNMR (400 MHz, DMSO-de, 60 °C) 5 11.95 (brs, 1H), 8.23 - 8.11 (m, 2H), 7.48 - 7.26 (m, 4H), 7.10 -6.48 (m, 4H), 6.47 - 6.41 (m, 1H), 5.94 - 5.47 (m, 1H), 5.18 - 4.69 (m, 1H), 4.23 - 4.01 (m, 5H), 4.00 - 3.94 (m, 2H), 3.82 (brs, 1H), 3.48 (t, J = 12.0 Hz, 2H), 2.88 - 2.71 (m, 5H), 2.27 (s, 3H), ...

Claims

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof,wherein:N is heteroaryl;X1 is N and X2isC;or X1 is C and X2is N;Y1 is -C(=O)-, -C(Ra)2-, or -S(=O)2-;Ring A is heteroaryl optionally substituted with one or more RA;each Ra is independently halogen, hydroxy, oxo, SF5, alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein the alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with one or more RA1;each RA1 is independently halogen, hydroxy, oxo, alkyl or alkoxy;Y2 is -Y2a-Y2b-Y2c-'each of Y2a and Y2c is a bond or alkyl;Y2b is alkyl, SF5, haloalkyl or cycloalkyl, wherein the alkyl, haloalkyl and cycloalkyl are optionally substituted with one or more groups independently selected from alkyl, haloalkyl or cycloalkyl;T is -C(=O)O(Rb), -C(=O)N(Rb)-alkyl, -C(=0)N(Rb)C(=0)(Rb), -C(=0)N(Rb)-S(=O)(Rb), -C(=O)N(Rb)-S(=O)2(Rb), heterocyclyl or heteroaryl, wherein the alkyl, heterocyclyl and heteroaryl are optionally substituted with one or more RT;each Rx is independently halogen, hydroxyl, cyano, alkyl, SF5, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy or alkoxyalkyl;or two Rx taken together with the intervening atom(s) form a cycloalkyl or heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more Rxx;each Rxx is independently halogen, hydroxy, oxo, alkyl, SF5, haloalkyl, hydroxyalkyl, alkoxy or alkoxyalkyl;Q is cycloalkyl, aryl, heterocyclyl or heteroaryl, each optionally substituted with one or more RQ;Z1 is a bond, -N(RC)-, -N(Rc)-alkyl-, -N(RC)-C(=O)-, -N(RC)-C(=O)-N(RC)-, heterocyclyl, heteroaryl, heterocyclylalkyl or heteroarylalkyl, wherein the alkyl, heterocyclyl, heteroaryl, heterocyclylalkyl and heteroarylalkyl are optionally substituted with one or more groups independently selected from halogen, hydroxy, cyano, oxo, alkyl, haloalkyl, hydroxyalkyl, or alkoxy;Z2 is alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, each optionally substituted with one or more Rz;each Rt is independently halogen, hydroxy, oxo, alkyl, SF5, haloalkyl, hydroxy alkyl, alkoxy or alkoxyalkyl;each Rq is independently halogen, hydroxy, cyano, alkyl, SF5, haloalkyl, hydroxyalkyl, alkoxy or cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more groups independently selected from halogen, haloalkyl, or alkyl;each Rz is independently halogen, hydroxyl, cyano, oxo, alkyl, SF5, haloalkyl, alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, -N(Rd)2, -C(=0)N(Rd)2, -S(=O)(Rd), -S(=O)2(Rd), or -P(=O)(Rd)2, wherein the alkyl, alkoxyl, cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxy, oxo, alkyl or alkoxy;or two Rz together with the same atom to which they are both attached form a C2-C6 alkylidenyl optionally substituted with one or more groups independently selected from halogen, hydroxy, oxo, SF5, haloalkyl, alkyl or alkoxy;or one RT together with one RQ form a linking moiety L connecting T and Q;or one Rz together with one RQ form a linking moiety L connecting Z2 and Q;or one RT together with one Rx form a linking moiety L connecting T and Rx;each L is a bond or a linear C1-20 bivalent hydrocarbon chain optionally substituted with one or more Ry, wherein one or more methylene units of the chain are optionally and independently replaced by cycloalkyl, heterocyclyl, -C(RL)=C(RL)-, I ==   , -0-, -S-, -N(Rl)-, -C(=O)-, -00(=0)-, -0(=0)0-, -S(=0)-, -S(=0)2-, -N(Rl)C(=0)-, - C(=0)N(Rl)-, -N(Rl)S(=0)2-, or -S(=0)2N(Rl)-;each Rl is independently hydrogen, alkyl, or cycloalkyl;each Ry is independently halogen, oxo, cyano, nitro, -0Ryl, -0C(=0)Ryl, -0C(=0)0Ryl, -OC(=O)N(Ry2)2, -SRyl, -S(=O)Ryl, -S(=O)2Ryl, -S(=O)2N(Ry2)2, -S(=0)(=NRy2)Ryl, -N(Ry2)2, -NRy2C(=O)N(Ry2)2, -NRy2C(=0)Ryl, -NRy2C(=0)0Ryl, -NRy2S(=O)2Ryl, -N=S(=0)(Ryl)2, -C(=0)Ryl, -C(=0)0Ry2, -C(=O)N(Ry2)2, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, SF5, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl or heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl and heterocyclyl are optionally substituted with one or more Ry3;each Ryl is independently hydrogen, alkyl, SF5, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl, each optionally substituted with one or more Ry3;each Ry2 is independently hydrogen, alkyl, SF5, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -alkyl-cycloalkyl, or -alkyl-heterocyclyl, optionally substituted with one or more Ry3;or two Ry2 on the same atom are taken together with the atom to which they are attached to form a heterocyclyl optionally substituted with one or more Ry3; andeach Ry3 is independently halogen, cyano, hydroxy, oxo, -SF5, -SH, -S(=O)-alkyl, -S(=O)2-alkyl, -S(=O)2NH2, -S(=O)2NH-alkyl, -S(=O)2N(alkyl)2, -S(=O)(=N-alkyl)(alkyl), -NH2, -NH-alkyl, -N(alkyl)2, -N=S(=O)(alkyl)2, -C(=O)-alkyl, -C(=0)0H, -C(=O)O-alkyl, -C(=0)NH2, -C(=O)NH-alkyl, -C(=O)N(alkyl)2, -P(=O)(alkyl)2, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, heteroalkyl or cycloalkyl;each of Ra, Rb and Rc is independently hydrogen or alkyl;or two Ra taken together with the same atom to which they are attached form a cycloalkyl or heterocyclyl;each Rd is independently hydrogen, alkyl, or cycloalkyl;n is any integer of 0-6; andq is any integer of 1-3;provided that the compound comprises at least one linking moiety L.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Q is aryl optionally substituted with one or more RQ.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Q is phenyl optionally substituted with one or more RQ.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein T is heterocyclyl or heteroaryl, each optionally substituted with one or more RT.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein T is selected from oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, oxadiazolonyl, thiadiazolonyl, triazolyl, dihydrotriazolyl, or dihydro triazolonyl.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein one RT and one RQ form a linking moiety L connecting T and Q.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula selected from:z2 R3 Z1 Rai rQ2 R          / —\ R2       / r<m Y2 N HNS o Formula (A-l), z2 R3 Z1 rQi rQ2 A J \= / R1^A^n  )—[ \ r2    RQ5 rQ4 \ y2 n 'n-— 0 z2 R3 z1 RQ1 RQ2 R1      N )— / o       pQ5 / R2     R Y2 N                I N------------L HNY 0 Formula (A-2), z2 R3 Z1 R«1   R°2 QaXMzX r” r1^Y^n )— / R2     R°5 / Y2____-L ----- U NH 0Formula (A-3) or wherein:Formula (A-4),each of RQ1, RQ2, RQ3, RQ4 and RQ5 is independently hydrogen or RQ;or RQ1 and RQ2, RQ2 and RQ3, RQ3 and RQ4, or RQ4 and RQ5 together with the intervening atoms form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted with one or more group independently selected from halogen, hydroxy, cyano, alkyl, haloalkyl, hydroxylalkyl, alkoxy or cycloalkyl;each of R1, R2 and R3 is independently hydrogen or Rx.8.9.The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Q is aryl optionally substituted with one or more RQ, Z2 is aryl optionally substituted with one or more Rz, and one Rz and one RQ form a linking moiety L connecting Z2 and Q. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein thecompound is of formula selected from:Formula (B-l),Formula (B-2),Formula (B-3),Formula (B-4),Formula (B-5),Formula (B-6),Formula (B-8) orFormula (B-7),Formula (B-9), wherein:each of RQ1, RQ2, RQ3, RQ4 and RQ5 is independently hydrogen or RQ;each of RZ1, RZ2, RZ3, R24 and RZ5 is independently hydrogen or Rz;or RQ1 and RQ2, RQ2 and RQ3, RQ3 and RQ4, RQ4 and RQ5, RZ1 and RZ2, RZ2 and RZ3, RZ3 and R24, or R24 and R25 together with the intervening atoms form a cycloalkyl, aryl, heterocyclyl or heteroaryl, each optionally substituted with one or more group independently selected from halogen, hydroxy, alkyl, haloalkyl, alkoxy or cycloalkyl; andeach of R1, R2a, R2b and R3 is independently hydrogen or Rx.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R1 and R2a are taken together with the atoms they attached to form a cycloalkyl or heterocyclyl.

11. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R2a and R2b are taken together with the atom they attached to form a cycloalkyl or heterocyclyl.

12. The compound of claim 7 or 9, or a pharmaceutically acceptable salt thereof, wherein each of RQ1, RQ2, RQ3, RQ4 and RQ5 is independently hydrogen, halogen, alkyl or cycloalkyl.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein one Rt together with one Rx form a linking moiety L connecting T and Rx.

14. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein thecompound is of formula(C-l):z2 R3 zlY\ / L T N HM 0Formula (C-l), wherein R3 is hydrogen or Rx.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt H11__। 12__। 13__। 14__। 15___I,                                                ’, each of L11, L12, L13, L14, andL15 is independently selected from a bond, -S-, -C(=O)-, -0-, -NH-, -S(=O)2-, -S(=O)-, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, or heterocyclyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, or heterocyclyl are optionally substituted with one or more Ry.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein each of L11, L12, L13, L14, and L15 is independently selected from a bond, -S-, -C(=O)-, -0-, -NH-, -S(=O)2-, -S(=O)-, -CH2-, -CH2CH2-, -CH=CH-, I = I or , wherein -NH-, -CH2-, -CH2CH2-, -CH=CH-, or         are optionally substitutedwith one or more Ry.

17. The compound of any one of claims 7, 9, 14-16, or a pharmaceutically acceptable salt thereof, wherein L is -CH2CH2-#, -CH2CH2CH2-#, -CH2CH2CH2CH2-#, -CH2CH2C=CH-#, -CH2CH2O-#, -OCH2CH2-#, -NHCH2CH2-# or -CH2CH2NH-#, -CH2CH2CH2O-#, -OCH2CH2CH2-#, -CH2CH2CH2CH2O-#, -OCH2CH2CH2CH2-#, -OCH2CH2O-#, -OCH2CH2CH2O-#, -CH=CHCH20-#, -0CH2CH=CH-#, -CH2CH2CH2NH-#, -NHCH2CH2CH2-#, -CH2CH2OCH2CH2-#, -CH2CH2OCH2-#, -CH2-cyclobutyl-O-# or -CH2-cyclopropyl-O-#, wherein # end of L is connected to Q or Z2 or Rx.

18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Q is cycloalkyl or heterocyclyl, each are optionally substituted with one or more RQ.

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein Q o-\is                  .

20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Q is aryl substituted with one or more RQ, and one RQ is cycloalkyl substituted with one or more groups independently selected from halogen or haloalkyl.21.The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein Qis aryl substituted with one or more RQ, and one RQ is22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein q is2 or 3.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein Ring A is a bicyclic heteroaryl optionally substituted with one or more RA.

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, whereinRing A is selected from the group consisting of:„ each optionally substituted with one or more RA.

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein each RA is independently halogen, hydroxy, oxo, cycloalkyl or heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with one or more RA1.26.27.The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein each RA1 is independently oxo, alkyl or alkoxy.The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring o=sCZ^A is a bicyclic heteroaryl substituted with one or more RA, and one of RA is oor            ; or Ring A is a tricyclic or tetracyclic heteroaryl optionally substitutedwith one or more RA.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt29. The compound of any one of claims 1-28, or a pharmaceutically acceptable saltthereof, wherein Y1 is -C(=O)- or .

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein Y2 is alkyl or cycloalkyl optionally substituted with alkyl.

31. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein Y232. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein T is heterocyclyl or heteroaryl, each optionally substituted with one or more RT.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein each RT is independently oxo, halogen or alkyl.

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable saltthereof, wherein T is35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein n is 1 and Rx is Ci-6 alkyl.

36. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein n is 3, one Rx is Ci-6 alkyl and the other two Rx taken together with the same atom to which they are attached form a cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more Rxx.

37. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein n is 3, one Rx is Ci-6 alkyl and the other two Rx taken together with the adjacent atoms to which they are attached form a cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more Rxx.

38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, wherein Z1 is a bond, -N(RC)-, -N(RC)-C(=O)-, -N(RC)-C(=O)-N(RC)-, heterocyclyl, heteroaryl, heterocyclylalkyl or heteroarylalkyl, wherein the heterocyclyl or heteroaryl, heterocyclylalkyl or heteroarylalkyl are optionally substituted with one or more groups independently selected from halogen, hydroxy, oxo, alkyl or haloalkyl.

39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, wherein Z1 is selected from the group consisting of:are optionally substituted with one or more groups independently selected from halogen, hydroxy, oxo, alkyl or haloalkyl,pl is any integer of 1-3;p2 is any integer of 0-10;p3 is any integer of 0-10;Rza is hydrogen, Ci-6 alkyl, or (Ci-6 alkyl)carbonyl;Rzb and Rzc are independently hydrogen or Ci-6 alkyl; and * end of Z1 is connected to X2.

40. The compound of any one of claims 1-7 and 11-39, or a pharmaceutically acceptable salt thereof, wherein Z2 is aryl or heteroaryl, each optionally substituted with one or more Rz.

41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein Z242. The compound of any one of claims 1-7 and 11-39, or a pharmaceutically acceptable salt thereof, wherein Z2 is cycloalkyl or heterocyclyl, each optionally substituted with one or more Rz.

43. The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein Z2is or , each optionally substituted with one or more Rz.

44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein each Rz is independently halogen, alkyl, oxo, haloalkyl, -N(Rd)2, -C(=0)N(Rd)2, -S(=0)2(Rd), -P(=O)(Rd)2 or heterocyclyl optionally substituted with one or more groups independently selected from halogen, hydroxy, oxo, alkyl or alkoxy.

45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt X* .0thereof, wherein each Rz is independently          , methyl, oxo, -CHF2, -CH2F, -CF3, -CH2CH2OCH3, F, -NH(CH3), -C(=O)N(CH3)2, -S(=O)2(cyclopropyl) or -P(=O)(CH2CH3)2.

46. The compound of any one of claims 1-45, or a pharmaceutically acceptable saltthereof, wherein Z2 is selected from47. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any compound set forth in Table 1.1, Table 1.2, Table 2.1, Table 2.2 and Table 3.

48. A pharmaceutical composition comprising the compound of any one of claims 1-47, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

49. A method of treating or preventing a GLP-1 associated disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of claims 1-47 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 48.

50. The method of claim 49, wherein the GLP-1 associated disease or disorder is noninsulin-dependent diabetes mellitus (Type 2 diabetes), hyperglycemia, impairedglucose tolerance, insulin dependent diabetes mellitus (Type 1 diabetes), diabetic complication, obesity, hypertension, hyperlipidemia, arteriosclerosis, coronary heart disease, brain infarction, non-alcoholic steatohepatitis, Parkinson’s disease or dementia.