PRMT5 inhibitor compounds and uses thereof

Abstract

This application provides novel PRMT5 inhibitory compounds and / or MTA-cooperative PRMT5 inhibitory compounds, or pharmaceutically acceptable salts thereof. This application also provides pharmaceutical compositions containing one or more of these compounds or pharmaceutically acceptable salts thereof as active ingredients, and uses of these compounds or pharmaceutically acceptable salts thereof in the treatment of diseases or disorders, including cancer.

Description

[Technical Field]

[0001] This application relates to novel compounds or pharmaceutically acceptable salts thereof that are PRMT5 inhibitors, particularly MTA-cooperative PRMT5 inhibitors. This application also relates to pharmaceutical compositions containing the compounds or pharmaceutically acceptable salts thereof, and to the use of the compounds or pharmaceutically acceptable salts thereof in the treatment of diseases or disorders, including cancer. [Background technology]

[0002] Epigenetic modifications are important mediators that drive and maintain the malignant phenotype of tumors. Alterations in DNA methylation, histone acetylation and methylation, non-coding RNAs, and post-translational modifications are all epigenetic drivers of cancer development, independent of DNA sequence changes. Arginine methylation is a key post-translational modification that influences cell growth and proliferation, apoptosis, angiogenesis, and metastasis by regulating transcriptional and post-transcriptional RNA processing. The PRMT (protein arginine methyltransferase) family enzymes function as "writers" of PTMs (post-translational modifications) that catalyze methylation.

[0003] PRMT5 is a ω-N G -Monomethylarginine (MMA) and ω-N G , N G PRMT5 is a type II PRMT that catalyzes the modification of symmetric dimethylarginine (sDMA). This modification induces steric effects, altering the hydrogen-bonding interactions of the methylated side chain, further altering the molecular properties and function of the denatured protein. PRMT5 also forms a complex with MEP50 (methylosomal protein 50), which is required for substrate recognition and orientation, and is required for the histone 2A and histone 4 methyltransferase activity catalyzed by PRMT5.

[0004] The gene encoding methylthioadenosine phosphorylase (MTAP) is ubiquitously expressed in normal tissues. However, due to its proximity to CDKN2A, one of the most commonly deleted tumor suppressor genes, homozygous deletion of MTAP frequently occurs in cancer. For example, MTAP is deleted in 40% of glioblastomas, 25% of melanomas, urothelial carcinomas, and pancreatic adenocarcinomas, and 15% of non-small cell lung cancers (NSCLCs). MTAP is required for the methionine salvage pathway, and homozygous gene deletion leads to the accumulation of methylthioadenosine (MTA) in MTAP-deficient (MTAP-del) cells. The accumulation of MTA in cells due to MTAP deletion partially inhibits the methylation activity of PRMT5, further reducing the level of symmetric arginine dimethylation throughout the proteome, thus sensitizing cells to modulation of methylosome activity. Therapeutic targeting of PRMT5 in homozygous MTAP-deficient cancers represents a promising strategy for selectively killing genetically defined cancer cells. Therefore, inhibition of PRMT5 activity merits further investigation as a potential treatment for MTAP-deficient tumors. Summary of the Invention

[0005] In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt, or a deuterated derivative thereof, During the ceremony, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , and X 9 are each independently selected from C, CH, or N, with the proviso that X 8 and X 9 At least one of is N, each [ka] are independently a single bond or a double bond; Y is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, or —C(O)—, and cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally joined by one or more R a optionally replaced by R a is selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen, cyano, oxo, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and haloalkyl; R 1 is cycloalkyl, heterocyclyl, aryl, heteroaryl, or -N(R b )2, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are selected from one or more R c optionally replaced by Each R b are independently selected from the group consisting of hydrogen, deuterium, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of one or more R d optionally substituted with, or The Two R's b together with the nitrogen atom to which they are attached, one or more R c forming an optionally substituted heterocyclyl with Each R c is deuterium, cyano, halogen, hydroxyl, oxo, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and OR dwherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from oxo, cyano, halogen, hydroxyl, alkyl, or haloalkyl; R d is selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen, cyano, oxo, alkoxyl, alkyl, haloalkyl, haloalkoxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from deuterium, oxo, cyano, halogen, hydroxyl, alkoxyl, alkyl, haloalkyl, and haloalkoxyl; R 2 and R 3 are each independently selected from the group consisting of hydrogen, deuterium, cyano, halogen, hydroxyl, amino, oxo, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from cyano, halogen, hydroxyl, or amino; n is 0, 1, 2, or 3; i is 0, 1, 2, or 3.

[0006] In another aspect, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0007] In a further aspect, the present disclosure provides a method for inhibiting PRMT5 activity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.

[0008] In a further aspect, the present disclosure provides a method for treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. [Brief explanation of the drawings]

[0009] [Figure 1A] FIG. 1 shows the in vivo efficacy of exemplary compounds in the human colon cancer cell line HCT116 (MTAP KO). [Figure 1B] Same as above. [Figure 2A] FIG. 1 shows the in vivo efficacy of exemplary compounds in the human colon cancer cell line HCT116 (WT). [Figure 2B] Same as above. DETAILED DESCRIPTION OF THE INVENTION

[0010] Reference will now be made in detail to specific embodiments of the present disclosure. Examples of such embodiments are shown in the accompanying structures and formulas. While the present disclosure will be described in conjunction with the enumerated embodiments, it will be understood that these embodiments do not limit the disclosure to these embodiments. Rather, the present disclosure is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the present disclosure as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that can be used to practice the present disclosure. The present disclosure is in no way limited to the methods and materials described. In the event that one or more of the incorporated references and similar materials, including but not limited to defined terms, term usage, described techniques, etc., differ or contradict this application, the present disclosure shall control. All references, patents, and patent applications cited in this disclosure are incorporated herein by reference in their entirety.

[0011] It will be understood that certain features of the present disclosure, which are for clarity described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are for brevity described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. It should be noted that, as used in this specification and the appended claims, the singular forms "one," "one," and "the" include plural forms of the same unless the context clearly dictates otherwise. Thus, for example, reference to a "compound" includes a plurality of compounds.

[0012] definition The definition of specific functional groups and chemical terms will be explained in more detail below.For the purpose of this disclosure, chemical elements are identified according to the inside cover of the CAS Periodic Table of Elements (Handbook of Chemistry and Physics, 75th Edition), and specific functional groups are generally defined as described herein.In addition, the general principles of organic chemistry, and 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 which are incorporated herein by reference.

[0013] At various points in this disclosure, linking substituents are described. When a structure explicitly requires a linking group, the Markush variable listed for that group is understood to be the linking group. For example, when a structure requires a linking group and "alkyl" is listed in the Markush group definition for that variable, it is understood that "alkyl" represents a linking alkylene group.

[0014] Where a bond is shown as a dashed line, such bond may be absent or may be present in the form of a single bond.

[0015] 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 through which such substituent is bonded to the remainder of the compound of a given formula, then such substituent may be bonded through any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0016] In the components or formula of a compound, any variable (e.g., R i ) occurs more than one time, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, when a group consists of 0 to 2 R i When a group is shown to be substituted, the group may contain up to two R i R i Part and R i is R i Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0017] As used herein, "C i~j " denotes a range of carbon atoms, where i and j are integers, and the range of carbon atoms includes the endpoints (i.e., i and j) and each integer point therebetween, where j is greater than i. For example, C 1~6indicates a range of 1 to 6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. In some embodiments, "C 1~12 " refers to 1 to 12, specifically 1 to 10, specifically 1 to 8, specifically 1 to 6, specifically 1 to 5, specifically 1 to 4, specifically 1 to 3, or specifically 1 to 2 carbon atoms.

[0018] As used herein, the term "alkyl," whether used as part of another term or independently, means a saturated, straight- or branched-chain hydrocarbon radical that may be optionally substituted independently with one or more substituents described below. i~j "Alkyl" means an alkyl having i to j carbon atoms. In some embodiments, an alkyl group contains 1 to 12 carbon atoms. In some embodiments, an alkyl group contains 1 to 11 carbon atoms. In some embodiments, an alkyl group contains 1 to 10 carbon atoms. In some embodiments, an alkyl group contains 1 to 9 carbon atoms. In some embodiments, an alkyl group contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. "C 1~10 Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. 1~6 Examples of "alkyl" include methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, and the like.

[0019] Alkyl groups may be further substituted with substituents that independently replace one or more hydrogen atoms on one or more carbons of the alkyl group. Examples of such substituents include, but are not limited to, acyl, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, haloalkyl, haloalkoxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, nitro, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. The alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups described below may also be similarly substituted.

[0020] As used herein, the term "alkenyl," whether used as part of another term or independently, means a straight- or branched-chain hydrocarbon radical having at least one carbon-carbon double bond, which radical may be optionally substituted independently with one or more substituents described herein, including radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. In some embodiments, alkenyl groups contain 2-12 carbon atoms. In some embodiments, alkenyl groups contain 2-11 carbon atoms. In some embodiments, alkenyl groups contain 2-11 carbon atoms, 2-10 carbon atoms, 2-9 carbon atoms, 2-8 carbon atoms, 2-7 carbon atoms, 2-6 carbon atoms, 2-5 carbon atoms, 2-4 carbon atoms, 2-3 carbon atoms, and in some embodiments, alkenyl groups contain 2 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethylenyl (or vinyl), propenyl, butenyl, pentenyl, 1-methyl-2-buten-1-yl, 5-hexenyl, and the like.

[0021] As used herein, the term "alkynyl," whether used as part of another term or independently, refers to a straight- or branched-chain hydrocarbon radical having at least one carbon-carbon triple bond, which may be optionally and independently substituted with one or more substituents described herein. In some embodiments, alkynyl groups contain 2 to 12 carbon atoms. In some embodiments, alkynyl groups contain 2 to 11 carbon atoms. In some embodiments, alkynyl groups contain 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, alkynyl groups contain 2 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.

[0022] As used herein, the term "alkoxy" or "alkoxyl," whether used as part of another term or independently, refers to an alkyl group, as previously defined, attached to the parent molecule through an oxygen atom. i~j The term "alkoxyl" means the alkyl portion of the alkoxy group has i to j carbon atoms. In some embodiments, an alkoxyl group contains 1 to 12 carbon atoms. In some embodiments, an alkoxyl group contains 1 to 11 carbon atoms. In some embodiments, an alkoxyl group contains 1 to 10 carbon atoms. In some embodiments, an alkoxyl group contains 1 to 9 carbon atoms. In some embodiments, an alkoxyl group contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. "C 1~6 Examples of "alkoxyl" include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), t-butoxy, neopentoxy, n-hexoxy, and the like.

[0023] As used herein, the term "amino" means --NH.sub.2.

[0024] As used herein, the term "aryl," whether used as part of another term or independently, refers to monocyclic and polycyclic ring systems having a total of 5 to 20 ring members, wherein at least one ring in the ring system is aromatic, and each ring in the ring system contains 3 to 12 ring members. Examples of "aryl" include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like, which may bear one or more substituents. As used herein, the term "aryl" also includes groups in which an aromatic ring is fused to one or more additional rings. In polycyclic ring systems, only one of the rings need be aromatic (e.g., 2,3-dihydro-1H-indene), but all rings may be aromatic (e.g., naphthalene). The second ring may also be fused or bridged. Examples of polycyclic aryls include, but are not limited to, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, dihydroindene, and the like. Aryl groups may be substituted at one or more ring positions with the substituents described above.

[0025] As used herein, the term "cycloalkyl," whether used as part of another term or independently, refers to monovalent non-aromatic, saturated or partially unsaturated, monocyclic and polycyclic ring systems in which all ring atoms are carbon and contain at least three ring-forming carbon atoms. In some embodiments, cycloalkyls can contain 3 to 12 ring-forming carbon atoms, 3 to 11 ring-forming carbon atoms, 3 to 10 ring-forming carbon atoms, 3 to 9 ring-forming carbon atoms, 3 to 8 ring-forming carbon atoms, 3 to 7 ring-forming carbon atoms, 3 to 6 ring-forming carbon atoms, 3 to 5 ring-forming carbon atoms, 3 to 4 ring-forming carbon atoms, 4 to 12 ring-forming carbon atoms, 4 to 11 ring-forming carbon atoms, 4 to 10 ring-forming carbon atoms, 4 to 9 ring-forming carbon atoms, 4 to 8 ring-forming carbon atoms, 4 to 7 ring-forming carbon atoms, 4 to 6 ring-forming carbon atoms, or 4 to 5 ring-forming carbon atoms. Cycloalkyl groups can be saturated or partially unsaturated. Cycloalkyl groups can be substituted. In some embodiments, cycloalkyl groups can be saturated cyclic alkyl groups. In some embodiments, a cycloalkyl group can be a partially unsaturated cyclic alkyl group that includes at least one double or triple bond in its ring system.

[0026] In some embodiments, cycloalkyl groups can be monocyclic or polycyclic. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl.

[0027] In some embodiments, cycloalkyl groups may be saturated or partially unsaturated polycyclic (e.g., bicyclic and tricyclic) carbocyclic ring systems that can be arranged as fused, spiro, or bridged ring systems. As used herein, the term "fused ring" refers to a ring system in which two rings share two adjacent atoms, the term "spiro ring" refers to a ring system in which two rings are connected through a common single atom, and the term "bridged ring" refers to a ring system in which two rings share three or more atoms. Examples of fused cycloalkyls include, but are not limited to, decahydronaphthyl, icosahydrobenzopyrenyl, tetradecahydroanthracenyl, dodecahydroacenaphthyl, dodecahydrofluorenyl, and the like. Examples of spirocycloalkyls include, but are not limited to, spiro[5.5]undecanyl, spiro[3.6]decanyl, and the like. Examples of bridged cycloalkyls include, but are not limited to, bicyclo[1.1.1]pentenyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[3.3.3]undecanyl, adamantyl, and the like.

[0028] As used herein, the term "carboxyl" means --C(O)OH.

[0029] As used herein, the term "cyano" means --CN.

[0030] As used herein, the term "halogen" means an atom selected from fluorine (or fluoro), chlorine (or chloro), bromine (or bromo), and iodine (or iodo).

[0031] As used herein, the term "haloalkyl," whether used as part of another term or independently, refers to an alkyl group having one or more halogen substituents. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl (-CF), pentafluoroethyl (-CF), difluoromethyl (-CHF), trichloromethyl (-CCl), dichloromethyl (-CHCl), pentachloroethyl (-CCl), and the like.

[0032] As used herein, the term "haloalkoxy" or "haloalkoxyl" refers to a haloalkyl group, as previously defined, attached to the parent molecule through an oxygen atom. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy (-OCF), pentafluoroethoxy (-OCF), difluoromethoxy (-OCHF), trichloromethoxy (-OCCl), dichloromethoxy (-OCHCl), pentachloroethoxy (-OCCl), and the like.

[0033] As used herein, the term "heteroatom" means nitrogen (N), oxygen (O), sulfur (S), and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen (including N-oxide).

[0034] As used herein, the terms "heteroalkyl," "heteroalkenyl," or "heteroalkynyl," whether used as part of another term or independently, refer to an alkyl, alkenyl, or alkynyl group that contains one or more heteroatoms. Consequently, the term "hetero-C i~j alkyl," "hetero-C i~j alkenyl," or "hetero-C i~j "Alkynyl," whether used as part of another term or independently, refers to a C-alkynyl group containing one or more heteroatoms. i~j Alkyl, C i~j Alkenyl, or C i~j For example, the term "hetero-C1~6 "Alkyl" whether used as part of another term or independently means a C group containing one or more heteroatoms. 1~6 It means alkyl.

[0035] As used herein, the term "heteroaryl," whether used as part of another term or independently, refers to an aryl group having, in addition to carbon atoms, one or more heteroatoms, such as oxygen, sulfur, nitrogen, or phosphorus. Heteroaryl groups can be monocyclic. Examples of monocyclic heteroaryls include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl, and pteridinyl. Heteroaryl groups also include polycyclic groups. Examples of polycyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuranyl, dihydrobenzofuranyl, furopyridinyl, dihydrofuropyridinyl, benzo[1,3]dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, chromanyl, isochromanyl, pyrrolopyridine, dihydropyrrolopyridine, and the like.

[0036] As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated carbocyclyl group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, etc., and the remaining ring atoms are carbon, and one or more ring atoms may be independently optionally substituted with one or more substituents. In some embodiments, the heterocyclyl is a saturated heterocyclyl. In some embodiments, the heterocyclyl is a partially unsaturated heterocyclyl having one or more double or triple bonds in the ring system. In some embodiments, the heterocyclyl may contain any oxidized form of carbon, nitrogen, or sulfur, and any quaternized form of a basic nitrogen. The heterocyclyl radical may be carbon- or nitrogen-linked, where possible. In some embodiments, the heterocycle is carbon-linked. In some embodiments, the heterocycle is nitrogen-linked. For example, a group derived from pyrrolidine may be pyrrolidin-1-yl (nitrogen-linked) or pyrrolidin-3-yl (carbon-linked).

[0037] Heterocyclyl groups may be monocyclic. Examples of monocyclic heterocyclyls include, but are not limited to, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, pyrrolidinyl, and the like.

[0038] Heterocyclyl groups may be polycyclic, including fused, spiro, and bridged ring systems. Fused heterocyclyl groups include radicals in which a monocyclic heterocyclyl is fused with a saturated or partially unsaturated carbocyclic or heterocyclic ring. Examples of fused heterocyclyls include, but are not limited to, phenyl- or pyridinyl-fused rings such as decahydroquinolinyl, decahydroisoquinolinyl, decahydroquinoxalinyl, decahydroquinolidinyl, decahydroquinazolinyl, octahydroazaindolidinyl, decahydropteridinyl, octahydrochromenyl, and octahydroisochromenyl groups. Examples of spiroheterocyclyls include, but are not limited to, 5-aza-spiro[2.4]heptanyl, 6-aza-spiro[2.5]octanyl, 6-aza-spiro[3.4]octanyl, 2-oxa-6-aza-spiro[3.3]heptanyl, 2-oxa-6-aza-spiro[3.4]octanyl, 6-aza-spiro[3.5]nonanyl, 7-aza-spiro[3.5]nonanyl, 1-oxa-7-aza-spiro[3.5]nonanyl, etc. Examples of bridged heterocyclyls include, but are not limited to, 8-azabicyclo[3,2,1]octanyl, 1-azabicyclo[2,2,2]octanyl, 2-azabicyclo[2,2,1]heptanyl, 1,4-diazabicyclo[2,2,2]octanyl, etc.

[0039] As used herein, the term "hydroxyl" or "hydroxy" means --OH.

[0040] As used herein, the term "partially unsaturated" means a radical that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.

[0041] As used herein, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. It will be understood that the terms "substituted" or "substituted with" include the implicit proviso that such substitution is subject to the allowed valence of the substituted atom and that the substitution results in a stable or chemically feasible compound (e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, etc.). Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when multiple positions in any given structure may be substituted with multiple substituents selected from a specified group, the substituents may be the same or different at each position. Those of skill in the art will understand that the substituents themselves may also be substituted, where appropriate. Reference to a chemical moiety herein is understood to include substituted variants, unless expressly specified as "unsubstituted." For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0042] compound The present disclosure provides novel compounds or pharmaceutically acceptable salts thereof, synthetic methods for making the compounds, pharmaceutical compositions containing them, and various uses of the disclosed compounds.

[0043] In some embodiments, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt, or a deuterated derivative thereof, During the ceremony, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , and X 9are each independently selected from C, CH, or N, with the proviso that X 8 and X 9 At least one of is N, each [ka] are independently a single bond or a double bond; Y is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, or —C(O)—, and cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally joined by one or more R a optionally replaced by R a is selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen, cyano, oxo, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and haloalkyl; R 1 is cycloalkyl, heterocyclyl, aryl, heteroaryl, or -N(R b )2, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are selected from one or more R c optionally replaced by Each R b are independently selected from the group consisting of hydrogen, deuterium, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of one or more R d optionally substituted with, or The Two R's b together with the nitrogen atom to which they are attached, one or more R c forming an optionally substituted heterocyclyl with Each R cis deuterium, cyano, halogen, hydroxyl, oxo, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and OR d wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from oxo, cyano, halogen, hydroxyl, alkyl, or haloalkyl; R d is selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen, cyano, oxo, alkoxyl, alkyl, haloalkyl, haloalkoxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from oxo, cyano, halogen, hydroxyl, alkoxyl, alkyl, haloalkyl, and haloalkoxyl; R 2 and R 3 are each independently selected from the group consisting of hydrogen, deuterium, cyano, halogen, hydroxyl, amino, oxo, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from deuterium, cyano, halogen, hydroxyl, or amino; n is 0, 1, 2, or 3; i is 0, 1, 2, or 3.

[0044] In some embodiments, X 5 , X 6 , and X 7 One of them is N and the other two are C or CH.

[0045] In some embodiments, X 8is N and X 9 is C or CH.

[0046] In some embodiments, X 5 and X 7 is C or CH, and X 6 is N.

[0047] In some embodiments, X 5 and X 7 is C or CH, and X 6 is N and X 8 is N and X 9 is C or CH.

[0048] In some embodiments, [ka] Part [ka] is.

[0049] In some embodiments, X 5 and X 6 is C or CH, and X 7 is N.

[0050] In some embodiments, X 5 and X 6 is C or CH, and X 7 is N and X 8 is N and X 9 is C or CH.

[0051] In some embodiments, [ka] Part [ka] is.

[0052] In some embodiments, X 8 is C or CH, and X 9 is N.

[0053] In some embodiments, X 5 and X 7 is C or CH, and X 6 is N and X 8 is C or CH, and X 9 is N.

[0054] In some embodiments, [ka] Part [ka] is.

[0055] In some embodiments, X 5 and X 6 are C or CH, and X 7 is N and X 8 is C or CH, and X 9 is N.

[0056] In some embodiments, [ka] The part is [ka] is.

[0057] In some embodiments, X 5 is N and X 6 and X 7 is C or CH, and X 8 is C or CH, and X 9 is N.

[0058] In some embodiments, [ka] Part [ka] is.

[0059] In some embodiments, each R 2 are independently selected from hydrogen, cyano, halogen, amino, oxo, or alkyl, each of which is optionally substituted with one or more groups independently selected from cyano, halogen, or hydroxyl.

[0060] In some embodiments, R 2 is hydrogen.

[0061] In some embodiments, R 2 is alkyl. In certain embodiments, R 2 is C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, or C 1~3 In certain embodiments, R 2 is methyl.

[0062] In some embodiments, [ka] teeth, [ka] is selected from the group consisting of:

[0063] In some embodiments, X 1 , X 2 , X 3 , and X 4 is C or CH.

[0064] In some embodiments, X 1 is N and X 2 , X 3 , and X4 is C or CH.

[0065] In some embodiments, X 2 is N and X 1 , X 3 , and X 4 is C or CH.

[0066] In some embodiments, X 4 is N and X 1 , X 2 , and X 3 is C or CH.

[0067] In some embodiments, [ka] The part is [ka] is selected from the group consisting of:

[0068] In some embodiments, R 3 is hydrogen.

[0069] In some embodiments, R 3 is halogen. In certain embodiments, R 3 is F.

[0070] In some embodiments, Y is —C(O)—.

[0071] In some embodiments, Y is —C(O)— and R 1 -N(R b )2.

[0072] In some embodiments, Y is —C(O)— and R 1 -N(R b )2, and each R b are independently selected from hydrogen, deuterium, alkyl, or heteroaryl, and alkyl and heteroaryl are each independently selected from one or more Rd and each R d are independently selected from hydrogen, deuterium, hydroxyl, halogen, cyano, oxo, alkoxyl, alkyl, haloalkyl, haloalkoxyl, or heteroaryl, each of which is optionally substituted with one or more groups independently selected from oxo, cyano, halogen, hydroxyl, alkyl, alkoxyl, haloalkyl, or haloalkoxyl. In certain embodiments, each R b are hydrogen, deuterium, and C 1~6 alkyl, or 5- to 10-membered heteroaryl, and the alkyl and heteroaryl are each independently selected from one or more R d and each R d is hydrogen, deuterium, hydroxyl, halogen, cyano, oxo, C 1~6 Alkoxyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 haloalkoxyl, or 5- to 10-membered heteroaryl, each of which is independently selected from oxo, cyano, halogen, hydroxyl, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, or C 1~6 and optionally substituted with one or more groups independently selected from haloalkoxyl.

[0073] In certain embodiments, Y is —C(O)— and R 1 -N(R b )2, and each R b are independently selected from deuterium, alkyl, -alkyl-heteroaryl, heteroaryl, or -heteroaryl-heteroaryl, where alkyl and heteroaryl are optionally substituted with one or more groups independently selected from deuterium, hydroxyl, halogen, cyano, oxo, alkyl, alkoxyl, haloalkyl, or haloalkoxyl. In certain embodiments, each R b is deuterium, C 1~6 Alkyl, -C 1~6 Alkyl-(5-10 membered heteroaryl), C 5~10aryl, 5- to 10-membered heteroaryl, or -(5- to 10-membered heteroaryl)-(5- to 10-membered heteroaryl), wherein alkyl, aryl, and heteroaryl are independently selected from deuterium, hydroxyl, halogen, cyano, oxo, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, or C 1~6 In certain embodiments, the heteroaryl in the -alkyl-heteroaryl, heteroaryl, and -heteroaryl-heteroaryl is optionally substituted with one or more groups independently selected from: [ka] each of which is optionally substituted with one or more groups independently selected from deuterium, hydroxyl, halogen, cyano, oxo, alkyl, alkoxyl, haloalkyl, or haloalkoxyl. In certain embodiments, aryl is optionally substituted with one or more groups independently selected from deuterium, hydroxyl, halogen, cyano, oxo, alkyl, alkoxyl, haloalkyl, or haloalkoxyl. [ka] is.

[0074] In some embodiments, Y is —C(O)— and R 1 -N(R b )2, while R b is alkyl, and the other R b is -heteroaryl-heteroaryl, where the alkyl and heteroaryl are optionally substituted with one or more groups independently selected from deuterium, hydroxyl, halogen, cyano, oxo, alkyl, alkoxyl, haloalkyl, or haloalkoxyl. In certain embodiments, one R b is C 1~6 alkyl, and the other R bis -(5-10 membered heteroaryl)-(5-10 membered heteroaryl), where alkyl and heteroaryl are selected from the group consisting of deuterium, hydroxyl, halogen, cyano, oxo, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, or C 1~6 In certain embodiments, one R is optionally substituted with one or more groups independently selected from haloalkoxyl. b is methyl optionally substituted with one or more deuterium atoms, and the other R b teeth, [ka] is.

[0075] In some embodiments, Y is —C(O)— and R 1 -N(R b )2, and each R b is independently -alkyl-heteroaryl, wherein the alkyl and heteroaryl are optionally substituted with one or more groups independently selected from deuterium, hydroxyl, halogen, cyano, oxo, alkyl, alkoxyl, haloalkyl, or haloalkoxyl. In certain embodiments, each R b is independently -C 1~6 Alkyl-(5-10 membered heteroaryl), where alkyl and heteroaryl are substituted with deuterium, hydroxyl, halogen, cyano, oxo, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, or C 1~6 In certain embodiments, one R is optionally substituted with one or more groups independently selected from haloalkoxyl. b teeth [ka] and the other R b teeth [ka] is.

[0076] In some embodiments, Y is —C(O)— and R 1 -N(R b )2, while R b is alkyl, and the other R b is aryl or heteroaryl, wherein the alkyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from deuterium, hydroxyl, halogen, cyano, oxo, alkyl, alkoxyl, haloalkyl, or haloalkoxyl. In certain embodiments, one R b is C 1~6 alkyl, and the other R b is C 5~10 aryl or 5-10 membered heteroaryl, and alkyl, aryl, and heteroaryl are substituted with deuterium, hydroxyl, halogen, cyano, oxo, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, or C 1~6 and optionally substituted with one or more groups independently selected from haloalkoxyl.

[0077] In certain embodiments, Y is —C(O)— and R 1 -N(R b )2, while R b is methyl optionally substituted with one or more deuterium atoms, and the other R b teeth, [ka] [ka] is.

[0078] In some embodiments, Y is —C(O)— and R 1 -N(R b )2 and two R b together with the nitrogen atom to which they are attached, one or more R c In certain embodiments, two Rb together with the nitrogen atom to which they are attached, one or more R c In certain embodiments, two R b together with the nitrogen atom to which they are attached, one or more R c In certain embodiments, each R c are independently selected from alkyl or heteroaryl, each of which is optionally substituted with one or more groups independently selected from oxo, cyano, halogen, hydroxyl, alkyl, or haloalkyl. In certain embodiments, each R c is C 1~6 Alkyl or C 5~10 heteroaryl, each of which is independently selected from oxo, cyano, halogen, hydroxyl, C 1~6 Alkyl, or C 1~6 and optionally substituted with one or more groups independently selected from haloalkyl.

[0079] In certain embodiments, Y is —C(O)— and R 1 -N(R b )2 and two R b together with the nitrogen atoms to which they are attached, [ka] one or more R independently selected from the group consisting of c to form an optionally substituted piperidinyl.

[0080] In some embodiments, Y is heteroaryl optionally substituted with one or more groups independently selected from halogen, cyano, alkyl, alkenyl, or alkynyl. In certain embodiments, Y is heteroaryl optionally substituted with one or more groups independently selected from halogen, cyano, C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 and 5-10 membered heteroaryl optionally substituted with one or more groups independently selected from alkynyl.

[0081] In certain embodiments, Y is pyrazolyl optionally substituted with one or more groups independently selected from halogen, cyano, hydroxyl, or alkyl. In certain embodiments, Y is halogen, cyano, hydroxyl, or C 1~6 and pyrazolyl optionally substituted with one or more groups independently selected from alkyl.

[0082] In some embodiments, Y is [ka] is.

[0083] In some embodiments, R 1 is one or more R c In certain embodiments, R 1 is one or more R c C optionally substituted with 6~12 It is aryl.

[0084] In certain embodiments, R 1 is one or more R c and n is phenyl or naphthalinyl optionally substituted by

[0085] In certain embodiments, each R c is cyano, halogen, hydroxyl, alkyl, or OR d are independently selected from R d is selected from alkyl, haloalkyl, or cycloalkyl. In certain embodiments, each R c is cyano, halogen, hydroxyl, C 1~6 Alkyl, or OR d are independently selected from R d is C 1~6 Alkyl, C 1~6 Haloalkyl, or C 3~6 cycloalkyl.

[0086] Exemplary compounds of the present disclosure are shown below. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is.

[0087] The compounds provided herein are described with reference to both general formulas and specific compounds. Furthermore, the compounds of the present disclosure may exist in many different forms or derivatives, including, but not limited to, stereoisomers, racemic mixtures, positional isomers, tautomers, salts, prodrugs, soft drugs, active metabolic derivatives (active metabolites), solvated forms, different crystalline forms, or polymorphs, all of which are within the scope of the present disclosure.

[0088] The compounds of the present disclosure may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, for example, enantiomers and / or diastereomers.Therefore, the compounds of the present disclosure and their compositions may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers.In certain embodiments, the compounds of the present disclosure are enantiopure compounds.In certain embodiments, a mixture of enantiomers or diastereomers is provided.

[0089] The term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. The term "diastereomers" refers to a pair of optical isomers that are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities.

[0090] Additionally, certain compounds described herein may have one or more double bonds that can exist as Z or E isomers, unless otherwise specified. The present disclosure further encompasses the compounds as individual isomers substantially free of other isomers, or as mixtures of various isomers, e.g., racemic mixtures of enantiomers. In addition to the compounds themselves, the present disclosure also encompasses compositions comprising one or more compounds.

[0091] As used herein, the term "isomer" includes all geometric and stereoisomers. For example, "isomer" includes cis and trans isomers, E and Z isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures thereof, and other mixtures thereof as being within the scope of the present invention. For example, in some embodiments, a stereoisomer is provided substantially free of one or more of the corresponding stereoisomers, and may also be referred to as "stereochemically enriched."

[0092] When a particular enantiomer is preferred, it may be provided substantially free of the opposite enantiomer in some embodiments, sometimes referred to as "optically enriched." As used herein, "optically enriched" means that the compound contains a significantly higher proportion of one enantiomer. In certain embodiments, the compound is composed of at least about 90% by weight of the preferred enantiomer. In other embodiments, the compound is composed of at least about 95%, 98%, or 99% by weight of the preferred enantiomer. The preferred enantiomer may be isolated from a racemic mixture according to any method known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and chiral salt formation and crystallization, or may be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, SH et al., Tetrahedron 33:2725 (1977); Eliel, ELS Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972).

[0093] The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. The existence and concentration of isomeric forms may depend on the environment in which the compound is found, for example, whether the compound is a solid or an organic or aqueous solution. By way of example, proton tautomers (also called prototropic tautomers) include interconversions via migration of a proton, such as keto-enol, amide-imidic acid, lactam-lactim, imine-enamine isomerizations, and cyclic forms in which a proton can occupy more than one position on a heterocyclic ring system. Valence tautomers include interconversions via reorganization of some bonding electrons. Tautomers may be in equilibrium or sterically locked into one form by appropriate substitution. Compounds of the present disclosure identified by name or structure as a particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0094] As used herein, the term "prodrug" refers to a compound or its pharmaceutically acceptable salt that is metabolized under physiological conditions or converted by solvolysis to yield the desired active compound. Prodrugs include, but are not limited to, esters, amides, carbamates, carbonates, ureides, solvates, or hydrates of the active compound. Typically, prodrugs are inactive or less active than the active compound, but may offer one or more advantageous handling, administration, and / or metabolic properties. For example, some prodrugs are esters of the active compound, and the ester group is cleaved during metabolism to yield the active drug. Other prodrugs are enzymatically activated to yield the active compound or a compound that can be further chemically reacted to yield the active compound. Prodrugs may progress from the prodrug form to the active form in a single step, or they may have one or more intermediate forms that may themselves be active or inactive. The preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series, in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987; in Prodrugs: Challenges and Rewards, ed. V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag, J. Tilley, Springer-Verlag New York, 2007, the entire texts of which are incorporated herein by reference.

[0095] As used herein, the term "soft drug" refers to a compound that exerts a pharmacological effect but whose activity is limited in time due to its degradation into inactive metabolites. See, e.g., "Soft drugs: Principles and methods for the design of safe drugs," Nicholas Bodor, Medicinal Research Reviews, Vol. 4, No. 4, 449-469, 1984, the entire contents of which are incorporated herein by reference.

[0096] As used herein, the term "metabolite," e.g., active metabolite, overlaps with prodrug, as described above. Thus, such metabolites are compounds that are further metabolized into pharmacologically active compounds or derivatives thereof produced by metabolic processes in the subject's body. For example, such metabolites may be produced by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic degradation, etc. of administered compounds, salts, or prodrugs. Among these, active metabolites are such pharmacologically active derivative compounds. In the case of prodrugs, prodrug compounds are generally inactive or less active than metabolites. In the case of active metabolites, the parent compound may be an active compound or an inactive prodrug.

[0097] Prodrugs and active metabolites may be identified using routine techniques known in the art. See, for example, Bertolini et al., 1997, J Med Chem 40:2011-2016; Shan et al., J Pharm Sci 86:756-757; Bagshawe, 1995, Drug Dev Res 34:220-230.

[0098] As used herein, the term "active intermediate" means an intermediate compound in a synthetic process that exhibits the same or essentially the same biological activity as the compound that is ultimately synthesized.

[0099] The compounds of the present disclosure can be formulated as or in the form of pharmaceutically acceptable salts. Unless specified to the contrary, the compounds provided herein include pharmaceutically acceptable salts of such compounds.

[0100] As used herein, the term "pharmaceutically acceptable" indicates that a substance or composition is chemically and / or toxicologically compatible with the other ingredients that make up the formulation and / or the subject being treated therewith.

[0101] As used herein, the term "pharmaceutically acceptable salts," unless otherwise specified, includes salts that retain the biological effects of the free acids and bases of a particular compound and are not biologically or otherwise undesirable. Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono-, bis-, tris-, tetrakis-, etc. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate pharmacological use by modifying physical properties without preventing the compound from exerting its physiological effects. Useful physical property modifications include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate the administration of relatively high drug concentrations.

[0102] Pharmaceutically acceptable salts include acid addition salts such as sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, and quinate. Pharmaceutically acceptable salts are derived from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.

[0103] Pharmaceutically acceptable salts also include base addition salts containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamines, and zinc when an acidic functional group, such as a carboxylic acid or phenol, is present. See, for example, Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth, Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using the appropriate corresponding base.

[0104] Pharmaceutically acceptable salts can be prepared by standard techniques.For example, the free base form of the compound can be dissolved in a suitable solvent, such as aqueous or aqueous alcoholic solution containing a suitable acid, and then isolated by evaporating the solution.Therefore, when a particular compound is a base, the desired pharmaceutically acceptable salt can be prepared according to any suitable method available in the art.For example, this method is to treat the free base with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid (such as glucuronic acid or galacturonic acid), α-hydroxy acid (such as citric acid or tartaric acid), amino acid (such as aspartic acid or glutamic acid), aromatic acid (such as benzoic acid or cinnamic acid), sulfonic acid (such as p-toluenesulfonic acid or ethanesulfonic acid), etc.

[0105] Similarly, when a particular compound is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method.For example, the method is to treat the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, or an alkaline earth metal hydroxide.Examples of suitable salts include organic salts derived from amino acids such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines (such as hydroxyethylpyrrolidine, piperidine, morpholine, or piperazine), and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0106] It is also to be understood that the compounds of the present disclosure can exist in unsolvated forms, solvated forms (e.g., hydrated forms), and solid forms (e.g., crystalline or polymorphic forms), and that the present disclosure is intended to encompass all such forms.

[0107] As used herein, the term "solvate" or "solvate form" refers to a solvent addition form containing stoichiometric or non-stoichiometric amounts of solvent.Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate.When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate.A hydrate is formed by combining one or more water molecules with one molecule of a substance in which water maintains its molecular state as H2O.Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0108] As used herein, the terms "crystalline form," "crystalline form," "polymorphic form," and "polymorph" are used interchangeably and refer to crystalline structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all having the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors may result in one crystalline form predominating. Crystalline polymorphs of a compound can be prepared by crystallization under different conditions.

[0109] The compounds of the present disclosure also include all isotopic forms thereof. An "isotopic form" of a compound indicates that an atom in the compound is replaced by an isotope of such atom. Isotopes of an atom include atoms with the same atomic number but different mass numbers. Examples of isotopes that can be incorporated into the compounds of the present disclosure include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromide, or iodine ( 1 H, 2 H, 3 H, 11 C. 12 C. 13 C. 14 C. 14 N, 15 N, 16 O. 17 O. 18 O. 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 18 F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 124 I, 127 I, and 131In some embodiments, hydrogen in the compounds provided herein includes protium, deuterium, and tritium. In some embodiments, carbon in the compounds provided herein includes: 12 C and 13 Contains C.

[0110] Compound synthesis The synthesis of the compounds provided herein (including pharmaceutically acceptable salts thereof) is shown in the synthetic schemes in the Examples. The compounds provided herein can be prepared using any known organic synthesis technique and can be synthesized according to any of a number of possible synthetic routes. Therefore, these schemes are merely illustrative and do not limit other possible methods that can be used to prepare the compounds provided herein. Furthermore, the steps in the schemes are for better illustration and can be modified as needed. The compound embodiments in the Examples were synthesized for research purposes and, in some cases, for regulatory submission purposes.

[0111] The reaction for preparing the compounds of the present disclosure can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis.A suitable solvent can be one that does not substantially react with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out, for example, a temperature ranging from the freezing temperature of the solvent to the boiling temperature of the solvent.A given reaction can be carried out in one solvent or a mixture of two or more solvents.Depending on the specific reaction step, a suitable solvent for the specific reaction step can be selected by those skilled in the art.

[0112] The preparation of the compounds of the present disclosure may involve the protection and deprotection of various chemical groups.The need for protection and deprotection, and the selection of suitable protecting groups, can be easily determined by those skilled in the art.The chemical properties of protecting groups can be found, for example, in TW Greene and PG M Butts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), the entire contents of which are incorporated herein by reference.

[0113] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 The purity of the compound can be monitored by spectroscopic means such as infrared spectroscopy, spectrophotometer (e.g., UV-visible), mass spectrometry, or chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin-layer chromatography (TLC). Compounds can be purified by those skilled in the art according to a variety of methods, including high performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization," Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6(6), 874-883, the entire contents of which are incorporated herein by reference) and normal-phase silica chromatography.

[0114] The structures of the compounds in the examples are characterized by nuclear magnetic resonance (NMR) or / and liquid chromatography mass spectrometry (LC-MS). The NMR chemical shifts (δ) are 10 -6 It is given in (ppm). 1H-NMR spectra are recorded in CDCl3, CD3OD, or DMSO-d6 solutions (reported in ppm) on a Bruker instrument (400 MHz or 500 MHz) using tetramethylsilane (TMS) as the reference standard (0.0 ppm).

[0115] Reactions in this disclosure were typically carried out under a positive pressure of nitrogen or argon, or using drying tubes in anhydrous solvents, unless otherwise noted; reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven-dried and / or heat-dried.

[0116] Use of the compound In one aspect, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof that exhibit PRMT5 inhibitory activity.

[0117] As used herein, the term "PRMT5" refers to the protein arginine N-methyltransferase 5 (PRMT5) enzyme.

[0118] As used herein, the term "PRMT5 inhibitor" means any compound capable of inhibiting the production, level, activity, expression, or presence of PRMT5. The term "MTA-cooperative PRMT5 inhibitor" means any compound capable of inhibiting the production, level, activity, expression, or presence of PRMT5 in vitro or in vitro in cells with elevated MTA levels and in the presence of bound MTA.

[0119] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a PRMT5 inhibitor. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof has an IC of less than 5000 nM, less than 4000 nM, less than 3000 nM, less than 2000 nM, less than 1000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 150 nM, less than 120 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, or less than 20 nM when tested according to the assays described herein. 50 It exhibits PRMT5 inhibitory activity.

[0120] In some embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof has an IC50 or IC60 for inhibiting PRMT5 in the absence of bound MTA, e.g., in at least one assay (e.g., biochemical or cellular) described herein. 50 but IC for inhibiting PRMT5 in the presence of bound MTA 50 In some embodiments, the compound exhibits selective MTA-cooperative PRMT5 inhibitory activity that is at least 1000-fold higher, at least 500-fold higher, at least 400-fold higher, at least 300-fold higher, at least 200-fold higher, at least 100-fold higher, at least 90-fold higher, at least 80-fold higher, at least 70-fold higher, at least 60-fold higher, at least 50-fold higher, at least 40-fold higher, at least 30-fold higher, at least 20-fold higher, at least 10-fold higher, at least 5-fold higher, at least 2-fold higher, or at least 1.5-fold higher than

[0121] The compound of formula (I) or a pharmaceutically acceptable salt thereof is useful in a method for inhibiting PRMT5 in a cell through its PRMT5 inhibitory activity and / or MTA-cooperative PRMT5 inhibitory activity, the method comprising contacting the cell with an effective amount of a compound or composition described herein to inhibit PRMT5 in the cell. In certain embodiments, the cell is a cancer cell. In certain embodiments, the cancer is an MTAP-associated cancer. In certain embodiments, the method comprises administering an effective amount of a compound or composition described herein to a subject in need thereof.

[0122] In some embodiments, the compounds of formula (I) or pharmaceutically acceptable salts thereof are useful in therapy, for example, in the treatment of PRMT5-related diseases or disorders, including cancer.

[0123] As used herein, the term "therapy" is intended to have its ordinary meaning of addressing a disease in order to completely or partially alleviate one, some, or all of the symptoms of the disease, or to correct or rectify the underlying pathology. The term "therapy" also includes "prophylaxis" unless specifically indicated to the contrary. The terms "therapeutic" and "therapeutically" should be construed correspondingly.

[0124] As used herein, the term "prevention" is intended to have its ordinary meaning and includes primary prevention, to prevent the onset of disease, and secondary prevention, where the disease has already developed and the patient is temporarily or permanently protected from progression or worsening of the disease or the development of new symptoms associated with the disease.

[0125] The terms "treatment," "treat," or "treating" are used synonymously with "therapy." Similarly, the term "treat" can be considered as "applying therapy," as "therapy" is defined herein.

[0126] Thus, in one aspect there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.

[0127] In some embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a PRMT5-related disease or disorder.

[0128] As used herein, the term "PRMT5-associated disease or disorder" means any disease, disorder, or other condition in which PRMT5 is known to play a role.

[0129] In some embodiments, PRMT5-related disease or disorder is associated with MTAP deficiency and MTA accumulation.In some embodiments, disease or disorder is cancer.As used herein, the term "cancer" is intended to include both non-metastatic cancer and metastatic cancer.In this context, cancer treatment involves the treatment of both primary tumor and tumor metastasis.

[0130] In some embodiments, the cancer is a cardiac tumor, including sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; a lung cancer, including bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, and mesothelioma; a gastrointestinal cancer, including esophageal (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), and pancreatic (tubular adenocarcinoma, islet cell adenoma, glucagonoma, gastrinoma, carcinoid tumor, and VIP tumor). , small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), genitourinary cancers: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma), liver cancer: hepatoma (hepatocellular carcinoma)carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary tract cancer, gallbladder cancer, ampulla carcinoma, bile duct cancer, bone cancer, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoma Fibroma, osteoid and giant cell tumor, nervous system tumors, skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma), gynecological cancers, Uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), fallopian tube (cancer), blood cancer (myeloid leukemia (acute and chronic), acute myeloid leukemia), These include, but are not limited to, myeloproliferative disorders (myelodysplastic syndromes), myeloblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, and myelodysplastic syndromes (MDS), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), skin cancers such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles, dysplastic nevi, lipomas, hemangiomas, dermatofibromas, keloids, and psoriasis, and adrenal tumors such as neuroblastoma.

[0131] In some embodiments, the cancer is an MTAP-associated cancer. In some embodiments, the MTAP-associated cancer is liver cancer, breast cancer, skin cancer, bladder cancer, pancreatic cancer, or head and neck cancer.

[0132] In some embodiments, the liver cancer can be hepatocellular carcinoma (HCC) or malignant hepatocellular carcinoma.

[0133] In some embodiments, the breast cancer can be lobular carcinoma in situ (LCIS), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC), inflammatory breast cancer, Paget's disease of the nipple, phyllodes tumor, angiosarcoma, adenoid cystic carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma, mixed carcinoma, or other breast cancers, including but not limited to triple negative, HER positive, estrogen receptor positive, progesterone receptor positive, HER and estrogen receptor positive, HER and progesterone receptor positive, estrogen and progesterone receptor positive, and HER, estrogen and progesterone receptor positive.

[0134] In some embodiments, the skin cancer may be squamous cell carcinoma (SCO), keratoacanthoma (KA), melanoma, or basal cell carcinoma (BCC).

[0135] In some embodiments, the pancreatic cancer can be pancreatic adenocarcinoma.

[0136] In some embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

[0137] In some embodiments, provided is a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of a disease or disorder. In some embodiments, the disease or disorder is cancer.

[0138] In some embodiments, the compounds disclosed herein exhibit desirable metabolic stability, including hepatic metabolic stability (HMS) and hepatic microsomal metabolic stability (LMS). In some embodiments, the compounds disclosed herein exhibit desirable hepatic metabolic stability, with a half-life in mammalian (e.g., human, mouse, rat, dog, monkey) hepatocytes of 50 minutes or more, 75 minutes or more, 80 minutes or more, or 100 minutes or more. In some embodiments, the compounds disclosed herein exhibit desirable hepatic microsomal metabolic stability, with a half-life in mammalian (e.g., human, mouse, rat, dog, monkey) liver microsomes of 50 minutes or more, 75 minutes or more, 80 minutes or more, or 100 minutes or more.

[0139] In some embodiments, the compounds disclosed herein exhibit desirable gastrointestinal or intestinal absorption. In some embodiments, the compounds disclosed herein exhibit a 5×10 serotonin concentration or greater than 5×10 serotonin concentration, as measured by the Caco-2 model, as exemplified in the Examples. -8 cm / s and 5 × 10 -5 cm / s to 1×10 -6 cm / s and 5 × 10 -5 cm / s or 5 x 10 -6 cm / s and 2 × 10 -5 P between cm / s app (For example, P app(A-B) or P app(B-A) In some embodiments, the compounds disclosed herein exhibit an efflux ratio of about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 as measured by a Caco-2 model as exemplified in the Examples.

[0140] In some embodiments, the compounds disclosed herein exhibit desirable hERG potassium ion channel inhibitory activity. In some embodiments, the compounds disclosed herein exhibit IC 50 The compounds exhibit low hERG potassium ion channel inhibitory activity of 10 μM, 11 μM, 12 μM, 13 μM, 15 μM, or 20 μM or more.

[0141] In some embodiments, the compounds disclosed herein are brain-penetrable in vivo, ie, compounds of the present disclosure exhibit a brain-to-plasma concentration ratio (B / P) of greater than about 0.1, greater than about 0.15, greater than about 0.2, greater than about 0.25, greater than about 0.3, greater than about 0.35, greater than about 0.4, greater than about 0.45, or greater than about 0.5, as exemplified in the Examples.

[0142] In some embodiments, the compounds disclosed herein exhibit desirable pharmacokinetic properties, including drug exposure, clearance, plasma protein binding, etc. In some embodiments, the compounds disclosed herein exhibit high drug exposure, low clearance, and / or favorable unbound fraction.

[0143] Pharmaceutical Composition The present disclosure provides pharmaceutical compositions comprising one or more compounds of the present disclosure or pharmaceutically acceptable salts thereof.In some embodiments, the pharmaceutical compositions comprise one or more compounds of the present disclosure or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient.

[0144] As used herein, a "pharmaceutical composition" is a formulation containing a compound of the present disclosure in a form suitable for administration to a subject. In some embodiments, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form may be in any of a variety of forms, such as, for example, tablets, capsules, pills, powders, granules, sachets, cachets, lozenges, suspensions, emulsions, solutions, syrups, aerosols (as solid or liquid media), sprays, ointments, pastes, creams, lotions, gels, patches, inhalants, or suppositories. The amount of active ingredient (e.g., a formulation of the disclosed compound or its salt, hydrate, solvate, or isomer) in a unit dose composition is a therapeutically effective amount and varies depending on the specific treatment involved. Those skilled in the art will recognize that it may be necessary to routinely vary the dosage depending on the age and condition of the patient. The dosage also varies depending on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intraspinal, intranasal, etc. Dosage forms for topical or transdermal administration of a compound of the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In some embodiments, the compounds of the present disclosure are mixed under sterile conditions with a pharmaceutically acceptable excipient, and any required preservatives, buffers, or propellants.

[0145] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, and includes excipients that are acceptable for veterinary and human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable excipient" includes both one and more such excipients.

[0146] As used herein, the term "therapeutically effective amount" refers to the amount of a drug to treat, ameliorate, or prevent a particular disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. This effect can be detected according to any assay known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health, the nature and extent of the condition, and the treatment or combination of treatments selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0147] The pharmaceutical composition may be formulated to allow administration of a dosage of 0.01 to 1000 mg / kg body weight / day, e.g., 0.01 to 900 mg / kg body weight / day, 0.01 to 800 mg / kg body weight / day, 0.05 to 700 mg / kg body weight / day, 0.05 to 600 mg / kg body weight / day, 0.05 to 500 mg / kg body weight / day, 0.1 to 500 mg / kg body weight / day, 0.1 to 400 mg / kg body weight / day, 0.1 to 300 mg / kg body weight / day, 0.1 to 200 mg / kg body weight / day, 0.1 to 100 mg / kg body weight / day, 0.1 to 80 mg / kg body weight / day, 1 to 100 mg / kg body weight / day, or 1 to 80 mg / kg body weight / day of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In certain embodiments, this dose of compound can be administered once daily or divided into subdoses and administered in multiple doses (eg, two, three, or four times daily).

[0148] In some embodiments, the pharmaceutical composition comprises one or more compounds of the present disclosure or pharmaceutically acceptable salts thereof as a first active ingredient and further comprises a second active ingredient, which can be any anti-tumor agent known in the art, such as other anti-cancer agents, anti-tumor agents, anti-allergic agents, anti-emetic agents, analgesics, cytoprotective agents, and combinations thereof.

[0149] Thus, in some embodiments, a pharmaceutical composition is provided comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, and at least one additional anti-tumor agent. In some embodiments, there is one additional anti-tumor agent. In some embodiments, there are two additional anti-tumor agents. In some embodiments, there are three or more additional anti-tumor agents.

[0150] In some embodiments, the amount of additional anti-tumor agent present in the compositions of the present disclosure can be equal to or less than the amount normally administered in a composition comprising that anti-tumor agent as the only active agent, hi certain embodiments, the amount of additional anti-tumor agent in the compositions of the present disclosure is within the range of about 50% to 100% of the amount normally present in a composition comprising that anti-tumor agent as the only therapeutically active agent.

[0151] Thus, in another aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more anti-tumor agents listed above.

[0152] In some embodiments, the additional anti-tumor agent is selected from the group consisting of doxorubicin, irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, and bleomycin.

[0153] As used herein, the term "combined" refers to simultaneous, separate, or sequential administration. In some embodiments, "combined" refers to simultaneous administration. In some embodiments, "combined" refers to separate administration. In some embodiments, "combined" refers to sequential administration. When administration is sequential or separate, delaying the administration of the second component should not result in the beneficial effect of the combination being lost.

[0154] In a further aspect, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more anti-tumor agents listed above, in association with a pharmaceutically acceptable excipient.

[0155] In a further aspect, there is provided a kit comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more of the anti-tumor agents listed above.

[0156] In a further aspect, a kit is provided, comprising: (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof in a first unit dosage form; and (b) a second therapeutic agent, such as an anti-tumor agent, in a second unit dosage form; and (c) a container for containing the first and second unit dosage forms.

[0157] Treatment method In a further aspect, there is provided a method of utilizing the PRMT5 inhibitory activity and / or MTA-cooperative PRMT5 inhibitory activity of the compounds of the present disclosure to treat a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0158] In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer may be, for example, cardiac tumors, such as sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung cancers, such as bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, and mesothelioma; gastrointestinal cancers, such as esophageal (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreatic (tubular adenocarcinoma, islet cell adenoma, glucagonoma, gastrinoma, carcinoid tumor, VIP tumor). tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), genitourinary cancers: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma), liver cancer: hepatoma (hepatocellular carcinoma)carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary tract cancer, gallbladder cancer, ampulla carcinoma, bile duct cancer, bone cancer, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, carcinoma Bone myxofibroma, osteoid and giant cell tumor, nervous system tumors of the skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma), women Cancers of the uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), fallopian tube (cancer), and blood cancers (myeloid leukemia (acute myeloid leukemia)). Cancers include: acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes, Hodgkin's disease, non-Hodgkin's lymphoma, skin cancers including malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles, dysplastic nevi, lipomas, hemangiomas, dermatofibromas, keloids, psoriasis, and adrenal tumors including neuroblastoma.

[0159] In some embodiments, the cancer includes, for example, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, mantle cell lymphoma, gastrointestinal cancer, stomach cancer, vascular cancer, biliary tract cancer, pancreatic cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, melanoma, myeloma, oral cancer, ovarian cancer, small cell lung cancer, non-small cell lung cancer, myeloma, prostate cancer, bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, splenic cancer, glioblastoma, and head and neck squamous cell carcinoma.

[0160] In some embodiments, the cancer is head and neck squamous cell carcinoma, including, but not limited to, lip cancer, oral cavity cancer, oropharyngeal cancer, hypopharyngeal cancer, glottic laryngeal cancer, supraglottic laryngeal cancer, ethmoid sinus cancer, maxillary sinus cancer, and primary occult carcinoma.

[0161] In some embodiments, the cancer is a leukemia, including but not limited to lymphocytic leukemia, lymphocytic leukemia, chronic lymphocytic leukemia, small lymphocytic lymphoma, diffuse large B-cell lymphoma, acute myeloid leukemia, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, myeloid leukemia, granulocytic leukemia, polycythemia vera, erythrocytosis.

[0162] In some embodiments, the cancer is hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, or head and neck cancer. In some embodiments, the cancer is an MTAP-associated cancer.

[0163] In some embodiments, the cancer is metastatic cancer. In some embodiments, the metastatic cancer comprises central nervous system metastases. In some embodiments, the central nervous system metastases comprise brain metastases. In some embodiments, the central nervous system metastases comprise leptomeningeal metastases. "Liptomeningeal metastases" occur when cancer spreads to the meninges, which are layers of tissue that cover the brain and spinal cord. If metastases can spread to the meninges via the blood, they can also travel from brain metastases via cerebrospinal fluid (CSF) that flows through the meninges.

[0164] As used herein, the term "subject in need" refers to a subject who has a disease or disorder (e.g., cancer) or who is at increased risk of developing a disease or disorder (e.g., cancer) compared to the general population. In the case of cancer, the subject in need may be in a pre-cancerous condition. "Subject" includes warm-blooded animals. In some embodiments, the warm-blooded animal is a mammal, such as a human.

[0165] In this context, the term "therapeutically effective amount" refers to an amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof effective to provide "therapy" to a subject or to "treat" a disease or disorder in a subject. In the case of cancer, a therapeutically effective amount may cause any observable or measurable change in a subject, as described above in the definitions of "therapy," "treatment," and "prevention." For example, an effective amount may reduce the number of cancer or tumor cells, reduce overall tumor size, inhibit or stop tumor cell invasion into peripheral organs, including soft tissue and bone, inhibit and stop tumor metastasis, inhibit and stop tumor growth, alleviate to some extent one or more symptoms associated with cancer, reduce morbidity and mortality, improve quality of life, or a combination of these effects. In the case of cancer therapy, in vivo efficacy may be measured, for example, by assessing survival time, time to disease progression (TTP), response rate (RR), duration of response, and / or quality of life. As will be appreciated by those skilled in the art, the effective amount may vary depending on the route of administration, the use of excipients, and the use in combination with other drugs. For example, when a combination therapy is used, the amount of the compound of formula (I) or its pharmaceutically acceptable salt described herein and the amount of the other pharmaceutically active agent, when combined, are jointly effective to treat the target disease in an animal patient. In this context, the combined amount is a "therapeutically effective amount" if, when combined, it is sufficient to alleviate the symptoms of the above-mentioned disease or disorder.

[0166] In general, a "therapeutically effective amount" may be determined by one of skill in the art from, for example, the dosage ranges of the compounds of formula (I) or pharmaceutically acceptable salts thereof described herein and approved or published dosage ranges for other pharmaceutically active compounds.

[0167] The method for treating disease or disorder described herein can be used as monotherapy.As used herein, the term " monotherapy " means administering a single active compound or therapeutic compound to the subject who needs it.In some embodiments, monotherapy involves administering a therapeutically effective amount of one of the compounds of the present disclosure or its pharmaceutically acceptable salt to the subject who needs such treatment.

[0168] Depending on the specific disease or condition being treated, the methods for treating the diseases or disorders described herein involve administering the compounds of the present disclosure, as well as one or more additional therapies, such as conventional surgery, radiation therapy, chemotherapy, immunotherapy, or the combination of such additional therapies.As used herein, the term "combination therapy" refers to the combined administration of multiple active compounds.

[0169] Additional therapies, such as additional anti-tumor agents, may be administered separately from the compounds of the present disclosure, as part of a multiple dose regimen, or these additional therapies may be part of a single dosage form, mixed together with the compounds of the present disclosure in a single composition.

[0170] In some embodiments, compounds of the present disclosure may be administered simultaneously, sequentially, or separately from conventional surgical, radiotherapeutic, chemotherapy, or immunotherapeutic treatment.

[0171] Radiation therapy may include one or more of the following categories of treatment: (i) external beam radiation therapy with electromagnetic radiation and intraoperative radiation therapy with electromagnetic radiation; (ii) internal radiation therapy or brachytherapy, including interstitial or intracavitary radiation therapy; or (iii) whole body radiation therapy, including, but not limited to, iodine-131 and strontium-89.

[0172] Chemotherapy may include, for example, anti-neoplastic agents, anti-angiogenic agents, immunotherapies, efficacy enhancers, and the like, as known in the art.

[0173] Examples of antineoplastic agents include, but are not limited to, DNA alkylating agents (e.g., nitrogen mustards such as cisplatin, oxaliplatin, carboplatin, cyclophosphamide, ifosfamide, nitrosoureas such as bendamustine, melphalan, chlorambucil, busulfan, temozolamide, and carmustine), antimetabolites (e.g., fluoropyrimidines such as gemcitabine, 5-fluorouracil, and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea), antitumor antibiotics (e.g., anthracyclines such as adriamycin, bleomycin, doxorubicin, liposomal doxorubicin, pirarubicin, daunomycin, valrubicin, epirubicin, idarubicin, mitomycin, dactinomycin, amrubicin, and mithramycin), antimitotic ... These include anti-inflammatory drugs (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, taxoids such as taxol and taxotere, and polo kinase inhibitors), topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, irinotecan, topotecan, and camptothecin), inhibitors of DNA repair mechanisms such as CHK kinase, DNA-dependent protein kinase inhibitors, inhibitors of poly(ADP-ribose) polymerase (PARP inhibitors including olaparib, rucaparib, niraparib, talazoparib, pamiparib, and fluzoparib), Hsp90 inhibitors such as tanespimycin and letaspimycin, inhibitors of ATR kinase (e.g., AZD6738), and inhibitors of WEE1 kinase (e.g., AZD1775 / MK-1775).

[0174] Examples of anti-angiogenic agents include those that inhibit the effects of vascular endothelial growth factor, for example, but not limited to, the anti-vascular endothelial growth factor antibody bevacizumab, VEGF receptor tyrosine kinase inhibitors such as vandetanib (ZD6474), sorafenib, vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW786034), and cediranib (AZD2171), and the International Patent Application No. These include compounds such as those disclosed in applications WO97 / 22596, WO97 / 30035, WO97 / 32856, and WO98 / 13354, as well as compounds that act by other mechanisms (e.g., linomide, an inhibitor of integrin ανβ3 function, and angiostatin), or inhibitors of angiopoietin and its receptors (Tie-1 and Tie-2), PLGF inhibitors, and inhibitors of delta-like ligand (DLL-4).

[0175] Immunotherapy may include, for example, immune checkpoint modulators. Immune checkpoints are regulators of the immune system, belonging to the immune suppressive or immune stimulatory pathway, responsible for costimulatory or inhibitory interactions in T cell responses, and regulating and maintaining self-tolerance and physiological immune responses. Non-limiting immune inhibitory checkpoint molecules found in the immune inhibitory pathway may include, among others, LAG3 (CD223), A2AR, B7-H3 (CD276), B7-H4 (VTCN1), BTLA (CD272), BTLA, CD160, CTLA-4 (CD152), IDO1, IDO2, TDO, KIR, LAIR-1, NOX2, PD-1, PD-L1, PD-L2, TIM-3, VISTA, SIGLEC-7 (CD328), TIGIT, PVR (CD155), TGFβ, or SIGLEC9 (CD329). Non-limiting immune stimulatory checkpoint molecules found in immune stimulatory pathways can include, among others, CD2, CD3, CD7, CD16, CD27, CD30, CD70, CD83, CD28, CD80 (B7-1), CD86 (B7-2), CD40, CD40L (CD154), CD47, CD122, CD137, CD137L, OX40 (CD134), OX40L (CD252), NKG2C, 4-1BB, LIGHT, PVRIG, SLAMF7, HVEM, BAFFR, ICAM-1, 2B4, LFA-1, GITR, ICOS (CD278), or ICOSLG (CD275).

[0176] An example of an efficacy enhancer is leucovorin.

[0177] Thus, in one aspect, there is provided a method of treating a disease or disorder in a subject in need thereof, wherein a compound of Formula (I), Formula (Ia), Formula (Ia-1), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately, or sequentially with a second therapy. In some embodiments, the method comprises administering a therapeutically effective amount of the second therapeutic agent prior to, simultaneously with, or after administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0178] In some embodiments, the second therapy is chemotherapy or immunotherapy. In some embodiments, the second therapy is selected from the group consisting of chemotherapeutic agents, antitumor agents, radiation therapy agents, immunotherapy agents, antiangiogenic agents, targeted therapy agents, cell therapy agents, gene therapy agents, hormone therapy agents, antiviral agents, antibiotics, analgesics, antioxidants, metal chelators, and cytokines. In some embodiments, the second therapy is a BTK inhibitor, a BCR-ABL inhibitor, a JAK1 inhibitor, a JAK2 inhibitor, a JAK3 inhibitor, a PARP inhibitor, a MEK inhibitor, an ERK inhibitor, or a RAF inhibitor.

[0179] In some embodiments, the second therapy is selected from the group consisting of a platinating agent, an alkylating agent, an antibiotic, an antimetabolite, a topoisomerase inhibitor (e.g., a topoisomerase I inhibitor, a topoisomerase II inhibitor), a microtubule inhibitor, a hormonal agent, an anti-angiogenic agent, a differentiation inducer, a cell growth arrest inducer, an apoptosis inducer, a cytotoxic agent, and an immunotherapeutic agent.

[0180] In another aspect, there is provided a method of treating a disease or disorder in a subject in need thereof, wherein a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered simultaneously, separately, or sequentially with one or more additional anti-tumor agents.

[0181] In some embodiments, the disease or disorder is cancer. In certain embodiments, the amounts of the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the one or more additional anti-tumor agents are jointly effective to produce an anti-cancer effect. [Example]

[0182] The following examples are included for illustrative purposes. However, it should be understood that these examples do not limit the invention and are intended only to suggest a method of practicing the present disclosure. Those skilled in the art will recognize that the chemical reactions described can be readily adapted to prepare many other compounds of the present disclosure, and that alternative methods for preparing compounds of the present disclosure are considered to be within the scope of the present disclosure. For example, the synthesis of compounds of the present disclosure that are not exemplified may be successfully carried out by modifications obvious to one of skill in the art, such as appropriate protection of interfering groups, the use of other suitable reagents known in the art other than those described, and / or routine modification of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as adaptable to the preparation of other compounds of the present disclosure.

[0183] Abbreviation BPD: bis(pinacolato)diborane DCM: dichloromethane DEA: Diethylamine DIEA: Diisopropylethylamine DMA: Dimethylacetamide DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide DPPF: Bis(diphenylphosphino)ferrocene DPPP: 1,3-bis(diphenylphosphino)propane FA: Formic acid HATU: Hexafluorophosphate azabenzotriazole tetramethyl uronium IPA: Isopropyl alcohol MTBE: Methyl tert-butyl ether NaHMDS: sodium bis(trimethylsilyl)amide NBS: N-bromosuccinimide PE: Petroleum ether THF: tetrahydrofuran TEA: Triethylamine TFA: Trifluoroacetic acid

[0184] [Example 1] Synthesis of Compound 1 [ka]

[0185] Step 1: Synthesis of Compound 1-2 [ka] A mixture of compound 1-1 (5.00 g, 44.6 mmol) in SOCl (50 mL) was stirred at 80° C. for 12 hours. The reaction mixture was filtered, and the solid was collected and dried under reduced pressure to give compound 1-2 (4.70 g, 25.0 mmol, 56% yield).

[0186] Compound 1-2 1 H NMR: (400 MHz, DMSO-d) δ 8.87 (s, 2H), 8.24 (s, 2H).

[0187] Step 2: Synthesis of Compounds 1-4 [ka] To a solution of compound 1-3 (2.00 g, 10.5 mmol, 2 eq) in THF (10 mL) was added NaHMDS (1.00 M, 23.1 mL, 4.4 eq) at -10 °C. The mixture was stirred at -10 to 0 °C for 1 h. Next, a solution of compound 1-2 (990 mg, 5.26 mmol) in THF (15 mL) was added to the mixture, and the mixture was stirred at 25 °C for an additional 2 h. The pH of the reaction mixture was adjusted to 7 with AcOH. The resulting mixture was concentrated under reduced pressure to give a slurry. It was diluted with water (20 mL) and saturated NaHCO3 (30 mL). The mixture was filtered. The solid was washed with PE (20 mL) and dried to give crude compound 1-4 (1.00 g, 3.52 mmol, 33% yield). LCMS (M+H) + :283.8.

[0188] Compounds 1-4 1H NMR: (400 MHz, DMSO-d) δ 12.73 (brs, 1H), 9.49 (s, 1H), 8.07 (t, J = 8.8 Hz, 1H), 7.86-7.84 (m, 2H), 7.65-7.62 (m, 1H), 7.42 (d, J = 8.8 Hz, 1H).

[0189] Step 3: Synthesis of Compounds 1-5 [ka] To a solution of compound 1-4 (200 mg, 704 μmol) in DMA (10 mL) was added K2CO3 (195 mg, 1.41 mmol, 2.00 eq). The mixture was stirred at 140 °C for 10 hours under microwave irradiation. The reaction mixture was diluted with water (10 mL) and saturated NH4Cl (10 mL) and then filtered. The solid was washed with water (20 mL) and dried under reduced pressure to give compound 1-5 (50.0 mg, 189 μmol, 27% yield). LCMS (M+H) + :263.9. Compound 1-5 1 H NMR: (400 MHz, DMSO-d) δ 11.48 (brs, 1H), 9.06 (s, 1H), 8.15 (s, 1H), 7.87 (s, 1H), 7.46 (d, 2H).

[0190] Step 4: Synthesis of Compounds 1-6 [ka] A mixture of compound 1-5 (320 mg, 1.21 mmol) in POCl3 (5 mL) was stirred at 110 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give a slurry. It was carefully diluted with ice water (10 mL), and the pH of the mixture was adjusted to 7-8 with saturated NaHCO3. The resulting mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (15 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude compound 1-6 (300 mg). LCMS (M+H) + :281.8.

[0191] Step 5: Synthesis of Compounds 1-7 [ka] To a solution of compound 1-6 (200 mg) in 0.4 M NH3 / dioxane (6 mL) was added 4-methoxybenzylamine (PMBNH2) (486 mg, 3.54 mmol, 458 μL). The mixture was stirred at 120 °C for 3 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (15 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. It was purified by column chromatography (SiO2, PE / EtOAc = 100 / 1 to 1 / 1) to give pure compound 1-7 (100 mg, 261 μmol, 37% yield). LCMS (M+H) + :383.0.

[0192] Compounds 1-7 1 H NMR:(400MHz,CDCl3)δ8.56(s,1H),7.89(d,J=1.6Hz,1H),7.65(d,J=8.4Hz,2H) ,7.41-7.36(m,3H),6.93-6.91(m,2H),4.84(d,J=4.4Hz,2H),3.82(s,3H).

[0193] Step 6: Synthesis of Compounds 1-8 [ka] A mixture of compound 1-7 (80.0 mg, 209 μmol), BPD (79.5 mg, 313 μmol, 1.50 eq), Pd(dppf)Cl (15.3 mg, 20.9 μmol, 0.100 eq), and KOAc (87.8 mg, 626 μmol, 3.00 eq) in dioxane (2 mL) was degassed and purged with N three times. The mixture was stirred under N at 90 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give crude compound 1-8 (80.0 mg). LCMS (M+H) + :431.2.

[0194] Step 7: Synthesis of Compounds 1-10 [ka] A mixture of compound 1-8 (80.0 mg), compound 1-9 (70.1 mg, 186 μmol, synthesized according to a known method (J. Med. Chem., 2022, 65, 1749-1766)), cataCXium®A Pd G3 (CAS#1651823-59-4, 13.5 mg, 18.6 μmol), and KPO (118 mg, 558 μmol) in dioxane (2 mL) and HO (0.4 mL) was degassed and purged with N three times. The mixture was then stirred at 90 °C under a N atmosphere for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (15 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give the crude product. It was purified by preparative TLC (SiO2, PE:EA=1:1) to give pure compound 1-10 (50.0 mg, 90.3 μmol, 49% yield). LCMS (M+H) + :554.3.

[0195] Step 8: Synthesis of Compound 1 [ka] A mixture of compound 1-10 (25.0 mg, 45.2 μmol) in TFA (2 mL) was stirred at 110° C. for 5 hours under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in MeOH (5 mL). The pH of the solution was adjusted to 7-8 with solid KCO. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product. It was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm, 5 μm, mobile phase: [solvent A: 5 / 10000 ammonium hydroxide / water, solvent B: MeCN], gradient: 26-56% B, 9 min) to give compound 1 (5.03 mg, 11.3 μmol, 25% yield, 97% purity). LCMS (M+H) + :434.2.

[0196] Compound 1 1H NMR:(400MHz,CDCl3)δ8.53(s,1H),8.20-8.18(m,2H),7.98(d,J=8.8Hz,2H),7.9 1 (s, 1H), 7.71-7.64 (m, 3H), 7.40 (s, 1H), 7.14 (d, J = 7.6Hz, 1H), 3.86 (s, 3H).

[0197] [Example 2] Synthesis of Compound 2 [ka]

[0198] Step 1: Synthesis of Compound 2-1 [ka] A mixture of compound 1-8 (100 mg, 232 μmol), compound 2-1 (97.0 mg, 232 μmol, synthesized according to a known method (J. Med. Chem. 2022, 65, 1749-1766)), cataCXium®A Pd G3 (CAS#1651823-59-4, 16.9 mg, 23.2 μmol, 0.100 eq), and KPO (148 mg, 697 μmol, 3.00 eq) in dioxane (2.5 mL) and HO (0.5 mL) was degassed and purged with N three times. The mixture was stirred at 90 °C under a N atmosphere for 5 h. The residue was diluted with HO (20 mL) and extracted with DCM (20 mL × 2). The combined organic layer was washed with brine (15 mL), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (SiO, EtOAc) to give compound 2-2 (55.0 mg, 77.8 μmol, 34% yield, 84% purity) as a yellow solid. LC-MS (M+H) + :594.2.

[0199] Step 2: Synthesis of Compound 2 [ka] A mixture of compound 2-2 (45.0 mg, 75.8 μmol) in TFA (3 mL) was stirred at 100° C. for 2 hours under microwave irradiation. The mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm, 5 μm, mobile phase: [solvent A: 5 / 10000 ammonium hydroxide / water, solvent B: MeCN], gradient: 30-60% B, 9 min) to give compound 2 (10.66 mg, 22.0 μmol, 29% yield, 98% purity) as a white solid. LC-MS (M+H) + :474.1.

[0200] Compound 2 1 H NMR: (400 MHz, DMSO-d₆) δ 9.05 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.93 (s, 1H), 7.14 (s, 1H), 7.06 (d, J = 8.8 Hz, 1H), 4.21-4.17 (m, 1H), 3.74 (s, 3H), 0.94-0.88 (m, 2H), 0.81-0.78 (m, 2H).

[0201] [Example 3] Synthesis of Compound 3 [ka]

[0202] Step 1: Synthesis of compound 3-2 [ka] Similar to the synthesis of compound 1-4, compound 1-2 (990 mg, 5.26 mmol) was reacted with compound 3-1 (2.00 g, 10.52 mmol) to give compound 3-2 (1 g, 67% yield). LC-MS (M+H) + :283.8.

[0203] Compound 3-2 1H NMR:(400MHz,DMSO-d6)δ12.72(brs,1H),9.48(s,1H),8.08(t,J=8.8Hz,1H),7.85 (d,J=8.0Hz,2H),7.64(dd,J1=12.4Hz,J2=2.0Hz,1H),7.42(d,J=8.8Hz,1H).

[0204] Step 2: Synthesis of compound 3-3 [ka] Analogously to the synthesis of compound 1-5, compound 3-2 (800 mg, 2.82 mmol) was converted to compound 3-3 (400 mg, 1.21 mmol, 43% yield, 80% purity). LC-MS (M+H) + :263.9.

[0205] Compound 3-3 1 H NMR: (400 MHz, DMSO-d) δ 9.08 (s, 1H), 8.50 (s, 1H), 7.86 (s, 1H), 7.53 (dd, J = 8.4 Hz, J = 1.6 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H).

[0206] Step 3: Synthesis of Compound 3-4 [ka] Analogous to the synthesis of compound 1-6, compound 3-3 (400 mg, 1.51 mmol) was converted to compound 3-4 (400 mg, 1.19 mmol, 79% yield, 84% purity). LC-MS (M+H) + :281.8.

[0207] Step 4: Synthesis of Compounds 3-5 [ka] Analogous to the synthesis of compound 1-7, compound 3-4 (400 mg, 1.42 mmol) was converted to compound 3-5 (350 mg, 886 μmol, 63% yield, 97% purity). LC-MS (M+H) +:383.0.

[0208] Compounds 3-5 1 H NMR:(400MHz,DMSO-d6)δ9.12(s,1H),8.46(d,J=2.0Hz,1H),8.35(t,J=5.6Hz,1H),7.93(s,1H),7.49-7.46(m,1 H),7.40(d,J=8.8Hz,1H),7.33(d,J=8.8Hz,2H),6.88(d,J=8.8Hz,2H),4.68(d,J=5.6Hz,2H),3.71(s,3H).

[0209] Step 5: Synthesis of Compounds 3-6 [ka] To a solution of compound 3-5 (350 mg, 913 μmol) in DMF (5 mL) and MeOH (5 mL), Pd(OAc) (103 mg, 457 μmol, 0.500 eq), DPPF (253 mg, 457 μmol, 0.500 eq), and triethylamine (277 mg, 2.74 mmol, 381 μL, 3.00 eq) were added. The mixture was stirred at 80 °C under a CO atmosphere (50 psi) for 18 h. It was filtered, and the solid was washed with MeOH (20 mL). The combined filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL), and the resulting solution was washed with water (30 mL × 2). The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (SiO2, 100% PE to 2:1 PE / EtOAc) to give compound 3-6 (300 mg, 758 μmol, 83% yield, 92% purity). LC-MS (M+H) + :363.1.

[0210] Compounds 3-6 1H NMR:(DMSO-d6)δ8.69(brs,1H),8.49(s,1H),8.07(d,J=8.4Hz,1H),7.73(d,J=8.8Hz,1H),7.62-7. 45 (m, 1H), 7.38 (d, J = 8.4 Hz, 2 H), 6.92 (d, J = 8.4 Hz, 2 H), 4.87 (s, 2 H), 3.99 (s, 3 H), 3.82 (s, 3 H). Step 6: Synthesis of Compounds 3-7 [ka]

[0211] A mixture of compound 3-6 (250 mg, 688 μmol) in TFA (5 mL) was stirred at 110° C. for 2 hours under microwave conditions. The mixture was concentrated under reduced pressure to give crude compound 3-7 (160 mg) as a brown oil. LC-MS (M+H) + :243.1. Step 7: Synthesis of Compounds 3-8 [ka]

[0212] A mixture of compound 3-7 (160 mg, 660 μmol) and aqueous NaOH (1 M, 3.3 mL, 5.00 eq) in THF (5 mL) and MeOH (5 mL) was stirred at 70 °C for 3 h. The mixture was concentrated to remove the organic solvent. The aqueous solution was acidified with 1.0 M HCl to pH 6.0-7.0. The resulting suspension was filtered, and the solid was dried to give compound 3-8 (120 mg, 446 μmol, 68% yield, 85% purity). LC-MS (M+H) + :228.9. Step 8: Synthesis of Compounds 3-9 [ka]

[0213] A solution of compound 3-8 (50.0 mg) and SOCl (130 mg, 1.10 mmol, 79.5 μL) in toluene (2 mL) was stirred for 2 h at 110° C. The mixture was concentrated under reduced pressure to give crude compound 3-9 (50.0 mg) as a yellow solid, which was used directly in the next step. Step 9: Synthesis of Compound 3 [ka]

[0214] A mixture of compound 3-9 (50.0 mg, 203 μmol), compound 3-10 (45.8 mg, 162 μmol, synthesized according to a known method (WO2021163344A1)), and DIEA (82.9 μL, 476 μmol) in DCM (2 mL) was stirred at 25 °C for 1 h. The mixture was concentrated and purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm, 5 μm, mobile phase: [solvent A: 5 / 10000 ammonium hydroxide / water, solvent B: MeCN], gradient: 22 to 52% B, 9 min) to give compound 3 (14.95 mg, 29.3 μmol, 15% yield, 97% purity). LC-MS (M+H) + :493.2.

[0215] Compound 3 1 H NMR:(400MHz,DMSO-d6)δ9.14(s,1H),8.43(s,1H),8.79(t,J=5.2Hz,2H),8.38(s,1H),8.05-8.12(m,1H),7.91(s,1H),7.55 (t,J=2.0Hz,2H),7.48-7.38(m,4H),5.44-5.42(m,1H),4.92(t,J=17.2Hz,1H),4.(d,J=12.4Hz,1H),1.62(d,J=6.0Hz,3H).

[0216] [Example 4] Synthesis of Compound 4 [ka] A solution of compound 3-8 (20.0 mg, 87.6 μmol), the (2R,5S) homochiral compound 4-1 (21.4 mg, 87.6 μmol, synthesized according to a known method (WO2022026892A1)), HATU (50.0 mg, 131.5 μmol), and DIEA (34.0 mg, 263 μmol, 45.8 μL) in DMSO (1 mL) was degassed and purged with N three times. The mixture was stirred under N atmosphere at 25 °C for 2 h. The mixture was purified by preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm, 10 μm, mobile phase: [solvent A: water (0.1% FA), solvent B: MeCN], gradient: 14–44% B, 10 min). The fractions containing the product were concentrated. To the resulting residue was added saturated NaHCO3 (5 mL). The mixture was extracted with DCM (20 mL x 3). The combined organic layer was washed with water (15 mL) and then concentrated under reduced pressure to give compound 4 (21.88 mg, 47.5 μmol, 57% yield). LC-MS (M+H) + :455.2.

[0217] Compound 4 1 H NMR:(400MHz,DMSO-d6)δ10.07(s,1H),9.16(s,1H),8.24(s,1H),8.13(s,1H) ,7.44-7.34(m,4H),7.13(s,2H),6.89(d,J=8.8Hz,1H),5.38-5.31(m,1H),3.1 5-3.05(m,1H),2.90-2.60(m,2H),2.24-2.05(m,2H),1.85-1.78(m,1H),1.70- 1.65 (m, 1H), 1.37-1.26 (m, 2H), 1.21-1.13 (m, 2H), 1.00 (d, J = 6.0Hz, 3H).

[0218] Analytical chiral SFC (column: Chiralpak AS-3 50 × 4.6 mm, 3 m, mobile phase: [solvent A: CO2, solvent B: 3:1 IPA / MeCN with 0.05% DEA], gradient: isocratic 50% B, flow rate: 3 mL / min, column temperature: 35 °C, back pressure: 100 Bar).

[0219] Trans (2R, 5S) isomer: Rt = 1.174 min (92%).

[0220] Cis (2S,5S) isomer: Rt = 1.838 min (8%).

[0221] [Example 5] Synthesis of Compound 5 [ka]

[0222] Step 1: Synthesis of compound 5-2 [ka] A mixture of compound 5-1 (10.0 g, 43.5 mmol), BPD (16.6 g, 65.2 mmol, 1.50 eq), Pd(dppf)Cl2·CHCl2 (1.77 g, 2.17 mmol, 0.05 eq), and KOAc (12.8 g, 130 mmol, 3.00 eq) in dioxane (150 mL) was degassed and purged with N2 three times. The mixture was then stirred at 100 °C under a N2 atmosphere for 3 h. The reaction mixture was cooled and filtered. The solid was washed with DCM (50 mL). The combined filtrate was concentrated to give a semi-solid residue. This solid was triturated with DCM (30 × 2 mL) and dried to give crude compound 5-2 (7.00 g, 25.3 mmol, 58% yield) as an off-white solid. LC-MS (M+H) + :278.0.

[0223] Compound 5-2 1 H NMR: (400MHz, CDCl3) δ8.32(d,J=2.0Hz,1H),7.88(dd,J1=8.8Hz,J2=2.0Hz,1H),6.56(d,J=8.4Hz,1H),5.20(brs,2H),3.85(s,3H),1.35(s,12H).

[0224] Step 2: Synthesis of compound 5-4 [ka] A mixture of compound 5-2 (2.00 g, 7.22 mmol, 1.2 eq), compound 5-3 (1.68 g, 5.78 mmol), Na2CO3 (1.89 g, 17.9 mmol, 15.9 μL, 3 eq), and Pd(dppf)Cl2·CHCl2 (583 mg, 714 μmol, 0.12 eq) in dioxane (30 mL) and water (6 mL) was degassed and purged with N2 three times. The mixture was stirred at 90 °C under N2 atmosphere for 12 h. After cooling, the reaction mixture was filtered. The solid was washed with EtOAc (50 mL), and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, gradient: 100 / 1 PE / EtOAc to 100% EtOAc) to give compound 5-4 (800 mg, 3.68 mmol, 51% yield) as a yellow oil. LC-MS (M+H) + :218.0.

[0225] Compound 5-4 1 H NMR: (400 MHz, DMSO-d) δ 12.36 (brs, 1H), 8.03 (s, 1H), 7.79 (s, 1H), 7.60-7.58 (m, 1H), 7.55-7.52 (m, 1H), 7.16 (s, 2H), 6.70 (d, J=8.8 Hz, 1H), 3.76 (s, 3H).

[0226] Step 3: Synthesis of compounds 5-7 [ka] To a solution of compound 5-4 (800 mg, 3.68 mmol) and thiophosgene (424 mg, 3.68 mmol, 282 μL) in THF (3 mL) was added DIEA (2.38 g, 18.4 mmol, 3.21 mL, 5.00 eq) slowly at 0 °C. The mixture was warmed and stirred at 25 °C for 1 h. MeI (628 mg, 4.40 mmol, 275 μL, 1.20 eq) was added, and the mixture was stirred at 25 °C for an additional 1 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layer was washed with brine (15 mL × 2), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, PE:EA=1:1) to give compound 5-7 (200 mg, 732 μmol, 21% yield) as a brown solid. LC-MS (M+H) + :274.0.

[0227] Compounds 5-7 1 H NMR: (400 MHz, CDCl) δ 8.65 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 8.18-8.14 (m, 1H), 7.91 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 4.00 (s, 3H), 2.88 (s, 3H).

[0228] Step 4: Synthesis of Compounds 5-8 [ka] A solution of compound 5-7 (200 mg, 732 μmol) and 2,4-dimethoxybenzylamine (612 mg, 3.66 mmol, 550 μL, 5.00 eq) in dioxane (1 mL) was stirred under N at 120 °C for 1 h. The reaction mixture was diluted with EtOAc (10 mL) and washed with saturated NH Cl (30 mL). The organic layer was dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO , 100% EA) to give compound 5-8 (100 mg, 255 μmol, 35% yield) as a yellow solid. LC-MS (M+H) + :393.2.

[0229] Compounds 5-8 1 H NMR: (400 MHz, CDCl) δ 8.50-8.49 (m, 1H), 8.25 (s, 1H), 8.06-8.03 (m, 1H), 7.71 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 8.45-8.43 (m, 3H), 4.82 (s, 2H), 3.96 (s, 3H), 3.83 (s, 3H), 3.76 (s, 3H).

[0230] Step 5: Synthesis of Compounds 5-9 [ka] A solution of compound 5-8 (120 mg, 306 μmol) in TFA (2 mL) was stirred under N at 70° C. for 12 hours. The reaction mixture was concentrated to give crude compound 5-9 (100 mg) as a yellow solid. LC-MS (M+H) + :243.1.

[0231] Step 6: Synthesis of Compounds 5-10 [ka] To a solution of compound 5-9 (100 mg, 413 μmol) in THF (1 mL) and MeOH (1 mL) was added 1 M NaOH solution (1 mL). The mixture was stirred at 50 °C for 2 h and then concentrated. The residue was diluted with water (5 mL) and washed with EtOAc (10 mL × 2). The aqueous phase was acidified with 1 M HCl (pH = 5-6). The resulting suspension was filtered, and the solid was dried to give compound 5-10 (40 mg, 175 μmol, 42% yield) as a yellow solid. LC-MS (M+H) + :229.1.

[0232] Step 7: Synthesis of Compounds 5-11 [ka] To a solution of compound 5-10 (40 mg, 175 μmol) in toluene (2 mL) was added SOCl (130 mg, 876 μmol, 63.7 μL, 5 eq). The mixture was stirred under N at 100 °C for 2 h and then concentrated under reduced pressure to give crude compound 5-11 (40.0 mg) as a yellow solid, which was used in the next step without further purification.

[0233] Step 8: Synthesis of Compound 5 [ka] To a solution of compound 3-10 (45.8 mg, 162 μmol) in DCM (3 mL) was added dropwise DIEA (62.9 mg, 487 μmol, 84.7 μL) and compound 5-11 (40.0 mg) at 0°C. The mixture was warmed and stirred at 25°C under N2 for 0.5 h. The reaction mixture was concentrated to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm, 5 μm, mobile phase: [solvent A: 5 / 10000 ammonium hydroxide / water, B: MeCN], gradient: 25-55% B, 9 min) to give compound 5 (1.89 mg) as a white solid. LC-MS (M+H) + :493.2.

[0234] Compound 5 1 H NMR: (400 MHz, CDCl) δ 8.76-8.70 (m, 3H), 8.45 (s, 1H), 8.04 (s, 1H), 7.92-7.90 (m, 1H), 7.68-7.66 (m, 2H), 7.53-7.51 (m, 2H), 7.21 (t, J = 5.2 Hz, 1H), 5.45-5.44 (m, 1H), 5.12-5.08 (m, 1H), 4.28-4.70 (m, 1H), 1.65 (d, J = 6.4 Hz, 3H).

[0235] Analytical chiral SFC (column: Chiralcel OJ-3 50 × 4.6 mm, 3 μm, mobile phase [solvent A: CO2, solvent B: 0.05% DEA-EtOH], gradient elution: 5–40% B, flow rate: 3 mL / min, column temperature: 35 °C, back pressure: 100 Bar), Rt = 1.363 min (100% ee).

[0236] [Example 6] Synthesis of Compound 6 [ka] Similar to the 9-step synthesis of compound 3, compound 6 (1.93 mg, 98% purity) was obtained as a pale yellow solid. LC-MS (M+H) + :511.3.

[0237] Compound 6 1 H NMR: (400 MHz, CDCl) δ 8.78-8.69 (m, 3H), 8.51 (s, 1H), 8.08-8.07 (m, 1H), 7.92-7.90 (m, 1H), 7.72 (s, 1H), 7.62-7.60 (m, 1H), 7.38-7.36 (m, 1H), 7.21-7.19 (m, 1H), 5.39-5.24 (m, 3H), 4.58 (brs, 1H), 1.68 (d, J = 7.2 Hz, 3H).

[0238] Analytical chiral SFC (column: Chiralpak AD-3 50 × 4.6 mm, 3 m, mobile phase [solvent A: CO; solvent B: 3:1 IPA / MeCN with 0.05% DEA], gradient: isocratic 60% B, flow rate: 3 mL / min, column temperature: 35 °C, back pressure: 100 Bar). Rt = 0.979 min (100% ee).

[0239] [Example 7] Synthesis of Compounds 7, 8, and 9 [ka]

[0240] Step 1: Synthesis of compounds 7-1, 8-1, and 9-1 [ka] To a solution of the TFA salt of 3-7 (500 mg) in DMF (20 mL) was added NBS (255 mg) at 0° C. The mixture was stirred at 0° C. for 2 h. Additional NBS (31.9 mg) was added, and the mixture was stirred at 25° C. for an additional 1 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (150 mL × 3). The combined organic layers were concentrated under reduced pressure. The resulting residue was triturated with DCM (100 mL) and then filtered. The yellow solid was recovered as a mixture of compounds 7-1, 8-1, and 9-1 (400 mg).

[0241] LC-MS of the mixture:

[0242] Compounds 7-1 and 8-1 (M+H) + :321.0.

[0243] Compound 9-1(M+H) + :398.9.

[0244] Step 2: Synthesis of compounds 7-2, 8-2, and 9-2 [ka] A solution of compounds 7-1, 8-1, and 9-1 (350 mg), 3.5 M trimethylboroxine, Cs2CO3 (1.07 g, 3.27 mmol), and Pd(PPh3)2Cl2 (76.5 mg, 109 mmol) in THF (3.11 mL) in dioxane (15 mL) and water (3 mL) was degassed and purged with N2 three times. The mixture was heated at 120 °C for 4 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was triturated with DCM (20 mL) and then filtered. The yellow solid was recovered as a mixture of compounds 7-2, 8-2, and 9-2 (250 mg).

[0245] LC-MS of the mixture:

[0246] Compounds 7-2 and 8-2 (M+H) + :257.1.

[0247] Compound 9-2(M+H) + :271.1.

[0248] Step 3: Synthesis of compounds 7-3, 8-3, and 9-3 [ka] A mixture of compounds 7-2, 8-2, and 9-2 (200 mg) and a solution of 1 M NaOH (3.90 mL) in THF (5 mL) and MeOH (5 mL) was stirred at 70 °C for 2 h. The mixture was concentrated. The residue was diluted with water (10 mL) and washed with EtOAc (10 mL × 2). The pH of the aqueous layer was adjusted to 6. The resulting suspension was filtered, and a brown solid was recovered as a mixture of compounds 7-3, 8-3, and 9-3 (130 mg).

[0249] LC-MS of the mixture:

[0250] Compounds 7-3 and 8-3 (M+H) + :243.0.

[0251] Compound 9-3(M+H) + :257.0.

[0252] Step 4: Synthesis of compounds 7-4, 8-4, and 9-4 [ka] A mixture of compounds 7-3, 8-3, and 9-3 (145 mg) and a solution of SOCl (356 mg, 2.99 mmol, 217 μL) in toluene (5 mL) was stirred at 110° C. for 2 h. The mixture was concentrated to give a mixture of compounds 7-4, 8-4, and 9-4 (150 mg) as a yellow solid, which was used directly in the next step.

[0253] Step 5: Synthesis of compounds 7, 8, and 9 [ka] Compound 3-10 (126 mg, 445 μmol) was added to a solution of compounds 7-4, 8-4, and 9-4 (145 mg) in DCM (5 mL) with DIEA (215 mg, 1.67 mmol, 291 μL) at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixture was concentrated, and the resulting residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm, 10 μm, mobile phase: [solvent A: 0.1% FA in water, solvent B: MeCN], gradient: 10–40% B, 10 min) to give a mixture of compounds 7, 8, and 9. This mixture was further separated by preparative chiral SFC (column: REGIS(R,R) WHELK-O1, 250 × 25 mm, 10 μm, mobile phase [solvent A: CO2, solvent B: 0.1% ammonium hydroxide in EtOH], gradient: isocratic 55% B) to give pure compounds 7 and 9. Impure compound 8 was further purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm, 10 μm, mobile phase: [solvent A: 5 / 10000 ammonium hydroxide in water, solvent B: MeCN], gradient: 25–55% B, 9 min).

[0254] Analytical chiral SFC method: (Column: Kromasil (S,S) Whelk-O1, 50 × 4.6 mm, 3.5 μm, Mobile phase: [Solvent A: CO2, Solvent B: 0.05% DEA in EtOH], Gradient: Isocratic 60% B, Flow rate: 3 mL / min, Column temperature: 35 °C, Back pressure: 100 Bar).

[0255] Compound 7 (3.36 mg, 6.53 μmol, purity 99%) was obtained as a yellow solid.

[0256] Analytical chiral SFC: Rt=1.007 min (100% ee).

[0257] Compound 7(M+H) + LC-MS: 507.2.

[0258] Compound 7 1H NMR:(400MHz,DMSO-d6)δ8.47(s,1H),8.79(t,J=5.2Hz,2H),8.29(brs,1H),8.10(t,J=7.6Hz,1H),7.79(s,1H),7.55(t,J=7.2Hz,2H),7.51-7. 44(m,1H),7.41(t,J=4.8Hz,1H),7.29(s,2H),5.47-5.32(m,1H),4.90- 4.88 (m, 1H), 4.58-4.55 (m, 1H), 2.89 (s, 3H), 1.60 (d, J = 6.8Hz, 3H).

[0259] Compound 8 (3.37 mg, 6.53 μmol, purity 98%) was obtained as a yellow solid.

[0260] Analytical chiral SFC: Rt=1.144 min (100% ee).

[0261] Compound 8(M+H) + LC-MS: 507.4.

[0262] Compound 8 1 H NMR:(400MHz,DMSO-d6)δ9.01(s,1H),8.87(s,1H),8.78(t,J=4.8Hz,2H),8.30(brs,1H),8.08(d,J=10.4Hz,1H),7.58(d,J=6.4Hz,1H),7.54-7. 51(m,1H),7.43-7.36(m,2H),6.88(s,2H),5.44-5.41(m,1H),4.92(d,J= 16.8Hz, 1H), 4.58-4.54 (m, 1H), 2.66 (s, 3H), 1.62 (d, J = 5.6Hz, 3H).

[0263] Compound 9 (2.58 mg, 4.92 μmol, purity 99%) was obtained as a white solid.

[0264] Analytical chiral SFC: Rt=1.405 min (100% ee).

[0265] Compound 9(M+H) +LC-MS: 521.4.

[0266] Compound 9 1 H NMR:(400MHz,DMSO-d6)δ8.82(s,1H),8.78(t,J=4.8Hz,2H),8.20(brs,1H),8.10(dd,J1=8.4Hz,J2=2.4Hz1H),7.56(d,J=10.8Hz,1H),7.53-7.43(m,2 H),7.40(t,J=4.8Hz,1H),6.76(s,2H),5.46-5.41(m,1H),4.89-4.85(m,1H) ), 4.60-4.54 (m, 1H), 2.81 (s, 3H), 2.58 (s, 3H), 1.62 (d, J = 7.2Hz, 3H).

[0267] [Example 8] Synthesis of Compound 10 [ka]

[0268] Step 1: Synthesis of compound 10-2 [ka] To a solution of compound 10-1 (1.07 g, 4.48 mmol, synthesized according to a known method (WO9945009A1)) in 0.4 M NH3 / dioxane (20 mL) was added (2,4-dimethoxyphenyl)methanamine (898.06 mg, 5.37 mmol, 806.88 μL, 1.2 eq). The mixture was heated at 110 °C for 2 h and then concentrated in vacuo. The residue was diluted with saturated NH4Cl solution (30 mL), and the resulting suspension was extracted with DCM (25 mL × 3). The combined organic layer was washed with brine (25 mL × 2), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, gradient from 4:1 PE / EtOAc to 100% EtOAc followed by 10:1 EtOAc / MeOH) to give compound 10-2 (1.50 g, 4.06 mmol, 91% yield) as an off-white solid.

[0269] LC-MS (M+H) + :370.1.

[0270] Compound 10-2 1 H NMR:(400MHz,DMSO-d6)δ9.19(s,1H),8.50(s,1H),8.41-8.33(m,2H),8.06(s,1H),7.21(d,J=8.4Hz,1H) ,6.59(d,J=2.4Hz,1H),6.48(dd,J=2.4,8.4Hz,1H),4.65(d,J=5.6Hz,2H),3.83(s,3H),3.74(s,3H).

[0271] Step 2: Synthesis of compound 10-3 [ka] To a solution of compound 10-2 (0.8 g, 2.16 mmol) in DMF (10 mL) and MeOH (10 mL) was added Pd(OAc)2 (97.14 mg, 432.66 μmol, 0.2 eq), DPPP (178.45 mg, 432.66 μmol, 0.2 eq), and TEA (656.71 mg, 6.49 mmol, 903.31 μL, 3 eq). The mixture was heated at 80 °C under a CO atmosphere (50 psi) for 16 h. The reaction mixture was diluted with water (20 mL), and the resulting suspension was filtered. The solid was washed with water and dried in vacuo to give compound 10-3 (0.728 g, 1.85 mmol, 86% yield) as a red solid. LC-MS (M+H) + :394.1.

[0272] Compound 10-3 1 H NMR: (400 MHz, DMSO-d₆) δ 9.38 (s, 1H), 8.82 (s, 1H), 8.74 (s, 1H), 8.62 (t, J = 5.4 Hz, 1H), 8.10 (s, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 6.48 (dd, J = 2.4, 8.4 Hz, 1H), 4.70 (d, J = 5.6 Hz, 2H), 3.91 (s, 3H), 3.83 (s, 3H), 3.74 (s, 3H).

[0273] Step 3: Synthesis of compound 10-4 [ka] A solution of compound 10-3 (0.080 g, 203.36 μmol) in TFA (4 mL) was heated at 75° C. for 30 min. The reaction mixture was concentrated in vacuo to give crude compound 10-4 (0.050 g) as a red solid. LC-MS (M+H) + :244.1. Step 4: Synthesis of compound 10-5 [ka]

[0274] To a solution of compound 10-4 (0.050 g) in MeOH (4 mL) and water (1 mL) was added LiOH·HO (25.88 mg, 616.72 μmol). The reaction mixture was heated at 50 °C for 12 h. It was diluted with water (10 mL) and MTBE (10 mL). The pH of the aqueous phase was adjusted to 6 with 2 M HCl, and the resulting suspension was filtered. The solid was washed with water and then dried in vacuo to give crude compound 10-5 (0.050 g) as a white solid. LC-MS (M+H) + :229.9.

[0275] Step 5: Synthesis of compound 10-6 [ka] To a solution of compound 10-5 (0.050 g) in toluene (4 mL) was added SOCl (129.77 mg, 1.09 mmol, 79.22 μL). The reaction mixture was heated at 110 °C for 2 hours. The reaction mixture was concentrated in vacuo to give crude compound 10-6 (0.050 g) as a brown solid.

[0276] Step 6: Synthesis of Compound 10 [ka] To a solution of compound 3-10 (51.29 mg, 181.72 μmol) in DCM (5 mL) was added DIEA (78.28 mg, 605.72 μmol, 105.51 μL) and crude compound 10-6 (0.050 g). The mixture was stirred at 25 °C for 12 h. It was diluted with water (15 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm, 10 μm, mobile phase: [solvent A: 0.1% FA in water, solvent B: MeCN], gradient: 18–48% B, 10 min) to give the FA salt of compound 10. This salt was dissolved in water (10 mL) and washed with DCM (10 mL). The pH of the aqueous layer was adjusted to 9 with saturated NaHCO solution, and then extracted with DCM (10 mL × 3). The combined organic layers were washed with water (10 mL) and concentrated in vacuo to give the free base of compound 10 (2 mg, 3.87 μmol, 95% purity) as a white solid.

[0277] LC-MS (M+H) + :494.1.

[0278] Compound 10 1 H NMR:(400MHz,CDCl3)δ8.87(s,1H),8.74(s,1H),8.67-8.64(m,2H),8.37-8. 30(m,1H),7.87-7.84(m,1H),7.78-7.74(m,1H),7.60(d,J=7.8Hz,1H),7.14 (t,J=4.8Hz,1H),6.18(d,J=6.8Hz,1H),5.48-5.37(m,2H),5.26-5.16(m,1H ), 4.62 (d, J = 17.2 Hz, 1 H), 3.77 (d, J = 10.8 Hz, 1 H), 1.81 (d, J = 6.8 Hz, 3 H).

[0279] Analytical chiral SFC (column: Chiralpak IC-3, 50 × 4.6 mm, 3 μm, mobile phase: [solvent A: CO2, solvent B: 0.05% DEA in 3:1 IPA-MeCN], gradient: isocratic 50% B, flow rate: 3 mL / min, temperature: 35 °C, back pressure: 100 Bar).

[0280] Rt=1.484 min (97.73% ee).

[0281] Other compounds of the present disclosure are synthesized by methods similar to those described above, with modified conditions and different starting materials.

[0282] [Example 9] Synthesis of Compound 11 [ka]

[0283] Step 1: Synthesis of compound 11-2 [ka] To a solution of compound 11-1 (1.25 g, 6.18 mmol) in EtOH (15 mL), NaOAc (1.52 g, 18.55 mmol, 3 eq) and hydroxylamine hydrochloride (1.29 g, 18.55 mmol) were added, and the reaction was stirred at 25 °C for 1 h. The reaction was diluted with water (20 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with saturated NaCl solution (15 mL × 2), dried over NaSO, filtered, and concentrated in vacuo. The crude product was used directly in the next step to give compound 11-2 (1.2 g, crude) as a yellow solid.

[0284] Step 2: Synthesis of compound 11-3 [ka] To a solution of compound 11-2 (1.08 g, 4.97 mmol) in MeOH (10 mL) and NH3.H2O (1 mL), Raney nickel (0.216 g) was added and stirred at 45 °C under H2 atmosphere (50 psi) for 12 h. The reaction mixture was then heated to 80 °C and stirred for 12 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The crude product was used directly in the next step. Compound 11-3 (0.9 g, crude) was obtained as a yellow solid. LCMS (M-14) + :189.1.

[0285] Step 3: Synthesis of compound 11-4 [ka] To a solution of compound 11-3 (0.9 g) and TEA (448.27 mg, 4.43 mmol, 616.60 μL) in DCM (20 mL) was added (Boc)2O (966.83 mg, 4.43 mmol, 1.02 mL) at 0 °C in an ice bath. The reaction mixture was then warmed to 25 °C and stirred for 12 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE:EA = 20:1 to 10:1). Compound 11-4 (0.7 g, 2.00 mmol) was obtained as a yellow solid. LCMS (M-55) + :248.1.

[0286] Step 4: Synthesis of compound 11-5 [ka] To a solution of compound 11-4 (0.7 g, 2.31 mmol) in THF (20 mL) was added NaH (184.65 mg, 4.62 mmol, 60% purity) under a N2 atmosphere at 0 °C. The mixture was stirred for 15 min, and then CHCl (491.42 mg, 3.46 mmol, 215.53 μL) was added to the mixture. The reaction mixture was stirred at 25 °C for 18 h. The reaction mixture was quenched by adding MeOH (15 mL) in an ice bath, and then the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE:EA = 20:1 to 10:1). Compound 5 (0.62 g, 1.95 mmol, 85% yield) was obtained as a yellow oil. LC-MS: (M-55) + :262.1.

[0287] Step 5: Synthesis of compound 11-6 [ka] To a solution of compound 11-5 (0.62 g, 1.95 mmol) in EtOAc (10 mL) was added HCl / dioxane (4 M, 6.20 mL) at 25 °C, and the reaction was stirred for 12 h. The reaction was concentrated in vacuo. The crude product was used directly in the next step to give compound 11-6 (0.4 g, crude, HCl salt) as a white solid.

[0288] LC-MS: (M+H) + :218.1.

[0289] H NMR: (400 MHz, DMSO-d) δ 9.73-9.60 (m, 1H), 8.00-7.76 (m, 1H), 7.44-7.17 (m, 2H), 5.21-5.09 (m, 1H), 4.96-4.83 (m, 1H), 4.78-4.61 (m, 1H), 2.54 (s, 3H).

[0290] Step 6: Synthesis of Compound 11 [ka] To a solution of 3-8 (0.040 g, 175.28 μmol) in DMF (4 mL), HATU (99.97 mg, 262.92 μmol) and DIEA (45.31 mg, 350.56 μmol, 61.06 μL) were added and stirred for 15 min. After that, 11-6 (66.69 mg, 262.92 μmol, HCl salt) was added to the mixture and the reaction was stirred at 25 °C for 12 h. The reaction was diluted with water (15 mL) and extracted with EtOAc (10 mL × 3). The combined organic layer was washed with saturated NaCl solution (10 mL × 2), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm, 5 μm, mobile phase: [solvent A: 5 / 10000 ammonium hydroxide / water, solvent B: MeCN], gradient: 27–57% B, 9 min) to give compound 11 (0.025 g, 58.43 μmol, yield 33%, purity 99.88%).

[0291] LC-MS: (M+H) + :428.2.

[0292] H NMR: (400 MHz, DMSO-d₆) δ 9.17 (s, 1H), 8.33 (s, 1H), 7.91 (s, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.49-7.40 (m, 4H), 7.37-7.30 (m, 1H), 7.28-7.23 (m, 1H), 6.71-6.08 (m, 1H), 4.88-4.66 (m, 2H), 2.68 (s, 3H).

[0293] HPLC: Purity was 99.88%.

[0294] [Example 10] Synthesis of Compound 12 [ka]

[0295] Step 1: Synthesis of compound 12-1 [ka] To a solution of compound 11-5 (1.80 g, 5.67 mmol) in DCM (20.0 mL) was added HCl / EtOAc (4 M, 20.0 mL). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The compounds were separated by SFC (column: DAICEL CHIRALPAK IG 250 mm × 30 mm × 5 μm, mobile phase: [CO2-MeOH (0.1% NH3H2O)], B%: 20%, isocratic elution mode) to give compound 12-1 (crude, 700 mg, 2.77 mmol, HCl salt) (Rt = 0.791 min). The crude product was then purified by preparative HPLC (column: Phenomenex luna C18 150 × 40 mm × 15 μm, mobile phase: [solvent A: 0.1% HCl in water, solvent B: MeCN], gradient: 5% to 35% B over 10 min) to give compound 12-1 (280 mg, 1.29 mmol, 40% yield) (SFC: 100% ee) as a white solid.

[0296] Step 2: Synthesis of compound 12 [ka] To a solution of 3-8 (0.080 g, 350.56 μmol) in DMF (2 mL), HATU (199.94 mg, 525.84 μmol) and DIEA (90.61 mg, 701.12 μmol, 122.12 μL) were added and stirred for 15 minutes. After that, compound 12-1 (133.38 mg, 525.84 μmol, HCl salt) was added to the mixture, and the reaction was stirred at 25 °C for 12 hours. The reaction was diluted with water (15 mL) and extracted with EtOAc (10 mL × 3). The combined organic layer was washed with saturated NaCl solution (10 mL × 2), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm, 5 μm, mobile phase: [solvent A: 5 / 10000 ammonium hydroxide / water, solvent B: MeCN], gradient: 27–57% B, 9 min) to give compound 12 (0.070 g, 161.55 μmol, 46% yield, 99% purity).

[0297] H NMR: (400 MHz, DMSO-d₆) δ 9.18 (s, 1H), 8.35 (s, 1H), 7.91 (s, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.50-7.42 (m, 4H), 7.38-7.30 (m, 1H), 7.28-7.23 (m, 1H), 6.81-5.89 (m, 1H), 4.94-4.62 (m, 2H), 2.68 (s, 3H).

[0298] LC-MS: (M+H) + :428.1.

[0299] HPLC: Purity was 98.6% (220 nm).

[0300] [Example 11] Synthesis of Compound 13 [ka] Compound 13-1 was obtained in a similar manner to the synthesis of compound 10-5. LC-MS (M+H) + :230.1. 1 H NMR (400 MHz, DMSO-d6) δ 13.25 (brs, 1H), 9.34 (s, 1H), 8.99 (d, J = 1.8 Hz, 1H), 8.92 (s, 1H), 8.12 (brs, 2H), 7.98 (s, 1H).

[0301] To a solution of compound 13-1 (20.0 mg, 43.6 μmol) in DMF (2.00 mL), HATU (49.6 mg, 65.5 μmol), DIEA (22.5 mg, 87.2 μmol, 30.4 μL), and compound 12-1 (28.4 mg, 65.4 μmol) were added, and the mixture was stirred at 25 °C for 2 hours. The mixture was diluted with water (20.0 mL) and extracted with EtOAc (10.0 mL × 3). The combined organic layer was washed with water (20.0 mL × 4), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm, 5 μm, mobile phase: [solvent A: 5 / 10000 ammonium hydroxide / water, solvent B: MeCN], gradient: 24–54% B, 10 min) to give the desired product 13 (25.9 mg, 58.2 μmol, 67% yield, 96% purity).

[0302] H NMR: (400 MHz, DMSO-d₆) δ 9.22 (s, 1H), 8.71 (d, J = 2.0 Hz, 1H), 8.60-8.59 (m, 1H), 7.95 (s, 1H), 7.90 (s, 2H), 7.66-7.64 (m, 1H), 7.34-7.32 (s, 1H), 7.26 (s, 1H), 6.39 (s, 1H), 4.85-4.72 (m, 2H), 2.72 (s, 3H).

[0303] LC-MS: (M+H) + :429.2.

[0304] [Example 12] Synthesis of Compound 14 [ka] To a solution of compound 10-5 (30.0 mg, 131 μmol) and compound 12-1 (28.4 mg, 131 μmol) in DMF (0.5 mL), DIEA (50.8 mg, 393 μmol, 68.4 L) and HATU (99.5 mg, 262 μmol) were added, and the mixture was stirred at 25 °C for 2 h. The mixture was diluted with HO (20.0 mL) and extracted with EtOAc (20.0 mL × 3). The combined organic phase was washed with brine (20.0 mL × 2), dried over NaSO, and concentrated to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm, 5 μm, mobile phase: [solvent A: 5 / 10000 ammonium hydroxide / water, solvent B: MeCN], gradient: 24–54% B, 10 min) to give compound 14 (25.15 mg, 57.1 μmol, 44% yield, 97% purity).

[0305] H NMR: (400 MHz, DMSO-d₆) δ 9.32-9.30 (m, 1H), 8.70-8.65 (m, 1H), 8.56-8.51 (m, 1H), 7.99-7.98 (m, 1H), 7.76-7.72 (m, 3H), 7.34 (t, J = 7.2 Hz, 1H), 7.28-7.25 (m, 1H), 6.46-6.02 (m, 1H), 4.89-4.68 (m, 2H), 2.76-2.69 (m, 3H).

[0306] LC-MS: (M+H) + :429.1.

[0307] [Example 13] Synthesis of compounds 15, 16, 19, and 20 [ka]

[0308] Step 1: Synthesis of compound 15-2 [ka] To a solution of compound 15-1 (300 mg, 1.20 mmol, 1.00 eq, FA) in DCM (5.00 mL) was added TEA (244 mg, 2.41 mmol, 335 μL, 2.00 eq) and BocO (315 mg, 1.44 mmol, 332 μL, 1.20 eq). The mixture was stirred at 20 °C for 1 h. LC-MS showed complete consumption of compound 15-1, with one major peak having the desired m / z. The reaction mixture was diluted with 10.0 mL of water and extracted with 15.0 mL of DCM (5.00 mL × 3). The combined organic layers were washed with 30.0 mL of brine (15.0 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1, plate 1, PE:EA = 5:1, R f =0.41) to give compound 15-2 (300 mg, 989 μmol, 82.2% yield) as a yellow solid.

[0309] H NMR: (400 MHz, CDCl) δ 7.45 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.08 (s, 1H), 5.43 (s, 1H), 4.88 (s, 1H), 4.77-4.73 (m, 1H), 4.42-4.38 (m, 1H), 1.47 (s, 9H).

[0310] Step 2: Synthesis of compound 15-3 [ka] To a solution of compound 15-2 (300 mg, 989 μmol, 1.00 eq) in THF (100 mL) was added NaH (59.4 mg, 1.48 mmol, 60% purity, 1.50 eq) at 0 °C, and the mixture was stirred at 0 °C for 0.25 h. Next, trideuterio(iodo)methane (172 mg, 1.19 mmol, 73.9 μL, 1.20 eq) was added to the mixture. The mixture was stirred at 20 °C for another 0.25 h. LC-MS showed complete consumption of compound 15-2, with one major peak having the desired m / z. The reaction mixture was diluted with 10 mL of water and extracted with 30 mL of EtOAc (10 mL × 3). The combined organic layers were washed with 30 mL of brine (15 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1, plate 1, PE:EA = 5:1, R f =0.40) to give compound 15-3 (250 mg, 780 μmol, yield 78.9%) as a yellow oil.

[0311] H NMR: (400 MHz, CDCl) δ 7.35 (d, J = 7.2 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.08 (s, 1H), 6.12-5.84 (m, 1H), 4.71-4.66 (m, 1H), 4.45-4.43 (m, 1H), 1.50 (s, 9H).

[0312] Step 3: Synthesis of compound 15-4 [ka] To a solution of compound 15-3 (250 mg, 780 μmol, 1.00 eq) in DCM (5.00 mL) was added HCl / EtOAc (2 M, 10.0 mL, 25.0 eq). The mixture was stirred at 20 °C for 2 h. LC-MS showed complete consumption of compound 15-3, with one major peak having the desired m / z. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product, compound 15-4 (180 mg, 701 μmol, 89.9% yield, HCl), was used in the next step without further purification as a white solid.

[0313] Step 4: Synthesis of compounds 19 and 20 [ka] To a solution of compound 15-5 (40.0 mg, 175 μmol, 1.00 eq) and compound 15-4 (44.8 mg, 175 μmol, 1.00 eq, HCl) in DMF (3.00 mL) was added HATU (79.6 mg, 210 μmol, 1.20 eq) and DIEA (113 mg, 873 μmol, 5.00 eq). The mixture was stirred at 25 °C for 0.5 h. LC-MS showed complete consumption of compound 15-5, with one major peak having the desired m / z. The reaction mixture was diluted with 30.0 mL and extracted with 60.0 mL of EtOAc (20.0 mL × 3). The combined organic layers were washed with 30.0 mL of brine (15.0 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA conditions, column: Phenomenex luna C18 150 × 25 mm × 10 μm, mobile phase: [water (FA)-ACN], gradient: 16% to 46% B over 10 min) to give a mixture of compounds 19 and 20 (30.0 mg, 63.0 μmol, yield 35.9%, FA) as a white solid.

[0314] Step 5: Synthesis of compounds 15 and 16 [ka] To a solution of compound 15-6 (40.0 mg, 175 μmol, 1.00 eq) and compound 15-4 (45.0 mg, 175 μmol, 1.00 eq, HCl) in DMF (3.00 mL) was added HATU (80.0 mg, 210 μmol, 1.20 eq) and DIEA (113 mg, 876 μmol, 5.00 eq). The mixture was stirred at 25 °C for 0.5 h. LC-MS showed complete consumption of compound 15-6, with one major peak having the desired m / z. The reaction mixture was diluted with 30.0 mL and extracted with 60.0 mL of EtOAc (20.0 mL × 3). The combined organic layers were washed with 30.0 mL of brine (15.0 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA conditions, column: Phenomenex luna C18 150 × 25 mm × 10 μm, mobile phase: [water (FA)-ACN], gradient: 16% to 46% B over 10 min) to give a mixture of compounds 15 and 16 (30.0 mg, 63.0 μmol, yield 35.9%, FA) as a white solid.

[0315] Step 6: Separation of compounds 19 and 20 [ka] The mixture of compounds 19 and 20 was separated by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm), mobile phase: [CO₂-EtOH], B%: 45%, isocratic elution mode) to give compound 20 (10.44 mg, 24.0 μmol, 28.6% yield, 99.12% purity) (Rt = 1.969 min) and compound 19 (7.61 mg, 17.6 μmol, 21.0% yield, 99.72% purity) (Rt = 2.193 min). Compound 19 was purified by preparative HPLC (Neu conditions, column: Waters Xbridge C18 150 × 50 mm × 10 μm, mobile phase: [water (NH₄HCO₃)-ACN], gradient: 22% to 52% B over 10 min). Compound 20 was purified by preparative HPLC (Neu conditions, column: Waters Xbridge C18 150 × 50 mm × 10 μm, mobile phase: [water (NH4HCO3)-ACN], gradient: 22% to 52% B over 10 min). Compound 19 (7.61 mg, 17.6 μmol, yield 21.0%, purity 99.72%) was obtained. Compound 20 (10.44 mg, 24.0 μmol, yield 28.6%, purity 99.12%) was obtained.

[0316] H NMR of compound 19 (400 MHz, DMSO-d) δ 9.34-9.30 (m, 1H), 8.71-8.64 (m, 1H), 8.56-8.51 (m, 1H), 7.99-7.98 (m, 1H), 7.76-7.56 (m, 3H), 7.37-7.25 (m, 2H), 6.46-6.02 (m, 1H), 4.85-4.69 (m, 2H).

[0317] H NMR of compound 20 (400 MHz, DMSO-d) δ 9.33-9.30 (m, 1H), 8.71-8.65 (m, 1H), 8.58-8.51 (m, 1H), 8.01-7.98 (m, 1H), 7.80-7.55 (m, 3H), 7.36-7.25 (m, 2H), 6.45-6.02 (m, 1H), 4.89-4.68 (m, 2H).

[0318] Step 7: Separation of compounds 15 and 16 [ka] The mixture of compounds 15 and 16 was separated by SFC (column: DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm), mobile phase: [CO₂-EtOH (0.1% NH₃H₂O)], B%: 35%, isocratic elution mode) to give compound 16 (8.71 mg, 19.1 μmol, 30.3% yield, 94.14% purity) (Rt = 1.837 min) and compound 15 (5.92 mg, 13.6 μmol, 21.6% yield, 99.06% purity) (Rt = 2.051 min). Peak 1 was purified by preparative HPLC (Neu conditions, column: Waters Xbridge C18 150 × 50 mm × 10 μm, mobile phase: [water (NH₄HCO₃)-ACN], gradient: 24% to 54% B over 10 min). Peak 2 was purified by preparative HPLC (Neutron conditions, column: Waters Xbridge C18 150 × 50 mm × 10 μm, mobile phase: [water (NH4HCO3)-ACN], gradient: 24% to 54% B over 10 min). Compound 15 (5.92 mg, 13.6 μmol, yield 21.6%, purity 99.06%) was obtained. Compound 16 (8.71 mg, 19.1 μmol, yield 30.3%, purity 94.14%) was obtained.

[0319] H NMR of compound 15 (400 MHz, DMSO-d) δ 9.18 (s, 1H), 8.33 (s, 1H), 7.91 (s, 1H), 7.65-7.63 (m, 1H), 7.48-7.45 (m, 4H), 7.34-7.32 (m, 1H), 7.26 (s, 1H), 6.42-5.67 (m, 1H), 4.84-4.69 (m, 2H).

[0320] H NMR of compound 16 (400 MHz, DMSO-d) δ 9.18 (s, 1H), 8.33 (s, 1H), 7.91 (s, 1H), 7.65-7.63 (m, 1H), 7.48-7.45 (m, 4H), 7.34-7.26 (m, 2H), 6.65-6.34 (m, 1H), 4.83-4.69 (m, 2H).

[0321] [Example 15] Compounds 17, 18, 21, and 22 [ka]

[0322] Step 1: Synthesis of compound 17-2 [ka] To a solution of compound 17-1 (100 g, 454 mmol, 1.00 eq) in acetone (500 mL), K2CO3 (89.2 g, 645 mmol, 1.42 eq) and compound 17-1A (114 g, 681 mmol, 1.50 eq) were added. The mixture was stirred at 60 °C for 12 h. TLC (PE: EtOAc = 3:1) showed that compound 17-1 was consumed and one new major spot with relatively high polarity was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 3 / 1, plate 1, PE: EA = 3:1, R f =0.43) to give compound 17-2 (135 g, 441 mmol, 97.1% yield) as a colorless oil.

[0323] H NMR: (400 MHz, CDCl) δ 7.92 (d, J = 8.0 Hz, 1H), 7.33-7.31 (m, 1H), 7.10 (s, 1H), 4.76 (s, 2H), 4.29 (q, J = 14.4 Hz, 2H), 3.94 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H).

[0324] Step 2: Synthesis of compound 17-3 [ka] To a solution of compound 17-2 (135 g, 441 mmol, 1.00 eq) in MeOH (200 mL) was added NaOH (4 M, 355 mL, 3.00 eq). The mixture was stirred at 20 °C for 2 h. LC-MS showed complete consumption of compound 17-2, with one major peak having the desired m / z. The reaction mixture was concentrated under reduced pressure to give a residue. The aqueous phase was acidified to pH = 3 with 1 M HCl, and the solid that appeared was filtered and dried to give a residue. The crude product, compound 17-3 (100 g, 379 mmol, 85.9% yield), was used in the next step without further purification as a white solid.

[0325] Step 3: Synthesis of compound 17-4 [ka] To a solution of compound 17-3 (100 g, 379 mmol, 1.00 eq) in AcO (400 mL) was added AcOH (83.1 g, 1.38 mol, 79.2 mL, 3.65 eq) and NaOAc (34.7 g, 422 mmol, 1.12 eq). The mixture was stirred at 140 °C for 2 h. LC-MS showed complete consumption of compound 17-3, with one major peak having the desired m / z. The reaction mixture was diluted with 1000 mL of water and extracted with 1500 mL of EtOAc (500 mL × 3). The combined organic layers were washed with 2000 mL of brine (1000 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give the residue. The crude product, compound 17-4 (77.0 g, 315 mmol, 83.2% yield), was used in the next step without further purification as a yellow solid.

[0326] H NMR: (400 MHz, CDCl) δ 8.17 (s, 1H), 7.76 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 2.41 (s, 3H).

[0327] Step 4: Synthesis of compound 17-5 [ka] To a solution of compound 17-4 (77.0 g, 315 mmol, 1.00 eq) in MeOH (500 mL) and HO (250 mL), HCl (1 M, 88.2 mL, 0.28 eq) was added. The mixture was stirred at 100 °C for 12 h. LC-MS showed complete consumption of compound 17-4, with one major peak having the desired m / z. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 17-5 (50.0 g, 173 mmol, 70% purity, 55.0% yield) was obtained as a red solid.

[0328] H NMR: (400 MHz, CDCl) δ 7.80 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 4.73 (s, 2H).

[0329] Step 5: Synthesis of compound 17-6 [ka] To a solution of compound 17-5 (5.00 g, 24.7 mmol, 1.00 eq) in MeOH (50.0 mL) was added NaBD4 (1.03 g, 27.2 mmol, 1.10 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. LC-MS showed complete consumption of compound 17-5, with one major peak having the desired m / z. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA conditions, column: Phenomenex Luna C18 (250 × 70 mm, 10 μm), mobile phase: [water (FA)-ACN], gradient: 25% to 55% B over 22 min). Compound 17-6 (3.00 g, 14.6 mmol, 59.1% yield) was obtained as a pale yellow solid.

[0330] H NMR: (400 MHz, CDCl) δ 7.53 (d, J = 7.6 Hz, 1H), 7.24-7.22 (m, 1H), 7.14 (s, 1H), 4.66-4.51 (m, 2H).

[0331] Step 6: Synthesis of compound 17-7 [ka] To a solution of compound 17-6 (3.00 g, 14.6 mmol, 1.00 eq) in toluene (45.0 mL) was added dropwise a solution of DPPA (4.43 g, 16.1 mmol, 3.47 mL, 1.10 eq) and DBU (2.45 g, 16.1 mmol, 2.42 mL, 1.10 eq) in toluene (5.00 mL) under N2 at 0 °C for 30 min. The mixture was stirred at 25 °C for 12 h. TLC (PE: EtOAc = 5:1) showed that compound 17-6 was consumed and one new major spot with relatively low polarity was detected. The reaction mixture was diluted with 100 mL of water and extracted with 300 mL of EtOAc (100 mL × 3). The combined organic layers were washed with 300 mL of brine (150 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1, PE: EtOAc = 5:1, R f =0.43) to give compound 17-7 (2.00 g, 8.69 mmol, 59.4% yield) as a yellow oil.

[0332] H NMR: (400 MHz, CDCl) δ 7.52 (d, J = 8.0 Hz, 1H), 7.28-7.26 (m, 1H), 7.17 (s, 1H), 4.67-4.56 (m, 2H).

[0333] Step 7: Synthesis of compound 17-8 [ka] To a solution of compound 17-7 (2.00 g, 8.69 mmol, 1.00 eq) in THF (20.0 mL) was added PPh (3.42 g, 13.0 mmol, 1.50 eq) under N and stirred at 20 °C for 1 h. Next, a solution of KOH (1.22 g, 21.7 mmol, 2.50 eq) in HO (5.00 mL) was added and stirred at 20 °C for an additional 12 h. LC-MS showed complete consumption of compound 17-7, with one major peak having the desired m / z. The reaction mixture was diluted with 10.0 mL of water and extracted with 30.0 mL of EtOAc (10.0 mL × 3). The combined organic layers were washed with 30.0 mL of brine (15.0 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1, plate 1, PE: EtOAc = 0:1, R f =0.11) to give compound 17-8 (1.00 g, 4.90 mmol, 56.4% yield) as a white solid.

[0334] Step 8: Synthesis of compound 17-9 [ka] To a solution of compound 17-8 (1.00 g, 4.90 mmol, 1.00 eq) in DCM (20.0 mL) was added TEA (0.993 g, 9.80 mmol, 2.00 eq) and BocO (1.28 g, 5.88 mmol, 1.20 eq). The mixture was stirred at 25 °C for 0.5 h. LC-MS showed complete consumption of compound 17-8, with one major peak having the desired m / z. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1, plate 1, PE:EA = 5:1, R f =0.41) to give compound 17-9 (1.00 g, 3.29 mmol, 67.1% yield) as a white solid.

[0335] H NMR: (400 MHz, CDCl) δ 7.45 (d, J = 7.6 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.08 (s, 1H), 4.88 (brs, 1H), 4.75 (d, J = 10.4 Hz, 1H), 4.40 (d, J = 10.0 Hz, 1H), 1.47 (s, 9H).

[0336] Step 9: Synthesis of compound 17-10 [ka] To a solution of compound 17-9 (1.00 g, 3.29 mmol, 1.00 eq) in THF (100 mL) was added NaH (197 mg, 4.93 mmol, 60% purity, 1.50 eq) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Next, CD3I (476 mg, 3.29 mmol, 205 μL, 1.00 eq) was added to the mixture. The mixture was stirred at 25 °C for an additional 1 h. LC-MS showed that compound 17-9 was completely consumed, with one major peak having the desired m / z. The reaction mixture was diluted with 100 mL of water and extracted with 300 mL of EA (100 mL × 3). The combined organic layers were washed with 300 mL of brine (150 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1, PE: EtOAc = 5:1, R f =0.40) to give compound 17-10 (550 mg, 1.71 mmol, 52.1% yield) as a colorless oil.

[0337] H NMR: (400 MHz, CDCl) δ 7.34 (d, J = 6.8 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.08 (s, 1H), 4.68 (d, J = 10.0 Hz, 1H), 4.44 (d, J = 10.0 Hz, 1H), 1.50 (s, 9H).

[0338] Step 10: Synthesis of Compound 17-11 [ka] To a solution of compound 17-10 (550 mg, 1.71 mmol, 1.00 eq) in DCM (5.00 mL), HCl / EtOAc (2 M, 20.0 mL, 25.0 eq) was added. The mixture was stirred at 20 °C for 1 h. LC-MS showed complete consumption of compound 17-10, with one major peak having the desired m / z. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product, compound 17-11 (400 mg, 1.55 mmol, 90.7% yield, HCl), was used in the next step without further purification as a white solid.

[0339] Step 11: Synthesis of Compounds 21 and 22 [ka] To a solution of compound 17-12 (80.0 mg, 349 μmol, 1.00 eq) and compound 17-11 (89.9 mg, 349 μmol, 1.00 eq, HCl) in DMF (3.00 mL) was added HATU (159 mg, 419 μmol, 1.20 eq) and DIEA (226 mg, 1.75 mmol, 5.00 eq). The mixture was stirred at 25 °C for 0.5 h. LC-MS showed complete consumption of compound 17-12, with one major peak having the desired m / z. The reaction mixture was diluted with 30.0 mL and extracted with 60.0 mL of EtOAc (20.0 mL × 3). The combined organic layers were washed with 30.0 mL of brine (15.0 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA conditions, column: Phenomenex luna C18 150 × 25 mm × 10 μm, mobile phase: [water (FA)-ACN], gradient: 28% to 58% B over 10 min) to give a mixture of compounds 21 and 22 (60.0 mg, 125 μmol, yield 35.9%, FA) as a white solid.

[0340] Step 12: Synthesis of Compounds 17 and 18 [ka] To a solution of compound 17-13 (80.0 mg, 351 μmol, 1.00 eq) and compound 17-11 (90.3 mg, 351 μmol, 1.00 eq, HCl) in DMF (3.00 mL) was added HATU (160 mg, 421 μmol, 1.20 eq) and DIEA (227 mg, 1.75 mmol, 5.00 eq). The mixture was stirred at 25 °C for 0.5 h. LC-MS showed complete consumption of compound 17-13, with one major peak having the desired m / z. The reaction mixture was diluted with 30.0 mL and extracted with 60.0 mL of EtOAc (20.0 mL × 3). The combined organic layers were washed with 30.0 mL of brine (15.0 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA conditions, column: Phenomenex luna C18 150 × 25 mm × 10 μm, mobile phase: [water (FA)-ACN], gradient: 18% to 48% B over 10 min) to give a mixture of compounds 17 and 18 (60.0 mg, 126 μmol, yield 35.9%, FA) as a white solid.

[0341] Step 13: Separation of compounds 21 and 22 [ka] The mixture of compounds 21 and 22 was separated by SFC (column: DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm), mobile phase: [CO₂-EtOH], B%: 45%, isocratic elution mode) to give compound 21 (22.02 mg, 50.7 μmol, 40.4% yield, 99.51% purity) (Rt = 1.972 min) and compound 22 (19.47 mg, 44.2 μmol, 35.2% yield, 98.15% purity) (Rt = 2.213 min). Compound 21 was purified by preparative HPLC (basic conditions, column: Waters Xbridge C18 150 × 25 mm × 5 μm, mobile phase: [water (ammonium hydroxide v / v)-ACN], gradient: 27% to 57% B over 10 min). Compound 22 was purified by preparative HPLC (basic conditions: column: Waters Xbridge C18 150 × 25 mm × 5 μm, mobile phase: [water (ammonium hydroxide v / v)-ACN], gradient: 27% to 57% B over 10 min). Compound 21 (22.02 mg, 50.7 μmol, 40.4% yield, 99.51% purity) was obtained. Compound 22 (19.47 mg, 44.2 μmol, 35.2% yield, 98.15% purity) was obtained.

[0342] H NMR of compound 21 (400 MHz, DMSO-d) δ 9.32-9.30 (m, 1H), 8.70-8.65 (m, 1H), 8.56-8.50 (m, 1H), 7.99-7.98 (m, 1H), 7.76-7.56 (m, 3H), 7.36-7.25 (m, 2H), 4.88-4.68 (m, 2H).

[0343] H NMR of compound 22 (400 MHz, DMSO-d) δ 9.32-9.30 (m, 1H), 8.70-8.65 (m, 1H), 8.56-8.51 (m, 1H), 7.99-7.98 (m, 1H), 7.76-7.56 (m, 3H), 7.35-7.25 (m, 2H), 4.88-4.68 (m, 2H).

[0344] Step 14: Separation of compounds 17 and 18 [ka] The mixture of compounds 17 and 18 was separated by SFC (column: DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm), mobile phase: [CO₂-EtOH (0.1% NH₃H₂O)], B%: 35%, isocratic elution mode) to give compound 17 (18.98 mg, 43.6 μmol, 34.7% yield, 99.07% purity) (Rt = 1.852 min) and compound 18 (25.69 mg, 58.8 μmol, 46.8% yield, 98.77% purity) (Rt = 2.050 min). Compound 17 was purified by preparative HPLC (Neu conditions, column: Waters Xbridge C18 150 × 50 mm × 10 μm, mobile phase: [water (NH₄HCO₃)-ACN], gradient: 24% to 54% B over 10 min). Compound 18 was purified by preparative HPLC (Neu conditions, column: Waters Xbridge C18 150 × 50 mm × 10 μm, mobile phase: [water (NH4HCO3)-ACN], gradient: 24% to 54% B over 10 min). Compound 17 (18.98 mg, 43.6 μmol, yield 34.7%, purity 99.07%) was obtained. Compound 18 (25.69 mg, 58.8 μmol, yield 46.8%, purity 98.77%) was obtained.

[0345] H NMR of compound 17 (400 MHz, DMSO-d) δ 9.18 (s, 1H), 8.33 (s, 1H), 7.91 (s, 1H), 7.65-7.63 (m, 1H), 7.50-7.45 (m, 4H), 7.35-7.26 (m, 2H), 4.84-4.70 (m, 2H).

[0346] H NMR of compound 18 (400 MHz, DMSO-d) δ 9.18 (s, 1H), 8.33 (s, 1H), 7.91 (s, 1H), 7.65-7.63 (m, 1H), 7.48-7.45 (m, 4H), 7.34-7.26 (m, 2H), 4.85-4.70 (m, 2H).

[0347] [Example 16] Synthesis of Compound 23 [ka]

[0348] Step 1: Synthesis of compound 23-3 [ka] To a solution of compound 23-1 (10.0 g, 39.1 mmol, 1.00 eq) in DCM (120 mL) was added compound 23-2 (4.74 g, 39.1 mmol, 1.00 eq), tetrabutylammonium hydrogen sulfate (2.00 g, 5.88 mmol, 0.150 eq), and KOH (4.18 g, 74.5 mmol, 1.90 eq). The mixture was stirred at 25 °C for 2 h. TLC (Plate 1, PE: EtOAc = 10:1) showed that compound 23-1 had been consumed and one new major spot with relatively low polarity was detected. The reaction mixture was diluted with 200 mL of water and extracted with 300 mL of DCM (100 mL × 3). The combined organic layers were washed with 300 mL of brine (150 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1, plate 1, PE:EA = 10:1, R f =0.60) to give compound 23-3 (10.0 g, 33.9 mmol, 86.7% yield) as a colorless oil.

[0349] H NMR: (400 MHz, CDCl) δ 7.80 (d, J = 1.2 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.42-7.40 (m, 1H), 6.04-5.96 (m, 1H), 5.40-5.26 (m, 2H), 4.60 (s, 2H), 4.17-4.15 (m, 2H).

[0350] Step 2: Synthesis of compound 23-4 [ka] A mixture of compound 23-3 (10.0 g, 33.9 mmol, 1.00 eq), Pd(OAc) (1.14 g, 5.08 mmol, 0.150 eq), PPh (4.00 g, 15.3 mmol, 0.450 eq), and CsCO (13.3 g, 40.7 mmol, 1.20 eq) in DMF (200 mL) was degassed and purged with N three times. The mixture was then stirred under N at 90 °C for 12 h. TLC (Plate 1, PE: EtOAc = 10:1) showed that compound 23-3 had been consumed and one new major spot with relatively high polarity was detected. The reaction mixture was filtered, and the filtrate was diluted with 200 mL of water and extracted with 600 mL of EtOAc (200 mL × 3). The combined organic layers were washed with 300 mL of brine (150 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1, plate 1, PE:EA = 10:1, R f =0.43) to give compound 23-4 (6.00 g, 28.0 mmol, 82.7% yield) as a yellow oil.

[0351] H NMR: (400 MHz, CDCl) δ 7.79 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.31 (s, 1H), 5.73 (s, 1H), 5.16 (s, 1H), 4.85 (s, 2H), 4.48 (s, 2H).

[0352] Step 3: Synthesis of compound 23-5 [ka] To a solution of compound 23-4 (6.00 g, 28.0 mmol, 1.00 eq) in acetone (60.0 mL) and HO (12.0 mL), KOsO 2HO (1.03 g, 2.80 mmol, 0.100 eq) and NMO (11.5 g, 98.1 mmol, 10.4 mL, 3.50 eq) were added. The mixture was then degassed and purged with N three times. The mixture was then stirred under N at 25 °C for 12 h. TLC (PE: EtOAc = 3:1) showed that compound 23-4 had been consumed, and one new major spot with relatively high polarity was detected. The reaction mixture was quenched with 100 mL of NaSO (saturated) and extracted with 600 mL of EtOAc (200 mL × 3). The combined organic layers were washed with 300 mL of brine (150 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1, PE: EtOAc = 5:1, R f =0.27) to give compound 23-5 (4.00 g, 16.2 mmol, 57.7% yield) as a white solid.

[0353] H NMR:(400MHz,CDCl3)δ7.72(d,J=8.4Hz,1H),7.55(d,J=8.0Hz,1H),7.28(s,1H),4.83(s,2H),4. 17(d,J=11.2Hz,1H),3.90(d,J=11.2Hz,1H),3.71-3.62(m,2H),2.95(s,1H),2.35(brs,1H).

[0354] Step 4: Synthesis of compound 23-6 [ka] To a solution of compound 23-5 (4.00 g, 16.2 mmol, 1.00 eq) in THF (90.0 mL), NaIO (14.7 g, 68.5 mmol, 3.80 mL, 3.40 eq) and HO (3.00 mL) were added, followed by degassing and purging with N three times. The mixture was then stirred under N at 25 °C for 12 h. TLC (PE: EtOAc = 3:1) showed that compound 23-5 was consumed, with one new major spot of relatively low polarity. LC-MS showed that compound 23-5 was completely consumed, with one major peak of the desired m / z. The reaction mixture was filtered and washed with EtOAc (100 mL × 2). The filtrate was washed with 200 mL of saturated NaHCO and 200 mL of brine, dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1, PE:EA = 3:1, R f =0.48) to give compound 23-6 (3.00 g, 13.9 mmol, 86.0% yield) as a white solid.

[0355] H NMR: (400MHz, CDCl3) δ8.17(d,J=8.0Hz,1H), 7.69(d,J=8.0Hz,1H), 7.52(s,1H), 4.96(s,2H), 4.43(s,2H).

[0356] Step 5: Synthesis of compound 23-7 [ka] To a solution of compound 23-6 (3.00 g, 13.9 mmol, 1.00 eq) in MeOH (50.0 mL), NaBH4 (683 mg, 18.0 mmol, 1.30 eq) was added portionwise at 0 °C, and the mixture was stirred at 25 °C for 1 h. TLC (PE: EtOAc = 3:1) showed that compound 23-6 had been consumed and one new major spot with relatively high polarity was detected. The reaction mixture was filtered and concentrated under reduced pressure to remove MeOH. It was then diluted with 50.0 mL of brine and extracted with 100 mL of DCM (50.0 mL × 2). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Compound 23-7 (3.00 g, 13.8 mmol, 99.1% yield) was obtained as a colorless oil.

[0357] H NMR: (400 MHz, CDCl) δ 7.61-7.54 (m, 2H), 7.30 (s, 1H), 4.87-4.71 (m, 2H), 4.63-4.61 (m, 1H), 4.13-4.09 (m, 1H), 3.94-3.90 (m, 1H), 2.38-2.36 (m, 1H).

[0358] Step 6: Synthesis of compound 23-8 [ka] To a solution of compound 23-7 (1.50 g, 6.87 mmol, 1.00 eq) in toluene (15.0 mL) under N2, a solution of DPPA (1.39 g, 5.04 mmol, 1.09 mL, 1.10 eq) and DBU (768 mg, 5.04 mmol, 760 μL, 1.10 eq) in toluene (3.00 mL) was added dropwise over a period of 30 min at 0 °C. The mixture was stirred at 25 °C for 12 h. TLC (Plate 1, PE: EtOAc = 3:1) showed that compound 23-7 was consumed and one new major spot with relatively low polarity was detected. The reaction mixture was diluted with 50.0 mL of water and extracted with 150 mL of EtOAc (50.0 mL × 3). The combined organic layers were washed with 300 mL of brine (150 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1, plate 1, PE: EtOAc = 3:1, R f =0.48) to give compound 23-8 (500 mg, 2.06 mmol, 29.9% yield) as a colorless oil.

[0359] H NMR: (400 MHz, CDCl) δ 7.59 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.37 (s, 1H), 4.93 (d, J = 15.2 Hz, 1H), 4.77 (d, J = 15.6 Hz, 1H), 4.27-4.21 (m, 2H), 4.03-3.99 (m, 1H).

[0360] Step 7: Synthesis of compound 23-9 [ka] To a solution of PPh3 (647 mg, 2.46 mmol, 2.00 eq) in THF (5.00 mL) was added a solution of compound 23-8 (300 mg, 1.23 mmol, 1.00 eq) in THF (3.00 mL). The mixture was stirred at 25 °C for 4 h. Next, MeI (117 mg, 1.23 mmol, 1.00 eq) was added to the mixture and stirred at 25 °C for 12 h. The solid that appeared was filtered and washed with THF (10.0 mL) and MeOH (10.0 mL). The filter cake was suspended in MeOH (3.00 mL), and then KOH (102 mg, 1.81 mmol, 2.20 eq) was added to the mixture. The resulting mixture was stirred at 65 °C for 4 h. LC-MS showed complete consumption of compound 23-8, with one major peak having the desired m / z. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA conditions, column: Phenomenex luna C18 150 × 25 mm × 10 μm, mobile phase: [water (FA)-ACN], gradient: 0% to 30% B over 10 min) to give compound 23-9 (80.0 mg, 289 μmol, yield 23.5%, FA) as a colorless oil.

[0361] H NMR: (400 MHz, CDCl) δ 7.70 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H), 4.98 (d, J = 16.0 Hz, 1H), 4.77 (d, J = 15.6 Hz, 1H), 4.53 (d, J = 12.8 Hz, 1H), 4.11 (s, 1H), 3.88-3.84 (m, 1H), 2.59 (s, 3H).

[0362] Step 8: Synthesis of Compound 23 [ka] To a solution of compound 23-10 (30.0 mg, 131 μmol, 1.00 eq) and compound 23-9 (36.5 mg, 131 μmol, 1.00 eq, FA) in DMF (3.00 mL) was added HATU (60.0 mg, 158 μmol, 1.20 eq) and DIEA (85.0 mg, 657 μmol, 5.00 eq). The mixture was stirred at 25 °C for 0.5 h. LC-MS showed complete consumption of compound 23-10, with one major peak having the desired m / z. The reaction mixture was diluted with 30.0 mL and extracted with 60.0 mL of EtOAc (20.0 mL × 3). The combined organic layers were washed with 30.0 mL of brine (15.0 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Neu conditions, column: Waters Xbridge C18 150 × 50 mm × 10 μm, mobile phase: [water (NH4HCO3)-ACN], gradient: 22% to 52% B over 10 min) to give compound 23 (15.74 mg, 35.0 μmol, yield 26.6%, purity 98.11%) as a white solid.

[0363] H NMR: (400 MHz, DMSO-d) δ 9.21-9.17 (m, 1H), 8.40-8.35 (m, 1H), 7.91 (s, 1H), 7.71-7.43 (m, 7H), 5.78 (brs, 1H), 4.93-4.67 (m, 2H), 4.17-4.08 (m, 2H), 2.75 (s, 3H).

[0364] [Example 17] Synthesis of Compounds 24 and 25 [ka]

[0365] Step 1: Synthesis of compound 24-2 [ka] To a solution of compound 24-1 (5.00 g, 25.0 mmol, 1.00 eq) in MeCN (50.0 mL) was added AIBN (410 mg, 2.50 mmol, 0.100 eq) and NBS (4.45 g, 25.0 mmol, 1.00 eq). The mixture was stirred at 70 °C for 2 h. LC-MS showed complete consumption of compound 24-1, with one major peak having the desired m / z. The reaction mixture was cooled to 20 °C, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1, PE: EtOAc = 3:1, R f =0.40) to give compound 24-2 (5.00 g, 17.8 mmol, 71.2% yield) as a yellow oil.

[0366] H NMR: (400 MHz, CDCl) δ 8.04 (s, 1H), 7.97-7.95 (m, 1H), 7.87-7.85 (m, 1H), 5.63-5.60 (m, 1H), 3.48-3.42 (m, 1H), 3.15-3.10 (m, 1H).

[0367] Step 2: Synthesis of compound 24-3 [ka] To a solution of compound 24-2 (5.00 g, 17.8 mmol, 1.00 eq) in DCM (50.0 mL), CDNHHCl (3.79 g, 53.4 mmol, 3.00 eq) was added. The mixture was stirred at 20 °C for 5 min. Next, Py (2.84 g, 35.6 mmol, 2.00 eq) was added to the mixture, followed by a solution of TFAA (5.64 g, 26.7 mmol, 1.50 eq) in DCM (20.0 mL) at 0 °C, and the mixture was stirred at 0 °C for an additional 0.5 h. LC-MS showed complete consumption of compound 24-2, with one major peak having the desired m / z. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1, PE:EtOAc = 3:1, R f=0.40) to give compound 24-3 (2.00 g, 6.10 mmol, 34.2% yield) as a yellow oil.

[0368] H NMR: (400 MHz, CDCl) δ 8.13-8.11 (m, 1H), 8.02-7.96 (m, 1H), 7.69-7.62 (m, 1H), 6.40-6.37 (m, 0.6H), 5.84-5.81 (m, 0.3H), 3.25-3.17 (m, 1H), 2.81-2.67 (m, 1H).

[0369] Step 3: Synthesis of compound 24-4 [ka] To a solution of compound 24-3 (2.00 g, 6.10 mmol, 1.00 eq) and 1,2-ethanedithiol (1.81 g, 19.2 mmol, 3.15 eq) in DCM (50.0 mL) was added BF₃·Et₂O (2.59 g, 18.3 mmol, 2.25 mL, 3.00 eq) at −15 °C. The mixture was stirred at −15 °C for 2 h, then warmed to 20 °C and stirred for an additional 2 h. LC-MS showed complete consumption of compound 24-3, with one major peak having the desired m / z. The reaction mixture was quenched with 100 mL of saturated NaHCO₃ and extracted with 300 mL of DCM (100 mL × 3). The combined organic layers were washed with 300 mL of brine (150 mL × 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1, PE: EtOAc = 5:1, R f =0.37) to give compound 24-4 (2.00 g, 4.95 mmol, 81.1% yield) as a yellow oil.

[0370] H NMR: (400 MHz, DMSO-d) δ 7.90-7.89 (m, 1H), 7.63-7.58 (m, 1H), 7.24-7.17 (m, 1H), 6.28-6.24 (m, 0.6H), 5.67-5.64 (m, 0.4H), 3.68-3.57 (m, 3H), 3.46-3.40 (m, 1H), 3.18-3.09 (m, 1H), 2.82-2.67 (m, 1H).

[0371] Step 4: Synthesis of compound 24-6 [ka] To a solution of HF / pyridine (5.60 g, 39.6 mmol, 5.09 mL, 70.0% purity, 8.00 eq) in DCM (60.0 mL) was added compound 24-5 (5.66 g, 19.8 mmol, 4.00 eq) in DCM (20.0 mL) at −70° C. under N 2 . The mixture was stirred at −70° C. for 30 min under N 2 . Next, a solution of compound 24-4 (2.00 g, 4.95 mmol, 1.00 eq) in DCM (20.0 mL) was added to the mixture. The mixture was stirred at −70° C. for an additional 1 hr and at 20° C. for an additional 3 hr. TLC (petroleum ether:ethyl acetate=3:1, R f According to the (P1) = 0.800), the starting material was completely consumed and a new spot with relatively low polarity was present. The reaction mixture was quenched by adding saturated aqueous NaHCO3 (50.0 mL) at 0 °C, and then extracted with 100 mL of DCM (50.0 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was analyzed by preparative TLC (petroleum ether:ethyl acetate = 3:1, R f (P1) = 0.800) Compound 24-6 (600 mg, 1.71 mmol, 34.6% yield) was obtained as a yellow oil and characterized by H NMR and F NMR.

[0372] H NMR: (400 MHz, CDCl) δ 7.94-7.93 (m, 1H), 7.89-7.84 (m, 1H), 7.47-7.41 (m, 1H), 6.36-6.31 (m, 0.6H), 5.74-5.70 (m, 0.3H), 3.20-3.08 (m, 1H), 2.74-2.53 (m, 1H).

[0373] Step 5: Synthesis of compound 24-7 [ka] To a solution of compound 24-6 (300 mg, 857 μmol, 1.00 eq) in MeOH (5.00 mL) was added K2CO3 (355 mg, 2.57 mmol, 3.00 eq). The mixture was then stirred at 45 °C for 2 h. LC-MS showed the desired mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA conditions, column: Phenomenex luna C18 150 × 25.0 mm × 10.0 μm, mobile phase: [water (FA)-ACN], gradient: 6.00% to 26.0% B over 10 min). The mixture was then concentrated under reduced pressure to give the product. Compound 24-7 (160 mg, 533 μmol, 62.2% yield, FA) was obtained as a yellow solid, which was confirmed by H NMR and F NMR.

[0374] H NMR: (400 MHz, CDCl) δ 8.18 (s, 1H), 7.90-7.84 (m, 3H), 4.87-4.82 (m, 1H), 3.15-3.03 (m, 1H), 2.86-2.75 (m, 1H).

[0375] Step 6: Synthesis of compound 24-9 [ka] To a solution of compound 24-8 (120 mg, 524 μmol, 1.00 eq) in DMF (3.00 mL), HATU (239 mg, 628 μmol, 1.20 eq), DIEA (338 mg, 2.62 mmol, 456 μL, 5.00 eq), and compound 24-7 (157 mg, 524 μmol, 1.00 eq, FA) were added, and the mixture was stirred at 25 °C for 1 h. LC-MS showed the desired mass. The mixture was filtered, and the filtrate was purified by preparative HPLC (FA conditions, column: Waters Xbridge 150 × 25.0 mm × 5.00 μm, mobile phase: [water (FA)-ACN], gradient: 35.0% to 55.0% B over 10 min). Compound 24-9 (a mixture of compounds 24 and 25) (80.0 mg, 156 μmol, yield 30.0%, FA) was obtained as a white solid.

[0376] Step 7: Separation of compounds 24 and 25 [ka] Compound 24-9 was separated by SFC (column: DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm), mobile phase: [CO₂-ACN / i-PrOH (0.1% NH₃·HO)], B%: 25%, isocratic elution mode) to give compound 24 (18.58 mg, 39.8 μmol, yield 25.5%, purity 99.8%) (Rt = 1.645 min) and compound 25 (22.50 mg, 47.5 μmol, yield 30.4%, purity 98.2%) (Rt = 1.86 min). Compound 24 (18.58 mg, 39.8 μmol, yield 25.5%, purity 99.8%) was obtained. Compound 25 (22.50 mg, 47.5 μmol, yield 30.4%, purity 98.2%) was obtained.

[0377] H NMR of compound 24 (400 MHz, DMSO-d) δ 9.31 (s, 1H), 8.68-8.65 (m, 1H), 8.57-8.55 (m, 1H), 8.09-8.05 (m, 2H), 7.99 (s, 1H), 7.87-7.67 (m, 3H), 6.31-6.02 (m, 1H), 3.21-3.08 (m, 1H), 2.93-2.82 (m, 1H).

[0378] H NMR of compound 25 (400 MHz, DMSO-d) δ 9.31 (s, 1H), 8.68-8.65 (m, 1H), 8.57-8.55 (m, 1H), 8.09-8.05 (m, 2H), 7.99 (s, 1H), 7.87-7.67 (m, 3H), 6.31-6.01 (m, 1H), 3.22-3.07 (m, 1H), 2.92-2.84 (m, 1H).

[0379] [Example 18] Synthesis of compounds 26 and 27 [ka] To a solution of compound 26-1 (0.12 g, 523.57 μmol, 1 eq) in DMF (4 mL) was added HATU (298.62 mg, 785.36 μmol, 1.5 eq) and DIEA (338.34 mg, 2.62 mmol, 455.98 μL, 5 eq) at 25 °C. After stirring for 15 min, compound 26-2 (131.52 mg, 523.57 μmol, 1 eq) was added to the mixture and the reaction was stirred for 15 min. LCMS showed no remaining starting material and the desired product was observed. The reaction was diluted with water (15 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with saturated NaCl (10 mL × 2), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150 × 50 mm × 10 μm, mobile phase: [water (NH4HCO3)-ACN], gradient: 34% to 54% B over 10 min) and SFC (column: DAICEL CHIRALCEL Purification by OJ (250 mm × 30 mm, 10 μm), mobile phase: [CO-i-PrOH (0.1% NHHO)], B%: 35%, isocratic elution mode) gave compound 26 (0.025 g, 53.33 μmol, 10.19% yield, 98.63% purity) (Rt = 1.642 min), which was confirmed by NMR, FNMR, LCMS, HPLC, and SFC. Compound 27 (0.025 g, 54.07 μmol, 10.33% yield, 100% purity) (Rt = 1.867 min), which was confirmed by NMR, FNMR, LCMS, HPLC, and SFC.

[0380] H NMR of compound 26 (400 MHz, DMSO-d) δ 9.30 (s, 1H), 8.66 (d, J = 10.8 Hz, 1H), 8.55 (d, J = 8.0 Hz, 1H), 8.11-8.02 (m, 2H), 7.99 (s, 1H), 7.89-7.61 (m, 3H), 6.39-5.79 (m, 1H), 3.10-2.58 (m, 5H).

[0381] Compound 26(M+H) + LC-MS: 463.1.

[0382] HPLC of compound 26: purity was 98.63% (220 nm).

[0383] SFC of compound 26: chiral purity was 100%.

[0384] H NMR of compound 27 (400 MHz, DMSO-d) δ 9.30 (s, 1H), 8.66 (d, J = 11.2 Hz, 1H), 8.55 (d, J = 8.4 Hz, 1H), 8.13-8.02 (m, 2H), 7.99 (s, 1H), 7.88-7.64 (m, 3H), 6.37-5.87 (m, 1H), 3.05-2.65 (m, 5H).

[0385] Compound 27(M+H) + LC-MS: 463.1.

[0386] HPLC of compound 27: purity 100% (220 nm).

[0387] SFC of compound 27: chiral purity was 98.56%. [Example 19] Synthesis of Compounds 28 and 29 [ka]

[0388] Step 1: Synthesis of compound 28-2 [ka] To a solution of compound 28-1 (25 g, 110.84 mmol, 1 eq) in DMF (250 mL) was added Na2CO3 (23.50 g, 221.68 mmol, 2 eq) and MeI (47.20 g, 332.52 mmol, 20.70 mL, 3 eq). The mixture was stirred at 25 °C for 1 h. LC-MS showed complete consumption of the reactants, with one major peak having the desired m / z. The reaction mixture was quenched with NaHCO3 (300 mL) and extracted with EA (600 mL x 3, 200 mL). The combined organic layers were washed with brine (600 mL x 2, 300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that did not require further purification. Compound 28-2 (25 g, 104.35 mmol, 94.15% yield) was obtained as a yellow oil.

[0389] H NMR: (400 MHz, CDCl) δ 8.33 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 4.01 (s, 3H).

[0390] Step 2: Synthesis of compound 28-4 [ka] To a solution of compound 28-2 (6.75 g, 26.62 mmol, 1 eq) and compound 28-3 (6.93 g, 66.54 mmol, 6.41 mL, 2.5 eq) in THF (150 mL) was added CS2CO3 (21.68 g, 66.54 mmol, 2.5 eq) at 25 °C, and the reaction was stirred at 65 °C for 12 h. No starting material remained and the desired product was observed by LCMS. The reaction was diluted with water (150 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with saturated NaCl (100 mL × 2), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 5:1 to 0:1, then dichloromethane:methanol = 10:1). Compound 28-4 (2.5 g, 9.08 mmol, 34.13% yield) was obtained as a yellow solid and was confirmed by NMR.

[0391] H NMR:(400MHz,DMSO-d6)δ8.64(d,J=8.4Hz,1H),7.89(d,J=8.0Hz,1H),5.65-5.42(m,1H),4.33(q,J=7.2Hz,2H),1.32(t,J=6.8Hz,3H).

[0392] Step 3: Synthesis of compound 28-5 [ka] A mixture of compound 28-4 (2.5 g, 9.08 mmol, 1 eq) in H2SO4 (20 mL) was stirred at 100 °C for 1 h. No starting material remained and the desired product was observed by LCMS. The reaction was cooled to room temperature and poured into ice water (20 mL), followed by extraction with EA (15 mL × 3). The combined organic layers were washed with saturated NaHCO3 (15 mL × 2), saturated NaCl (15 mL × 2), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was used directly in the next step. Compound 28-5 (1.5 g, crude) was obtained as a red solid.

[0393] Step 4: Synthesis of compound 28-6 [ka] To a solution of compound 28-5 (1.5 g, 7.38 mmol, 1 eq) in EtOH (25 mL), NaOAc (1.82 g, 22.15 mmol, 3 eq) and NH2OH.HCl (1.54 g, 22.15 mmol, 3 eq) were added, and the reaction was stirred at 25 °C for 1 h. No starting material remained and the desired product was observed by LCMS. The reaction was diluted with water (40 mL) and extracted with EA (25 mL × 3). The combined organic layers were washed with saturated NaCl (20 mL × 2), dried over Na2SO4, filtered, and concentrated in vacuo. A major spot was observed by TLC (PE:EA = 2:1). The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 5:1 to 2:1). Compound 28-6 (0.85 g, crude) was obtained as a red solid.

[0394] Step 5: Synthesis of compound 28-7 [ka] A mixture of compound 28-6 (0.85 g, 3.90 mmol, 1 eq) and Raney nickel (0.5 g, 5.84 mmol, 1.50 eq) in MeOH (10 mL) and NH₃·HO (0.5 mL) was stirred at 80 °C under H₂ atmosphere (50 psi) for 12 h. LCMS showed no remaining starting material and the desired product was observed. The reaction was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 3:1 to 0:1, then dichloromethane:methanol = 10:1). Compound 28-7 (0.120 g, 587.81 μmol, 15.08% yield) was obtained as a yellow oil.

[0395] Step 6: Synthesis of compound 28-8 [ka] To a solution of compound 28-7 (0.120 g, 587.81 μmol, 1 eq) in DCM (10 mL), TEA (118.96 mg, 1.18 mmol, 163.63 μL, 2 eq) and (Boc)2O (134.70 mg, 617.20 μmol, 141.79 μL, 1.05 eq) were added at 25 °C, and the reaction was stirred for 12 h. Almost no starting material remained, and the desired product was observed by LCMS. The reaction was diluted with water (15 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with saturated NaCl (10 mL × 2), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (PE:EA = 3:1). Compound 28-8 (0.040 g, 131.46 μmol, 22.37% yield) was obtained as a yellow solid.

[0396] Step 7: Synthesis of compound 28-9 [ka] To a solution of compound 28-8 (0.040 g, 131.46 μmol, 1 eq) in THF (4 mL), NaH (13.15 mg, 328.66 μmol, 60% purity, 2.5 eq) was added under ice bath at 0 °C, and after stirring for 15 min, MeI (37.32 mg, 262.93 μmol, 16.37 μL, 2.0 eq ) was added to the mixture, and the reaction was stirred at 25 °C for 12 h. No starting material remained and the desired product was observed by LCMS. The reaction was quenched by adding MeOH (5 mL) and concentrated in vacuo. The residue was purified by preparative TLC (PE:EA = 3:1). Compound 28-9 (0.025 g, 78.54 μmol, 59.75% yield) was obtained as a colorless oil.

[0397] Step 8: Synthesis of compound 28-10 [ka] To a solution of compound 28-9 (0.025 g, 78.54 μmol, 1 eq) in EA (4 mL), HCl / dioxane (2 M, 4 mL, 101.85 eq) was added and the reaction was stirred at 25 °C for 2 h. No starting material remained and the desired product was observed by LCMS. The reaction was concentrated in vacuo. The crude product was used directly in the next step. Compound 28-10 (0.020 g, crude, HCl) was obtained as a yellow solid.

[0398] Step 9: Synthesis of Compound 28 [ka] To a solution of compound 28-11 (0.020 g, 87.64 μmol, 1 eq) and compound 28-10 (19.64 mg, 77.12 μmol, 0.88 eq, HCl) in DMF (2 mL), HATU (66.65 mg, 175.28 μmol, 2 eq) and DIEA (56.63 mg, 438.20 μmol, 76.32 μL, 5 eq) were added, and the reaction was stirred at 25 °C for 12 h. No starting material remained and the desired product was observed by LCMS. The reaction was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with saturated NaCl (10 mL × 3), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium hydroxide v / v)-ACN], gradient: 22% to 52% B over 9 min) to give compound 28 (0.007 g, 16.14 μmol, 18.41% yield, 98.75% purity), which was confirmed by H NMR, F NMR, LCMS, HPLC, and SFC.

[0399] H NMR: (400 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.32 (s, 1H), 8.12 (d, J = 7.2 Hz, 1H), 7.92 (s, 1H), 7.59-7.42 (m, 5H), 6.54-5.92 (m, 1H), 5.04-4.80 (m, 1H), 4.78-4.62 (m, 1H), 2.77 (brs, 3H).

[0400] Step 10: Synthesis of Compound 29 [ka] To a solution of compound 28-12 (0.04 g, 174.52 μmol, 1 eq) in DMF (2 mL), HATU (99.54 mg, 261.79 μmol, 1.5 eq) and DIEA (112.78 mg, 872.62 μmol, 151.99 μL, 5 eq) were added. After stirring for 15 min, compound 28-10 (42.22 mg, 165.80 μmol, 0.95 eq, HCl) was added to the mixture, and the reaction was stirred at 25 °C for 12 h. No starting material remained and the desired product was observed by LCMS. The reaction was diluted with water (15 mL) and extracted with EA (15 mL × 3). The combined organic layers were washed with saturated NaCl (15 mL × 2), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm × 10 μm, mobile phase: [water (HCl)-ACN], gradient: 14% to 44% B over 9 min) and (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: [water (ammonium hydroxide v / v)-ACN], gradient: 10% to 40% B over 9 min) to give compound 29 (0.011 g, 25.12 μmol, 14.39% yield, 98.03% purity), which was characterized by NMR, FNMR, LCMS, HPLC, and SFC.

[0401] H NMR: (400 MHz, DMSO-d) δ 9.39-9.27 (m, 1H), 8.73-8.64 (m, 1H), 8.59-8.47 (m, 1H), 8.22-7.94 (m, 2H), 7.82-7.69 (m, 2H), 7.51 (d, J = 7.6 Hz, 1H), 6.37-6.01 (m, 1H), 5.01-4.66 (m, 2H), 2.97-2.71 (m, 3H).

[0402] [Example 20] Synthesis of Compounds 30 and 31 [ka]

[0403] Step 1: Synthesis of compound 30-3 [ka] To a solution of compound 30-2 (4.93 g, 47.3 mmol, 4.56 mL, 1.20 eq) in DMA (100 mL) was added NaH (3.15 g, 78.9 mmol, 60.0% purity, 2.00 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then, a solution of compound 30-1 (10.0 g, 39.4 mmol, 1.00 eq) in DMA (20.0 mL) was added dropwise at 0 °C, and the mixture was stirred at 25 °C for 1 h. LC-MS showed that compound 30-1 was consumed, and a peak corresponding to the desired mass was detected. Saturated NH4Cl solution (150 mL) was added to the mixture at 0 °C. The mixture was then filtered, and the filtrate cake was concentrated to give a residue. Compound 30-3 (5.50 g, 20.0 mmol, 50.7% yield) was obtained as a yellow solid, which was confirmed by H NMR and F NMR.

[0404] H NMR: (400 MHz, DMSO-d) δ 8.70 (s, 1H), 8.24 (s, 1H), 4.19 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H).

[0405] Step 2: Synthesis of compound 30-4 [ka] A mixture of compound 30-3 (5.50 g, 20.0 mmol, 1.00 eq) in HCl (12.0 M, 50.0 mL, 30.0 eq) was stirred at 100 °C for 2 h. LC-MS showed that compound 30-3 was consumed, and a peak with the desired mass was detected. The mixture was diluted with HO (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic phases were washed with brine (100 mL × 2), dried over NaSO, and concentrated to give a residue. Compound 30-4 (3.20 g, 15.8 mmol, 78.8% yield) was obtained as a yellow solid, which was confirmed by H NMR and F NMR.

[0406] H NMR: (400 MHz, DMSO-d) δ 10.06 (s, 1H), 8.86 (s, 1H), 8.44 (s, 1H), 8.09 (s, 1H).

[0407] Step 3: Synthesis of compound 30-5 [ka] To a solution of compound 30-4 (2.00 g, 9.85 mmol, 1.00 eq) in EtOH (20.0 mL) was added NaBH (745 mg, 19.7 mmol, 2.00 eq) at 0 °C, and the mixture was stirred at 25 °C for 1 h. LC-MS showed that compound 30-4 was consumed, and a peak with the desired mass was detected. Saturated NH Cl solution (30.0 mL) was added to the mixture at 0 °C, followed by extraction with DCM (30.0 mL × 3). The combined organic phases were dried over Na SO and concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 100:1 to 3:1). TLC (petroleum ether:ethyl acetate = 3:1, R f =0.30). Compound 30-5 (1.30 g, 6.34 mmol, 64.4% yield) was obtained as a yellow solid, which was characterized by H NMR and F NMR.

[0408] H NMR:(400MHz,DMSO-d6)δ8.49(s,1H),7.70(d,J=0.8Hz,1H),6.11(d,J=6.0Hz,1H),5.27-5 .23(m,1H),4.74(dd,J1=10.8Hz,J2=7.2Hz,1H),4.42(dd,J1=10.8Hz,J2=3.2Hz,1H).

[0409] Step 4: Synthesis of compound 30-6 [ka] To a solution of compound 30-5 (500 mg, 2.44 mmol, 1.00 eq) in Toluene (10.0 mL), DPPA (805 mg, 2.92 mmol, 631 μL, 1.20 eq) and a solution of DBU (445 mg, 2.92 mmol, 441 μL, 1.20 eq) in Toluene (1.00 mL) were added, and the mixture was stirred at 25 °C for 2 h. LC-MS showed that compound 30-5 was consumed, and a peak corresponding to the desired mass was detected. Saturated NH4Cl solution (30.0 mL) was added to the mixture at 0 °C, followed by extraction with DCM (30.0 mL × 3). The combined organic phases were dried over Na2SO4 and concentrated to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 100:1 to 5:1). TLC (petroleum ether:ethyl acetate = 5:1, R f =0.70). Compound 30-6 (500 mg, 2.17 mmol, 89.1% yield) was obtained as a yellow oil and characterized by H NMR and F NMR.

[0410] H NMR:(400MHz,DMSO-d6)δ8.58(s,1H),7.84(d,J=1.2Hz,1H),5.59(dd,J1=8.0Hz,J2=3. 2Hz, 1H), 4.83 (dd, J1=10.8Hz, J2=8.0Hz, 1H), 4.42 (dd, J1=10.8Hz, J2=3.2Hz, 1H).

[0411] Step 5: Synthesis of compound 30-7 [ka] To a solution of compound 30-6 (450 mg, 1.96 mmol, 1.00 eq) in THF (2.00 mL), PPh3 (769 mg, 2.93 mmol, 1.50 eq) was added, and the mixture was stirred at 25 °C for 1 h. After that, KOH (274 mg, 4.89 mmol, 2.50 eq) in HO (1.00 mL) was added, and the mixture was stirred at 25 °C for 12 h. LC-MS showed that compound 30-6 was consumed, and a peak corresponding to the desired mass was detected. The mixture was diluted with HO (20.0 mL) and extracted with EtOAc (20.0 mL × 3). The combined organic phases were dried over Na2SO4 and concentrated to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 100:1 to 0:1). TLC (petroleum ether:ethyl acetate = 0:1, R f =0.20). Compound 30-7 (300 mg, 1.47 mmol, yield 75.2%) was obtained as a yellow solid.

[0412] Step 6: Synthesis of compound 30-8 [ka] To a solution of compound 30-7 (300 mg, 1.47 mmol, 1.00 eq) in DCM (5.00 mL), TEA (446 mg, 4.41 mmol, 614 μL, 3.00 eq) and (Boc)O (641 mg, 2.94 mmol, 675 μL, 2.00 eq) were added, and the mixture was stirred at 25 °C for 2 h. LC-MS showed that compound 30-7 was consumed, indicating a peak corresponding to the desired mass. The mixture was diluted with HO (20.0 mL) and extracted with EtOAc (20.0 mL × 3). The combined organic phases were dried over NaSO and concentrated to give the residue. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 100:1 to 5:1). TLC (petroleum ether:ethyl acetate = 3:1, R f =0.60). Compound 30-8 (300 mg, 986 μmol, 67.1% yield) was obtained as a yellow solid and was characterized by H NMR and F NMR.

[0413] H NMR: (400 MHz, DMSO-d) δ 8.45 (s, 1H), 7.63 (s, 2H), 5.35-5.30 (m, 1H), 4.88 (t, J = 9.2 Hz, 1H), 4.36-4.32 (m, 1H), 1.39 (s, 9H).

[0414] Step 7: Synthesis of compound 30-9 [ka] To a solution of compound 30-8 (300 mg, 986 μmol, 1.00 eq) in THF (5.00 mL) was added NaH (59.2 mg, 1.48 mmol, 60.0% purity, 1.50 eq) at 0 °C, followed by CHCl (420 mg, 2.96 mmol, 184 μL, 3.00 eq), and the mixture was stirred at 25 °C for 2 h. LC-MS showed that compound 30-8 was consumed, and a peak corresponding to the desired mass was detected. A solution of saturated NH Cl (20.0 mL) was added to the mixture at 0 °C, followed by extraction with EtOAc (20.0 mL × 3). The combined organic phase was washed with brine (20.0 mL × 2), dried over Na SO , and concentrated to give a residue. The residue was purified by preparative HPLC (Waters Xbridge 150 × 25 mm × 5 μm column, mobile phase: [water (NH4HCO3)-ACN], gradient: 37% to 57% B over 10 min) to give compound 30-9 (200 mg, 628 μmol, 63.7% yield) as a yellow solid, which was characterized by H NMR and F NMR.

[0415] H NMR: (400 MHz, DMSO-d) δ 8.47 (s, 1H), 7.67 (s, 1H), 5.91-5.52 (m, 1H), 4.88 (t, J = 9.6 Hz, 1H), 4.59 (dd, J = 10.0 Hz, J = 6.0 Hz, 1H), 2.54 (s, 3H), 1.41-1.21 (m, 9H).

[0416] Step 8: Synthesis of compound 30-10 [ka] To a solution of compound 30-9 (200 mg, 628 μmol, 1.00 eq) in DCM (2.00 mL) was added HCl / dioxane (2 M, 4.00 mL, 12.7 eq) at 0 °C, followed by stirring at 25 °C for 1 h. LC-MS showed that compound 30-9 was consumed and a peak with the desired mass was detected. The mixture was concentrated to give a residue. Compound 30-10 (160 mg, crude, HCl) was obtained as a yellow solid.

[0417] Step 9: Synthesis of Compound 30 [ka] To a solution of compound 30-10 (30.0 mg, 118 μmol, 1.00 eq, HCl) and compound 30-11 (26.9 mg, 118 μmol, 1.00 eq) in DMF (1.00 mL), HATU (67.2 mg, 177 μmol, 1.50 eq) and DIEA (76.1 mg, 589 μmol, 103 μL, 5.00 eq) were added, and the mixture was stirred at 25 °C for 2 h. LC-MS showed that compound 30-10 was consumed, and a peak corresponding to the desired mass was detected. The mixture was diluted with HO (20.0 mL) and extracted with EtOAc (20.0 mL × 3). The combined organic phase was washed with brine (20.0 mL × 2), dried over NaSO, and concentrated to give a residue. The residue was purified by preparative HPLC (Waters Xbridge 150 × 25 mm × 5 μm column, mobile phase: [water (ammonium hydroxide v / v)-ACN], gradient: 22% to 52% B over 9 min) to give compound 30 (10.66 mg, 24.6 μmol, 20.9% yield, 99.0% purity), which was characterized by H NMR, F NMR, LC-MS, HPLC, and SFC.

[0418] H NMR: (400 MHz, DMSO-d) δ 9.18-9.13 (m, 1H), 8.62-8.34 (m, 2H), 7.91 (s, 1H), 7.77 (s, 1H), 7.48-7.46 (m, 4H), 6.27-5.86 (m, 1H), 5.02-4.79 (m, 2H), 2.82-2.67 (m, 3H).

[0419] H NMR: (400 MHz, DMSO-d₆) δ 9.04 (s, 1H), 8.55 (s, 1H), 8.34 (s, 1H), 7.92 (s, 1H), 7.61 (s, 1H), 7.50 (s, 2H), 7.08 (s, 2H), 6.06-6.03 (m, 1H), 4.94 (t, J = 9.6 Hz, 1H), 4.81 (dd, J = 10.4 Hz, J = 5.2 Hz, 1H), 2.80 (s, 3H).

[0420] Step 10: Synthesis of Compound 31 [ka] To a solution of compound 30-10 (30.0 mg, 118 μmol, 1.00 eq, HCl) and compound 12 (27.0 mg, 118 μmol, 1.00 eq) in DMF (1.00 mL), HATU (67.2 mg, 177 μmol, 1.50 eq) and DIEA (76.1 mg, 589 μmol, 103 μL, 5.00 eq) were added, and the mixture was stirred at 25 °C for 2 h. LC-MS showed that compound 30-12 was consumed, and a peak corresponding to the desired mass was detected. The mixture was diluted with HO (20.0 mL) and extracted with EtOAc (20.0 mL × 3). The combined organic phase was washed with brine (20.0 mL × 2), dried over NaSO, and concentrated to give a residue. The residue was purified by preparative HPLC (Waters Xbridge 150 × 25 mm × 5 μm column, mobile phase: [water (ammonium hydroxide v / v)-ACN], gradient: 20% to 50% B over 9 min) to give compound 31 (8.52 mg, 18.8 μmol, 15.9% yield, 94.5% purity), which was characterized by H NMR, F NMR, LC-MS, HPLC, and SFC.

[0421] H NMR:(400MHz,DMSO-d6)δ9.32(d,J=9.2Hz,1H),8.66(t,J=10.0Hz,1H),8.60-8.50(m,2H),7.98(d,J=4.8H z, 1H), 7.75-7.32 (m, 3H), 6.26-6.08 (m, 1H), 5.05-5.00 (m, 1H), 4.90-4.75 (m, 1H), 2.91-2.71 (m, 3H).

[0422] H NMR:(400MHz,DMSO-d6)δ9.18(s,1H),8.67(s,1H),8.47(d,J=6.8Hz,2H),7.99(s,1H),7.58(s,1H),7.34(s,2H), 6.21 (dd, J1=9.6Hz, J2=5.6Hz, 1H), 5.02 (t, J=10.0Hz, 1H), 4.80 (dd, J1=10.0Hz, J2=5.6Hz, 1H), 2.87 (s, 3H).

[0423] [Example 21] Synthesis of Compounds 32 and 33 [ka]

[0424] Step 1: Synthesis of compound 32-2 [ka] To a solution of 2,2,6,6-tetramethylpiperidine (122 g, 863 mmol, 147 mL, 3.00 eq) in THF (1000 mL), n-BuLi (2.5 M, 345 mL, 3.00 eq) was added dropwise at -70 °C. The reaction mixture was then stirred at -70 °C to -30 °C for 30 min. The mixture was then cooled to -70 °C, and a solution of compound 32-1 (55.0 g, 288 mmol, 1.00 eq) in THF (1000 mL) was added dropwise at -70 °C. The mixture was then stirred at -70 °C to -40 °C for another 1 h. The mixture was then cooled to -70 °C, and a solution of 1,1,1,2,2,2-hexachloroethane (136 g, 576 mmol, 65.2 mL, 2.00 eq) in THF (300 mL) was added dropwise to the above solution. The reaction mixture was stirred at -70 °C for 3 h. LC-MS showed that compound 32-1 was completely consumed, with one major peak having the desired m / z. The reaction mixture was quenched with NH4Cl (1000 mL) and extracted with 3000 mL of EtOAc (1000 mL x 3). The combined organic layers were washed with 3000 mL of brine (1500 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1, plate 1, PE:EtOAc = 0:1, R f =0.24) to give compound 32-2 (35.0 g, 155 mmol, 53.9% yield) as a yellow solid.

[0425] H NMR: (400 MHz, CD3OD) δ 9.10 (s, 1H), 8.03 (s, 1H).

[0426] Step 2: Synthesis of compound 32-3 [ka] To a solution of compound 32-2 (10.0 g, 44.3 mmol, 1.00 eq) in DMF (100 mL) was added Na2CO3 (9.40 g, 88.7 mmol, 2.00 eq) and MeI (18.9 g, 133 mmol, 8.28 mL, 3.00 eq). The mixture was stirred at 25 °C for 2 h. LC-MS showed complete consumption of compound 32-2, with one major peak having the desired m / z. The reaction mixture was quenched with NaHCO3 (100 mL) and extracted with 300 mL of EtOAc (100 mL × 3). The combined organic layers were washed with 300 mL of brine (150 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA conditions, column: Phenomenex luna C18 150 × 25 mm × 10 μm, mobile phase: [water (FA)-ACN], gradient: 42% to 62% B over 10 min) to give compound 32-3 (10.0 g, 41.7 mmol, 94.2% yield) as a yellow oil.

[0427] H NMR: (400 MHz, CDCl) δ 9.12 (s, 1H), 7.80 (s, 1H), 4.02 (s, 3H).

[0428] Step 3: Synthesis of compound 32-5 [ka] To a solution of compound 32-4 (4.69 g, 45.1 mmol, 1.00 eq) in DMF (20 mL) was added NaH (3.45 g, 90.2 mmol, 2.00 eq) dropwise at 0 °C, and the mixture was stirred at 25 °C for 0.5 h. Next, compound 32-3 (9.00 g, 90.2 mmol, 1.00 eq) was added. The resulting mixture was stirred at 25 °C for 2 h. LC-MS showed complete consumption of compound 32-3, with one major peak having the desired m / z. The reaction mixture was quenched with NH4Cl (100 mL) and extracted with 300 mL of EtOAc (100 mL × 3). The combined organic layers were washed with 300 mL of brine (150 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1, PE: EtOAc = 1:1, R f =0.40) to give compound 32-5 (6.80 g, 24.7 mmol, 65.8% yield) as a brown solid.

[0429] H NMR: (400 MHz, CDCl) δ 9.17 (s, 1H), 7.81 (s, 1H), 4.55-4.50 (m, 2H), 4.06 (s, 1H), 1.48 (d, J = 7.2 Hz, 3H).

[0430] Step 4: Synthesis of compound 32-6 [ka] A solution of compound 32-5 (6.8 g, 24.7 mmol, 1.00 eq) in HCl (12 M, 20 mL, 10.0 eq) was stirred at 110 °C for 2 h. LC-MS showed complete consumption of compound 32-5, with one major peak having the desired m / z. The reaction mixture was diluted (30.0 mL) and extracted with 60.0 mL of EtOAc (20.0 mL × 3). The combined organic layers were washed with 30.0 mL of brine (15.0 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Compound 32-6 (5.00 g, crude) was obtained as a yellow solid.

[0431] Step 5: Synthesis of compound 32-7 [ka] To a solution of compound 32-6 (5.00 g, crude, 1.00 eq) in EtOH (50.0 mL), NaOAc (4.85 g, 59.1 mmol, 3.00 eq) and hydroxylamine hydrochloride (4.11 g, 59.08 mmol, 3.00 eq) were added. The mixture was stirred at 25 °C for 1 h. LC-MS showed complete consumption of compound 32-6, with one major peak having the desired m / z. The reaction mixture was concentrated under reduced pressure to remove EtOH, then diluted with 100 mL of water and extracted with 300 mL of EtOAc (100 mL × 3). The combined organic layers were washed with 300 mL of brine (150 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1, PE:EtOAc = 1:1, R f =0.40) to give compound 32-7 (2.10 g, 9.34 mmol, 39% yield over two steps) as a yellow solid.

[0432] Step 6: Synthesis of compound 32-8 [ka] To a solution of compound 32-7 (2.00 g, 9.34 mmol, 1.00 eq) in MeOH (50.0 mL) under N2, Raney nickel (50.0 mg, 5.84 mmol, 0.200 eq) and NH3·HO (3.29 g, 23.50 mmol, 3.62 mL, 25% purity, 2.50 eq) were added. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (50 psi) at 80 °C for 16 h. LC-MS showed that compound 32-7 was consumed, with one major peak having the desired m / z. The reaction mixture was filtered, and the solid was collected and concentrated under reduced pressure to give a residue. The crude product, compound 32-8 (2.0 g, crude), was used in the next step without further purification as a brown oil.

[0433] Step 7: Synthesis of compound 32-9 [ka] To a solution of compound 32-8 (2.00 g, crude, 1.00 eq) in DCM (20.0 mL) was added TEA (3.47 g, 34.29 mmol, 4.77 mL, 4.00 eq) and BocO (4.12 g, 18.9 mmol, 4.33 mL, 2.00 eq). The mixture was stirred at 25 °C for 2 h. LC-MS showed complete consumption of compound 32-8, with one major peak having the desired m / z. The reaction mixture was diluted with 10.0 mL of water and extracted with DCM (15.0 mL × 3). The combined organic layers were washed with 30.0 mL of brine (15.0 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA conditions: column: Phenomenex luna C18 (250 × 70 mm, 10 μm), mobile phase: [water (FA)-ACN], gradient: 35% to 65% B over 22 min) to give compound 32-9 (400 mg, 1.31 mmol, 14.3% yield over two steps) as a yellow oil.

[0434] H NMR: (400 MHz, CDCl) δ 8.62 (s, 1H), 7.18 (s, 1H), 5.51 (brs, 1H), 4.96-4.91 (m, 2H), 4.56-4.52 (m, 1H), 1.48 (s, 9H).

[0435] Step 8: Synthesis of compound 32-10 [ka] To a solution of compound 32-9 (400 mg, 1.31 mmol, 1.00 eq) in THF (5.00 mL) was added NaH (78.9 mg, 1.97 mmol, 60% purity, 1.50 eq) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Next, MeI (187 mg, 1.31 mmol, 81.8 μL, 1.00 eq) was added to the mixture. The mixture was stirred at 20 °C for an additional 2 h. LC-MS showed that compound 32-9 was completely consumed, with one major peak having the desired m / z. The reaction mixture was diluted with 100 mL of water and extracted with 300 mL of EA (100 mL × 3). The combined organic layers were washed with 300 mL of brine (150 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1, PE: EtOAc = 5:1, R f =0.40) to give compound 32-10 (350 mg, 1.10 mmol, 83.64% yield) as a yellow oil.

[0436] H NMR: (400 MHz, CDCl) δ 8.51 (s, 1H), 7.18 (s, 1H), 6.19-5.89 (m, 1H), 4.81-4.76 (m, 1H), 4.57-4.55 (m, 1H), 2.60 (brs, 3H), 1.50 (s, 9H).

[0437] Step 9: Synthesis of compound 32-11 [ka] To a solution of compound 32-10 (350 mg, 1.10 mmol, 1.00 eq) in DCM (10.0 mL) was added HCl / dioxane (2 M, 10 mL, 18.19 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed complete consumption of compound 32-10, with one major peak having the desired m / z. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 32-11 (250 mg, 0.981 mmol, 89.3% yield, HCl) was obtained as a yellow oil.

[0438] Step 10: Synthesis of Compound 32 [ka] To a solution of compound 32-12 (40.0 mg, 175 μmol, 1.00 eq) and compound 32-11 (44.6 mg, 175 μmol, 1.00 eq, HCl) in DMF (2.00 mL) was added HATU (99.5 mg, 262 μmol, 1.50 eq) and DIEA (67.7 mg, 524 μmol, 5.00 eq). The mixture was stirred at 25 °C for 1 h. LC-MS showed that compound 32-12 was consumed, with one peak having the desired m / z. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (neutral conditions, column: Waters Xbridge C18 150 × 50 mm × 10 μm, mobile phase: [water (NH4HCO3)-ACN], gradient: 20% to 50% B over 10 min). Compound 32 (21.6 mg, 49.0 μmol, yield 28.0%, purity 97.18%) was obtained.

[0439] H NMR: (400 MHz, DMSO-d) δ 9.18 (s, 1H), 8.73 (s, 1H), 8.33 (s, 1H), 7.91 (s, 1H), 7.53-7.46 (m, 5H), 6.38-6.28 (m, 0.5H), 4.99-4.82 (m, 2H), 2.74 (s, 3H).

[0440] Step 11: Synthesis of Compound 33 [ka] To a solution of compound 32-13 (40.0 mg, 175 μmol, 1.00 eq) and compound 32-11 (44.4 mg, 175 μmol, 1.00 eq, HCl) in DMF (2.00 mL) was added HATU (99.5 mg, 262 μmol, 1.50 eq) and DIEA (67.7 mg, 524 μmol, 5.00 eq). The mixture was stirred at 25 °C for 1 h. LC-MS showed that compound 32-13 was consumed, with one peak having the desired m / z. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (neutral conditions, column: Waters Xbridge C18 150 × 50 mm × 10 μm, mobile phase: [water (NH4HCO3)-ACN], gradient: 21% to 51% B over 10 min). Compound 33 (18.53 mg, 41.2 μmol, yield 23.6%, purity 95.44%) was obtained.

[0441] H NMR: (400 MHz, DMSO-d) δ 9.33-9.29 (m, 1H), 8.82-8.83 (m, 1H), 8.65-8.51 (m, 2H), 8.00-7.98 (m, 1H), 7.80-7.74 (m, 2H), 7.55-7.53 (m, 1H), 6.42-6.11 (m, 1H), 5.02-4.82 (m, 2H), 2.86-2.72 (m, 3H).

[0442] [Example 22] Synthesis of Compound 34 [ka]

[0443] Step 1: Synthesis of compound 34-2 [ka] To a solution of compound 34-1 (7.00 g, 38.9 mmol, 4.89 mL, 1.00 eq) in DCM (70.0 mL) was added DIEA (10.1 g, 77.7 mmol, 13.5 mL, 2.00 eq) and MOMCl (5.10 g, 40.8 mmol, 3.33 mL, 1.05 eq) at 0 °C, and the mixture was stirred at 25 °C for 2 h. TLC (petroleum ether:ethyl acetate = 5:1) showed that compound 34-1 was consumed and a new spot formed. The mixture was diluted with saturated NH4Cl solution (100 mL) and then extracted with DCM (100 mL × 3). The combined organic phases were dried over Na2SO4 and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:0 to 10:1). Compound 34-2 (8.00 g, 35.7 mmol, 91.8% yield) was obtained as a yellow liquid and was confirmed by H NMR and F NMR.

[0444] H NMR: (400 MHz, DMSO-d) δ 7.62-7.58 (m, 1H), 7.38-7.34 (m, 2H), 5.33 (s, 2H), 3.42 (s, 3H).

[0445] Step 2: Synthesis of compound 34-3 [ka] To a solution of compound 34-2 (8.00 g, 35.7 mmol, 1.00 eq) in THF (80.0 mL), n-BuLi (2.5 M, 17.1 mL, 1.20 eq) was added dropwise at −78 °C. The mixture was stirred at −78 °C for 1 h. Then, I2 (10.9 g, 42.8 mmol, 8.63 mL, 1.20 eq) in THF (20.0 mL) was added dropwise, and the mixture was stirred at 25 °C for 1 h. TLC (petroleum ether:ethyl acetate = 5:1) showed that approximately 40% of compound 34-2 remained, and a new spot formed. The mixture was diluted with saturated NH4Cl solution (200 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic phase was washed with brine (200 mL × 2), dried over Na2SO4, and concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate=1:0 to 10:1) to give compound 34-3 (8.00 g, crude) as a yellow liquid, which was confirmed by H NMR and F NMR.

[0446] H NMR: (400 MHz, DMSO-d) δ 7.90 (d, J = 4.8 Hz, 1H), 7.30-7.28 (m, 1H), 5.23 (s, 2H), 3.55 (s, 3H).

[0447] Step 3: Synthesis of compound 34-4 [ka] To a solution of compound 34-3 (8.00 g, 22.9 mmol, 1.00 eq) in DMF (50.0 mL) and MeOH (50.0 mL), TEA (11.6 g, 114 mmol, 15.9 mL, 5.00 eq) and Pd(dppf)Cl₂·CHCl₂ (1.87 g, 2.29 mmol, 0.100 eq) were added under N₂, and the mixture was stirred at 80 °C for 12 h under a CO₂ (50 Psi) atmosphere. TLC (petroleum ether:ethyl acetate = 10:1) showed that compound 34-3 was completely consumed and a new spot formed. The mixture was concentrated to remove MeOH, then diluted with H₂ (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The combined organic phase was washed with brine (50.0 mL × 2), dried over Na₂SO₄, and concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate=1:0 to 10:1) to give compound 34-4 (4.50 g, crude) as a yellow solid, which was confirmed by H NMR and F NMR.

[0448] H NMR: (400 MHz, DMSO-d) δ 10.81 (brs, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.28-7.27 (m, 1H), 3.91 (s, 3H).

[0449] Step 4: Synthesis of compound 34-6 [ka] To a solution of compound 34-4 (2.00 g, 8.40 mmol, 1.00 eq) and compound 34-5 (1.68 g, 10.1 mmol, 1.12 mL, 1.20 eq) in acetone (25.0 mL), K2CO3 (5.80 g, 42.0 mmol, 5.00 eq) was added, and the mixture was stirred at 60 °C for 12 h. LC-MS showed that compound 34-4 was consumed, and a peak with the desired mass was detected. The mixture was filtered, and the filtrate was concentrated to give a residue. The residue was purified by preparative HPLC (column: Welch Ultimate XB-CN2 50 × 50 × 10 μm, mobile phase: [hexane-EtOH], B%: 0%, isocratic elution mode). Compound 34-6 (1.10 g, 3.39 mmol, 40.4% yield) was obtained as a yellow liquid, and was confirmed by H NMR and F NMR.

[0450] H NMR: (400 MHz, DMSO-d) δ 7.69 (d, J = 8.4 Hz, 1H), 7.63-7.60 (m, 1H), 4.84 (s, 2H), 4.17-4.15 (m, 2H), 3.96 (s, 3H), 1.21 (s, 3H).

[0451] Step 5: Synthesis of compound 34-7 [ka] To a solution of compound 34-6 (1.10 g, 3.39 mmol, 1.00 eq) in MeOH (11.0 mL), NaOH (2.00 M, 5.09 mL, 3.00 eq) was added, and the mixture was stirred at 25 °C for 3 h. LC-MS showed the consumption of compound 34-6. The mixture was concentrated to give a residue. The pH was adjusted to approximately 3 by adding HCl (1 M) at 0 °C, diluted with HO (30.0 mL), and extracted with ethyl acetate (30.0 mL × 3). The combined organic phases were dried over NaSO and concentrated to give a residue. Compound 34-7 (780 mg, 2.76 mmol, 81.5% yield) was obtained as a yellow solid, which was confirmed by H NMR and F NMR.

[0452] LC-MS: (M+H) + :283.0.

[0453] H NMR: (400 MHz, DMSO-d) δ 7.65-7.63 (m, 1H), 7.57-7.54 (m, 1H), 4.74 (s, 2H).

[0454] Step 6: Synthesis of compound 34-8 [ka] To a solution of compound 34-7 (780 mg, 2.76 mmol, 1.00 eq) in AcO (8.00 mL), NaOAc (272 mg, 3.32 mmol, 1.20 eq) and AcOH (606 mg, 10.1 mmol, 578 μL, 3.65 eq) were added, and the mixture was stirred at 140 °C for 2 h. LC-MS showed that compound 34-7 was consumed, and a peak corresponding to the desired mass was detected. The mixture was diluted with HO (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic phases were washed with brine (20.0 mL × 2), dried over NaSO, and concentrated to give a residue. Compound 34-8 (650 mg, 2.48 mmol, 89.7% yield) was obtained as a yellow solid, which was confirmed by H NMR and F NMR.

[0455] LC-MS: (M+H) + :263.0.

[0456] H NMR: (400 MHz, DMSO-d) δ 8.56 (s, 1H), 7.66-7.65 (m, 2H), 2.40 (s, 3H).

[0457] Step 7: Synthesis of compound 34-9 [ka] To a solution of compound 34-8 (650 mg, 2.48 mmol, 1.00 eq) in MeOH (10.0 mL) and HO (2.00 mL), KCO (1.03 g, 7.44 mmol, 3.00 eq) was added, and the mixture was stirred at 25 °C for 0.5 h. LC-MS showed that compound 34-8 was consumed, and a peak corresponding to the desired mass was detected. The pH was adjusted to approximately 5 by adding HCl (1.00 M) at 0 °C, diluted with HO (20.0 mL), and extracted with DCM (20.0 mL × 3). The combined organic phases were dried over NaSO and concentrated to give a residue. Compound 34-9 (500 mg, crude) was obtained as a yellow solid, which was confirmed by H NMR and F NMR.

[0458] H NMR: (400 MHz, DMSO-d) δ 7.67 (d, J = 8.0 Hz, 1H), 7.50-7.47 (m, 1H), 5.03 (s, 2H).

[0459] Step 8: Synthesis of compound 34-10 [ka] To a solution of compound 34-9 (500 mg, 2.27 mmol, 1.00 eq) in EtOH (10.0 mL), NaOAc (559 mg, 6.81 mmol, 3.00 eq) and NHOH·HCl (316 mg, 4.54 mmol, 2.00 eq) were added, and the mixture was stirred at 25 °C for 2 h. LC-MS showed that compound 34-9 was consumed, and a peak corresponding to the desired mass was detected. The mixture was diluted with HO (20.0 mL) and extracted with DCM (20.0 mL × 3). The combined organic phases were dried over NaSO and concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 100:1 to 5:1). TLC (petroleum ether:ethyl acetate = 5:1, R f =0.60). Compound 34-10 (400 mg, crude) was obtained as a yellow solid and was characterized by H NMR and F NMR.

[0460] LC-MS: (M+H) + :236.0.

[0461] H NMR: (400 MHz, DMSO-d) δ 11.94 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.35 (dd, J = 8.0 Hz, J = 6.0 Hz, 1H), 5.37 (s, 2H).

[0462] Step 9: Synthesis of compound 34-11 [ka] To a solution of compound 34-10 (400 mg, 1.70 mmol, 1.00 eq) in MeOH (10.0 mL), NH3·HO (910 mg, 6.49 mmol, 1.00 mL, 25.0% purity, 3.82 eq) and Raney nickel (100 mg) were added under N2, and the mixture was stirred at 80 °C under H2 (50 Psi) for 12 h. LC-MS showed that compound 34-10 was consumed, and a peak corresponding to the desired mass was detected. The mixture was filtered, and the filtrate was concentrated to give a residue. Compound 34-11 (350 mg, crude) was obtained as a yellow solid, which was confirmed by H NMR and F NMR.

[0463] H NMR: (400 MHz, DMSO-d) δ 7.37-7.35 (m, 1H), 7.27-7.24 (m, 1H), 6.99-6.76 (m, 1H), 4.82-4.74 (m, 1H), 4.35-4.25 (m, 1H).

[0464] Step 10: Synthesis of compound 34-12 [ka] To a solution of compound 34-10 (350 mg, 1.58 mmol, 1.00 eq) in DCM (5.00 mL), TEA (480 mg, 4.75 mmol, 661 μL, 3.00 eq) and BocO (691 mg, 3.17 mmol, 727 μL, 2.00 eq) were added, and the mixture was stirred at 25 °C for 1 h. LC-MS showed the peak of compound 34-11, indicating its consumption. The mixture was diluted with HO (20.0 mL) and extracted with DCM (20.0 mL × 3). The combined organic phases were dried over NaSO and concentrated to give the residue. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 100:1 to 5:1). TLC (petroleum ether:ethyl acetate = 5:1, R f =0.50). Compound 34-12 (180 mg, 560 μmol, yield 35.4%) was obtained as a yellow solid and was characterized by H NMR and F NMR.

[0465] H NMR: (400 MHz, DMSO-d) δ 7.72-7.67 (m, 1H), 7.30-7.24 (m, 2H), 5.42-5.38 (m, 1H), 4.85 (t, J = 9.2 Hz, 1H), 4.44-4.40 (m, 1H), 1.40 (s, 9H).

[0466] Step 11: Synthesis of compound 34-13 [ka] To a solution of compound 34-12 (180 mg, 560 μmol, 1.00 eq) in THF (5.00 mL), NaH (33.6 mg, 840 μmol, 60.0% purity, 1.50 eq) was added at 0 °C. The mixture was stirred at 0 °C for 0.5 h, and then CD3I (238 mg, 1.68 mmol, 102 μL, 3.00 eq) was added, and the mixture was stirred at 25 °C for 4 h. LC-MS showed that compound 34-12 had been consumed, indicating a peak. A solution of saturated NH4Cl (20.0 mL) was added to the mixture at 0 °C, followed by extraction with ethyl acetate (20.0 mL × 3). The combined organic phases were washed with brine (20.0 mL × 2), dried over Na2SO4, and concentrated to give a residue. The residue was analyzed by preparative TLC (petroleum ether:ethyl acetate = 5:1, R f =0.60), Compound 34-13 (120 mg, 355 μmol, 63.3% yield) was obtained as a yellow solid, which was characterized by H NMR and F NMR.

[0467] H NMR: (400 MHz, DMSO-d) δ 7.31-7.28 (m, 2H), 6.04-5.68 (m, 1H), 4.83 (t, J = 10.0 Hz, 1H), 4.65 (dd, J = 10.0 Hz, J = 4.4 Hz, 1H), 1.35 (s, 9H).

[0468] Step 12: Synthesis of compound 34-14 [ka] To a solution of compound 34-13 (120 mg, 355 μmol, 1.00 eq) in DCM (1.00 mL) was added HCl / dioxane (2.00 M, 2.00 mL, 11.3 eq) at 0 °C, and the mixture was stirred at 25 °C for 2 h. LC-MS showed that compound 34-13 was consumed and a new peak was detected. The mixture was concentrated to give a residue. Compound 34-14 (95.0 mg, crude, HCl) was obtained as a yellow solid.

[0469] Step 12: Synthesis of Compound 34 [ka] To a solution of compound 34-14 (95.0 mg, 346 μmol, 1.00 eq, HCl) and compound 34-15 (83.2 mg, 363 μmol, 1.05 eq) in DMF (2.00 mL), HATU (197 mg, 519 μmol, 1.50 eq) and DIEA (134 mg, 1.04 mmol, 181 μL, 3.00 eq) were added, and the mixture was stirred at 25 °C for 1 h. LC-MS showed that compound 34-14 was consumed and a new peak was detected. The mixture was diluted with HO (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic phase was washed with brine (20.0 mL × 2), dried over NaSO, and concentrated to give a residue. The residue was purified by preparative HPLC (Waters Xbridge C18 150 × 50 mm × 10 μm column, mobile phase: [water (NH4HCO3)-ACN], gradient: 22% to 52% B over 10 min), affording compound 34 (21.11 mg, 47.0 μmol, 13.6% yield) as a yellow solid, which was characterized by H NMR, F NMR, LC-MS, HPLC, and SFC.

[0470] H NMR: (400 MHz, DMSO-d) δ 9.22 (s, 1H), 8.68 (s, 1H), 8.48 (s, 1H), 8.00 (s, 1H), 7.51-7.45 (m, 3H), 7.33-7.30 (m, 1H), 6.25 (brs, 1H), 4.92-4.80 (m, 2H).

[0471] LC-MS: (M+H) + :450.2.

[0472] HPLC: Purity was 91.1% (220 nm).

[0473] [Example 23] Synthesis of Compound 35 [ka]

[0474] Step 1: Synthesis of compound 35-2 [ka] To a solution of compound 35-1 (10.0 g, 55.5 mmol, 1.00 eq) in HOAc (50.0 mL), Br2 (8.87 g, 55.5 mmol, 2.86 mL, 1.00 eq) was added, and the mixture was stirred at 25 °C for 10 h. TLC (Plate 1: petroleum ether: ethyl acetate = 5:1) showed that compound 35-1 had been completely consumed, and one new major spot was detected. The mixture was diluted with DCM (150 mL) and washed with saturated Na2SO3 (100 mL × 2). The organic layer was washed with saturated NaHCO3 (100 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure.

[0475] The residue was purified by preparative HPLC (column: Welch UltimateXB-SiOH 250 × 70 × 10 μm, mobile phase: [hexane-EtOH (0.1% NH3.HO)], gradient: 1% to 5% B over 15 min). Compound 35-2 (5.50 g, 21.2 mmol, 38.3% yield) was obtained as a yellow oil, which was characterized by H NMR, F NMR, 2D NMR, and LC-MS.

[0476] H NMR: (400 MHz, CDCl) δ 10.93 (brs, 1H), 7.81 (d, J = 10.0 Hz, 1H), 7.19 (d, J = 6.4 Hz, 1H).

[0477] LC-MS: (M-H) + :258.9.

[0478] Step 2: Synthesis of compound 35-3 [ka] To a solution of compound 35-2 (5.00 g, 19.3 mmol, 1.00 eq) and TEA (5.86 g, 57.9 mmol, 8.06 mL, 3.00 eq) in DMF (15.0 mL) and MeOH (35.0 mL) was added Pd(dppf)Cl·CHCl (788 mg, 965 μmol, 0.05 eq) under N. The suspension was degassed under vacuum and purged with CO several times. The mixture was stirred under CO (50 psi) at 80 °C for 10 h. LC-MS showed that all of compound 35-2 was consumed, and a new major peak with the desired mass was detected. The mixture was filtered, and the filtrate was concentrated to remove MeOH. The residue was diluted with EtOAc (100 mL) and washed with H2O (100 mL × 2) and brine (50.0 mL × 1). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 1 / 0 to 10 / 1) to give compound 35-3 (3.20 g, 13.4 mmol, 69.6% yield) as a white solid, which was confirmed by H NMR and F NMR.

[0479] LC-MS: (M-H) + :236.9.

[0480] H NMR: (400 MHz, CDCl) δ 10.60 (brs, 1H), 7.65 (d, J = 10.0 Hz, 1H), 7.24 (d, J = 5.6 Hz, 1H), 4.01 (s, 3H).

[0481] Step 3: Synthesis of compound 35-5 [ka] To a solution of compound 35-3 (3.20 g, 13.4 mmol, 1.00 eq) in acetone (30.0 mL), K2CO3 (2.79 g, 20.2 mmol, 1.50 eq) and compound 35-4 (3.37 g, 20.2 mmol, 2.23 mL, 1.50 eq) were added. The mixture was stirred at 60 °C for 12 h. LC-MS showed that compound 35-3 was completely consumed, with approximately 63.3% of the desired mass remaining. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1 / 0 to 10 / 1). Compound 35-5 (3.00 g, 9.25 mmol, 68.9% yield) was obtained as a colorless oil, which was characterized by H NMR, F NMR, and LC-MS.

[0482] LC-MS: (M-H) + :325.1.

[0483] H NMR: (400MHz, CDCl3) δ7.65(d,J=10.0Hz,1H),7.14(d,J=5.6Hz,1H),4.72(s,2H),4.28(q,J=6.0Hz,2H),3.94(s,3H),1.31(d,J=7.8Hz,1H).

[0484] Step 4: Synthesis of compound 35-6 [ka] A mixture of compound 35-5 (3.50 g, 10.8 mmol, 1.00 eq) and NaOH (2 M, 16.2 mL, 3.00 eq) in MeOH (30.0 mL) was stirred at 25 °C for 2 h under a N2 atmosphere. LC-MS showed that compound 35-5 was consumed and a new peak was detected. The mixture was concentrated to remove MeOH, and the pH was adjusted to approximately 2 with HCl (1.00 M). The solid was filtered and concentrated under reduced pressure. Compound 35-6 (2.60 g, 9.22 mmol, 85.4% yield) was obtained as a white solid, which was confirmed by H NMR and F NMR.

[0485] LC-MS: (M+23) + =305.0.

[0486] H NMR: (400 MHz, DMSO-d) δ 7.75 (d, J = 6.4 Hz, 1H), 7.47 (d, J = 10.4 Hz, 1H), 4.69 (s, 2H).

[0487] Step 5: Synthesis of compound 35-7 [ka] To a solution of compound 35-6 (1.60 g, 5.67 mmol, 1.00 eq) in AcO (8.00 mL) was added AcOH (1.24 g, 20.7 mmol, 1.18 mL, 3.65 eq) and NaOAc (521 mg, 6.35 mmol, 1.12 eq). The mixture was stirred at 140 °C for 6 h. LC-MS showed that compound 35-6 was completely consumed, and a new peak with the desired mass was detected. The reaction mixture was diluted with 50 mL of water and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. Compound 35-7 (1.35 g, crude) was obtained as a yellow solid, which was confirmed by H NMR and F NMR.

[0488] H NMR: (400 MHz, CDCl) δ 8.18 (s, 1H), 7.72 (d, J = 4.2 Hz, 1H), 7.38 (d, J = 9.6 Hz, 1H), 2.39 (s, 3H).

[0489] Step 6: Synthesis of compound 35-8 [ka] A solution of compound 35-7 (200 mg, 763 μmol, 1.00 eq) and KCO (316 mg, 2.29 mmol, 3.00 eq) in MeOH (5.00 mL) and HO (1.00 mL) was stirred at 25 °C for 0.5 h. LC-MS showed that compound 35-7 was completely consumed, and a new peak with the desired mass was detected. The mixture was diluted with HO (20.0 mL), and the pH was adjusted to approximately 2 with HCl (1 M) at 0 °C, followed by extraction with EtOAc (25.0 mL × 3). The combined organic layers were washed with brine (20.0 mL × 1), dried over NaSO, filtered, and concentrated under reduced pressure. Compound 35-8 (150 mg, crude) was obtained as a red solid, which was confirmed by H NMR and F NMR.

[0490] H NMR: (400MHz, CDCl3) δ7.48 (d, J=8.0Hz, 1H), 7.43 (d, J=4.8Hz, 1H), 4.75 (s, 2H).

[0491] Step 7: Synthesis of compound 35-9 [ka] To a solution of compound 35-8 (500 mg, 2.27 mmol, 1.00 eq) in EtOH (10.0 mL), NaOAc (559 mg, 6.81 mmol, 3.00 eq) and NHOH·HCl (474 ​​mg, 6.81 mmol, 3.00 eq) were added. The mixture was stirred at 25 °C for 1 h. LC-MS revealed approximately 54.5% of the desired mass. The reaction mixture was concentrated under reduced pressure to remove EtOH, then diluted with 20.0 mL of water and extracted with EtOAc (15.0 mL × 2). The combined organic layers were washed with brine (15.0 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1 / 0 to 10 / 1). Compound 35-9 (300 mg, crude) was obtained as a yellow solid, which was confirmed by H NMR and F NMR.

[0492] H NMR: (400 MHz, CDCl) δ 7.61 (s, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.17 (d, J = 5.2 Hz, 1H), 5.24 (s, 2H).

[0493] Step 8: Synthesis of compound 35-10 [ka] To a solution of compound 35-9 (300 mg, 1.28 mmol, 1.00 eq) and NH₃·H₂O (910 mg, 6.49 mmol, 1.00 mL, 25% purity, 5.09 eq) in MeOH (10.0 mL) was added Raney nickel (109 mg, 1.28 mmol, 1.00 eq) under N₂. The suspension was degassed under vacuum and purged with H₂ several times. The mixture was stirred under H₂ (50 psi) at 80 °C for 10 h. LC-MS showed that compound 35-9 was completely consumed and a new peak was detected. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Compound 35-10 (250 mg, crude) was obtained as a yellow solid.

[0494] Step 9: Synthesis of compound 35-11 [ka] A solution of compound 35-10 (250 mg, 1.13 mmol, 1.00 eq), BocO (370 mg, 1.70 mmol, 390 μL, 1.50 eq), and TEA (343 mg, 3.39 mmol, 472 μL, 3.00 eq) in DCM (10 mL) was stirred at 25 °C for 1 h. LC-MS showed that compound 35-10 was completely consumed. The mixture was diluted with HO (20 mL) and extracted with DCM (15 mL × 2). The combined organic layers were washed with brine (15 mL × 1), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 1 / 0 to 10 / 1). Compound 35-11 (170 mg, crude) was obtained as a yellow solid, which was confirmed by H NMR and F NMR.

[0495] H NMR: (400 MHz, CDCl) δ 7.18 (d, J = 10.0 Hz, 1H), 7.02 (d, J = 5.2 Hz, 1H), 5.43 (s, 1H), 4.88 (s, 1H), 4.76 (s, 1H), 4.37 (dd, J = 10.0 Hz, J = 4.8 Hz, 1H), 1.47 (s, 9H).

[0496] Step 10: Synthesis of compound 35-12 [ka] To a solution of compound 35-11 (70.0 mg, 218 μmol, 1.00 eq) in THF (5.00 mL) was added NaH (13.1 mg, 327 μmol, 60% purity, 1.50 eq) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Next, trideuterio(iodo)methane (37.9 mg, 261 μmol, 16.3 μL, 1.20 eq) was added to the mixture. The mixture was stirred at 20 °C for an additional 10 h. LC-MS showed that compound 35-11 was completely consumed, and a new peak with the desired mass was detected. The mixture was quenched with saturated NH4Cl (20.0 mL) and extracted with EtOAc (15.0 mL × 2). The combined organic layers were washed with brine (15.0 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm, mobile phase: [water (FA)-ACN], gradient: 48% to 78% B over 10 min) to give compound 35-12 (30.0 mg, 88.7 μmol, 40.7% yield) as a colorless oil, which was characterized by H NMR and F NMR.

[0497] H NMR: (400 MHz, CDCl) δ 7.08 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 5.6 Hz, 1H), 6.17 (s, 1H), 4.68 (t, J = 5.6 Hz, 1H), 1.50 (s, 9H).

[0498] Step 11: Synthesis of compound 35-13 [ka] A mixture of compound 35-12 (70.0 mg, 207 μmol, 1.00 eq) in DCM (5.00 mL) and HCl / dioxane (2 M, 1.50 mL, 14.5 eq) was stirred at 20 °C for 10 h. LC-MS showed that compound 35-12 was completely consumed, and a new major peak with the desired mass was detected. The mixture was concentrated under reduced pressure. Compound 35-13 (56.0 mg, 204 μmol, 98.5% yield, HCl) was obtained as an off-white solid.

[0499] Step 12: Synthesis of Compound 35 [ka] A solution of compound 35-14 (43.3 mg, 189 μmol, 1.00 eq), HATU (108 mg, 283 μmol, 1.50 eq), and DIEA (122 mg, 945 μmol, 165 μL, 5.00 eq) in DMF (2.00 mL) was stirred at 20 °C for 15 min, followed by the addition of compound 35-13 (45.0 mg, 189 μmol, 1.00 eq). The mixture was stirred at 20 °C for 30 min. LC-MS showed that all of compound 35-13 was consumed, and a new major peak with the desired mass was detected. The mixture was purified by preparative HPLC (column: Waters Xbridge C18 150 × 50 mm × 10 μm, mobile phase: [water (NH4HCO3)-ACN], gradient: 22% to 52% B over 10 min). Compound 35 (18.36 mg, 39.4 μmol, 20.9% yield, 96.5% purity) was obtained and characterized by H NMR, F NMR, LC-MS, HPLC, and SFC.

[0500] H NMR: (400 MHz, DMSO-d) δ 9.31-9.28 (m, 1H), 8.71-8.64 (m, 1H), 8.54-8.50 (m, 1H), 7.99 (s, 1H), 7.76-7.49 (m, 3H), 7.32-7.29 (m, 1H), 6.39-6.03 (m, 1H), 4.90-4.68 (m, 2H).

[0501] LC-MS: (M-H)+ :450.2.

[0502] HPLC: Purity was 96.4% (220 nm).

[0503] [Example 24] Synthesis of Compound 36 [ka]

[0504] Step 1: Synthesis of compound 36-2 [ka] To a solution of compound 36-1 (20 g, 111.66 mmol, 1 eq) in DMF (250 mL) was added NBS (20.87 g, 117.24 mmol, 1.05 eq) at -10 °C, and the reaction mixture was continuously stirred at 25 °C for 1 h. No starting material remained and the desired product was observed by LCMS. The reaction mixture was diluted with water (300 mL) and extracted with EA (100 mL × 2). The combined organic layers were washed with saturated NaCl (100 mL × 3), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by MPLC (SiO, petroleum ether / ethyl acetate = 1:0 to 10:1). Compound 36-2 (32 g, crude) was obtained as a yellow oil and characterized by H NMR.

[0505] LC-MS: (M+H) + :258.0, 259.9.

[0506] H NMR: (400 MHz, chloroform-d) δ 7.49 (s, 1H), 7.22 (d, J = 10.4 Hz, 1H), 4.48 (brs, 2H).

[0507] Step 2: Synthesis of compound 36-3 [ka] A mixture of compound 36-2 (21 g, 81.39 mmol, 1 eq), BPD (41.34 g, 162.78 mmol, 2 eq), KOAc (19.97 g, 203.48 mmol, 2.5 eq), and Pd(dppf)Cl₂·CHCl₂ (3.32 g, 4.07 mmol, 0.05 eq) in dioxane (300 mL) was stirred at 100 °C for 3 h. No starting material remained, and the desired product was observed by LCMS. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate = 1:0 to 50:1). Compound 36-3 (35 g, crude) was obtained as a yellow solid, which was confirmed by H NMR.

[0508] H NMR: (400 MHz, chloroform-d) δ 7.65 (s, 1H), 7.25 (d, J = 12.0 Hz, 1H), 5.17 (brs, 2H), 1.36 (s, 12H).

[0509] Step 3: Synthesis of compound 36-4 [ka] To a solution of compound 36-3 (20 g, 65.56 mmol, 1 eq) in THF (300 mL) was added NaOH (2 M, 98.34 mL, 3 eq) and HO (41.30 g, 364.26 mmol, 35.00 mL, 30% purity, 5.56 eq) at 0 °C, and the reaction was stirred at 25 °C for 2 h. No starting material remained and the desired product was observed by LCMS. The reaction was diluted with water (100 mL), neutralized to pH = 7 with HCl (2 M), and then extracted with EA (150 mL × 3). The combined organic layers were washed with saturated NaSO solution (150 mL × 2), saturated NaCl solution (150 mL × 2), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 5:1). Compound 36-4 (5.44 g, 27.88 mmol, 42.53% yield) was obtained as a brown solid.

[0510] Step 4: Synthesis of compound 36-5 [ka] To a solution of compound 36-4 (3.33 g, 17.07 mmol, 1 eq) in HO (60 mL) and acetone (15 mL), HSO (12.00 g, 122.37 mmol, 6.52 mL, 7.17 eq) and NaNO (2.36 g, 34.13 mmol, 2 eq) were added under an ice bath at 0 °C. After stirring for 30 min, CuI (8.13 g, 42.67 mmol, 2.5 eq) and NaI (6.40 g, 42.67 mmol, 2.5 eq) were added to the mixture, and the reaction mixture was continuously stirred at 25 °C for 12 h. LCMS showed no remaining starting material and the desired product was observed. The reaction mixture was filtered, the cake was washed with EA, and the filtrate was extracted with EA (30 mL × 3). The combined organic layer was washed with saturated NaCl (30 mL × 2), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 4:1). Compound 36-5 (7 g, crude) was obtained as a red oil.

[0511] LC-MS: (M+Na) + :329.0.

[0512] Step 5: Synthesis of compound 36-6 [ka] To a solution of compound 36-5 (7 g, 22.88 mmol, 1 eq) in MeOH (100 mL), TEA (6.94 g, 68.63 mmol, 9.55 mL, 3 eq) and Pd(dppf)Cl₂·CHCl₂ (1.87 g, 2.29 mmol, 0.1 eq) were added, and the reaction mixture was stirred at 80 °C under a CO atmosphere (50 psi) for 12 h. No starting material remained, and the desired product was observed by TLC (PE:EA = 5:1). The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 4:1). Compound 36-6 (2.10 g, 8.82 mmol, 38.55% yield) was obtained as a red oil, which was confirmed by NMR.

[0513] H NMR: (400 MHz, chloroform-d) δ 11.43 (s, 1H), 7.27 (s, 1H), 7.08 (s, 1H), 6.87 (dd, J = 1.2, 10.8 Hz, 1H), 4.04 (s, 3H).

[0514] Step 6: Synthesis of compound 36-8 [ka] To a solution of compound 36-6 (2.1 g, 8.82 mmol, 1 eq) in acetone (25 mL), K2CO3 (1.83 g, 13.23 mmol, 1.5 eq) and compound 36-7 (1.84 g, 11.02 mmol, 1.22 mL, 1.25 eq) were added, and the reaction mixture was stirred at 50 °C for 12 h. No starting material remained, and the desired product was observed by LCMS. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:0 to 5:1). Compound 36-8 (2.1 g, 6.48 mmol, 73.45% yield) was obtained as a yellow oil, which was confirmed by H NMR.

[0515] H NMR: (400 MHz, chloroform-d) δ 7.08 (d, J = 8.8 Hz, 1H), 6.85 (s, 1H), 4.72 (s, 2H), 4.28 (q, J = 7.2 Hz, 2H), 3.97 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H).

[0516] Step 7: Synthesis of compound 36-9 [ka] To a solution of compound 36-8 (2.9 g, 8.94 mmol, 1 eq) in MeOH (40 mL), NaOH (10.73 g, 26.83 mmol, 10% purity, 3 eq) was added and the reaction was stirred at 25 °C for 12 h. No starting material remained and the desired product was observed by LCMS. The reaction was concentrated in vacuo, neutralized with HCl (2 M) to pH = 2, and then extracted with EA (35 mL × 3). The combined organic layers were washed with saturated NaCl (35 mL × 2), dried over NaSO, filtered, and concentrated in vacuo. The crude product was used directly in the next step. Compound 36-9 (2.52 g, crude) was obtained as a red solid.

[0517] LC-MS: (M+Na) + :305.0.

[0518] Step 8: Synthesis of compound 36-10 [ka] To a solution of compound 36-9 (2 g, 7.09 mmol, 1 eq) in AcO (20 mL), HOAc (1.55 g, 25.87 mmol, 1.48 mL, 3.65 eq) and NaOAc (651.28 mg, 7.94 mmol, 1.12 eq) were added, and the reaction was stirred at 140 °C for 2 h. No starting material remained and the desired product was observed by LCMS. The reaction was diluted with water (15 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with saturated NaCl (10 mL × 2), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 5:1). Compound 36-10 (1.28 g, 4.88 mmol, 68.88% yield) was obtained as a red oil, which was confirmed by H NMR.

[0519] H NMR: (400 MHz, chloroform-d) δ 8.05 (s, 1H), 7.60 (s, 1H), 7.23 (d, J = 9.6 Hz, 1H), 2.41 (s, 3H).

[0520] Step 9: Synthesis of compound 36-11 [ka] To a solution of compound 36-10 (0.5 g, 1.91 mmol, 1 eq) in MeOH (16 mL) and HO (2 mL), KCO (790.78 mg, 5.72 mmol, 3 eq) was added, and the reaction was stirred at 25 °C for 30 min. No starting material remained and the desired product was observed by LCMS. The reaction was neutralized with HCl (2 M) to pH = 2 and extracted with EA (15 mL × 3). The combined organic layers were washed with saturated NaCl (15 mL × 2), dried over NaSO, filtered, and concentrated in vacuo. The crude product was used directly in the next step. Compound 36-11 (0.35 g, crude) was obtained as a red oil and confirmed by H NMR.

[0521] H NMR: (400 MHz, chloroform-d) δ 7.23 (s, 1H), 6.99 (d, J = 8.0 Hz, 1H), 4.75 (s, 2H).

[0522] Step 10: Synthesis of compound 36-12 [ka] To a solution of compound 36-11 (0.350 g, 1.59 mmol, 1 eq) in EtOH (12 mL), NaOAc (391.31 mg, 4.77 mmol, 3 eq) and NH2OH.HCl (331.48 mg, 4.77 mmol, 3 eq) were added, and the reaction was stirred at 25 °C for 12 h. No starting material remained, and the desired product was observed by LCMS. The reaction was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with saturated NaCl (10 mL × 2), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:0 to 3:1). Compound 36-12 (0.3 g, 1.28 mmol, 80.24% yield) was obtained as a pale yellow solid.

[0523] LC-MS: (M-H) +:234.1.

[0524] Step 11: Synthesis of compound 36-13 [ka] A mixture of compound 36-12 (0.3 g, 1.28 mmol, 1 eq) and Raney nickel (0.030 g, 350.18 μmol, 2.74 e-1 eq) in MeOH (10 mL) and NH3.HO (1 mL) was stirred at 80 °C under H2 atmosphere (50 PSI) for 12 h. No starting material remained and the desired product was observed by LCMS. The reaction was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was used directly in the next step. Compound 36-13 (0.308 g, crude) was obtained as a yellow solid.

[0525] LC-MS: (M-NH2) + :205.1.

[0526] Step 12: Synthesis of compound 36-14 [ka] To a solution of compound 36-13 (0.308 g, 1.39 mmol, 1 eq) in DCM (15 mL), TEA (281.85 mg, 2.79 mmol, 387.69 μL, 2 eq) and (Boc)2O (319.15 mg, 1.46 mmol, 335.95 μL, 1.05 eq) were added at 25 °C, and the reaction mixture was stirred continuously for 2 h. LCMS showed no remaining starting material, and the desired product was observed. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:0 to 5:1). Compound 36-14 (0.170 g, 529.16 μmol, 37.99% yield) was obtained as a red solid, which was confirmed by H NMR.

[0527] LC-MS: (M-55) + :266.0.

[0528] H NMR: (400 MHz, chloroform-d) δ 6.98-6.84 (m, 2H), 5.66-5.47 (m, 1H), 5.02-4.88 (m, 1H), 4.83-4.70 (m, 1H), 4.53-4.48 (m, 1H), 1.47 (s, 9H).

[0529] Step 13: Synthesis of compound 36-15 [ka] To a solution of compound 36-14 (0.170 g, 529.16 μmol, 1 eq) in THF (15 mL) was added NaH (52.92 mg, 1.32 mmol, 60% purity, 2.5 eq) under ice bath at 0 °C. After stirring for 15 min, trideuterio(iodo)methane (153.41 mg, 1.06 mmol, 65.87 μL, 2.0 eq) was added to the mixture, and the reaction was stirred at 25 °C for 12 h. No starting material remained, and the desired product was observed by LCMS. The reaction was quenched by adding MeOH (10 mL) under ice bath and then concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 1:0 to 5:1). Compound 36-15 (0.170 g, 502.49 μmol, 94.96% yield) was obtained as a red solid and was confirmed by H NMR.

[0530] LC-MS: (M-55) + :283.1.

[0531] H NMR: (400 MHz, chloroform-d) δ 6.94-6.88 (m, 2H), 6.34-5.84 (m, 1H), 4.87-4.66 (m, 1H), 4.57-4.34 (m, 1H), 1.49 (s, 9H).

[0532] Step 14: Synthesis of compound 36-16 [ka] To a solution of compound 36-15 (0.170 g, 502.49 μmol, 1 eq) in EA (4 mL) was added HCl / dioxane (2 M, 17.00 mL) and the reaction was stirred at 25 °C for 12 h. No starting material remained and the desired product was observed by LCMS. The reaction was concentrated in vacuo to give compound 36-16 (0.140 g, crude, HCl) as a yellow solid.

[0533] LC-MS: (M+H) + :239.1.

[0534] Step 15: Synthesis of Compound 36 [ka] To a solution of compound 36-17 (0.070 g, 305.42 μmol, 1 eq) in DMF (2 mL) was added HATU (232.26 mg, 610.83 μmol, 2 eq) and DIEA (197.37 mg, 1.53 mmol, 265.99 μL, 5 eq). After stirring for 15 min, compound 36-16 (71.30 mg, 259.60 μmol, 0.85 eq, HCl) was added to the mixture, and the reaction was stirred at 25 °C for 1 h. No starting material remained and the desired product was observed by LCMS. The reaction was diluted with water (15 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with saturated NaCl (10 mL × 2), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Waters Xbridge C18 150 × 50 mm × 10 μm column, mobile phase: [water (NH4HCO3)-ACN], gradient: 22% to 52% B over 10 min) to give compound 36 (0.027 g, 59.52 μmol, 19.49% yield, 99.06% purity), which was characterized by H NMR, F NMR, LCMS, HPLC, and SFC.

[0535] LC-MS: (M+Na) + :472.1, (M+H) + :450.1.

[0536] H NMR: (400 MHz, DMSO-d) δ 9.33 (d, J = 14.4 Hz, 1H), 8.66 (d, J = 10.4 Hz, 1H), 8.62-8.42 (m, 1H), 7.98 (d, J = 5.2 Hz, 1H), 7.83-7.67 (m, 2H), 7.34-7.16 (m, 2H), 6.66-6.28 (m, 1H), 5.04-4.69 (m, 2H).

[0537] HPLC: Purity was 99.06% (220 nm).

[0538] [Example 25] Synthesis of Compound 37 [ka]

[0539] Step 1: Synthesis of compound 37-2 [ka] To a solution of compound 37-1 (10.0 g, 66.6 mmol, 1.00 eq) in DMF (100 mL), K2CO3 (9.21 g, 66.6 mmol, 1.00 eq) and compound 37-2 (14.4 g, 99.9 mmol, 1.50 eq) were added, and the mixture was stirred at 75 °C for 2 h. LC-MS showed that compound 37-1 was consumed, and a peak corresponding to the desired mass was detected. The mixture was diluted with HO (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine (100 mL x 3), dried over Na2SO4, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 100:1 to 3:1). TLC (petroleum ether:ethyl acetate = 3:1, R f =0.60). Compound 37-2 (3.00 mg, 15.0 mmol, 22.5% yield) was obtained as a yellow solid and was characterized by H NMR and F NMR.

[0540] H NMR:(400MHz,DMSO-d6)δ7.70(d,J=8.8Hz,1H),7.46(brt,J=72.8Hz,1H),7.10(d,J=2.0Hz,1H),6.92(dd,J1=8.4Hz,J1=2.0Hz,1H),4.85(s,2H).

[0541] Step 2: Synthesis of compound 37-4 [ka] To a solution of compound 37-3 (1.00 g, 5.00 mmol, 1.00 eq) in EtOH (15.0 mL) was added NaBH (378 mg, 9.99 mmol, 2.00 eq) at 0 °C, and the mixture was stirred at 25 °C for 0.5 h. LC-MS showed that compound 37-3 was consumed, and a peak corresponding to the desired mass was detected. A solution of saturated NH Cl (30.0 mL) was added to the mixture at 0 °C, followed by extraction with DCM (30.0 mL × 3). The combined organic phases were washed with brine (30.0 mL × 2), dried over Na SO , and concentrated to give a residue. Compound 37-4 (900 mg, 4.45 mmol, 89.1% yield) was obtained as a yellow solid, which was confirmed by H NMR and F NMR.

[0542] H NMR: (400 MHz, DMSO-d) δ 7.39-7.36 (m, 1H), 7.20 (brt, J=74.4 Hz, 1H), 6.70-6.67 (m, 2H), 5.62 (d, J=5.6 Hz, 1H), 5.25-5.21 (m, 1H), 4.56 (dd, J=10.0 Hz, J=6.8 Hz, 1H), 4.27 (dd, J=10.4 Hz, J=3.2 Hz, 1H).

[0543] Step 3: Synthesis of compound 37-5 [ka] To a solution of compound 37-4 (300 mg, 1.48 mmol, 1.00 eq) in Toluene (5.00 mL), DPPA (613 mg, 2.23 mmol, 480 μL, 1.50 eq) and a solution of DBU (339 mg, 2.23 mmol, 336 μL, 1.50 eq) in Toluene (1.00 mL) were added at 0 °C, followed by stirring at 25 °C for 12 h. LC-MS showed the peak of compound 37-4, indicating its consumption. Saturated NH4Cl solution (20.0 mL) was added to the mixture at 0 °C, followed by extraction with DCM (20.0 mL × 3). The combined organic phases were dried over Na2SO4 and concentrated to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 100:1 to 5:1). TLC (petroleum ether:ethyl acetate = 5:1, R f =0.50). Compound 37-5 (250 mg, 1.10 mmol, 74.2% yield) was obtained as a yellow solid and was characterized by H NMR and F NMR.

[0544] H NMR:(400MHz,DMSO-d6)δ7.54(d,J=7.6Hz,1H),7.47-7.46(m,1H),6.79-6.76(m,2H),5.34(dd,J1=6 .8Hz,J1=2.0Hz,1H),4.63(dd,J1=10.8Hz,J1=6.8Hz,1H),4.53(dd,J1=10.8Hz,J1=2.0Hz,1H).

[0545] Step 4: Synthesis of compound 37-6 [ka] To a solution of compound 37-5 (250 mg, 1.10 mmol, 1.00 eq) in THF (3.00 mL) was added PPh3 (433 mg, 1.65 mmol, 1.50 eq). The mixture was stirred at 25 °C for 1 h. After that, a solution of KOH (154 mg, 2.75 mmol, 2.50 eq) in HO (1.00 mL) was added, and the mixture was stirred at 25 °C for 12 h. LC-MS showed that compound 37-5 was consumed, and a peak corresponding to the desired mass was detected. The mixture was diluted with HO (10.0 mL) and extracted with EtOAc (10.0 mL × 3). The combined organic phases were dried over Na2SO4 and concentrated to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 100:1 to 0:1). TLC (petroleum ether:ethyl acetate = 0:1, R f =0.20). Compound 37-6 (200 mg, 994 μmol, yield 90.3%) was obtained as a yellow solid.

[0546] Step 5: Synthesis of compound 37-7 [ka] To a solution of compound 37-6 (200 mg, 994 μmol, 1.00 eq) in DCM (5.00 mL), TEA (302 mg, 2.98 mmol, 415 μL, 3.00 eq) and BocO (434 mg, 1.99 mmol, 457 μL, 2.00 eq) were added, and the mixture was stirred at 25 °C for 1 h. LC-MS showed the consumption of compound 37-6, indicating a peak. The mixture was diluted with HO (20.0 mL) and extracted with DCM (20.0 mL × 3). The combined organic phases were dried over NaSO and concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 100:1 to 5:1). TLC (petroleum ether:ethyl acetate = 5:1, R f =0.50). Compound 37-7 (100 mg, 332 μmol, 33.4% yield) was obtained as a yellow solid and was characterized by H NMR and F NMR.

[0547] H NMR: (400 MHz, DMSO-d) δ 7.54 (d, J = 7.6 Hz, 1H), 7.37-7.00 (m, 2H), 6.68-6.65 (m, 2H), 5.26-5.21 (m, 1H), 4.69 (t, J = 9.2 Hz, 1H), 4.28-4.25 (m, 1H), 1.40 (s, 9H).

[0548] Step 6: Synthesis of compound 37-8 [ka] To a solution of compound 37-7 (100 mg, 332 μmol, 1.00 eq) in THF (3.00 mL) was added NaH (19.9 mg, 498 μmol, 60.0% purity, 1.50 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, and then CD3I (141 mg, 996 μmol, 60.7 μL, 3.00 eq) was added and the mixture was stirred at 25 °C for 4 h. LC-MS showed that compound 37-7 was consumed and a new peak was detected. A solution of saturated NH4Cl (20.0 mL) was added to the mixture at 0 °C, followed by extraction with EtOAc (20.0 mL × 3). The combined organic phase was washed with brine (20.0 mL × 2), dried over Na2SO4, and concentrated to give a residue. Compound 37-8 (100 mg, crude) was obtained as a yellow solid and characterized by H NMR and F NMR.

[0549] H NMR: (400 MHz, DMSO-d) δ 7.41-7.04 (m, 2H), 6.73-6.71 (m, 2H), 5.88-5.64 (m, 1H), 4.66 (t, J=10.0 Hz, 1H), 4.49-4.47 (m, 1H), 1.41 (s, 9H).

[0550] Step 7: Synthesis of compound 37-9 [ka] To a solution of compound 37-8 (100 mg, 314 μmol, 1.00 eq) in DCM (1.00 mL) was added HCl / dioxane (2 M, 2.00 mL, 12.7 eq) at 0 °C, and the mixture was stirred at 25 °C for 4 h. LC-MS showed that compound 37-8 was consumed and a new peak was detected. The mixture was concentrated to give a residue. Compound 37-9 (80.0 mg, crude, HCl) was obtained as a yellow solid.

[0551] Step 8: Synthesis of Compound 37 [ka] To a solution of compound 37-9 (80.0 mg, 314 μmol, 1.00 eq, HCl) and compound 37-10 (75.3 mg, 330 μmol, 1.05 eq) in DMF (1.00 mL), DIEA (122 mg, 942 μmol, 164 μL, 3.00 eq) and HATU (179 mg, 471 μmol, 1.50 eq) were added, and the mixture was stirred at 25 °C for 1 h. LC-MS showed that compound 37-9 was consumed, and a peak corresponding to the desired mass was detected. The mixture was diluted with HO (20.0 mL) and extracted with EtOAc (20.0 mL × 3). The combined organic phase was washed with brine (20.0 mL × 2), dried over NaSO, and concentrated to give a residue. The residue was purified by preparative HPLC (Waters Xbridge BEH C18 150 × 25 mm × 5 μm column, mobile phase: [water (NH4HCO3)-ACN], gradient: 18% to 48% B over 10 min) to give compound 37 (29.15 mg, 68.0 μmol, 21.7% yield), which was characterized by H NMR, F NMR, LC-MS, HPLC, and SFC.

[0552] H NMR: (400 MHz, DMSO-d) δ 9.18 (s, 1H), 8.31 (s, 1H), 7.91 (s, 1H), 7.48-7.07 (m, 6H), 6.78-6.72 (m, 2H), 6.31-4.65 (m, 2H).

[0553] LC-MS: (M+H) + :429.1.

[0554] HPLC: Purity was 98.1% (220 nm).

[0555] [Example 26] MTase-Glo methyltransferase assay MTase-Glo, which monitors the product of the methyltransferase reaction (S-adenosylhomocysteine ​​or SAH) TM The PRMT5 inhibitory activity of test compounds was determined using a Promega assay. The PRMT5 MTase-Glo assay was performed in a 384-well white ProxiPlate (PerkinElmer, catalog number: 6008280) in a total volume of 12 μL. The PRMT5 enzyme reaction mixture (4 μL) contained 50 μM MPRMT5 / MEP50 (Reaction Biology, catalog number: HMT-22-148), 25 μM S-adenosylmethionine (SAM, Promega), 5 μM histone H4 peptide (1-21) (BPS Bioscience, catalog number: 52018-2), and 5-fold serial dilutions of compound in a reaction buffer consisting of 50 mM Tris (pH 8.0), 50 mM NaCl, 0.01% Tween 20, 0.01% BSA, and 1 mM DTT. Test compounds were pre-incubated with PRMT5 / MEP50 and histone H4 peptide for 20 minutes at room temperature, after which SAM was added to initiate the PRMT5 reaction. The reaction was allowed to proceed at 37°C for 1 hour and 2 μL of 3X MTase-Glo was added. TM The reaction was stopped with 150 μM EPZ015666 (Promega, Catalog No. 1616391-65-1) and incubated at room temperature for 30 minutes. TM Detection solution (Promega) was added, and the plate was incubated for an additional 30 minutes at room temperature. The optical signal, corresponding to the amount of SAH produced by the PRMT5 reaction, was then measured using an Envision multimode reader (PerkinElmer). 50 value and K i Values ​​were obtained by analyzing dose-response curves using GraphPad Prism.

[0556] Table 1 shows the IC for PRMT5 inhibition of exemplary compounds described herein. 50 Show the data. [Table 1]

[0557] [Example 27] PRMT5 / MEP50 hotspot methyltransferase assay In this assay, recombinant full-length histone H2A was used as a substrate for PRMT5. S-adenosyl-L-[methyl-3H]methionine ( 3 The activity of PRMT5 enzyme in the presence and absence of compounds was determined by enzymatic transfer of a tritium-labeled methyl group from histone H2A (H-SAM) to histone H2A protein, generating radiolabeled histone H2A as measured by scintillation counting. Assay reactions were performed in the presence of 100 nM MMTA. Briefly, compounds were dissolved in 100% DMSO at a maximum concentration of 10 mM. IC 50 For the determination of PRMT5 activity, the initial starting concentration of serial dilutions of each compound was 50 μM. Control samples lacking compound, PRTM5 / MEP50 complex, or various reaction components were also prepared and processed in parallel with the test compound samples. SAH was used as a positive control for assay validation. To measure PRMT5 inhibitory activity, 1 nM PRTM5 / MEP50 complex was preincubated with test compound in assay buffer containing 5 μM full-length histone H2A for 15 min at room temperature. 3 The enzyme reaction was initiated by adding H-SAM (final concentration), and the mixture was incubated at 30°C for 1 hour. The reaction was stopped and transferred to filter paper for detection. The amount of tritium-labeled H2A in each sample was determined using a scintillation counter. The IC of each compound was determined. 50 Values ​​were calculated from 10-point dose-response curves of the samples using GraphPad Prism software.

[0558] Table 2 shows the IC for the PRMT5 / MEP50 hotspot methyltransferase assay for exemplary compounds described herein. 50 Binding data is shown. [Table 2]

[0559] [Example 28] HCT116 cell proliferation assay To demonstrate the enhanced efficacy of the compounds of the present invention in MTAP-deficient cells, proliferation assays were performed using the HCT116 parental cell line and the HCT116 homozygous MTAP knockout cell line. Control samples were also analyzed in parallel.

[0560] On day 0, 150 HCT116 parental cell line or HCT116 homozygous MTAP knockout cells were seeded into 96-well plates in McCoy's 5A medium containing 10% fetal bovine serum and penicillin / streptomycin. Cells were incubated overnight at 37°C, 5% CO.

[0561] On day 1, cells were treated with a 9-point serial dilution of compound (top concentration 50 μM, 1:5 serial dilution steps) and a DMSO-only control. Cells were incubated for 6 days.

[0562] On day 7, cell viability was measured using a CTG assay kit (CellTiter-Glo, Promega, Cat. No. G7573) according to the manufacturer's instructions. The assay plate was then visualized using an ultra-sensitive luminescence model. TM The data were read using a multi-label reader. The data were analyzed using GraphPad Prism 5.0 software, and dose-effect curves were obtained by fitting the data using nonlinear S-curve regression. IC values ​​were calculated from the dose-effect curves. 50 The value was calculated.

[0563] Table 3 shows the IC for the HCT116 cell line for exemplary compounds described herein. 50 Show the data. [Table 3]

[0564] [Example 29] Liver metabolic stability assay Hepatic metabolic stability (HMS) assays were performed on cryopreserved hepatocytes from five species (H: human, R: rat, M: mouse, D: dog, C: cynomolgus monkey) using 7-ethoxycoumarin (Reference 1) and 7-hydroxycoumarin (Reference 2) as positive controls.

[0565] Cryopreserved hepatocyte information: [Table A]

[0566] Buffer information:

[0567] Thawing medium: Williams medium E containing 5% fetal bovine serum, 30% Percoll solution, and other additives

[0568] Incubation medium: Williams medium E (phenol red-free) containing 2 mM L-glutamine and 25 mM HEPES

[0569] Stop solution: Acetonitrile containing tolbutamide and labetalol as internal standards

[0570] Diluent: Ultrapure water

[0571] Testing Procedure:

[0572] 1) 10 mM test compound was provided.

[0573] 2) 30 mM positive control stock solution: The correct amount of positive control compound was dissolved in dimethyl sulfoxide (DMSO).

[0574] 3) 1000x stock solutions: In a 96-well plate, 10 mM test compound and 30 mM positive control compound were diluted to 1 mM and 3 mM with DMSO.

[0575] 4) 100x dose solutions: 1 mM test compound and 3 mM positive control compound were diluted in ACN to 100 μM and 300 μM dose solutions.

[0576] 5) Preparation of 0.5×10 6 / mL cell suspension: Cryopreserved cells were thawed, isolated, suspended in incubation medium, and then diluted to 0.5×10 6 cells / mL with pre-warmed incubation medium.

[0577] 6) 198 μL of the pre-warmed cell suspension was added to a 96-well plate.

[0578] 7) Preparation of quenching plate: 125 μL of stop solution was transferred to a pre-labeled 96-well plate.

[0579] 8) 2 μL of the dosing solution was added in duplicate to each well of a 96-well plate.

[0580] 9) For TO samples, immediately after mixing for approximately 1 min to obtain a homogenous suspension, 25 μL of each sample was transferred to a well containing 125 μL of ice-cold stop solution and then mixed.

[0581] 10) All plates were incubated at 37°C in a 5% CO2, 95% humidity incubator with constant shaking to initiate the reaction.

[0582] 11) Samples were mixed at 15, 30, 60, and 90 minutes, and at each time point, 25 μL of each sample was transferred to a well containing 125 μL of ice-cold stop solution and then mixed.

[0583] 12) Medium control (MC) sample plates (labeled T0-MC and T90-MC) were prepared in the same manner as the cell incubations, except that medium was used instead of the cell suspension.

[0584] 13) At each corresponding time point, the plate was removed from the incubator and mixed with 125 μL of ice-cold stop solution to stop the reaction.

[0585] 14) The plates were immediately shaken at 600 rpm for 10 minutes on a plate shaker. Then, all sample plates were centrifuged at 3220 x g for 20 minutes at 4°C.

[0586] 15) After centrifugation, 80 μL / well of the supernatant from the sample plate was transferred to another set of pre-labeled 96-well plates containing 240 μL of ultrapure water according to the plate map.

[0587] 16) The analysis plate was sealed and stored at 4°C until LC-MS / MS analysis. [Table B]

[0588] Data analysis

[0589] The percentage of test substance remaining after incubation was calculated according to the following equation:

[0590] Residual rate (%) = (peak area ratio of analyte to internal standard at each time point) / (peak area ratio of analyte to internal standard at t = 0) × 100

[0591] Using the following first-order kinetic equation, T 1 / 2 and C.L. int was calculated.

number

[0592] Tables 4 and 5 show the half-lives (T 1 / 2 ) and CL int Shows. [Table 4] [Table 5]

[0593] [Example 30] Liver microsome metabolic stability assay A liver microsomal metabolic stability (LMS) assay was performed on liver microsomes from five species (H: human, R: rat, M: mouse, D: dog, C: cynomolgus monkey) using testosterone (Reference 4), diclofenac (Reference 5), and propafenone (Reference 6) as positive controls.

[0594] Testing Procedure:

[0595] 1. Preparation of test compound and control working solutions:

[0596] 1.1. Working solution: 5 μL of compound and control stock solution (10 mM in dimethyl sulfoxide (DMSO)) was diluted with 495 μL of acetonitrile (ACN).

[0597] 2. Preparation of NADPH cofactor:

[0598] 2.1. Materials: NADPH powder: β-nicotinamide adenine dinucleotide phosphate reduced form, tetrasodium salt, NADPH·4Na (sold by BONTAC, catalog number: BT04)

[0599] 2.2. Preparation procedure: An appropriate amount of NADPH powder was weighed and diluted with 10 mM MgCl2 solution (working solution concentration: 10 mM, final concentration in the reaction system: 1 mM).

[0600] 3. Preparation of Liver Microsomes:

[0601] 3.1.Materials: [Table C]

[0602] 3.2. Preparation Procedure:

[0603] A microsome working solution of appropriate concentration was prepared in 100 mM potassium phosphate buffer.

[0604] 4. Preparation of Stop Solution:

[0605] Cold (4°C) acetonitrile (ACN) containing 250 nM tolbutamide and 250 nM labetalol as internal standards (IS) was used as the stop solution.

[0606] 5. Assay Procedure:

[0607] 5.1. Empty "incubation" plates T60 and NCF60 were pre-warmed for 10 minutes.

[0608] 5.2. Liver microsomes were diluted to 0.56 mg / mL in 100 mM phosphate buffer.

[0609] 5.3. 445 μL of microsome working solution (0.56 mg / mL) was transferred to pre-warmed "incubation" plates T60 and NCF60. Then, pre-incubation was performed at 37°C for 10 min with constant shaking. 54 μL of liver microsomes was transferred to a blank plate, after which 6 μL of NAPDH cofactor was added to the blank plate, followed by 180 μL of quenching solution.

[0610] 5.4. 5 μL of compound working solution (100 μM) was added to the "incubation" plates (T60 and NCF60) containing microsomes and mixed thoroughly three times.

[0611] 5.5. For NCF60 plates, 50 μL of buffer was added and mixed thoroughly three times. Time was started and the plate was incubated at 37°C for 60 minutes with shaking.

[0612] 5.6. To the "Quenching" plate TO, add 180 μL of Quenching Solution and 6 μL of NAPDH cofactor. Ensure the plate is chilled to prevent evaporation.

[0613] 5.7. For the T60 plate, mix thoroughly three times and immediately transfer 54 μL of the mixture to the "quenching" plate at 0 min. Next, 44 μL of NAPDH cofactor was added to the incubation plate (T60). Time was started and the plate was incubated at 37°C for 60 min with shaking. [Table D]

[0614] 5.8. At 5, 15, 30, 45, and 60 min, 180 μL of quenching solution was added to the "quenching" plate, mixed once, and 60 μL of sample was transferred sequentially from the T60 plate to the "quenching" plate for each time point.

[0615] 5.9. For NCF60, mix once and transfer 60 μL of sample from the NCF60 incubation to the "Quenching" plate containing quenching solution at 60 min.

[0616] 5.10. All sampling plates were shaken for 10 minutes and then centrifuged at 4°C, 4000 rpm for 20 minutes.

[0617] 5.11. 80 μL of the supernatant was transferred to 240 μL of HPLC water and mixed on a plate shaker for 10 minutes.

[0618] 5.12. Each bioanalytical plate was sealed and shaken for 10 minutes before LC-MS / MS analysis.

[0619] 6. Data Analysis

[0620] Using the following first-order kinetic equation, T 1 / 2 and C.L. int(mic)(μL / min / mg) was calculated.

number

[0621] Tables 6 and 7 show the half-lives T of the positive control and exemplary compounds provided herein, respectively. 1 / 2 and C.L. int Shows. [Table 6] [Table 7]

[0622] [Example 31] Caco-2 cell monolayer model assay The Caco-2 cell model was used to evaluate the permeability of the compounds disclosed herein.Caco-2 cells were obtained from CO-BIOR, and the CO-BIOR number is CBP60025.The cell generation used in the experiment was P9.

[0623] 1. Monolayer Preparation

[0624] 1) 25 mL of cell culture medium was added to each well of the Transwell reservoir. The PET Transwell plate was then incubated at 37°C, 5% CO2 for 1 hour before seeding the cells.

[0625] 2) Caco-2 cells were cultured in culture medium at 3.43 x 10 5 The cells were diluted to 100 cells / mL and 100 μL of the cell suspension was dispensed into the filter wells of a 96-well PET Transwell plate. The cells were cultured in a cell culture incubator at 37°C, 5% CO2, and 95% relative humidity for 14–18 days. The cell culture medium was changed within 24 hours of initial seeding and continued to be changed every other day.

[0626] 3) Electrical resistance across the monolayer was measured using a Millicell epithelial cell voltage resistance measurement system. The electrical resistance of each well was recorded. Once all wells were measured, the plate was returned to the incubator.

[0627] 4) The TEER of each well was calculated according to the following equation: The TEER value of each well was 230 ohm·cm 2 It had to be more than that.

[0628]

number

[0629] 2. Transport Assay Procedure

[0630] 1) The Caco-2 plate was removed from the incubator. The monolayer was washed twice with pre-warmed HBSS (10 mM HEPES, pH 7.4). The plate was then incubated at 37°C for 30 minutes.

[0631] 2) A 5 mM stock solution of the control compound in DMSO was prepared and diluted with HBSS (10 mM HEPES, pH 7.4) to obtain a 5 μM working solution. A 1 mM stock solution of the test compound in DMSO was prepared and diluted with HBSS (10 mM HEPES, pH 7.4) to obtain a 1 μM working solution. Digoxin was used as the reference substrate for Pgp. Atenolol was used as the low permeability marker, and minoxidil was used as the high permeability marker.

[0632] 3) To determine the rate of drug transport from the apical to the basolateral direction, 100 μL of working donor solution (without inhibitor) was added to the Transwell insert (apical compartment). 300 μL of transport buffer was added to the wells of the receiver plate (basolateral compartment). To determine the rate of drug transport from the basolateral to the apical direction, 300 μL of working donor solution (without inhibitor) was added to the wells of the receiver plate (basolateral compartment). 100 μL of transport buffer was added to the Transwell insert (apical compartment).

[0633] 4) A 50 μL sample from the working solution was transferred to 300 μL of cold MeOH:acetonitrile (1:1) solution containing IS (50 ng / mL labetalol, 50 ng / mL tolbutamide) to prepare a time 0 sample. The Transwell plate was incubated at 37°C, 5% CO2 for 2 hours with shaking at 60 rpm on a rotary shaker.

[0634] 5) At the end of the transport period, 50 μL of sample was transferred from the apical and basolateral wells to a new 96-well plate. 300 μL of quenching solution (MeOH:acetonitrile = 1:1, containing IS (50 ng / mL labetalol, 50 ng / mL tolbutamide)) was added to each well of the plate and vortexed for 10 minutes. The sample was centrifuged at 4000 rpm for 30 minutes. Prior to LC-MS / MS analysis, 100 μL of the supernatant was aliquoted and mixed with an appropriate amount of ultrapure water (depending on the signal response and peak shape of the LC-MS / MS).

[0635] 6) To determine the rate of Lucifer Yellow leakage after a 2-hour transport period, a stock solution of Lucifer Yellow in DMSO was prepared and diluted with HBSS (10 mM HEPES, pH 7.4) to reach a final concentration of 100 μM. 100 μL of Lucifer Yellow solution was added to the apical compartment. The basolateral compartment was filled with 300 μL of HBSS (10 mM HEPES, pH 7.4). The plate was incubated at 37°C for 30 minutes, and 80 μL was directly removed from the apical and basolateral wells and transferred to a new 96-well plate. Lucifer Yellow fluorescence was measured in a fluorescence plate reader at excitation 485 nM and emission 530 nM (to monitor monolayer integrity).

[0636] 7) The remaining solution in the cell plate was discarded, and 300 μL of quenching solution (MeOH:acetonitrile = 1:1, containing IS (50 ng / mL labetalol, 50 ng / mL tolbutamide)) was added to each well of the plate and mixed thoroughly by blowing up and down five times. 50 μL of the lysate was transferred to a new 96-well plate. 300 μL of quenching solution (MeOH:acetonitrile = 1:1, containing IS (50 ng / mL labetalol, 50 ng / mL tolbutamide)) was added to each well of the plate. The plate was vortexed for 10 minutes. The sample was centrifuged at 4000 rpm for 10 minutes. Prior to LC-MS / MS analysis, 100 μL of the supernatant was aliquoted and mixed with an appropriate amount of ultrapure water (depending on the LC-MS / MS signal response and peak shape).

[0637] 3. Data Analysis

[0638] All calculations were performed using Microsoft Excel. The remaining percentage of the parent compound at each time point was estimated by determining the peak area ratio from the extracted ion chromatograms.

[0639] The apparent permeability coefficient (Papp) for the Caco-2 drug transport assay, in units of centimeters per second, can be calculated using the following equation:

number

[0640] The discharge ratio is determined using the following equation:

number

[0641] Recovery can be determined using the following equation:

[0642]

number

[0643] The leakage rate of Lucifer Yellow, in units of percentage (%), can be calculated using the following equation:

number

[0644] Table 8 shows data for exemplary compounds described herein measured in the Caco-2 cell assay. [Table 8]

[0645] [Example 32] hERG potassium ion channel inhibition assay Drug-hERG interactions were measured by automated patch clamp technique using cisapride as a positive control.

[0646] Experimental procedure

[0647] 1. Cell Preparation

[0648] 1.1 CHO-hERG cells were cultured at 175 cm 2 After the cell density increased to 60-80%, the culture medium was removed, the cells were washed with 7 mL of phosphate-buffered saline (PBS), and digested with 3 mL of Detachin.

[0649] 1.2 After digestion was complete, 7 mL of culture medium was added for neutralization, followed by centrifugation. The clear liquid was aspirated, and 5 mL of culture medium was added for resuspension until the cell density reached 2–5 × 10. 6 / mL.

[0650] 2. Solution Preparation [Table E]

[0651] 3. Electrophysiological Recordings

[0652] The single-cell high-impedance sealing and whole-cell patterning processes were all completed automatically by the Qpatch instrument. After entering whole-cell recording mode, the cell was pinched at -80 millivolts. A 50-millisecond pre-voltage of -50 millivolts was applied, followed by a 5-second repolarization to -50 millivolts, before a 5-second depolarizing stimulus of +40 millivolts was applied. The voltage stimulus was then applied every 15 seconds and recorded for 2 minutes. Next, extracellular fluid was administered, and after 5 minutes of recording, the administration process began. Test compound concentrations were administered for 2.5 minutes, starting with the lowest test concentration. After the sequential administration of all concentrations, 3 μM cisapride, a positive control, was administered. At least two cells were tested per concentration (n ≥ 2).

[0653] 4. Preparation of Test Compounds

[0654] 4.1 Compound stock solutions were diluted with DMSO, and 10 μL of compound stock solution was added to 20 μL of DMSO solution, followed by serial 3-fold dilutions to six DMSO concentrations.

[0655] 4.2 4 μL of test compound at six DMSO concentrations was added to 396 μL of extracellular solution and diluted 100-fold to six intermediate concentrations. Next, 80 μL of test compound at six intermediate concentrations was added to 320 μL of extracellular solution and diluted 5-fold to the final concentrations to be tested.

[0656] 4.3 The highest test concentration was 40.00 μM, and the six test concentrations were 40.00, 13.33, 4.44, 1.48, 0.49, and 0.16 μM, respectively.

[0657] 4.4 The DMSO content in the final test concentration did not exceed 0.2%, and this DMSO concentration did not affect the hERG potassium channel.

[0658] 4.5 The entire dilution process of test compound preparation was carried out on a Bravo instrument.

[0659] 5. Data Analysis

[0660] The experimental data were analyzed using GraphPad Prism 5.0 software.

[0661] Table 9 shows the IC for hERG inhibition of exemplary compounds described herein. 50 Shows. [Table 9]

[0662] It can be seen that the exemplary compounds provided herein do not exhibit hERG liability, indicating a significantly improved safety margin for the compounds. [Example 33] In vivo pharmacokinetic assay

[0663] Pharmacokinetic assays of test compounds were performed in mice via IV and PO.

[0664] 1. Preparation of Test Compounds

[0665] Test compound solutions were prepared on the day of administration.

[0666] Solvent: IV+PO: 5% DMSO + 10% Soultol + 85% H2O or saline

[0667] 2. Experimental Animals

[0668] Species: ICR mice, SPF level

[0669] Provided by: Beijing Wetong Lihua Experimental Animal Technology Co., Ltd.

[0670] Animal selection: male, no random grouping

[0671] 3. Experimental Design [Table F]

[0672] 4. Route of Administration

[0673] Before administration, the animals were weighed and the dose was calculated based on the body weight. Groups 1 to 3 received the drug intravenously or intragastrically. Group 4 received the drug intragastrically.

[0674] 5. Time of sample collection

[0675] For groups 1 to 3, the time points were 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. For group 4, the time points were 2 h and 4 h after administration.

[0676] Blood was collected from the cheek. For each sample, approximately 0.05 mL of blood was collected, anticoagulated with sodium heparin or EDTA-2K, and placed on wet ice.

[0677] 6. Plasma Sample Processing

[0678] Blood samples were collected, placed on ice, and centrifuged within 1 hour (6000 g, 3 min, 2–8°C) to separate plasma. Plasma samples were stored in a refrigerator at −80°C prior to analysis.

[0679] 7.Result analysis

[0680] Pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.2.0 based on the blood concentration data at different time points, and AUC 0-t , AUC 0-∞ , MRT 0-∞ , C max , T max , T 1 / 2 , as well as their mean values ​​and standard deviations.

[0681] Tables 10 and 11 show in vivo PK data for exemplary compounds described herein. [Table 10] [Table 11]

[0682] [Example 34] CYP isoform inhibition assay The CYP isoform inhibitory activity of the test compounds was measured in human liver microsomes.

[0683] Study design

[0684] 1. Equipment, Materials, and Reagents

[0685] 1.1. Phosphate buffer (100 mmol / L, pH 7.4)

[0686] 9.24291 g of K2HPO4·3H2O, 1.29286 g of KH2PO4, and 808.047 mg of dipotassium EDTA were weighed and dissolved in 500 mL of pure water to form PB buffer solution, which was stored in a freezer at 4 °C.

[0687] 1.2.12 mmol / L MgCl2 solution

[0688] 123.21 mg of magnesium chloride hexahydrate (mV=203.3, 99%) was weighed and dissolved in 50 mL of phosphate solution to prepare a magnesium chloride stock solution with a concentration of 12 mM.

[0689] 1.3. NADPH regenerator

[0690] 6.803 mg of NADPH powder (MV = 833.35, 98%) was weighed and 800 μL of PB was added to prepare a 10 mM NADPH solution.

[0691] 390 μL of the 10 mM NADPH solution was taken and 3900 μL of 12 mM magnesium chloride stock solution was added, followed by 3510 μL of phosphate buffer to form an NADPH regenerating solution containing 2 mM NADPH and 6 mM magnesium chloride.

[0692] 1.4. Substrate

[0693] The details of the preparation of these substrates are shown in the table below. The substrate stock solutions were stored in a -20°C freezer. Before use, the substrate stock solutions were removed from the freezer and allowed to warm to room temperature. The substrate stock solutions were then mixed in a Willy mixer for 30 seconds. [Table G]

[0694] 1.5. Human Liver Microsomes (HLM)

[0695] HLMs were stored in a freezer at −80° C. Before use, pooled HLMs were removed from the freezer, thawed in a 37° C. water bath, and then stored on wet ice.

[0696] Inhibitors

[0697] The positive control inhibitors used for each isozyme and their concentrations are summarized below. [Table H]

[0698] Inhibitor stock solutions were stored at -20°C. Prior to use, working solutions were removed from the freezer and allowed to warm to room temperature. Standard inhibitor stock solutions were then mixed for 30 seconds in a Willy mixer.

[0699] 1.7. Stop solution (tolbutamide 50 ng / mL in 50% ACN / MeOH (v:v))

[0700] 6.006 mg of tolbutamide was weighed out and 30 mL of acetonitrile was added to make a 200 μg / mL tolbutamide stock solution.

[0701] 250 μL of the 200 μg / mL tolbutamide stock solution was taken and 250 mL of acetonitrile and 250 mL of methanol were added.

[0702] 2. Assay Procedure

[0703] 2.1. Preparation of human liver microsome working solution

[0704] To obtain a mixture of substrate and HLM, a human liver microsome working solution was prepared according to the table below. [Table I]

[0705] 2.2. Compound Dilution

[0706] Working solutions of test compounds were made up according to final concentrations of 30, 10, 3, 1, 0.3, 0.1, 0.03, and 0.01 μM, and the appropriate solvent (DMSO or 30% DMSO / ACN) was selected according to the solubility of the compound.

[0707] Incubation

[0708] All samples were incubated in a 37°C water bath, with three parallel runs per test compound concentration and two parallel runs per positive control inhibitor concentration. 100 μL of microsome working solution was taken and 2 μL of test compound or positive inhibitor working solution was added. 2 μL of solvent was added to the solvent control and placed in the water bath for 10 minutes of preincubation. After preincubation, 98 μL of NADPH regenerating solution was added to all samples to initiate the reaction. The mixtures were then returned to the water bath and incubated for a set period. The experimental results for each isozyme are summarized in the table below. [Table J]

[0709] 2.4. Reaction Quenching

[0710] The reaction was quenched by adding 200 μL of stop solution. The plate was centrifuged at 3,220 g for 10 minutes. For LC-MS / MS analysis, an appropriate amount of the supernatant was transferred to an analytical plate, and water was added and mixed well. [Table K]

[0711] 3. Data Processing

[0712] Automated peak integration areas were checked for all samples. Analyte and internal standard peak areas were exported to an Excel spreadsheet.

[0713] Each P in human liver microsomes 450 Enzyme inhibition was measured as the percentage reduction in marker metabolite formation compared to the uninhibited DMSO control (=100% activity). IC was calculated using GraphPad Prism 7. 50 The IC value (the concentration of test compound that produces 50% inhibition) was calculated. 50Values ​​were determined using a three- or four-parameter logistic equation. If the inhibition rate at the highest concentration (30 μM) was less than 50%, the IC 50 Values ​​were reported as ">30 μM."

[0714] The residual activity rate was calculated as follows:

[0715]

number

[0716]

number

[0717] Table 12 shows the IC for CYP isoform inhibition of exemplary compounds described herein. 50 Shows. [Table 12]

[0718] Example 35: In vivo efficacy assay The antitumor efficacy or MTAP / MTA selectivity of the compounds provided herein was demonstrated in a Balb / C nude female mouse model subcutaneously implanted with the human colon cancer cell line HCT116 (WT and MTAP KO).

[0719] procedure

[0720] 1. Tumor Inoculation

[0721] Cell viability and cell number were determined. The cell number in the suspension was adjusted to 1 × 10 8 The cells were adjusted to 5 × 10 cells / mL and mixed with Matrigel at a 1:1 ratio. In this study, 5 × 10 cells were injected into the right anterior flank region of each mouse to develop tumors. 6 Tumor cells (0.1 mL) were inoculated subcutaneously.

[0722] 2. Randomization

[0723] The average tumor size is approximately 100-150 mm 3 Randomization began when the WT cells reached 0.5%. Mice inoculated with HCT 116 WT cells were randomized on day 7. Mice inoculated with HCT 116 MTAP KO cells were randomized on day 8. All animals were randomly assigned to five study groups (each group consisting of eight animals). Randomization was performed based on a randomized block design. [Table L]

[0724] 3. Observation and Data Collection

[0725] Tumor volume was measured two-dimensionally using calipers twice a week, and the volume was calculated in mm using the formula "V = (L × W × W) / 2". 3 The tumor volume was expressed in units of 1.0, where V is the tumor volume, L is the tumor length (longest tumor dimension), and W is the tumor width (longest tumor dimension perpendicular to L).

[0726] Table 13 and Figures 1 and 2 show the in vivo efficacy results of exemplary compounds described herein. [Table 13]

[0727] The compounds provided herein are found to exhibit potent in vivo efficacy, along with excellent MTAP / MTA selectivity and good tolerability.

[0728] The foregoing description is considered merely as illustrative of the principles of the present disclosure. Moreover, since numerous modifications and changes will be readily apparent to those skilled in the art, it is not desired to limit the invention to the exact construction and process shown above. Accordingly, all suitable modifications and equivalents may be considered to be within the scope of the invention as defined by the appended claims.

[0729] The words "comprises," "comprising," "includes," "including," and "including" when used in this specification and the appended claims are intended to specify the presence of stated features, integers, components, or steps, but do not exclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt, or deuterated derivative thereof, During the ceremony, X １ , X ２ , X ３ , X ４ , X ５ , X ６ , X ７ , X ８ , and X ９ are each independently selected from C, CH, or N, with the proviso that X ８ and X ９ at least one of is N, each 【Chemistry 2】 are independently a single bond or a double bond; Y is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, or —C(O)—, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are selected from one or more R ａ optionally replaced by R ａ is selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen, cyano, oxo, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and haloalkyl; R １ is cycloalkyl, heterocyclyl, aryl, heteroaryl, or —N(R ｂ ) ２ wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are selected from one or more R ｃ optionally replaced by Each R ｂ are independently selected from the group consisting of hydrogen, deuterium, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally selected from the group consisting of one or more R ｄ optionally substituted with, or Two R's ｂ together with the nitrogen atom to which they are attached, form one or more R ｃ forming an optionally substituted heterocyclyl with Each R ｃ is deuterium, cyano, halogen, hydroxyl, oxo, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and OR ｄ wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from oxo, cyano, halogen, hydroxyl, alkyl, or haloalkyl; R ｄ is selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen, cyano, oxo, alkoxyl, alkyl, haloalkyl, haloalkoxyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from oxo, cyano, halogen, hydroxyl, alkoxyl, alkyl, haloalkyl, and haloalkoxyl; R ２ and R ３ are each independently selected from the group consisting of hydrogen, deuterium, cyano, halogen, hydroxyl, amino, oxo, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from deuterium, cyano, halogen, hydroxyl, or amino; n is 0, 1, 2, or 3; A compound or a pharmaceutically acceptable salt thereof, wherein i is 0, 1, 2, or 3.

2. X ５ , X ６ , and X ７ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein one of the following is N and the other two are C or CH.

3. X ８ is N and X ９ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:

4. X ５ and X ７ is C or CH, and X ６ 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein: 【Request Item 5】 【Chemistry 3】 Part 【Chemistry 4】 5. The compound of claim 4, wherein:

6. X ５ and X ６ is C or CH, and X ７ 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein: 【Request Item 7】 【Chemistry 5】 Part 【Transformation 6】 7. The compound of claim 6, wherein:

8. X ８ is C or CH, and X ９ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:

9. X ５ and X ７ is C or CH, and X ６ 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein: 【Request Item 10】 【Chemistry 7】 Part 【Transformation 8】 10. The compound of claim 9, wherein:

11. X ５ and X ６ are each C or CH, and X ７ 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein: 【Request Item 12】 【Chemistry 9】 Part 【Chemistry 10】 12. The compound of claim 11, wherein:

13. X ５ is N and X ６ and X ７ is C or CH, or a pharmaceutically acceptable salt thereof. 【Request Item 14】 【Chemistry 11】 Part 【Chemistry 12】 14. The compound of claim 13, wherein:

15. Each R ２ are independently selected from hydrogen, cyano, halogen, amino, oxo, or alkyl, each of which is optionally substituted with one or more groups independently selected from cyano, halogen, or hydroxyl, or a pharmaceutically acceptable salt thereof.

16. R ２ 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

17. R ２ 17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein is alkyl.

18. R ２ 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein is methyl. 【Request Item 19】 【Chemistry 13】 but, 【Chemistry 14】 3. The compound of claim 1 or 2, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

20. X １ , X ２ , X ３ , and X ４ is C or CH, or a pharmaceutically acceptable salt thereof.

21. X １ is N and X ２ , X ３ , and X ４ is C or CH, or a pharmaceutically acceptable salt thereof.

22. X ２ is N and X １ , X ３ , and X ４ is C or CH, or a pharmaceutically acceptable salt thereof.

23. X ４ is N and X １ , X ２ , and X ３ is C or CH, or a pharmaceutically acceptable salt thereof. 【Request Item 24】 【Chemistry 15】 The part is, 【Chemistry 16】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

25. R ３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

26. R ３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is halogen.

27. R ３ 27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein:

28. 28. The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein Y is -C(O)-.

29. R １ -N (R ｂ ) ２ 29. The compound of claim 28, wherein:

30. Each R ｂ are independently selected from hydrogen, deuterium, alkyl, aryl, or heteroaryl, and the alkyl, aryl, and heteroaryl are each independently selected from one or more R ｄ optionally replaced by Each R ｄ is independently selected from hydrogen, deuterium, hydroxyl, halogen, cyano, oxo, alkoxyl, alkyl, haloalkyl, haloalkoxyl, or heteroaryl, each of which is optionally substituted with one or more groups independently selected from oxo, cyano, halogen, hydroxyl, alkyl, alkoxyl, haloalkyl, or haloalkoxyl, or a pharmaceutically acceptable salt thereof.

31. Each R ｂ is independently selected from alkyl, aryl, -alkyl-heteroaryl, heteroaryl, or -heteroaryl-heteroaryl, wherein said alkyl and heteroaryl are optionally substituted with one or more groups independently selected from deuterium, hydroxyl, halogen, cyano, oxo, alkyl, alkoxyl, haloalkyl, or haloalkoxyl, or a pharmaceutically acceptable salt thereof.

32. The heteroaryl in the -alkyl-heteroaryl, heteroaryl, and -heteroaryl-heteroaryl is 【Chemistry 17】 32. The compound of claim 31 , or a pharmaceutically acceptable salt thereof, selected from:

33. The aryl may be one or more R ｄ optionally replaced with [Chemistry 18] and each R ｄ 31. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein is independently selected from deuterium, hydroxyl, halogen, cyano, oxo, alkyl, alkoxyl, haloalkyl, or haloalkoxyl.

34. On the other hand, R ｂ is alkyl, and the other R ｂ 32. The compound of claim 31 , or a pharmaceutically acceptable salt thereof, wherein: is -heteroaryl-heteroaryl, wherein said alkyl and heteroaryl are optionally substituted with one or more groups independently selected from deuterium, hydroxyl, halogen, cyano, oxo, alkyl, alkoxyl, haloalkyl, or haloalkoxyl.

35. On the other hand, R ｂ is methyl optionally substituted with one or more deuterium atoms, and the other R ｂ but, 【Chemistry 19】 35. The compound of claim 34, wherein:

36. Each R ｂ is independently -alkyl-heteroaryl, wherein said alkyl and heteroaryl are optionally substituted with one or more groups independently selected from deuterium, hydroxyl, halogen, cyano, oxo, alkyl, alkoxyl, haloalkyl, or haloalkoxyl, or a pharmaceutically acceptable salt thereof.

37. On the other hand, R ｂ but 【Chemistry 20】 and the other R ｂ but 【Chemistry 21】 37. The compound of claim 36, wherein:

38. On the other hand, R ｂ is alkyl, and the other R ｂ is aryl or heteroaryl, and said alkyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from deuterium, hydroxyl, halogen, cyano, oxo, alkyl, alkoxyl, haloalkyl, or haloalkoxyl, or a pharmaceutically acceptable salt thereof.

39. On the other hand, R ｂ is methyl optionally substituted with one or more deuterium atoms; The other R ｂ but, 【Chemistry 22-1】 【Chemistry 22-2】 39. The compound of claim 38, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

40. Two R's ｂ together with the nitrogen atom to which they are attached, one or more R ｃ 30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein R is an optionally substituted heterocyclyl;

41. Two R's ｂ together with the nitrogen atom to which they are attached, one or more R ｃ 41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, which forms an optionally substituted piperidinyl.

42. Each R ｃ is independently selected from alkyl or heteroaryl optionally substituted with one or more groups independently selected from oxo, cyano, halogen, hydroxyl, alkyl, or haloalkyl, or a pharmaceutically acceptable salt thereof.

43. The one or more R ｃ piperidinyl optionally substituted with 【Chemistry 23】 43. The compound of claim 42, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

44. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is heteroaryl optionally substituted with one or more groups independently selected from halogen, cyano, alkyl, alkenyl, or alkynyl.

45. 45. The compound of claim 44, or a pharmaceutically acceptable salt thereof, wherein Y is pyrazolyl optionally substituted with one or more groups independently selected from halogen, cyano, hydroxyl, or alkyl.

46. Y is 【Chemistry 24】 46. ​​The compound of claim 45, wherein:

47. R １ However, one or more R ｃ 45. The compound of claim 44, or a pharmaceutically acceptable salt thereof, wherein R is aryl optionally substituted with R.

48. R １ However, one or more R ｃ 48. The compound of claim 47, wherein R is phenyl or naphthalinyl optionally substituted with R or a pharmaceutically acceptable salt thereof.

49. Each R ｃ is cyano, halogen, hydroxyl, alkyl, or OR ｄ and R ｄ 49. The compound of claim 47 or 48, or a pharmaceutically acceptable salt thereof, wherein is selected from alkyl, haloalkyl, or cycloalkyl.

50. The compound is 【Chemistry 25-1】 【Chemistry 25-2】 【Chemistry 25-3】 【Chemistry 25-4】 【Chemistry 25-5】 【Chemistry 25-6】 【Chemistry 25-7】 【Chemistry 25-8】 【Chemistry 25-9】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

51. 51. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 50, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

52. 52. A method for inhibiting PRMT5 activity in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 50 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 51.

53. 52. A method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1 to 50 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 51.

54. The cancers include cardiac tumors such as sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung cancers such as bronchogenic lung carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, and mesothelioma; digestive cancers such as esophageal (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (tubular adenocarcinoma, islet cell adenoma, glucagonoma, gastrinoma, carcinoid tumor, and VIP tumor); and small intestine (adenoma) cancers. Cancer, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), genitourinary cancers: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma), liver cancer: hepatocellular carcinoma (hepatocellular carcinoma)carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary tract cancer, gallbladder cancer, ampulla carcinoma, bile duct cancer, bone cancer, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma , osteoid and giant cell tumor, nervous system tumors, skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma), gynecological cancers, uterus (uterine 54. The method of claim 53, wherein the cancer is selected from the group consisting of endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (cancer), blood cancers including blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma, skin cancers including malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, mole, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, and adrenal tumors including neuroblastoma.

55. 55. The method of claim 53 or 54, wherein the cancer is an MTAP-associated cancer.

56. 54. The method of claim 53, wherein the cancer is hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, head and neck cancer, or brain glioma.

57. 55. The method of claim 53 or 54, wherein the cancer is a metastatic cancer.

58. 58. The method of claim 57, wherein the metastatic cancer is a brain metastatic cancer.

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