Amide compounds, pharmaceutical compositions containing them, and their use

Abstract

TIFF2026516768000124.tif4157(I) The present invention relates to a compound of formula (I), a pharmaceutical composition containing the same, and its use for the prevention or treatment of disease.

Description

[Technical Field]

[0001] The present invention relates to amide compounds, pharmaceutical compositions containing the same, and their use for preventing or treating diseases. [Background technology]

[0002] Arginine methylation is a type of histone methylation and one of the most common post-translational modifications in mammals, primarily regulated by the PRMT (protein arginine methyltransferase) gene family. PRMT can transfer a methyl group from S-adenosylmethionine (AdoMet / SAM) to the guanidino nitrogen atom of the protein arginine side chain, producing methylated arginine. PRMT can regulate arginine methylation in several different forms and plays a crucial role in biological processes such as gene expression, splicing, and DNA damage repair. Changes in PRMT enzyme activity, gene mutations, or deletions are usually closely associated with developmental abnormalities in animals, as well as the development and progression of cancer.

[0003] Within the PRMT gene family, PRMT5, as an epigenetic enzyme, is involved in many physiological processes, including transcriptional regulation, RNA metabolism, ribosome biosynthesis, and cell cycle regulation. It is particularly upregulated in many cancers, such as lymphoma, lung cancer, breast cancer, and ovarian cancer, which fully demonstrates its important role in tumor formation and progression.

[0004] MTAP (methylthioadenosine phosphorylase) frequently undergoes co-deletion with the common onco-inhibitor gene CDKN2A in the body, and this co-deletion phenomenon can occur in 9% to 15% of tumors. Further studies have reported that MTAP deletion leads to the accumulation of intracellular MTA (methylthioadenosine, an MTAP substrate), and that excess MTA binds to and inhibits some of the activity of PRMT5, thereby forming an MTAP-PRMT5 lethal effect. Currently, several PRMT5 inhibitors are in clinical trials, but most of them do not exhibit PRMT5-MTA selectivity, but rather relatively low selectivity for MTAP-deletion tumors and have relatively high toxicity. [Overview of the Initiative]

[0005] This application provides a compound used as a PRMT5 inhibitor, which exhibits excellent inhibitory activity against PRMT5 (particularly in MTAP-deficient cells). Furthermore, the compound of the present invention further possesses excellent properties such as good physicochemical properties (e.g., solubility, physical and / or chemical stability), good pharmacokinetic properties (e.g., improved bioavailability, good metabolic stability, appropriate half-life and duration of action), good safety (relatively low toxicity (e.g., reduced cardiotoxicity) and / or relatively few side effects), and low tolerance development.

[0006] One aspect of the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein the compound has the structure of formula (I), [ka] (I) During the ceremony, Ring A is C 3~10 Hydrocarbon ring, 3-10 membered heterocycle, C 6~10 It is an aromatic ring or a 5-14 membered heteroaromatic ring. Ring B is a benzene ring, X is CR X or N, Y is CR Y or N, Z is CR Z or N, R X 、R Y 、R Z 、R 1 、R 2 、R 3 、R 4 、R 5 and R 6 each, every time they appear, are independently H, halogen, -OH, -NH2, -CN, -NO2, C 1~6 alkyl group, deuterated C 1~6 alkyl group, C 2~6 alkenyl group, C 2~6 alkynyl group, C 3~6 cyclic hydrocarbon group, 3- to 10-membered heterocyclyl group, C 6~10 aryl group, 5- to 14-membered heteroaryl group, C 6~12 aralkyl group, -C(=O)R a 、-OC(=O)R a 、-C(=O)OR a 、-OR a 、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR a R b 、-NR a R b 、-C(=O)NR a R b 、-NR a -C(=O)R b 、-NR a -C(=O)OR b 、-NR a -S(=O)2-R b 、-NR a -C(=O)-NR a R b 、-C 1~6 alkylene-OR a 、-C 1~6 alkylene-NR a R b and -O-C 1~6 alkylene-NR a R b selected from, Alternatively, R 1 and R 2 They can optionally be linked together with the base C 3~10 Hydrocarbon ring, 3-10 membered heterocycle, C 6~10 Constituting an aromatic ring or a 5-14 membered heteroaromatic ring, and / or R 3 and R 4 These, along with the groups they link, optionally form a 3- to 10-membered complex ring. R a and R b Each time they appear, H and C appear independently. 1~6 Alkyl alkyl group, C 3~10 Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, C 6~10 Aryl group, 5-14 member heteroaryl group and C 6~12 Selected from aralkyl groups, Each of the alkyl groups, alkylene groups, alkenyl groups, alkynyl groups, cyclic hydrocarbon groups, hydrocarbon rings, heterocyclyl groups, heterocyclic rings, aryl groups, aromatic rings, heteroaryl groups, heteroaromatic rings, and aralkyl groups can be optionally represented by halogens, -OH, =O, -NH2, -CN, -NO2, and C, respectively, whenever they appear. 1~6 Alkyl alkyl group, C 3~6 Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, C 6~10 Aryl group, 5-14 member heteroaryl group, C 6~12 Aralkyl group, -C(=O)R c -OC(=O)R c , -C(=O)OR c , -OR c , -SR c -S(=O)R c -S(=O)2R c -S(=O)2NR c R d , -NR c R d -C(=O)NR c R d , -NR c -C(=O)R d , -NR c -C(=O)OR d , -NR c -S(=O)2-R d , -NRc -C(=O)-NR c R d 、 -C 1~6 alkylene-OR c 、 -C 1~6 alkylene-NR c R d and -O-C 1~6 alkylene-NR c R d is substituted with one or more substituents independently selected from, and the alkyl group, cyclic hydrocarbon group, heterocyclyl group, aryl group, heteroaryl group and aralkyl group are further optionally halogen, -OH, =O, -C(=O)O-tert-butyl group, -NH2, -CN, -NO2, C 1~6 alkyl group, C 1~6 haloalkyl group, C 3~6 cyclic hydrocarbon group, 3- to 10-membered heterocyclyl group, C 6~10 aryl group, 5- to 14-membered heteroaryl group, C 6~12 aralkyl group, -O-C 1~6 alkyl group and -C 1~6 alkylene-O-C 1~6 alkyl group is substituted with one or more substituents independently selected from, R c and R d each time it appears, is independently H, C 1~6 alkyl group, C 3~10 cyclic hydrocarbon group, 3- to 10-membered heterocyclyl group, C 6~10 aryl group, 5- to 14-membered heteroaryl group and C 6~12 aralkyl group is selected from, and the alkyl group, cyclic hydrocarbon group, heterocyclyl group, aryl group, heteroaryl group and aralkyl group are further optionally halogen, -OH, =O, -C(=O)O-tert-butyl group, -NH2, -CN, -NO2, C 1~6 alkyl group, C 1~6 haloalkyl group, C 3~6 cyclic hydrocarbon group, 3- to 10-membered heterocyclyl group, C 6~10 aryl group, 5- to 14-membered heteroaryl group, C 6~12 aralkyl group and -C 1~6 alkylene-O-C 1~6Substituted with one or more substituents independently selected from the alkyl group, and m and n are each an independent integer of 1, 2, 3, or 4, preferably an integer of 1, 2, or 3.

[0007] Another aspect of the present invention provides a pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0008] Another aspect of the present invention provides the use of the compounds of the present invention or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, crystalline polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs or pharmaceutical compositions of the present invention in the manufacture of drugs used as PRMT5 inhibitors.

[0009] Another aspect of the present invention provides the compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, crystalline polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs thereof, or pharmaceutical compositions of the present invention, for use as PRMT5 inhibitors.

[0010] Another aspect of the present invention provides a method for preventing or treating cancer (preferably MTAP-deficient cancer), comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound or prodrug or pharmaceutical composition of the present invention to an individual in need thereof.

[0011] (Detailed description of the invention) definition Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to the art used herein are intended to refer to the art commonly understood, including variations on the art or substitution of equivalent art that would be obvious to those skilled in the art. The following terms are expected to be well understood by those skilled in the art, but for the better interpretation of the present invention, the following definitions are provided.

[0012] The terms “include,” “contain,” “have,” “contain,” or “related to,” and other variations thereof herein, are inclusive or open and do not exclude other elements or method steps not listed.

[0013] As used herein, the term “alkylene group” refers to a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, such as a methylene group, ethylene group, propylene group, or butylene group.

[0014] As used herein, the term “alkyl group” is defined as a straight-chain or branched-chain saturated aliphatic hydrocarbon. In some embodiments, an alkyl group has 1 to 12 carbon atoms, for example, 1 to 6 carbon atoms. For example, as used herein, “C 1~6 The term "alkyl group" refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, or n-hexyl group) optionally substituted with one or more (e.g., 1 to 3) preferred substituents, such as halogens (in which case the group is called a "haloalkyl group") (e.g., CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl, or -CH2CH2CF3). 1-4The term "alkyl group" refers to a linear or branched aliphatic hydrocarbon chain consisting of 1 to 4 carbon atoms (i.e., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, or tert-butyl group).

[0015] As used herein, the term “alkenyl group” means a monovalent hydrocarbon group that contains one or more double bonds and has 2 to 6 carbon atoms in a straight or branched chain ("C"). 2~6 The term "alkenylene group" refers to, for example, -CH=CH2, -CH2CH=CH2, -C(CH3)=CH2, -CH2-CH=CH-CH3, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 2-methyl-2-propenyl group, and 4-methyl-3-pentenyl group. When a compound of the present invention contains an alkenyl group, the compound can exist in the form of a pure E (entgegen) form, a pure Z (zusammen) form, or any mixture thereof. The term "alkenylene group" refers to, for example, "C 2~6 "Alkenylene group", "C 2~4 This refers to the corresponding divalent group, including alkenylene groups, and specific examples include, but are not limited to, -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, butenylene group, pentenylene group, and hexenylene group.

[0016] As used herein, the term “alkynyl group” refers to a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5, or 6 carbon atoms, such as an ethynyl group, a 2-propynyl group, a 2-butynyl group, or a 1,3-butanyl group. The alkynyl group is optionally substituted with one or more (e.g., 1 to 3) homologous or heterologous substituents. The term “alkynylene group” refers to, for example, a C 2~8 "Alkynylene group", "C 2~6 "Alkynylene group", "C 2~4 It is a corresponding divalent group, including an "alkynylene group." An example of this is: [ka] This includes, but is not limited to, the alkynylene group being optionally substituted with one or more (e.g., 1 to 3) homologous or homologous substituents.

[0017] As used herein, the terms “bonding ring” or “fused ring” refer to a ring system formed by two or more cyclic structures sharing two adjacent atoms with one another.

[0018] As used herein, the term “spiro ring” refers to a ring system formed by two or more cyclic structures sharing one ring atom with one another.

[0019] As used herein, the term “bridged ring” refers to a ring system formed by two or more cyclic structures sharing two non-directly linked atoms with one another.

[0020] As used herein, the terms “cyclic hydrocarbon divalent group,” “cyclic hydrocarbon group,” and “hydrocarbon ring” refer to a monocyclic or polycyclic hydrocarbon ring (including spiro rings, bonding rings (condensed rings), or bridging ring systems) that is saturated (i.e., “cycloalkylene group” and “cycloalkyl group”) or partially unsaturated (i.e., has one or more double and / or triple bonds in the ring) having 3 to 10 (preferably 3 to 8, more preferably 3 to 6) ring carbon atoms, including, but not limited to, cyclopropyl(lene) groups (rings), cyclobutyl(lene) groups (rings), cyclopentyl(lene) groups (rings), cyclohexyl(lene) groups (rings), cycloheptyl(lene) groups (rings), cyclooctyl(lene) groups (rings), cyclononyl(lene) groups (rings), cyclohexenyl(lene) groups (rings), etc.

[0021] As used herein, the term “cycloalkyl group” refers to a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring (e.g., monocyclic groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononyl groups, or bicyclic groups including spirocycles, condensed, or crosslinked systems (e.g., bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, or bicyclo[5.2.0]nonyl, dekalinyl, etc.)) that is optionally substituted with one or more (e.g., 1 to 3) suitable substituents. The above cycloalkyl groups have 3 to 15 carbon atoms. For example, “C 3~6 The term "cycloalkyl group" refers to a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring (e.g., cyclopropyl group, cyclobutyl group, cyclopentyl group, or cyclohexyl group) of 3 to 6 ring-constituting carbon atoms, optionally substituted with one or more (e.g., 1 to 3) preferred substituents, such as a cyclopropyl group substituted with a methyl group.

[0022] As used herein, the term “heterocyclyl group” (or “heterocycle”) means a saturated or partially unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms selected from O, S, N, and P, and the “heterocyclyl group” (or “heterocycle”) may include -C(=O)- as a ring member. The heterocyclyl group can be linked to the rest of the molecule via the carbon atoms and / or heteroatoms (if present). In particular, 3-10 membered heterocyclyl groups are groups having 3-10 carbon atoms and heteroatoms in the ring, and include, but are not limited to, oxyranyl, azilidinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidone, imidazolidinyl, pyrazolidinyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl groups.

[0023] As used herein, the term “heterocyclyl group” (or “heterocyclic”) covers a bonded ring structure in which the bonding sites to other groups may be located on any one of the rings of the bonded ring structure. Accordingly, the heterocyclyl groups of the present invention include heterocycloheterocyclyl groups, heterocyclocycloalkyl groups, monoheterocyclomonoheterocyclyl groups, monoheterocyclomonoalkyl groups, arylheterocyclyl groups, heteroarylheterocyclyl groups, for example, 3-7 membered (mono)heterocyclo3-7 membered (mono)heterocyclyl groups, 3-7 membered (mono)heterocyclo(mono)cycloalkyl groups, and 3-7 membered (mono)heterocycloC 4~6 (Mono)cycloalkyl group, C 6~10It further includes, but is not limited to, aryl 3-7 membered heterocyclyl groups and 5-6 membered heteroaryl 3-7 membered heterocyclyl groups, and examples include pyrrolidinocyclopropyl group, cyclopentazacyclopropyl group, pyrrolidinocyclobutyl group, pyrrolidinopyrrolidinyl group, pyrrolidinopiperidinyl group, pyrrolidinopiperazinyl group, piperidinomorpholinyl group, [ka] This includes, but is not limited to, the following:

[0024] As used herein, the term “heterocyclyl group” (or “heterocycle”) encompasses both bridged heterocyclyl groups (bridged heterocycles) and spiroheterocyclyl groups (spiroheterocycles).

[0025] As used herein, the term “bridged heterocycle” refers to a cyclic structure containing one or more (e.g., one, two, three, or four) heteroatoms (e.g., oxygen, nitrogen, and / or sulfur atoms) formed by two rings sharing two directly non-linked ring atoms, such as 7-10 membered bridged heterocycles, 8-10 membered bridged heterocycles, 7-10 membered nitrogen-containing bridged heterocycles, 7-10 membered oxygen-containing bridged heterocycles, 7-10 membered sulfur-containing bridged heterocycles, etc. [ka] This includes, but is not limited to, the above-mentioned "nitrogen-containing bridged heterocycle," "oxygen-containing bridged heterocycle," and "sulfur-containing bridged heterocycle" further optionally include one or more other heteroatoms selected from oxygen, nitrogen, and sulfur.

[0026] As used herein, the term “spiroheterocycle” refers to a cyclic structure containing one or more (e.g., one, two, three, or four) heteroatoms (e.g., oxygen, nitrogen, sulfur atoms) formed by two or more rings sharing one ring atom, such as a 5-10 membered spiroheterocycle, a 6-10 membered spiroheterocycle, a 6-10 membered nitrogen-containing spiroheterocycle, a 6-10 membered oxygen-containing spiroheterocycle, a 6-10 membered sulfur-containing spiroheterocycle, and so on. [ka] This includes, but is not limited to, the above-mentioned "nitrogen-containing spiroheterocycle," "oxygen-containing spiroheterocycle," and "sulfur-containing spiroheterocycle." The above-mentioned "nitrogen-containing spiroheterocycle," "oxygen-containing spiroheterocycle," and "sulfur-containing spiroheterocycle" further optionally include one or more other heteroatoms selected from oxygen, nitrogen, and sulfur. The term "6-10 member nitrogen-containing spiroheterocyclyl group" refers to a spiroheterocyclyl group that contains a total of 6-10 ring atoms, where at least one ring atom is a nitrogen atom.

[0027] As used herein, the terms “aryl(lene) group” or “aromatic ring” refer to a monocyclic or polycyclic aromatic group of all carbon atoms having a conjugated π-electron system. For example, as used herein, “C 6~10 "Aryl(lene) group" and "C 6~10 The term "aromatic ring" refers to an aromatic group containing 6 to 10 carbon atoms, such as a phenyl(len) group (benzene ring) or a naphthyl(len) group (naphthalene ring). The aryl(len) group and aromatic ring may optionally have one or more (e.g., 1 to 3) preferred substituents (e.g., halogen, -OH, -CN, -NO2, C). 1~6 It is replaced with an alkyl group, etc.

[0028] The term "aralkyl group" refers to an alkyl group substituted with an aryl group, where the aryl group and alkyl group are as defined herein. Typically, the aryl group may have 6 to 14 carbon atoms, and the alkyl group may have 1 to 6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl groups.

[0029] As used herein, the terms “heteroaryl(len) group” and “heteroaromatic ring” refer to monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and comprising at least one homologous or heteroatom (such as oxygen, nitrogen or sulfur), and further in each case being benzo-condensed. In particular, the "heteroaryl(len) group" or "heteroaromatic ring" is selected from thienyl(len) group(ring), furanyl(len) group(ring), pyrrolyl(len) group(ring), oxazole(lylene) group(ring), thiazole(lylene) group(ring), imidazole(lylene) group(ring), pyrazole(lylene) group(ring), isoxazole(lylene) group(ring), isothiazole(lylene) group(ring), oxadiazole(lylene) group(ring), triazole(lylene) group(ring), thiadiazole(lylene) group(ring), etc., and their benzo derivatives, or from pyridyl(len) group(ring), pyridadinyl(len) group(ring), pyrimidinyl(len) group(ring), pyrazinyl(len) group(ring), triazinyl(len) group(ring), etc., and their benzo derivatives.

[0030] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0031] As used herein, the term “alkylthio group” means an alkyl group as defined above, which is linked to the parent molecule via a sulfur atom. 1~6Typical examples of alkylthio groups include, but are not limited to, methylthio groups, ethylthio groups, tert-butylthio groups, and hexylthio groups.

[0032] As used herein, the term “nitrogen-containing heterocycle” means a saturated or partially unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and at least one nitrogen atom in the ring, and optionally further comprising one or more (e.g., one, two, three, or four) ring members selected from N, O, S, S=O, and S(=O)2, wherein the nitrogen-containing heterocycle is linked to the rest of the molecule via any one of the ring members. The nitrogen-containing heterocycle is preferably a saturated nitrogen-containing monocycle. In particular, 3- to 14-membered nitrogen-containing heterocycles are groups having 3 to 14 carbon atoms and heteroatoms (where at least one is a nitrogen atom) within the ring, and include, but are not limited to, 3-membered nitrogen-containing heterocycles (e.g., azilidinyl group), 4-membered nitrogen-containing heterocycles (e.g., azetidinyl group), 5-membered nitrogen-containing heterocycles (e.g., pyrrolyl group, pyrrolidine group (pyrrolidine ring), pyrrolinyl group, pyrrolidone group, imidazole group, imidazolidinyl group, imidazolinyl group, pyrazole group, pyrazolinyl group), 6-membered nitrogen-containing heterocycles (e.g., piperidinyl group (piperidine ring), morpholinyl group, thiomorpholinyl group, piperazinyl group), and 7-membered nitrogen-containing heterocycles.

[0033] The term "substitution" refers to the substitution of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom with a group selected from the indicated group, provided that the substitution does not exceed the normal valence of the specified atom in its current state, and that the substitution forms a stable compound. A combination of substituents and / or variables is permissible only if such a combination forms a stable compound.

[0034] If a substituent is described as being "optionally substituted with...", the substituent may be (1) unsubstituted or (2) substituted. If the carbon of a substituent is described as being optionally substituted with one or more of the substituents in the list, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be substituted individually and / or together with independently selected optional substituents. If the nitrogen of a substituent is described as being optionally substituted with one or more of the substituents in the list, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be substituted with independently selected optional substituents.

[0035] When it is stated that substituents are "independently selected from" a group, each substituent is selected independently from the others. Therefore, each substituent may be homologous or different from another substituent.

[0036] As used herein, the term “one or more” means one or more in reasonable terms, for example, two, three, four, five or ten.

[0037] Unless otherwise specified herein, the bonding points of substituents may be from any suitable position on the substituent, as used herein.

[0038] If the substituent bond is described as a bond that penetrates the ring and connects two atoms, such substituent may be bonded to any one of the ring-constituting atoms in the substituteable ring.

[0039] The present invention further includes all pharmaceutically acceptable isotope-labeled compounds which are the same as the compounds of the present invention except that one or more atoms are substituted with atoms having the same atomic number but having a different mass or mass number from the atom that is dominant in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention are isotopes of hydrogen (e.g., deuterium (D), 2 H), tritium (T, 3 H)), carbon isotopes (for example, 11 C,13 C and 14 C) Isotopes of chlorine (for example, 36 Cl), fluorine isotopes (e.g., 18 F) Iodine isotopes (for example, 123 I and 125 I) Nitrogen isotopes (for example, 13 N and 15 N), oxygen isotopes (for example, 15 O, 17 O and 18 O), phosphorus isotopes (for example, 32 P), and sulfur isotopes (e.g., 35 Contains (but is not limited to) S). Some isotope-labeled compounds of the present invention (e.g., those incorporating radioactive isotopes) can be used for studying (e.g., analysis) the distribution of drugs and / or substrate tissues. The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) is particularly suitable for this purpose because it is easily incorporated and easily detected. Positron-emitting isotopes (e.g., 11 C, 18 F, 15 O and 13 Substitution with N) can be used to verify substrate receptor occupancy in positron emission tomography (PET) studies. The isotope-labeled compounds of the present invention can be prepared by using a suitable isotope-labeled reagent instead of previously employed unlabeled reagents, by a method similar to that described in the accompanying routes and / or examples and preparations. The pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotoped, such as D2O, acetone-d6, or DMSO-d6.

[0040] The term “stereoisomer” refers to an isomer formed by at least one chiral center. In a compound having one or more (e.g., one, two, three, or four) chiral centers, it can produce racemic mixtures, single enantiomers, diastereomer mixtures, and distinct diastereomers. Certain individual molecules may exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention may exist as mixtures of two or more structurally distinct forms (usually called tautomers) in rapid equilibrium. Typical examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. The scope of this application should be understood to cover all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0041] In this specification, solid lines [ka] wedge-shaped solid line [ka] or wedge-shaped dashed line [ka] The carbon-carbon bonds of the compounds of the present invention can be depicted using the diagram. Using a solid line to depict bonds to a chiral carbon atom is intended to indicate the presence of all possible stereoisomers at that carbon atom (e.g., specific enantiomers, racemic mixtures, etc.). Using a wedge-shaped solid or dashed line to depict bonds to a chiral carbon atom is intended to indicate the presence of the shown stereoisomers. In the case of racemic mixtures, wedge-shaped solid or dashed lines are used to define relative stereochemistry rather than absolute stereochemistry. Unless otherwise specified, the compounds of the present invention may exist in the form of stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof). The compounds of the present invention may exhibit one or more types of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0042] Atropisomers refer to compounds that can be separated into isomers with restricted rotation.

[0043] Furthermore, it should be understood that some compounds of the present invention may exist in a free form for therapeutic purposes, or, where appropriate, in the form of their pharmaceutically acceptable derivatives. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs, which may be administered to patients in need, and may directly or indirectly provide the compounds of the present invention or their metabolites or residues. Accordingly, when "compounds of the present invention" is referred to herein, it is also intended to cover the various derivative forms of the compounds described above.

[0044] The pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts.

[0045] For a general overview of suitable salts, see Stahl and Wermuth, “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0046] As used herein, the term “ester” means an ester derived from each of the compounds of the general formulas herein, including physiologically hydrolyzable esters (which can release the compounds of the present invention in the form of free acids or alcohols by hydrolysis under physiological conditions). The compounds of the present invention may themselves be esters.

[0047] The compounds of the present invention can exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention include a polar solvent that constitutes the crystal lattice of the compound, particularly water, methanol, or ethanol. The amount of the polar solvent, particularly water, can be in stoichiometric or non-stoichiometric ratios.

[0048] Within the scope of the present invention, the invention further includes metabolites of the compounds of the present invention, i.e., substances formed in the body upon administration of the compounds of the present invention. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic degradation, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention and compounds produced by a method of contacting the compounds of the present invention with a mammal for a time sufficient to produce the metabolites.

[0049] The present invention further includes, within its scope, prodrugs of the compounds of the present invention, which may themselves have relatively little pharmacological activity or may not have any pharmacological activity. When administered into or onto the body, several derivatives of the compounds of the present invention can be converted to the compounds of the present invention having the desired activity, for example, by hydrolysis. Typically, such prodrugs are functional group derivatives of the above-mentioned compounds that are readily converted in the body to the desired therapeutically active compound. Further information regarding the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E.B. Roche, American Pharmaceutical Association). Prodrugs of the present invention can be produced, for example, by substituting appropriate functional groups present in the compounds of the present invention with several parts known to those skilled in the art as "pro-moiety" (e.g., "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)).

[0050] The present invention further covers compounds of the present invention that contain protecting groups. In any process of producing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups in any relevant molecules, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. JFWMcOmie, Plenum Press, 1973, and TW Greene & PGMWuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, these references are incorporated herein by reference. The protecting group can be removed in an appropriate subsequent step using methods known in the art.

[0051] As used herein, the term “about” refers to a range of ±10%, preferably ±5%, and more preferably ±2% of the stated value.

[0052] compound In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein the compound has the structure of formula (I), [ka] (I) During the ceremony, Ring A is C 3~10 Hydrocarbon ring, 3-10 membered heterocycle, C 6~10 It is an aromatic ring or a 5-14 membered heteroaromatic ring. Ring B is a benzene ring, X is CR X or N, Y is CR Y or N, Z is CR Z or N, R X , R Y , R Z , R 1 , R 2 , R 3 , R 4 , R 5 and R 6 Each time it appears, it is independently identified as H, halogen, -OH, -NH2, -CN, -NO2, and C. 1~6 Alkyl groups, deuterated C 1~6 Alkyl alkyl group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, C 3~6 Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, C 6~10 Aryl group, 5-14 member heteroaryl group, C 6~12 Aralkyl group, -C(=O)R a -OC(=O)R a , -C(=O)OR a , -OR a , -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR a R b , -NR a R b -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O)2-R b , -NR a -C(=O)-NR a R b , -C 1~6 Alkilen-OR a , -C 1~6 Alkilen-NR a R b and -OC 1~6 Alkilen-NR a R b Selected from, Alternatively, R 1 and R 2 They can optionally be linked together with the base C3~10 Hydrocarbon ring, 3-10 membered heterocycle, C 6~10 Constituting an aromatic ring or a 5-14 membered heteroaromatic ring, and / or R 3 and R 4 These, along with the groups they link, optionally form a 3- to 10-membered complex ring. R a and R b Each time they appear, H and C appear independently. 1~6 Alkyl alkyl group, C 3~10 Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, C 6~10 Aryl group, 5-14 member heteroaryl group and C 6~12 Selected from aralkyl groups, Each of the alkyl groups, alkylene groups, alkenyl groups, alkynyl groups, cyclic hydrocarbon groups, hydrocarbon rings, heterocyclyl groups, heterocyclic rings, aryl groups, aromatic rings, heteroaryl groups, heteroaromatic rings, and aralkyl groups can be optionally represented by halogens, -OH, =O, -NH2, -CN, -NO2, and C, respectively, whenever they appear. 1~6 Alkyl alkyl group, C 3~6 Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, C 6~10 Aryl group, 5-14 member heteroaryl group, C 6~12 Aralkyl group, -C(=O)R c -OC(=O)R c , -C(=O)OR c , -OR c , -SR c -S(=O)R c -S(=O)2R c -S(=O)2NR c R d , -NR c R d -C(=O)NR c R d , -NR c -C(=O)R d , -NR c -C(=O)OR d , -NR c -S(=O)2-R d , -NR c -C(=O)-NR c R d , -C 1~6 Alkilen-ORc , -C 1~6 Alkilen-NR c R d and -OC 1~6 Alkilen-NR c R d Substituting with one or more substituents independently selected from the alkyl group, cyclic hydrocarbon group, heterocyclyl group, aryl group, heteroaryl group and aralkyl group, further optionally substituted with halogen, -OH, =O, -C(=O)O-tert-butyl group, -NH2, -CN, -NO2, C 1~6 Alkyl alkyl group, C 1~6 Haloalkyl group, C 3~6 Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, C 6~10 Aryl group, 5-14 member heteroaryl group, C 6~12 Aralkyl group, -OC 1~6 Alkyl and -C 1~6 Alkylene-OC 1~6 Substituted with one or more substituents independently selected from the alkyl group, R c and R d Each time they appear, H and C appear independently. 1~6 Alkyl alkyl group, C 3~10 Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, C 6~10 Aryl group, 5-14 member heteroaryl group and C 6~12 Selected from aralkyl groups, the alkyl groups, cyclic hydrocarbon groups, heterocyclyl groups, aryl groups, heteroaryl groups, and aralkyl groups may be further optionally selected from halogens, -OH, =O, -C(=O)O-tert-butyl groups, -NH2, -CN, -NO2, and C 1~6 Alkyl alkyl group, C 1~6 Haloalkyl group, C 3~6 Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, C 6~10 Aryl group, 5-14 member heteroaryl group, C 6~12 Aralkyl group and -C 1~6 Alkylene-OC 1~6 Substituted with one or more substituents independently selected from the alkyl group, and m and n are each an independent integer of 1, 2, 3, or 4, preferably an integer of 1, 2, or 3.

[0053] In some embodiments, the present disclosure provides compounds or pharmaceutically acceptable salts, esters, stereoisomers, atropisomers, tautomers, crystalline polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs thereof, wherein the compounds have the following structures: [ka] During the ceremony, Ring C is C 5~6 Selected from hydrocarbon rings, 5-6 membered heterocycles, and 5-6 membered heteroaromatic rings, Ring D is a 3- to 10-membered complex ring, R 7 and R 8 Each time they appear, H and C appear independently. 1~6 Alkyl and C 3~6 Selected from cyclic hydrocarbon groups, preferably R 7 and R 8 Each time they appear, H and C appear independently. 1~6 Selected from alkyl groups, p and q are each an integer of 1 or 2, and The remaining groups are as defined herein.

[0054] In some embodiments, in a general formula such as the one disclosed herein, R X , R Y and R Z These are H, halogen, -CN, and C, respectively, independently. 1~6 Alkyl, halo C 1~6 Alkyl and -O-(C 1~6 Selected from alkyl groups.

[0055] In a preferred embodiment, R X , R Y and R Z Each of these is independently selected from H, F, Cl, -CN, methyl group, trifluoromethyl group, and methoxy group.

[0056] In some embodiments, a general formula such as the one disclosed herein, X is CH or C-CH3, Y is CR Y Or N, where R Y H, halogen, -CN, C 1~6 Alkyl, halo C 1~6 Alkyl and -O-(C 1~6 Selected from alkyl groups, preferably selected from H, F, Cl, -CN, methyl group, trifluoromethyl group and methoxy group, Z is either CH or N.

[0057] In some embodiments, in a general formula such as the one disclosed herein, R 1 and R 2 These are H, halogen, and C, respectively, independently. 1~6 Alkyl and deuterated C 1~6 Selected from alkyl groups, preferably R 1 and R 2 Each of these is independently selected from H, Cl, Br, I, methyl group, -CD3, and ethyl group.

[0058] In some embodiments, in a general formula such as the one disclosed herein, R 1 and R 2 They can optionally be linked together with the base C 5~6 It constitutes a hydrocarbon ring, a 5-6 membered heterocycle, or a 5-6 membered heteroaromatic ring, preferably R 1 and R 2 They are optionally linked together with the base to which they connect. [ka] It constitutes.

[0059] In some embodiments, a general formula such as the one disclosed herein, [ka] teeth, [ka] [ka] They are selected from among them.

[0060] In some embodiments, in the general formula as disclosed herein, ring A is a 5-6 membered heterocycle or a 5-6 membered heteroaromatic ring.

[0061] In some embodiments, in the general formula as disclosed herein, ring A is an oxygen-containing five-membered heterocycle (e.g., a five-membered heterocycle containing one or two oxygen atoms).

[0062] In some embodiments, ring A is [ka] and In some embodiments, [ka] teeth, [ka] That is the case.

[0063] In some embodiments, in a general formula such as the one disclosed herein, R 3 and R 4 H and C are independent of each other. 1~6 Alkyl alkyl group, C 3~6 Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, -C 1~6 Alkylene-OH and -C 1~6 Alkylene-OC 1~6 Selected from alkyl groups, the alkylene group, alkyl group, cyclic hydrocarbon group and heterocyclyl group are optionally further C 3~6 Substituted with a cyclic hydrocarbon group, a 3-10 membered heterocyclyl group, or a 5-6 membered heteroaryl group, the cyclic hydrocarbon group, heterocyclyl group, or heteroaryl group may be further optionally accompanied by one or more C11s.1~6 It is replaced with an alkyl group.

[0064] In a preferred embodiment, R 3 and R 4 These are, independently, H, methyl group, ethyl group, isopropyl group, and cyclopropyl group. [ka] They are selected from among them.

[0065] In some embodiments, in a general formula such as the one disclosed herein, R 3 and R 4 They are, along with the base to which they are connected, optionally [ka] It constitutes a base selected from among them.

[0066] In some embodiments, in a general formula such as the one disclosed herein, R 3 and R 4 They are, along with the base to which they are connected, optionally [ka] It constitutes a base selected from among them.

[0067] In some embodiments, a general formula such as the one disclosed herein, [ka] teeth, [ka] [ka] They are selected from among them.

[0068] In some embodiments, a general formula such as the one disclosed herein, [ka] is selected from

Chem.

Chem.

[0069] selected from

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0070] Pharmaceutical composition and therapeutic method In some embodiments, the present invention provides a pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof, and one or more pharmaceutically acceptable carriers. The pharmaceutical composition is preferably a solid formulation, a semi-solid formulation, a liquid formulation, or a gaseous formulation. In some embodiments, the pharmaceutical composition may further comprise one or more other therapeutic agents.

[0071] In some embodiments, the present invention provides the use of the compounds of the present invention or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, crystalline polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs or pharmaceutical compositions of the present invention in the manufacture of drugs used as PRMT5 inhibitors.

[0072] In some embodiments, the present invention provides compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, crystalline polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs thereof, or pharmaceutical compositions of the present invention, which are used as PRMT5 inhibitors.

[0073] In some embodiments, the present invention provides a method for preventing or treating cancer (preferably MTAP-deficient cancer), comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound or prodrug or pharmaceutical composition of the present invention to an individual in need thereof.

[0074] In some embodiments, the cancers include pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck cancer, head and neck squamous cell carcinoma, lymphoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, skin cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer, and sarcoma.

[0075] The "pharmaceutically acceptable carrier" in the present invention refers to a diluent, adjuvant, excipient or vehicle administered together with a therapeutic agent, and it is within the scope of reasonable medical judgment, without excessive toxicity, irritation, allergic reaction or other problems or complications corresponding to a reasonable benefit-risk ratio, and is suitable for contact with human and / or other animal tissues.

[0076] Unless otherwise specified, as used herein, the term "treatment" means reversing, reducing, inhibiting the progression of a disease condition or disorder to which such term is applied or one or more symptoms thereof, or preventing such disease condition or disorder or one or more symptoms thereof.

[0077] "Individual" as used herein includes humans or non-human animals. Exemplary human individuals include human individuals (referred to as patients) suffering from a disease (e.g., a disease described herein) or normal individuals. The "non-human animals" in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and / or livestock animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0078] In another embodiment, the pharmaceutical composition of the present invention may further comprise one or more other therapeutic or prophylactic agents.

Examples

[0079] Hereinafter, the present invention will be further described in combination with examples, but these examples are not intended to limit the scope of the present invention.

[0080] The abbreviations in the present invention have the following meanings.

Table 1-1

Table 1-2

[0081] Common synthesis routes: [ka] Here, LG is a leaving group, preferably a halogen, and The remaining units are as defined above.

[0082] Example I-1: [ka] Step 1 I-1a (20g, 118 mmol) was dissolved in chloroform (500 mL), and NBS (21g, 118 mmol) was added. The reaction mixture was allowed to proceed at room temperature for 5 hours with stirring. After the reaction was complete, the mixture was diluted with water (200 mL) and extracted with dichloromethane (200 mL x 2). The dichloromethane phase was washed with saturated saline (200 mL x 2), dried, filtered, concentrated, and the residue was purified by column chromatography to obtain intermediate I-1b (25g, yield: 85%). LCMS (ESI) [M+H] + = 248.0.

[0083] Step 2 I-1b (11.5 g, 46 mmol), bis(pinacolato)diborone (14 g, 55.6 mmol), Pd(dppf)Cl2 (4.22 g, 5.8 mmol), and potassium acetate (9.1 g, 93 mmol) were dissolved in 1,4-dioxane (100 mL). After purging the reaction mixture with nitrogen gas, the reaction was carried out at 85°C for 18 hours with stirring. After the reaction was complete, the mixture was cooled to room temperature, filtered, the filtrate was concentrated, and the residue was purified by column chromatography to obtain intermediate I-1c (11.5 g, yield: 84%). 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 9.1 Hz, 1H), 6.23 (d, J = 13.4 Hz, 1H), 5.34 (brs, 2H), 3.85 (s, 3H), 1.34 (s, 12H). LCMS (ESI) [M+H] + = 296.1.

[0084] Step 3 I-1c (10 g, 33.9 mmol) was dissolved in 1,4-dioxane (120 mL), and I-1d (6.3 g, 33.9 mmol), Pd(PPh3)4 (4.7 g, 4.1 mmol), and potassium carbonate (9.4 g, 67.8 mmol) were added. After purging the reaction mixture with nitrogen gas, the reaction was carried out at 100°C for 18 hours with stirring. After the reaction was complete, the mixture was cooled to room temperature, the reaction mixture was filtered, the filtrate was diluted with water (200 mL), extracted with dichloromethane (200 mL x 2), the dichloromethane phase was washed with saturated brine (100 mL x 2), dried, filtered, concentrated, and the residue was purified by column chromatography to obtain intermediate I-1e (7.7 g, yield: 83%). 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 7.9 Hz, 1H), 8.27 (s, 1H), 7.56 (s, 2H), 7.28 (d, J = 13.4 Hz, 1H), 4.39 (s, 3H), 3.89 (s, 3H). LCMS (ESI) [M+H] + = 275.0.

[0085] Step 4 I-1e (200 mg, 0.73 mmol) was dissolved in a mixed solution of methanol / tetrahydrofuran / water (5 mL / 5 mL / 5 mL), and lithium hydroxide (52 mg, 2.2 mmol) was added. The reaction mixture was allowed to proceed at 50°C for 2 hours with stirring. After the reaction was complete, the mixture was diluted with water (20 mL), the pH was adjusted to 5 with 1 N hydrochloric acid, the solid was precipitated, filtered, and the solid was dried to obtain intermediate I-1f (120 mg, yield: 63%). 1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 8.1 Hz, 1H), 8.21 (s, 1H), 7.16 - 7.07 (m, 3H), 4.35 (s, 3H). LCMS (ESI) [M+H] + = 261.2.

[0086] Step 5 I-1g (200mg, 1.1 mmol) was dissolved in methanol (10 mL), and methylamine hydrochloride (220 mg, 3.2 mmol) and triethylamine (320 mg, 3.2 mmol) were added. The reaction was carried out at room temperature with stirring for 1 hour, and sodium borohydride (40 mg, 1.1 mmol) was added at 0°C, and the reaction was continued at room temperature with stirring for 1 hour. After the reaction was complete, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL x 2), the ethyl acetate phase was washed with saturated saline solution (50 mL x 2), the ethyl acetate phase was dried, filtered, concentrated, and the residue was purified by column chromatography to obtain intermediate I-1h (200 mg, yield: 92%). 1 H NMR (400 MHz, DMSO-d6) δ 7.34 (d, J = 1.5 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.13 (dd, J = 8.3, 1.6 Hz, 1H), 3.63 (s, 2H), 2.22 (s, 3H). LCMS (ESI) [M+H] + = 202.1.

[0087] Step 6 I-1h (50 mg, 0.25 mmol), I-1f (65 mg, 0.25 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (84 mg, 0.3 mmol), and N-methylimidazole (62 mg, 0.75 mmol) were dissolved in DMF (5 mL). The reaction mixture was allowed to react at room temperature for 16 hours with stirring. After the reaction was complete, ethyl acetate (30 mL) was added to dilute the mixture, and it was washed with saturated saline solution (30 mL x 3). The ethyl acetate phase was dried, filtered, concentrated, and the residue was purified by column chromatography and preparative chromatography to obtain I-1 (40 mg, yield: 36%). 1 H NMR (400 MHz, DMSO-d6) δ 8.28 - 8.13 (m, 2H), 7.48 - 7.03 (m, 6H), 4.64 (d, J = 96.4 Hz, 2H), 4.30 (d, J = 62.4 Hz, 3H), 2.92 (d, J = 52.0 Hz, 3H).LCMS (ESI) [M+H] + = 444.2.

[0088] Example I-2: [ka]

[0089] Step 1 I-2a (20 g, 86.9 mmol), bis(pinacolato)diborone (23.2 g, 91.3 mmol), Pd(dppf)Cl2 (6.33 g, 8.7 mmol), and potassium acetate (17.1 g, 174 mmol) were dissolved in 1,4-dioxane (200 mL). After purging the reaction mixture with nitrogen gas, the reaction was carried out at 90°C for 18 hours with stirring. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by column chromatography to obtain intermediate I-2b (21 g, yield: 87%). LCMS (ESI) [M+H] + = 278.2.

[0090] Step 2 I-2b (10.7 g, 38.7 mmol) was dissolved in 1,4-dioxane (50 mL), and I-1d (6 g, 32.2 mmol), Pd(PPh3)4 (3.73 g, 3.23 mmol), and potassium carbonate (8.92 g, 64.5 mmol) were added. After purging the reaction mixture with nitrogen gas, the reaction was carried out at 100 °C for 18 hours with stirring. After the reaction was complete, the mixture was cooled to room temperature, the reaction mixture was filtered, the filtrate was diluted with water (200 mL), extracted with dichloromethane (200 mL x 2), the dichloromethane phase was washed with saturated brine (100 mL x 2), dried, filtered, concentrated, and the residue was purified by column chromatography to obtain intermediate I-2c (5.1 g, yield: 62%). 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.28 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.38 (s, 2H), 4.42 (s, 3H), 3.89 (s, 3H). LCMS (ESI) [M+H] + = 257.1.

[0091] Step 3 I-2c (990 mg, 3.9 mmol) was dissolved in a mixed solution of methanol / tetrahydrofuran / water (10 mL / 10 mL / 5 mL), and lithium hydroxide (280 mg, 2.2 mmol) was added. The reaction mixture was allowed to proceed at 50°C for 2 hours with stirring. After the reaction was complete, water (20 mL) was added to dilute the mixture, the pH was adjusted to 5 with 1 N hydrochloric acid, the solid was precipitated, filtered, and the solid was dried to obtain intermediate I-2d (900 mg, yield: 96%). 1 H NMR (400 MHz, DMSO-d6) δ 13.57 (s, 1H), 8.86 (d, J = 1.7 Hz, 1H), 8.64 (s, 1H), 8.26 (dd, J = 8.7, 1.7 Hz, 1H), 7.87 (d, J = 8.7 Hz, 1H), 4.50 (s, 3H). LCMS (ESI) [M+H] + = 243.2.

[0092] Step 4 I-1h (52 mg, 0.26 mmol), I-2d (50 mg, 0.21 mmol), HATU (120 mg, 0.32 mmol), and DIPEA (81 mg, 0.63 mmol) were dissolved in DMAC (5 mL). The reaction mixture was allowed to react at 45°C for 16 hours with stirring. After the reaction was complete, ethyl acetate (30 mL) was added to dilute the mixture, and it was washed with saturated saline solution (30 mL x 3). The ethyl acetate phase was dried, filtered, concentrated, and the residue was purified by column chromatography and preparative chromatography to obtain I-2 (63 mg, yield: 71%). 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 7.28 (s, 3H), 4.68 (s, 2H), 4.49 - 4.04 (m, 3H), 2.97 (s, 3H). LCMS (ESI) [M+H] + = 426.2.

[0093] Example I-3: [ka]

[0094] Step 1 I-1g (380mg, 2.04 mmol) was dissolved in dichloromethane (10mL), then 2-((tributyltin)methoxy)ethane-1-amine (743g, 2.04 mmol) and molecular sieves (500mg) were added, and the mixture was reacted at room temperature for 16 hours under nitrogen gas protection. After monitoring the completion of the reaction by TLC, the reaction mixture was filtered, concentrated under reduced pressure, and then used directly in the next reaction.

[0095] Step 2 Copper(II) trifluoromethanesulfonate (680 mg, 1.88 mmol) was dissolved in dichloromethane (9 mL) and hexafluoroisopropanol (3 mL), and 2,6-dimethylpyridine (201 mg, 1.89 mmol) was added. The mixture was stirred at room temperature for 1 hour. A solution of I-3a (crude product) in dichloromethane (3 mL) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with dichloromethane, and a mixed solution of 12% aqueous ammonia and saturated sodium chloride (1:1, 30 mL) was added. The mixture was stirred for 20 minutes, the aqueous phase was extracted with dichloromethane (10 mL x 2), the organic phase was combined, washed with saturated sodium chloride (10 mL), dried, filtered, concentrated under reduced pressure, and the crude product was separated and purified by column chromatography to obtain I-3b (150 mg), with a two-step yield of 26.2%. LCMS (ESI) [M+H] + = 244.1.

[0096] Step 3 I-1f (86 mg, 0.33 mmol) and I-3b (80 mg, 0.33 mmol) were dissolved in acetonitrile (10 mL), and N,N-diisopropylethylamine (127.7 mg, 0.99 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (185.2 mg, 0.66 mmol) were added. The mixture was reacted at 25°C for 24 hours, and after monitoring the completion of the reaction by LC-MS, the reaction mixture was concentrated under reduced pressure. The crude product was separated by preparative HPLC to obtain I-3 (16.3 mg, yield: 10%). 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.14 (d, J = 7.4 Hz, 1H), 7.42 (s, 1H), 7.38 - 7.35 (m, 1H), 7.30 - 7.27 (m, 2H), 7.03 (s, 2H), 5.50 - 5.20 (m, 1H), 4.40 - 4.37 (m, 1H), 4.28 (s, 3H), 3.91 - 3.78 (m, 2H), 3.60 - 3.54 (m, 1H), 3.26 - 3.24 (m, 1H), 3.16 - 3.08 (m, 1H). LCMS (ESI) [M+H] += 486.1.

[0097] Example I-4: [ka]

[0098] Step 1 I-3b (50 mg, 0.21 mmol) was dissolved in anhydrous acetonitrile (3 mL), and then I-2d (50 mg, 0.21 mmol), N,N-diisopropylethylamine (64 mg, 0.495 mmol), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (93 mg, 0.330 mmol) were added. The mixture was reacted at room temperature for 24 hours, and after monitoring the completion of the reaction by LC-MS, water was added to the reaction mixture, and it was extracted several times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by preparative HPLC to obtain I-4 (47.0 mg, yield: 48%). 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.20 (d, J = 1.4 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.56 (dd, J = 8.5, 1.8 Hz, 1H), 7.45 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.04 (s, 2H), 5.40 - 5.35 (m, 1H), 4.38 - 4.34 (m, 1H), 4.26 (s, 3H), 3.94 - 3.79 (m, 3H), 3.66 - 3.57 (m, 1H), 3.30 - 3.20 (m, 1H). LCMS (ESI) [M+H] + = 468.2.

[0099] Example I-5: [ka]

[0100] Step 1 I-1g (300mg, 1.6 mmol) was dissolved in ethylamine / tetrahydrofuran solution (1.6 mL, 2 M) and reacted with stirring at room temperature for 2 hours. Then, sodium borohydride (73 mg, 1.9 mmol) was added at 0°C and the reaction was continued with stirring at room temperature for 1 hour. After the reaction was complete, water (2 mL) was added to quench the mixture, filtered, and the filtrate was concentrated. The residue was purified by column chromatography to obtain I-5a (200 mg, yield: 57%). 1 H NMR (400 MHz, DMSO-d6) δ 7.37 (d, J = 1.5 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.15 (dd, J = 8.2, 1.6 Hz, 1H), 3.69 (s, 2H), 2.47 (d, J = 7.1 Hz, 2H), 1.01 (t, J = 7.1 Hz, 3H). LCMS (ESI) [M+H] + =216.1.

[0101] Step 2 I-2d (80 mg, 0.3 mmol), I-5a (88 mg, 0.4 mmol), HATU (190 mg, 0.5 mmol), and DIPEA (130 mg, 1 mmol) were dissolved in DMAC (5 mL) and reacted with stirring at 45°C for 16 hours. After the reaction was complete, water (2 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 3). The ethyl acetate phase was washed with saturated saline solution (10 mL x 3), dried, filtered, concentrated, and the residue was purified by column chromatography to obtain I-5 (63 mg, yield: 43%). 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 2H), 7.58 (s, 2H), 7.46 - 7.36 (m, 2H), 7.22 (s, 1H), 7.14 (s, 2H), 4.69 (s, 2H), 4.20 (d, J = 97.5 Hz, 3H), 2.46 (s, 2H), 1.14 (t, J = 6.6 Hz, 3H). LCMS (ESI) [M+H] + = 440.2.

[0102] Example I-6: [ka] Step 1 I-1f (80 mg, 0.3 mmol), I-5a (83 mg, 0.4 mmol), HATU (180 mg, 0.46 mmol), and DIPEA (120 mg, 0.93 mmol) were dissolved in DMAC (5 mL). The mixture was reacted at 45°C for 16 hours with stirring. After the reaction was complete, water (2 mL) was added to quench the mixture, and it was extracted with ethyl acetate (20 mL x 2). The mixture was washed with saturated saline (10 mL x 3), the ethyl acetate phase was dried, filtered, concentrated, and the residue was purified by column chromatography to obtain I-6 (77 mg, yield: 54%). 1 H NMR (400 MHz, DMSO-d6) δ 8.33 - 8.09 (m, 2H), 7.47 - 7.01 (m, 6H), 4.64 (d, J = 108.0 Hz, 2H), 4.30 (d, J = 68.3 Hz, 3H), 3.55 - 3.40 (m, 1H), 3.20 (q, J = 7.0 Hz, 1H), 1.16 (t, J = 7.0 Hz, 1H), 1.03 (t, J = 7.0 Hz, 2H). LCMS (ESI) [M+H] + = 458.2.

[0103] Examples I-3 (PEAK1) and I-3 (PEAK2): [ka]

[0104] Step 1 I-3 was purified by preparative SFC (IA, Hex:EtOH:TFA=70:30:0.3, 25 mL / min, 230 nm, IA-3.0 column) to obtain I-3 (PEAK1, Rt=8.298 min) and I-3 (PEAK2, Rt=11.157 min).

[0105] I-3 (PEAK1): 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 2H), 7.63 - 7.23 (m, 6H), 5.71 (s, 1H), 4.44 (d, J = 39.6 Hz, 4H), 4.16 - 3.49 (m, 4H), 3.31 - 3.01 (m, 1H). LCMS (ESI) [M+H] + = 486.2. I-3 (PEAK2): 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 2H), 7.63 - 7.23 (m, 6H), 5.71 (s, 1H), 4.44 (d, J = 39.6 Hz, 4H), 4.16 - 3.49 (m, 4H), 3.31 - 3.01 (m, 1H). LCMS (ESI) [M+H] + = 486.2.

[0106] Examples I-4 (PEAK1) and I-4 (PEAK2): [ka]

[0107] Step 1 I-4 was purified by preparative SFC (IA, Hex:EtOH:TFA=70:30:0.3, 25 mL / min, 230 nm, IA-3.0 column) to obtain I-4 (PEAK1, Rt=6.841 min) and I-4 (PEAK2, Rt=10.851 min).

[0108] I-4 (PEAK1): 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.20 (d, J = 1.4 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.56 (dd, J = 8.5, 1.8 Hz, 1H), 7.45 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.04 (s, 2H), 5.40 - 5.35 (m, 1H), 4.38 - 4.34 (m, 1H), 4.26 (s, 3H), 3.94 - 3.79 (m, 3H), 3.66 - 3.57 (m, 1H), 3.30 - 3.20 (m, 1H). LCMS (ESI) [M+H] + = 468.2. I-4 (PEAK2): 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.20 (d, J = 1.4 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.56 (dd, J = 8.5, 1.8 Hz, 1H), 7.45 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.04 (s, 2H), 5.40 - 5.35 (m, 1H), 4.38 - 4.34 (m, 1H), 4.26 (s, 3H), 3.94 - 3.79 (m, 3H), 3.66 - 3.57 (m, 1H), 3.30 - 3.20 (m, 1H). LCMS (ESI) [M+H] + = 468.2.

[0109] Example 1-11:

change

[0110] ステップ1 I-11a (800 mg, 2.2 mmol) and I-1 g (400 mg, 2.2 mmol) were dissolved in dichloromethane (5 mL), and 4A molecular sieve (1 g) was added. After replacing the reaction mixture with nitrogen gas, the reaction was carried out at room temperature with stirring for 16 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to obtain the crude product I-11b, which could be used directly in the next reaction without any further purification.

[0111] Step 2 Copper(II) trifluoromethanesulfonate (660 mg, 1.8 mmol) was dissolved in a mixture of dichloromethane (30 mL) and hexafluoroisopropanol (10 mL), and 2,6-dimethylpyridine (200 mg, 1.8 mmol) was added. After stirring at room temperature for 1 hour, the crude product of I-11b was added, and the reaction was continued with stirring at room temperature for 16 hours. After the reaction was complete, the mixture was diluted with dichloromethane (20 mL), a mixture of 12% aqueous ammonia and saturated aqueous sodium chloride (1:1, 30 mL) was added, and the mixture was stirred for 20 minutes. The solution was separated, the aqueous phase was extracted with dichloromethane (20 mL x 2), the organic phase was combined, washed with saturated brine (50 mL), the organic phase was dried, filtered, concentrated, and the residue was purified by column chromatography to obtain I-11c (400 mg, 70% yield in two steps). 1 H NMR (400 MHz, DMSO-d6) δ 7.44 (s, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 3.88 (s, 1H), 3.68 (s, 2H), 3.05 - 2.90 (m, 3H), 0.93 (d, J = 4.7 Hz, 3H). LCMS (ESI) [M+H] + = 258.1.

[0112] Step 3 I-1f (100 mg, 0.4 mmol), I-11c (200 mg, 0.5 mmol), CMPI (120 mg, 0.5 mmol), and DIPEA (150 mg, 1.2 mmol) were dissolved in DMAC (5 mL). The reaction mixture was allowed to react at 45°C for 16 hours with stirring. After the reaction was complete, water (2 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 2). The ethyl acetate phase was washed with saturated saline solution (10 mL x 3), dried, filtered, concentrated, and the residue was purified by column chromatography to obtain I-11 (43 mg, yield: 21%). 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 8.9 Hz, 2H), 7.56 (s, 1H), 7.42 (d, J = 7.1 Hz, 2H), 7.36 (d, J = 11.8 Hz, 1H), 7.32 (s, 2H), 4.70 (d, J = 12.6 Hz, 1H), 4.38 (s, 3H), 3.78 (d, J = 44.2 Hz, 5H), 0.82 (d, J = 21.0 Hz, 3H). LCMS (ESI) [M+H] + = 500.1.

[0113] Example I-12: [ka] I-2d (100 mg, 0.41 mmol), I-11c (200 mg, 0.47 mmol), CMPI (130 mg, 0.49 mmol), and DIPEA (160 mg, 1.24 mmol) were dissolved in DMAC (5 mL). The mixture was reacted at 45°C for 16 hours with stirring. After the reaction was complete, water (2 mL) was added to quench the mixture, and it was extracted with ethyl acetate (20 mL x 2). The mixture was washed with saturated saline (10 mL x 3), the ethyl acetate phase was dried, filtered, concentrated, and the residue was purified by column chromatography to obtain I-12 (48 mg, yield: 25%). 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 8.22 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.67 - 7.62 (m, 1H), 7.48 - 7.37 (m, 2H), 7.03 (d, J = 8.3 Hz, 1H), 5.73 (s, 1H), 4.65 (d, J = 12.6 Hz, 1H), 4.44 (s, 3H), 3.91 (dd, J = 12.6, 3.9 Hz, 1H), 3.84 (s, 1H), 3.70 (s, 2H), 0.98 (d, J = 6.6 Hz, 3H). LCMS (ESI) [M+H] + = 482.2.

[0114] Example I-13: [ka]

[0115] Step 1 I-1g (1g, 5.4 mmol) was dissolved in methanol (20 mL), isopropylamine (630 mg, 10.7 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Then, sodium borohydride (240 mg, 6.4 mmol) was added at 0°C. The reaction was continued with stirring at room temperature for 1 hour, and after the reaction was complete, water (2 mL) was added to quench the mixture, it was filtered, the filtrate was concentrated, and the residue was purified by column chromatography to obtain intermediate I-13a (1g, 81%). 1 H NMR (400 MHz, DMSO-d6) δ 7.37 (d, J = 1.6 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.18 - 7.13 (m, 1H), 3.68 (s, 2H), 2.65 (hept, J = 6.2 Hz, 1H), 0.97 (d, J = 6.2 Hz, 6H). LCMS (ESI) [M+H] + = 230.1.

[0116] Step 2 I-13a (88 mg, 0.4 mmol), I-1f (80 mg, 0.3 mmol), HATU (180 mg, 0.46 mmol), and DIPEA (120 mg, 0.93 mmol) were dissolved in DMAC (5 mL). The reaction was carried out at 45°C for 16 hours with stirring. After the reaction was complete, the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated saline solution (30 mL x 3), dried the ethyl acetate phase, filtered, concentrated, and the residue was purified by column chromatography to obtain I-13 (71 mg, yield: 47%). 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 30.6 Hz, 2H), 7.49 - 6.93 (m, 6H), 4.67 (d, J = 23.5 Hz, 2H), 4.36 (s, 3H), 4.01 (s, 1H), 1.13 (s, 6H). LCMS (ESI) [M+H] + = 472.2.

[0117] Example I-14: [ka] I-13a (80 mg, 0.3 mmol), I-2d (94 mg, 0.4 mmol), HATU (190 mg, 0.5 mmol), and DIPEA (130 mg, 1 mmol) were dissolved in DMAC (5 mL). The reaction was carried out at 45°C for 5 hours with stirring. After the reaction was complete, the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated saline (30 mL x 3), dried the ethyl acetate phase, filtered, concentrated, and the residue was purified by column chromatography to obtain I-14 (55 mg, yield: 35%). 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.22 (s, 1H), 7.60 (s, 2H), 7.40 (s, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.16 (s, 2H), 4.63 (s, 2H), 4.33 (d, J = 29.7 Hz, 4H), 1.16 (d, J = 6.6 Hz, 6H). LCMS (ESI) [M+H] + = 454.2.

[0118] Example I-15: [ka]

[0119] Step 1 Compound I-1g (1.2g, 6.45 mmol) was dissolved in dry methanol (15 mL), cyclopropylamine (0.74 g, 12.9 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Sodium borohydride (490 mg, 12.9 mmol) was then added in several batches, and the reaction mixture was stirred at room temperature for 6 hours. After the reaction was complete, the reaction mixture was concentrated, diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), the ethyl acetate phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography to obtain I-15a (1.2 g, yield: 82%). LCMS (ESI) [M+H] + = 228.1.

[0120] Step 2 I-2d (80 mg, 0.33 mmol) and I-15a (110 mg, 0.49 mmol) were dissolved in dry DMF (1.5 mL), and DIEA (130 mg, 0.99 mmol) and HATU (190 mg, 0.49 mmol) were added in order. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), the ethyl acetate phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography to obtain I-15 (104 mg, yield: 70%). 1 H NMR (400 MHz, DMSO-d6) δ 8.57 - 8.37 (m, 2H), 7.88 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.49 - 7.38 (m, 2H), 7.25 (d, J = 8.2 Hz, 1H), 4.73 (s, 2H), 4.43 (s, 3H), 2.89 (m, 1 H), 0.50 (s, 4H). LCMS (ESI) [M+H] + = 452.2.

[0121] Example I-16: [ka] Compounds I-1f (80 mg, 0.31 mmol) and I-15a (110 mg, 0.46 mmol) were dissolved in dry DMF (1.5 mL), and DIEA (120 mg, 0.93 mmol) and HATU (180 mg, 0.46 mmol) were added in succession. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain I-16 (103 mg, yield: 71%). 1H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 17.4 Hz, 2H), 7.49 - 7.37 (m, 2H), 7.27 (dd, J = 26.3, 10.1 Hz, 4H), 4.76 (s, 2H), 4.37 (s, 3H), 2.69 (s, 1H), 0.48 (d, J = 50.5 Hz, 4H). LCMS (ESI) [M+H] + = 470.2.

[0122] Example I-17: [ka]

[0123] Step 1 I-17a (1 g, 5.3 mmol) was dissolved in tetrahydrofuran (30 mL), and lithium aluminum hydride (240 mg, 6.3 mmol) was added at 0°C. The reaction was continued at room temperature for 2 hours with stirring. After the reaction was complete, water (5 mL) was added to quench the mixture, the reaction solution was filtered, the filtrate was concentrated, and the residue was purified by column chromatography to obtain I-17b (750 mg, 88%). 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.61 (dd, J = 8.6, 0.8 Hz, 1H), 7.47 (q, J = 1.1 Hz, 1H), 6.97 (dd, J = 8.5, 1.3 Hz, 1H), 5.21 (t, J = 5.8 Hz, 1H), 4.55 (dd, J = 5.8, 1.0 Hz, 2H), 4.13 (s, 3H).

[0124] Step 2 I-17b (250 mg, 1.54 mmol) was dissolved in dichloromethane (5 mL), and thionyl chloride (220 mg, 1.9 mmol) was slowly added dropwise at room temperature. The reaction was continued with stirring at room temperature for 16 hours. After the reaction was complete, the solution was diluted with ethyl acetate (50 mL), washed with saturated sodium bicarbonate aqueous solution (20 mL x 3), and then washed with saturated saline solution (20 mL x 3). The ethyl acetate phase was dried, filtered, concentrated, and the residue was purified by column chromatography to obtain I-17c (250 mg, 90%). 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.70 (dd, J = 8.6, 0.9 Hz, 1H), 7.66 (s, 1H), 7.07 (dd, J = 8.6, 1.4 Hz, 1H), 4.85 (s, 2H), 4.16 (s, 3H).

[0125] Step 3 I-17c (130 mg, 0.7 mmol) was dissolved in dichloromethane (2 mL), methylamine / methanol solution (2 mL) was added, and the reaction was carried out at room temperature with stirring for 16 hours. After the reaction was complete, the reaction mixture was concentrated to obtain I-17d (100 mg, 79%). 1 H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.38 (s, 1H), 7.75 (dd, J = 7.0, 1.7 Hz, 2H), 7.17 (dd, J = 8.7, 1.2 Hz, 1H), 4.18 (s, 3H), 4.17 (s, 2H), 2.53 (s, 3H). LCMS (ESI) [M+H] + = 176.1.

[0126] Step 4 I-1f (60 mg, 0.23 mmol), I-17d (50 mg, 0.3 mmol), HATU (130 mg, 0.35 mmol), and DIPEA (90 mg, 0.7 mmol) were dissolved in DMF (5 mL). The mixture was reacted at 45°C for 16 hours with stirring. After the reaction was complete, water (5 mL) was added to dilute the mixture, and the solid precipitated. The solid was filtered and purified by column chromatography to obtain I-17 (36 mg, 37%). 1 H NMR (400 MHz, DMSO-d6) δ 8.35 - 8.12 (m, 3H), 7.68 (dd, J = 29.6, 8.6 Hz, 1H), 7.48 (d, J = 58.3 Hz, 1H), 7.37 - 7.21 (m, 3H), 6.94 (dd, J LCMS (ESI) [M+H] + = 418.2.

[0127] Example I-18: [ka]

[0128] Step 1 I-18a (500 mg, 2.6 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (120 mg, 3.2 mmol) was added at 0°C. The reaction was continued at room temperature for 2 hours with stirring. After the reaction was complete, water (5 mL) was added to quench the mixture, the reaction solution was filtered, the filtrate was concentrated, and the residue was purified by column chromatography to obtain I-18b (400 mg, 94%). 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 0.9 Hz, 1H), 7.68 (dq, J = 1.7, 0.9 Hz, 1H), 7.60 (dt, J = 8.6, 0.9 Hz, 1H), 7.38 (dd, J = 8.6, 1.5 Hz, 1H), 5.21 (t, J = 5.7 Hz, 1H), 4.61 (d, J = 5.6 Hz, 2H), 4.05 (s, 3H). LCMS (ESI) [M+H] + = 163.0.

[0129] Step 2 I-18b (400 mg, 2.5 mmol) was dissolved in dichloromethane (10 mL), and thionyl chloride (590 mg, 4.9 mmol) was slowly added dropwise at room temperature. The reaction was continued with stirring at room temperature for 16 hours. After the reaction was complete, the solution was diluted with ethyl acetate (50 mL), washed with saturated sodium bicarbonate aqueous solution (20 mL x 3), and then washed with saturated saline solution (20 mL x 3). The ethyl acetate phase was dried, filtered, concentrated, and the residue was purified by column chromatography to obtain I-18c (430 mg, 96%). 1 H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.82 (s, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.45 (dd, J = 8.7, 1.6 Hz, 1H), 4.90 (s, 2H), 4.04 (s, 3H).

[0130] Step 3 I-18c (430 mg, 2.4 mmol) was dissolved in dichloromethane (5 mL), methylamine / methanol solution (5 mL) was added, and the reaction was carried out at room temperature with stirring for 16 hours. After the reaction was complete, the reaction mixture was concentrated to obtain I-18d (400 mg, 76%). 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.90 (s, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.57 (dd, J = 8.7, 1.6 Hz, 1H), 4.19 (s, 2H), 4.06 (d, J = 1.9 Hz, 3H), 2.51 (d, J = 2.2 Hz, 3H).

[0131] Step 4 I-1f (100 mg, 0.38 mmol), I-18d (67 mg, 0.38 mmol), HATU (220 mg, 0.57 mmol), and DIPEA (150 mg, 1.1 mmol) were dissolved in DMAC (5 mL). The mixture was reacted at 45°C for 16 hours with stirring. After the reaction was complete, water (5 mL) was added to dilute the mixture, and the solid precipitated. The solid was filtered and purified by column chromatography to obtain I-18 (21 mg, 13%). 1 H NMR (400 MHz, DMSO-d6) δ 8.29 - 8.17 (m, 2H), 8.02 (d, J = 20.6 Hz, 1H), 7.79 - 7.56 (m, 2H), 7.47 - 7.15 (m, 4H), 4.72 (d, J = 99.2 Hz, LCMS (ESI) [M+H] + = 418.2.

[0132] Example I-19: [ka] The synthesis of Example I-19 was carried out by referring to the synthesis method of Example I-17, starting with I-19a and ultimately obtaining I-19 (67 mg, 52%). 1H NMR (400 MHz, DMSO-d6) δ 8.22 (dd, J = 26.5, 7.3 Hz, 2H), 8.01 (d, J = 16.7 Hz, 1H), 7.74 (dd, J = 33.8, 8.3 Hz, 1H), 7.53 (d, J = 41.8 Hz, 1H), 7.38 - 7.22 (m, 3H), 7.06 (dd, J = 89.1, 8.4 Hz, 1H), 4.78 (d, J = 101.6 Hz, 2H), 4.23 (d, J = 136.2 Hz, 3H), 4.01 (d, J = 12.2 Hz, 3H), 2.97 (d, J = 72.4 Hz, 3H). LCMS (ESI) [M+H] + = 418.2.

[0133] Example I-20:

change

[0134] Example I-21:

change

[0135] ステップ1 I-21a (300 mg, 1.6 mmol) and I-1 g (210 mg, 1.6 mmol) were dissolved in methanol (5 mL) and stirred at room temperature for 16 hours. Then, sodium borohydride (61 mg, 1.6 mmol) was added at 0 °C. The reaction was continued at room temperature for 1 hour. After the reaction was complete, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 3). The ethyl acetate phase was washed with saturated saline solution (30 mL x 3), dried, filtered, concentrated, and the residue was purified by column chromatography to obtain I-21b (400 mg, 82%). LC-MS (ESI) [M+H] + =301.1.

[0136] Step 2 I-1f (50 mg, 0.2 mmol) and I-21b (70 mg, 0.23 mmol) were dissolved in DMAC (5 mL), and HATU (87 mg, 0.23 mmol) and DIPEA (74 mg, 0.6 mmol) were added. The reaction was carried out at 45°C for 16 hours with stirring. After the reaction was complete, the mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), the ethyl acetate phase was dried, filtered, concentrated, and the residue was purified by column chromatography to obtain I-21 (30 mg, 29%). 1 H NMR (400 MHz, DMSO-d6) δ 8.30 - 8.08 (m, 2H), 7.49 - 7.02 (m, 6H), 4.82 (s, 1H), 4.56 (s, 1H), 4.30 (d, J = 67.9 Hz, 3H), 3.59 - 3.56 (m, 2H), 3.37 (d, J = 4.5 Hz, 2H), 3.34 - 3.29 (m, 2H), 2.55 (t, J = 6.6 Hz, 1H), 2.42 (s, 2H), 2.36 - 2.31 (m, 1H), 2.03 (t, J = 4.5 Hz, 2H).LCMS (ESI) [M+H] + =543.1.

[0137] Example I-22: [ka] The synthesis of Example I-22 followed the synthesis method of Example I-21, starting with I-22a and ultimately yielding I-22 (12 mg, 9%). 1 H NMR (400 MHz, DMSO-d6) δ9.82 (s, 1H), 8.66 (d, J = 22.6 Hz, 2H), 8.35 (dd, J = 76.5, 6.6 Hz, 1H), 7.71 (dd, J = 65.4, 10.3 Hz, 1H), 7.52 - 6.96 (m, 3H), 5.06 - 4.24 (m, 6H), 3.93 - 3.42 (m, 4H), 2.27 - 1.77 (m, 2H). LCMS (ESI) [M+H] + = 500.1

[0138] Example I-23: [ka] The synthesis of Example I-23 followed the synthesis method of Example I-21, starting with I-23a and ultimately yielding I-23 (80 mg, 50%). 1 H NMR (400 MHz, DMSO-d6) δ9.83 (s, 1H), 8.76 (s, 1H), 8.66 (d, J = 13.3 Hz, 1H), 8.35 (dd, J = 33.9, 6.6 Hz, 1H), 7.72 (dd, J = 21.6, 10.3 Hz, 1H), 7.47 - 6.99 (m, 3H), 4.68 (d, J = 114.6 Hz, 2H), 4.38 (d, J = 58.4 Hz, 3H), 3.60 (td, J = 6.6, 4.0 Hz, 1H), 3.36 (s, 3H), 3.29 (s, 1H), 3.12 (s, 2H). LCMS (ESI) [M+H] + = 488.2.

[0139] Example I-24: [ka] The synthesis of Example I-24 was carried out by referring to the synthesis method of Example I-21, starting with I-24a and ultimately obtaining I-24 (30 mg, 18%). 1 H NMR (400 MHz, DMSO-d6) δ9.77 (s, 1H), 8.75 (s, 1H), 8.64 (d, J = 18.5 Hz, 1H), 8.44 - 8.04 (m, 1H), 7.67 (dd, J = 68.3, 10.3 Hz, 1H), 7.47 - 6.94 (m, 3H), 4.91 - 4.57 (m, 2H), 4.37 (d, J = 54.0 Hz, 3H), 4.01 (s, 1H), 3.31 - 2.84 (m, 5H), 1.12 (d, J = 90.6 Hz, 3H). LCMS (ESI) [M+H] + = 502.2.

[0140] Example I-25: [ka] The synthesis of Example I-25 was carried out by referring to the synthesis method of Example I-21, starting with I-25a and ultimately obtaining I-25 (30 mg, 24%). 1 H NMR (400 MHz, DMSO-d6) δ 14.00 (s, 1H), 9.92 (s, 1H), 8.79 (s, 1H), 8.69 (d, J = 22.9 Hz, 1H), 8.35 (dd, J = 77.7, 6.6 Hz, 1H), 7.74 (dd, J = 64.4, 10.3 Hz, 1H), 7.48 - 6.97 (m, 3H), 5.02 - 4.22 (m, 6H), 3.95 - 3.41 (m, 4H), 2.27 - 1.78 (m, 2H). LCMS (ESI) [M+H] + = 500.2.

[0141] Example I-26: [ka] The synthesis of Example I-26 was carried out by referring to the synthesis method of Example I-21, starting with I-26a and ultimately obtaining I-26 (40 mg, 32%). 1 H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.79 (s, 1H), 8.69 (d, J = 19.4 Hz, 1H), 8.41 - 8.08 (m, 1H), 7.71 (dd, J = 67.8, 10.2 Hz, 1H), 7.47 - 6.94 (m, 3H), 4.88 - 4.53 (m, 2H), 4.37 (d, J = 54.8 Hz, 3H), 4.01 (s, 1H), 3.33 - 2.84 (m, 5H), 1.29 - 0.95 (m, 3H). LCMS (ESI) [M+H] + = 502.2.

[0142] Example I-27: [ka] The synthesis of Example I-27 was carried out by referring to the synthesis method of Example I-21, starting with I-27a and ultimately obtaining I-27 (80 mg, 60%). 1 H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.77 (s, 1H), 8.70 (d, J = 15.5 Hz, 1H), 8.34 (dd, J = 34.6, 6.6 Hz, 1H), 7.75 (dd, J = 16.9, 10.3 Hz, 1H), 7.47 - 7.38 (m, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.14 (ddd, J = 88.3, ​​8.3, 1.7 Hz, 1H), 4.56 (s, 2H), 4.37 (d, J = 61.2 Hz, 3H), 3.94 - 3.40 (m, 7H), 3.30 - 2.90 (m, 2H). LCMS (ESI) [M+H] + = 530.1.

[0143] Example I-28: [ka]

[0144] Step 1 I-28a (12 g, 67.7 mmol) was dissolved in DMF (60 mL), and cesium carbonate (44.1 g, 135.5 mmol) and iodomethane (12.5 g, 88.1 mmol) were added. The mixture was reacted at room temperature for 72 hours with stirring, then diluted with water (300 mL), extracted with ethyl acetate (200 mL x 3), washed the ethyl acetate phase with saturated saline solution (200 mL), dried over anhydrous sodium sulfate, filtered the organic phase, concentrated it, and purified the residue by column chromatography to obtain I-28b (10 g, 77%).

[0145]

[0146] Step 2 I-28b (7.3g, 38.0 mmol) was dissolved in DMSO (40 mL), potassium tert-butoxide (4.3g, 38.0 mmol) was added, and the mixture was stirred at room temperature for 30 minutes, after which I-28c (4.0g, 38.0 mmol) was added. The reaction mixture was heated to 65°C and stirred for 16 hours, then the temperature was raised to 80°C and stirred for 8 hours. After the reaction was complete, the mixture was cooled to room temperature, saturated ammonium chloride aqueous solution (100 mL) was slowly added dropwise in an ice bath, and the mixture was extracted with dichloromethane (200 mL x 3). The dichloromethane phase was washed with saturated saline solution (70 mL x 3), filtered, dried, concentrated, and the residue was purified by column chromatography to obtain I-28d (3g, 62%). 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 2.0 Hz, 1H), 7.94 - 7.86 (m, 2H), 7.47 (d, J = 8.8 Hz, 1H), 6.72 (s, 2H), 3.85 (s, 3H), 2.21 (d, J = 1.0 Hz, 3H). LCMS (ESI) [M+1] + = 217.1.

[0147] Step 3 I-28d (2.9 g, 13.4 mmol) was dissolved in a methanol / tetrahydrofuran (24 mL / 24 mL) mixture, and water (45 mL) and sodium hydroxide (1.1 g, 26.8 mmol) were added. The reaction mixture was allowed to proceed at 48 °C for 3 hours with stirring. After the reaction was complete, the mixture was cooled to room temperature, hydrochloric acid (2 M) solution was added to adjust the pH to 6.5, and the reaction mixture was concentrated. Then water (10 mL) was added, the mixture was stirred, and the solution was filtered to obtain I-28e (2 g, 74%). 1 H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(d, J = 2.0 Hz, 1H), 7.91 (dd, J = 8.7, 2.0 Hz, 1H), 7.86 (s, 1H), 7.45 (d, J = 8.7 Hz, 1H), 6.67 (s, 2H), 2.21 (s, 3H).

[0148] Step 4 I-28e (60 mg, 0.3 mmol) and I-1h (86 mg, 0.36 mmol) were dissolved in DMF (1.5 mL), DIPEA (120 mg, 0.9 mmol) was added, and HATU (170 mg, 0.45 mmol) was slowly added while stirring at room temperature. The reaction mixture was allowed to continue reacting with stirring at room temperature for 16 hours. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 2). The ethyl acetate phase was dried, filtered, concentrated, and the residue was purified by column chromatography to obtain I-28 (103 mg, 90%). 1 H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 19.9 Hz, 2H), 7.60 - 7.32 (m, 4H), 7.19 (s, 1H), 6.58 (s, 2H), 4.66 (s, 2H), 2.91 (s, 3H), 2.21 (s, 3H). LCMS (ESI) [M+1] + = 386.2.

[0149] Example I-29: [ka] The synthesis of Example I-29 was carried out by referring to the synthesis method of Example I-21, starting with I-29a and ultimately obtaining I-29 (74 mg, 50%). 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.20 (d, J = 7.4 Hz, 1H), 7.49 - 6.93 (m, 6H), 5.03 (dd, J = 14.8, 7.6 Hz, 2H), 4.81 - 4.44 (m, 5H), 4.30 (d, J = 54.3 Hz, 3H). LCMS (ESI) [M+H] + = 486.2.

[0150] Example I-30: [ka] The synthesis of Example I-30 was carried out by referring to the synthesis method of Example I-21, starting with I-30a and ultimately obtaining I-30 (72 mg, 41%). 1 H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.77 (s, 1H), 8.67 (d, J = 21.7 Hz, 1H), 8.35 (dd, J = 34.3, 6.6 Hz, 1H), 7.74 (dd, J = 17.7, 9.7 Hz, 1H), 7.47 - 7.38 (m, 1H), 7.36 - 7.29 (m, 1H), 7.14 (ddd, J = 88.4, 8.3, 1.7 Hz, 1H), 5.07 - 4.51 (m, 2H), 4.37 (d, J = 60.9 Hz, 3H), 3.95 - 3.41 (m, 7H), 3.27 - 2.88 (m, 2H). LCMS (ESI) [M+H] + = 530.1.

[0151] Example I-31: [ka] The synthesis of Example I-31 was carried out by referring to the synthesis method of Example I-21, starting with I-31a and ultimately obtaining I-31 (76 mg, 41%). 1 H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.96 - 8.45 (m, 3H), 7.77 (dd, J = 25.6, 10.3 Hz, 1H), 7.50 - 6.98 (m, 3H), 5.18 - 4.56 (m, LCMS (ESI) [M+H] + = 556.3.

[0152] Example I-32: [ka] I-28e (60 mg, 0.30 mmol), I-11c (88 mg, 0.3 mmol), CMPI (92 mg, 0.36 mmol), and DIEA (117 mg, 0.91 mmol) were dissolved in DMAC (5 mL) and reacted with stirring at 45°C for 16 hours. After the reaction was complete, water (20 mL) was added to quench the mixture, and it was extracted with ethyl acetate (30 mL x 3). The ethyl acetate phase was washed with saturated saline (10 mL x 3), dried, filtered, concentrated, and the residue was purified by column chromatography to obtain an intermediate. After that, methanol hydrochloride (5 mL) was added and freeze-dried to obtain I-32 (hydrochloride form, 54 mg, 38%). 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 8.65 (s, 2H), 8.31 (s, 1H), 8.01 (d, J = 1.7 Hz, 1H), 7.89 - 7.73 (m, 2H), 7.51 (s, 1H), 7.41 (d, J = 3.1 Hz, 2H), 5.55 (s, 1H), 4.68 (d, J = 12.6 Hz, 1H), 3.84 (dt, J = 11.4, 5.7 Hz, 2H), 3.71 (dd, J = 11.5, 3.4 Hz, 1H), 3.60 (d, J = 11.4 Hz, 1H), 2.32 (s, 3H), 0.80 (d, J = 7.0 Hz, 3H). LCMS (ESI) [M+H] + = 442.2.

[0153] Example I-33: [ka]

[0154] Step 1 I-33a (30 g, 126.6 mmol) was dissolved in tetrahydrofuran (100 mL), purged with nitrogen gas, and isopropyl magnesium chloride (63.3 mL, 126.6 mmol) was slowly added dropwise at 0°C. After the addition was complete, the mixture was allowed to rise to room temperature and reacted with stirring for 4 hours. At 0°C, this mixture was added dropwise to a tetrahydrofuran (100 mL) solution containing 2-chloroethoxyacetonitrile (15.1 g, 126.6 mmol). After the addition was complete, the mixture was raised to room temperature and continued to react with stirring for 1 hour. After the reaction was complete, the reaction solution was poured into saturated ammonium chloride aqueous solution (500 mL), extracted with ethyl acetate (300 mL x 2), the ethyl acetate phase was washed with saturated saline solution (100 mL x 3), the ethyl acetate phase was dried, filtered, concentrated, and the residue was purified by column chromatography to obtain I-33b (10 g, 28%). 1H NMR (400 MHz, DMSO-d6) δ 7.79 (dd, J = 8.4, 1.7 Hz, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 4.77 (s, 2H), 3.86 (dd, J = 5.7, 2.1 Hz, 2H), 3.71 (dd, J = 6.1, 5.2 Hz, 2H).

[0155] Step 2 I-33b (10 g, 35.9 mmol) was dissolved in tetrahydrofuran (100 mL), and (R)-(+)-tert-butylsulfenamide (5 g, 41.25 mmol) and tetraethyl titanate (24.6 g, 107.7 mmol) were added. The mixture was reacted at 30°C for 16 hours with stirring. After the reaction was complete, the reaction solution was diluted with ethyl acetate (500 mL), and water (100 mL) was added dropwise while rapidly stirring to quench the mixture. After stirring for 30 minutes, the mixture was filtered, the filtrate was separated, the organic phase was washed with saturated brine (100 mL), the ethyl acetate phase was dried, filtered, concentrated, and the residue was purified by column chromatography to obtain I-33c (7.6 g, 55%). 1 H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 1H), 7.65 (s, 1H), 7.10 (d, J = 8.5 Hz, 1H), 5.05 (q, J = 13.1 Hz, 2H), 3.84 - 3.74 (m, 2H), 3.62 (t, J = 5.5 Hz, 2H), 1.33 (s, 9H).

[0156] Step 3 A 500 mL three-necked flask was sealed and purged three times with nitrogen gas. DIBAL-H (24.9 mL, 49.8 mmol) was added, and the temperature was lowered to -78°C. A toluene (50 mL) solution of I-33c (7.6 g, 19.9 mmol) was slowly added dropwise. After the addition was complete, the reaction was continued at -78°C for 1 hour with stirring. After the reaction was complete, the reaction mixture was poured into a saturated ammonium chloride aqueous solution (300 mL), extracted with ethyl acetate (100 mL x 2), washed with saturated saline solution (100 mL x 3), dried the ethyl acetate phase, filtered, concentrated, and the residue was purified by column chromatography to obtain I-33d (5.6 g, yield: 73%). 1 H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 1.7 Hz, 1H), 7.16 (dd, J = 8.2, 1.7 Hz, 1H), 7.07 (d, J = 8.2 Hz, 1H), 4.59 (q, J = 5.2 Hz, 1H), 4.07 (d, LCMS (ESI) [M+H] + = 384.1.

[0157] Step 4 I-33d (5.1 g, 13.29 mmol) and 18-crown-6 (1.8 g, 6.81 mmol) were dissolved in tetrahydrofuran (50 mL), purged three times with nitrogen gas, and sodium hydride (1.6 g, 40.4 mmol, 60%) was added in several batches at 0°C. The reaction was continued at room temperature for 2 hours with stirring. After the reaction was complete, the reaction mixture was poured into saturated ammonium chloride aqueous solution (200 mL), extracted with ethyl acetate (100 mL x 2), the ethyl acetate phase was washed with saturated saline solution (100 mL x 3), the ethyl acetate phase was dried, filtered, concentrated, and the residue was purified by column chromatography to obtain I-33e (3.6 g, 78%). 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 1.7 Hz, 1H), 7.26 - 7.22 (m, 1H), 7.06 (d, J = 8.3 Hz, 1H), 4.35 (t, J = 3.5 Hz, 1H), 4.08 - 3.95 (m, LCMS (ESI) [M+H] + = 348.1.

[0158] Step 5 I-33e (3.6 g, 10.4 mmol) was dissolved in methanol (20 mL), hydrochloric acid / methanol solution (20 mL, 4 mol / L) was added, and the mixture was reacted at room temperature for 1 hour with stirring. After the reaction was complete, the reaction mixture was concentrated, ethyl acetate (5 mL) and petroleum ether (10 mL) were added, the mixture was stirred for 30 minutes, filtered, and the filtered cake was dried to obtain I-33f (2.8 g, 96%). 1 H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 9.83 (s, 1H), 7.81 (d, J = 1.5 Hz, 1H), 7.60 - 7.45 (m, 2H), 4.56 - 4.48 (m, 1H), 4.06 - 3.91 (m, 3H), 3.83 (dd, J = 12.3, 10.7 Hz, 1H), 3.34 - 3.28 (m, 1H), 3.25 - 3.15 (m, 1H). LCMS (ESI) [M+H] + = 244.1.

[0159] Step 6 I-33f (50 mg, 0.25 mmol), I-28e (100 mg, 0.36 mmol), TCFH (110 mg, 0.38 mmol), and NMI (62 mg, 0.75 mmol) were dissolved in DMAC (5 mL) and reacted with stirring at 45°C for 16 hours. After the reaction was complete, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 3). The ethyl acetate phase was washed with saturated saline solution (10 mL x 3), dried, filtered, concentrated, and the residue was purified by reverse-phase preparative chromatography to obtain I-33 (35 mg, 31%). 1 H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 1H), 7.73 (d, J = 1.5 Hz, 1H), 7.48 (d, J = 2.2 Hz, 3H), 7.43 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H), 6.53 (s, 2H), 5.38 (d, J = 50.0 Hz, 1H), 4.42 (d, J = 12.3 Hz, 1H), 3.88 (dd, J = 12.3, 3.5 Hz, 1H), 3.81 - 3.77 (m, 1H), 3.57 (td, J = 11.6, 2.8 Hz, 2H), 3.24 (d, J = 12.9 Hz, 1H), 2.21 (d, J = 1.1 Hz, 3H). LCMS (ESI) [M+H] + = 428.2.

[0160] Example I-7: [ka] I-33f (2.4g, 9.22 mmol, HCl), I-1f (2.58g, 9.22 mmol), TCFH (3.88g, 13.83 mmol), and NMI (2.27g, 27.66 mmol) were dissolved in DMAC (50 mL) and reacted with stirring at 45°C for 16 hours. After the reaction was complete, water (200 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (300 mL x 2). The ethyl acetate phase was washed with saturated saline solution (100 mL x 3), dried, filtered, concentrated, and the residue was purified by column chromatography to obtain I-7 (1.33 g, yield: 30%). 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 2H), 7.63 - 7.23 (m, 6H), 5.71 (s, 1H), 4.44 (d, J = 39.6 Hz, 4H), 4.16 - 3.49 (m, 4H), 3.31 - 3.01 (m, 1H). LCMS (ESI) [M+1] + = 486.2.

[0161] Example I-34: [ka]

[0162] Step 1 Sodium hydride (14.9 g, 372.6 mmol, 60%) was dissolved in tetrahydrofuran (1 L), protected with nitrogen gas, and then I-34a (77.6 g, 745.3 mmol) was added at room temperature. The reaction mixture was heated to 65°C, I-34b (50 g, 745.3 mmol) was added, and the reaction was continued at 65°C for 2 hours with stirring. After the reaction was complete, the mixture was cooled to room temperature, quenched with 2N sodium hydroxide solution, extracted with ethyl ether, the aqueous phase was adjusted to pH 1 with concentrated hydrochloric acid, and dichloromethane was added for extraction. The dichloromethane phase was dried, filtered, concentrated, and the residue was purified by column chromatography to obtain I-34c (19 g, 20%). LCMS (ESI) [M+H] + = 126.0.

[0163] Step 2 I-34c (5g, 40.0 mmol) was dissolved in dichloromethane (100 mL), and after purging with nitrogen gas, DIPEA (10.3 g, 80.0 mmol) and trifluoromethanesulfonic anhydride (15.8 g, 55.9 mmol) were added at -70°C. The reaction mixture was continued to react at -70°C for 30 minutes with stirring. After the reaction was complete, water (50 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (100 mL x 2). The dichloromethane phase was dried, filtered, and concentrated to obtain I-34d (9g, 88%). 1 HNMR (400 MHz, CDCl3) δ 5.14 - 5.05 (m, 1H), 4.94 - 4.78 (m, 2H), 1.49 (d, J = 6.3 Hz, 3H). LCMS (ESI) [M+H] + = 258.0.

[0164] Step 3 I-34d (27 g, 105.0 mmol), I-1c (24.8 g, 84.0 mmol), and tetrakistriphenylphosphine palladium (4.9 g, 4.2 mmol) were dissolved in a mixed solution of dioxane (360 mL) and water (36 mL). Potassium carbonate (43.5 g, 314.9 mmol) was added, and the reaction mixture was carried out at 80°C for 16 hours with stirring under nitrogen gas protection. After the reaction was complete, the mixture was concentrated, and the residue was purified by column chromatography to obtain I-34e (5.5 g, 19%). 1 HNMR (400 MHz, DMSO-d6) δ 8.04 (d, J = 8.1 Hz, 1H), 7.26 (d, J = 13.4 Hz, 1H), 7.03 (s, 2H), 5.46 - 5.21 (m, 3H), 3.85 (s, 3H), 1.39 (d, J = 6.0 Hz, 3H). LCMS (ESI) [M+H] + = 277.2.

[0165] Step 4 I-34e (300 mg, 1.1 mmol) was dissolved in a mixed solution of methanol (5 mL) / tetrahydrofuran (5 mL) / water (3 mL), and lithium hydroxide (78 mg, 3.3 mmol) was added. The reaction mixture was heated to 50°C and stirred for 20 hours. After the reaction was complete, water was added to dilute the mixture, and 1 N hydrochloric acid solution was added to adjust the pH to 5. A solid precipitated, which was then filtered and dried to obtain the intermediate I-34f (240 mg, 84%). 1 H NMR (400 MHz, DMSO-d6) δ 13.64 (s, 1H), 9.00 (s, 2H), 8.21 (d, J = 7.5 Hz, 1H), 7.68 (d, J = 11.6 Hz, 1H), 5.57 (ddd, J = 6.0, 3.7, 2.2 Hz, 1H), 5.51 - 5.35 (m, 2H), 1.42 (d, J = 6.1 Hz, 3H).

[0166] Step 5 I-34f (60 mg, 0.23 mmol), I-33f (92 mg, 0.33 mmol), TCFH (97 mg, 0.35 mmol), and NMI (57 mg, 0.69 mmol) were dissolved in DMAC (5 mL) and reacted at 45°C for 16 hours. After the reaction was complete, the reaction solution was added dropwise to water, extracted with ethyl acetate, washed the ethyl acetate phase with saturated saline solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography to obtain I-34 (48 mg, 42%). 1 H NMR (400 MHz, DMSO-d6) δ 7.65 (s, 1H), 7.58 - 7.03 (m, 4H), 6.77 (s, 2H), 5.68 (s, 1H), 5.49 - 5.17 (m, 3H), 4.82 - 4.22 (m, 2H), 3.95 - 3.70 (m, 2H), 3.51 (s, 1H), 3.27 (s, 1H), 1.39 (d, J = 6.1 Hz, 3H). LCMS (ESI) [M+H] + = 488.2.

[0167] Example I-35: [ka] I-28e (60 mg, 0.30 mmol), I-15a (85 mg, 0.37 mmol), HATU (141 mg, 0.37 mmol), and DIPEA (117 mg, 0.91 mmol) were dissolved in DMAC (1.5 mL) and reacted at 45°C for 16 hours. After the reaction was complete, the reaction solution was filtered and concentrated, and the residue was purified by column chromatography to obtain I-35 (79 mg, 59%). 1 H NMR (400 MHz, DMSO-d6) δ7.91 - 7.83 (m, 2H), 7.64 (dd, J = 8.6, 1.9 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.44 - 7.36 (m, 2H), 7.20 (d, J = LCMS (ESI) [M+H] + = 412.2.

[0168] Example I-36: [ka] I-34f (60 mg, 0.23 mmol), I-15a (65 mg, 0.29 mmol), HATU (110 mg, 0.29 mmol), and DIPEA (90 mg, 0.70 mmol) were dissolved in DMAC (1.5 mL) and reacted at 45°C for 16 hours. After the reaction was complete, the reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by column chromatography to obtain I-36 (47 mg, 41%). 1H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.37 (s, 1H), 7.28 (d, J = 12.1 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 6.80 (s, 2H), 5.46 - 5.19 (m, 3H), 4.73 (s, 2H), 2.67 (s, 1H), 2.08 (s, 0H), 1.40 (d, J = 6.1 Hz, 3H), 0.54 - 0.33 (m, 4H). LCMS (ESI) [M+H] + = 472.2.

[0169] Example I-37: [ka]

[0170] Step 1 I-37a (84 g, 552.1 mmol) was dissolved in acetonitrile (1.5 L), and a solution of NCS (73.7 g, 552.1 mmol) in acetonitrile (500 mL) was added. The reaction mixture was heated to 50°C and stirred for 16 hours. After the reaction was complete, the reaction mixture was concentrated, and the residue was purified by column chromatography to obtain I-37b (73 g, 71%).

[0171] Step 2 I-37b (74 g, 396.6 mmol) was dissolved in acetonitrile (1.5 L), and a solution of NBS (70.6 g, 396.6 mmol) in acetonitrile (500 mL) was added. The reaction mixture was heated to 50°C and stirred for 16 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and the residue was purified by column chromatography to obtain I-37c (86.0 g, 82%). LC-MS (ESI) [M+H] + = 264.9.

[0172] Step 3 I-37c (47 g, 177 mmol) and bis(pinacolato)diborone (89.9 g, 354 mmol) were dissolved in DMF (750 mL), and potassium acetate (42.3 g, 354 mmol) and Pd(dppf)Cl2 dichloromethane complex (15.9 g, 177 mmol) were added. After nitrogen gas protection, the reaction mixture was heated to 100 °C and stirred for 16 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and the residue was purified by column chromatography to obtain I-37d (33 g, 47%). LCMS (ESI) [M+H] + = 230.9.

[0173] Step 4 I-37d (36.7 g, 117 mmol) was dissolved in tetrahydrofuran (400 mL), triethylamine (35.6 g, 352 mmol) and 10% Pd / C (12.5 g, 11.7 mmol) were added, and the mixture was purged with hydrogen gas. The reaction was then carried out at 40°C for 1 hour with stirring. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to obtain I-37e (27.5 g, crude product), which was then used directly in the next reaction. LCMS (ESI) [M+H] + = 196.9.

[0174] Step 5 I-37e (27.3 g, 139 mmol) and I-1d (25.9 g, 139 mmol) were dissolved in a mixed solution of dioxane (350 mL) and water (35 mL), and potassium carbonate (56.7 g, 417.2 mmol) and Pd(PPh3)4 (8 g, 6.95 mmol) were added. The reaction mixture was carried out at 100 °C for 16 hours with stirring under nitrogen gas protection. After the reaction was complete, the reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by column chromatography to obtain I-37f (10.9 g, 31%). 1 H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.74 (s, 1H), 8.37 (s, 1H), 7.67 (s, 2H), 4.46 (s, 3H), 3.91 (s, 3H). LCMS (ESI) [M+H] + = 257.9.

[0175] Step 6 I-37f (200 mg, 0.78 mmol) was dissolved in a mixed solution of methanol (5 mL) / tetrahydrofuran (5 mL) / water (3 mL), and lithium hydroxide (56 mg, 2.34 mmol) was added. The reaction mixture was allowed to proceed at 50°C for 20 hours with stirring. After the reaction was complete, water was added to dilute the mixture, and 1 N hydrochloric acid solution was added to adjust the pH to 5. The solid was precipitated, filtered, and dried to obtain I-37 g (180 mg, 95%). 1 H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.23 (s, 1H), 9.14 (s, 1H), 8.97 (s, 1H), 8.77 (s, 1H), 4.52 (s, 3H).

[0176] Step 7 I-37g (60mg, 0.25 mmol), I-15a (70mg, 0.30 mmol), HATU (114mg, 0.30 mmol), and DIPEA (97mg, 0.75 mmol) were dissolved in DMAC (2 mL), and the reaction mixture was allowed to react at 45°C for 16 hours with stirring. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and the residue was purified by column chromatography to obtain I-37 (12mg, 10%). 1 H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.35 (s, 1H), 8.29 (s, 1H), 7.43 (d, J = 8.1 Hz, 4H), 7.26 (s, 1H), 4.76 (s, 2H), 4.43 (s, 3H), 2.92 (s, 1H), 0.44 (s, 2H), 0.39 (d, J = 8.3 Hz, 2H). LCMS (ESI) [M+H] + = 453.2.

[0177] Example I-38: [ka] I-37g (60mg, 0.25 mmol), I-33f (70mg, 0.25 mmol), TCFH (110mg, 0.38 mmol), and NMI (62mg, 0.75 mmol) were dissolved in DMAC (5 mL). The reaction mixture was allowed to react at 45°C for 16 hours with stirring. After the reaction was complete, the reaction mixture was poured into water and extracted with ethyl acetate (30 mL x 3). The ethyl acetate phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography to obtain I-38 (80mg, 69%). 1 H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.45 (d, J = 4.2 Hz, 2H), 8.08 (s, 2H), 7.71 - 7.20 (m, 3H), 5.58 (d, J = 93.5 Hz, 1H), 4.46 (s, 4H), 3.99 - 3.54 (m, 4H), 2.98 (d, J = 29.0 Hz, 1H). LCMS (ESI) [M+H] + = 469.2.

[0178] Example I-39: [ka] I-34f (60 mg, 0.23 mmol), I-11c (70 mg, 0.24 mmol), DIPEA (90 mg, 0.7 mmol), and CMPI (71 mg, 0.28 mmol) were dissolved in DMAC (5 mL). The reaction mixture was allowed to react at 45°C for 16 hours with stirring. After the reaction was complete, the reaction mixture was poured into water and extracted with ethyl acetate (30 mL x 3). The ethyl acetate phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography to obtain I-39 (20 mg, 17%). 1H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 7.6 Hz, 1H), 7.53 (s, 1H), 7.43 (s, 2H), 7.32 (d, J = 11.8 Hz, 1H), 6.74 (s, 2H), 5.68 - 5.37 (m, LCMS (ESI) [M+H] + = 502.2.

[0179] Example I-40: [ka]

[0180] Step 1 I-40a (100 mg, 1.13 mmol) was dissolved in DCM (5 mL), Dess-Martin reagent (480 mg, 1.13 mmol) was added, and the reaction mixture was allowed to react at room temperature for 1 hour with stirring. After the reaction was complete, the reaction mixture was diluted with petroleum ether (15 mL), stirred for 10 minutes, filtered, the filtrate was concentrated, and the residue was purified by column chromatography to obtain I-40b (90 mg, 94%). 1 H NMR (400 MHz, CDCl3) δ 9.96 (d, J = 2.4 Hz, 1H), 4.92 - 4.83 (m, 4H), 3.82 (ttd, J = 8.4, 6.1, 2.4 Hz, 1H).

[0181] Step 2 I-40b (78 mg, 0.9 mmol) and I-40c (100 mg, 0.53 mmol) were dissolved in methanol (5 mL) and reacted at room temperature with stirring for 1 hour. Then, sodium borohydride (20 mg, 0.53 mmol) was added at 0°C. The reaction mixture was continued at room temperature with stirring for 1 hour. After the reaction was complete, water was added to the reaction mixture to quench it, and the mixture was extracted with ethyl acetate (20 mL x 3). The ethyl acetate phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography to obtain I-40d (100 mg, 72%). LCMS (ESI) [M+H] + = 258.1.

[0182] Step 3 I-40d (59 mg, 0.23 mmol), I-1f (60 mg, 0.23 mmol), and DIPEA (80 mg, 0.7 mmol) were dissolved in DMAC (5 mL), and HATU (100 mg, 0.28 mmol) was added. The reaction mixture was allowed to react at 45°C for 16 hours with stirring. After the reaction was complete, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 2). The ethyl acetate phase was washed with saturated saline solution (10 mL x 3), dried, filtered, concentrated, and the residue was purified by column chromatography to obtain I-40 (26 mg, 21%). 1 H NMR (400 MHz, DMSO-d6) δ 8.31 - 8.11 (m, 2H), 7.50 - 7.01 (m, 6H), 4.85 - 4.56 (m, 2H), 4.48 (s, 1H), 4.43 - 4.19 (m, 5H), 3.99 (t, J = 6.3 Hz, 1H), 3.65 (dd, J = 74.2, 13.0 Hz, 3H). LCMS (ESI) [M+H] + = 500.2.

[0183] Example I-41: [ka]

[0184] Step 1 I-41a (300 mg, 2.7 mmol) was dissolved in DCM (10 mL), Dess-Martin reagent (1.24 g, 2.9 mmol) was added, and the reaction mixture was allowed to react at room temperature for 1 hour with stirring. After the reaction was complete, the reaction mixture was diluted with petroleum ether (15 mL), stirred for 10 minutes, filtered, the filtrate was concentrated, and the residue was purified by column chromatography to obtain I-41b (255 mg, 86%). 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (d, J = 0.6 Hz, 1H), 8.72 (s, 1H), 4.00 (s, 3H).

[0185] Step 2 I-41b (100 mg, 0.9 mmol) and I-40c (100 mg, 0.5 mmol) were dissolved in methanol (5 mL), stirred at room temperature for 1 hour, and then sodium borohydride (20 mg, 0.5 mmol) was slowly added at 0°C. The reaction was continued with stirring at room temperature for 1 hour, and after the reaction was complete, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 3). The ethyl acetate phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography to obtain the crude product. This crude product was dissolved in hydrogen chloride / methanol (5 mL) solution, stirred for 30 minutes, and then concentrated to obtain I-41c (150 mg, 88%). 1 H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 2H), 8.60 (s, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.40 (dd, J = 8.3, 1.7 Hz, 1H), 4.30 - 4.23 (m, 2H), 4.19 - 4.12 (m, 2H), 3.89 (s, 3H).

[0186] Step 3 I-41c (88 mg, 0.3 mmol), I-1f (60 mg, 0.23 mmol), and DIPEA (80 mg, 0.7 mmol) were dissolved in DMAC (5 mL), and HATU (100 mg, 0.28 mmol) was added. The reaction mixture was allowed to react at 45°C for 16 hours with stirring. After the reaction was complete, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 2). The ethyl acetate phase was washed with saturated saline solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography to obtain I-41 (64 mg, 50%). 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.46 - 8.39 (m, 1H), 8.25 (s, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.38 - 7.24 (m, 4H), 7.22 - 6.97 (m, 1H), 4.65 (d, J = 37.6 Hz, 2H), 4.45 - 4.17 (m, 5H), 3.84 (d, J = 13.8 Hz, 3H). LCMS (ESI) [M+H] + = 525.2.

[0187] Examples I-34(PEAK1) and I-34(PEAK2): [ka] I-34 was purified by preparative SFC (Shimadzu E-UC, IA-ED-30-8MIN, mobile phase A:CO2, mobile phase B:EtOH (0.05%DEA)) to obtain I-34 (PEAK1, Rt=3.106min) and I-34 (PEAK2, Rt=4.205min).

[0188] I-34 (PEAK 1): 1H NMR (400 MHz, DMSO-d6) δ 7.66 (s, 1H), 7.56 - 7.37 (m, 2H), 7.37 - 7.20 (m, 2H), 6.78 (s, 2H), 5.68 (s, 1H), 5.45 - 5.20 (m, 3H), 4.77 - 4.27 (m, 2H), 3.92 - 3.70 (m, 2H), 3.56 - 3.45 (m, 1H), 3.26 (s, 1H), 1.39 (d, J = 6.1 Hz, 3H). LCMS (ESI) [M+H] + = 488.2 I-34 (PEAK 2): 1 H NMR (400 MHz, DMSO-d6) δ 7.66 (s, 1H), 7.56 - 7.37 (m, 2H), 7.37 - 7.20 (m, 2H), 6.78 (s, 2H), 5.68 (s, 1H), 5.45 - 5.20 (m, 3H), 4.77 - 4.27 (m, 2H), 3.92 - 3.70 (m, 2H), 3.56 - 3.45 (m, 1H), 3.26 (s, 1H), 1.39 (d, J = 6.1 Hz, 3H). LCMS (ESI) [M+H] + = 488.2.

[0189] Example I-53 [ka]

[0190] Step 1 I-53a (5g, 27.91 mmol) was added to dry DMSO (30 mL), and 4-methoxybenzylamine (4.59 g, 33.49 mmol) and potassium carbonate (7.71 g, 55.82 mmol) were added. The mixture was reacted at 70°C for 16 hours. The reaction was monitored by TLC to ensure completeness. The reaction mixture was added to water, extracted with ethyl acetate, and the organic phase was washed five times with saturated brine. The mixture was dried over anhydrous sodium sulfate and separated by column chromatography to obtain a white solid I-53b (5g, 60%). 1H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J = 8.9 Hz, 1H), 7.51 (t, J = 5.8 Hz, 1H), 7.30 - 7.24 (m, 2H), 7.02 (d, J = 2.4 Hz, 1H), 6.96 - 6.83 (m, 3H), 4.31 (d, J = 5.8 Hz, 2H), 3.79 (s, 3H), 3.73 (s, 3H).

[0191] Step 2 I-53b (4000 mg, 13.55 mmol) was dissolved in DCM (20 mL), TFA (20 mL) was added dropwise, and the mixture was reacted at 25°C for 2 hours. Complete reaction was monitored by TLC, and the reaction mixture was added dropwise to a 1 N NaOH aqueous solution. The mixture was extracted twice with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain a white solid I-53c (2.2 g, 93%). 1 H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J = 8.8 Hz, 1H), 6.96 (d, J = 2.3 Hz, 1H), 6.81 (dd, J = 8.8, 2.4 Hz, 1H), 6.47 (s, 2H), 3.79 (s, 3H).

[0192] Step 3 I-53c (2.7g, 15.33 mmol) was dissolved in dichloromethane (30 mL), NBS (2730 mg, 15.33 mmol) was added, and the mixture was reacted at 25°C for 2 hours. Complete reaction was monitored by TLC, and the mixture was quenched with aqueous sodium thiosulfate. Extraction was performed with dichloromethane, the organic phase was washed with saturated saline solution, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain a grayish-white solid I-53d (530 mg, 35%). 1 H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.16 (s, 1H), 6.69 (s, 2H), 3.81 (s, 3H).

[0193] Step 4 I-53d (100 mg, 0.39 mmol), bis(pinacolato)diborone (200 mg, 0.78 mmol), potassium acetate (110 mg, 1.17 mmol), and Pd(dppf)Cl2 (29 mg, 0.039 mmol) were dissolved in dried dioxane (5 mL), purged three times with nitrogen gas, and reacted at 90°C for 16 hours. Complete reaction was monitored by TLC, diluted with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and tumble-dried to obtain a brown oily substance I-53e (110 mg, 93%).

[0194] Step 5 I-53e (110 mg, 0.36 mmol), 5-bromo-1-methyl-1H-pyrazole-4-carbonitrile (67 mg, 24.49 mmol), potassium phosphate (230 mg, 1.08 mmol), X-Phos (18 mg, 0.036 mmol), and X-Phos Pd G3 (31 mg, 0.036 mmol) were dissolved in dioxane (4 mL) and water (1 mL), purged three times with nitrogen gas, and reacted at 100°C for 16 hours. Complete reaction was monitored by LC-MS, diluted with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain a yellow-green solid I-53f (100 mg, yield 98%). 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.80 (s, 1H), 7.25 (s, 1H), 6.66 (s, 2H), 3.81 (s, 3H), 3.67 (s, 3H). LCMS ESI (m / z) =282.2 [M+H] + .

[0195] Step 6 I-53f (110 mg, 0.39 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), water (2 mL) and sodium hydroxide (49 mg, 1.17 mmol) were added, and the mixture was reacted at 50°C for 20 hours. Complete reaction was monitored by LC-MS, and the pH was adjusted to 5 by adding 1 N hydrochloric acid. The organic phase was removed by rotational drying, and a large amount of solid precipitated. This was filtered, and the filter cake was dried to obtain a gray solid I-53 g (45 mg, 43%). LC-MS ESI (m / z) = 268.1 [M+H] + .

[0196] Step 7 I-53g (40mg, 0.15 mmol), I-33f (42mg, 0.15 mmol), and NMI (37mg, 0.45 mmol) were dissolved in DMAC (1 mL), stirred, cooled to 0°C, and TCFH (63 mg, 0.22 mmol) was added. The mixture was then reacted at room temperature for 16 hours. Complete reaction was monitored by LC-MS, and the mixture was separated by reverse-phase preparative chromatography to obtain I-53 (41 mg, 56%). ESI (m / z) = 493.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.37 - 8.25 (m, 2H), 8.02 (s, 1H), 7.62 - 7.36 (m, 5H), 5.83 - 4.82 (m, -1H), 4.58 - 3.58 (m, 8H), 3.27 - 3.14 (m, 1H).

[0197] Example I-54 [ka] I-15a (34 mg, 0.15 mmol), I-53 g (40 mg, 0.15 mmol), TCFH (63 mg, 0.22 mmol), NMI (37 mg, 0.45 mmol), and DMAC (1 mL) were mixed and reacted at 45°C for 3 hours. Complete reaction was monitored by LC-MS, and the mixture was separated by reverse-phase preparative chromatography to obtain I-54 (18.8 mg, 25%). 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.33 (s, 1H), 8.01 (s, 1H), 7.46 (s, 3H), 7.41 (d, J = 8.2 Hz, 1H), 7.29 (s, 1H), 4.76 (s, 2H), 4.41 (s, 3H), 2.79 (s, 1H), 2.54 (s, 0H), 0.49 (d, J = 25.2 Hz, 4H). LCMS (ESI) [M+1]+ = 477.2.

[0198] Example I-80 [ka] Step 1 I-80a (5g, 36.61 mmol) and dried DCM (20 mL) were added to a 100 mL necked flask, the temperature was lowered to 0°C, oxalyl chloride (9.29 g, 73.22 mmol) was added, and 0.5 mL of DMF was added dropwise. The mixture was then allowed to react at room temperature for 3 hours. Complete reaction was detected by TLC, the reaction solution was rotated dry, and then diluted with another 100 mL of dried DCM, which was labeled Solution 1. Dimethylhydroxylamine hydrochloride (3.57 g, 36.61 mmol) and dried DCM (10 mL) were added to another 250 mL necked flask, and triethylamine (11.11 g, 109.83 mmol) was added while rapidly stirring. After the dropwise addition was complete, the temperature was controlled to 0°C, and Solution 1 was added dropwise. After the dropwise addition was complete, the mixture was returned to room temperature and allowed to react for 1 hour. After the reaction was complete, the reaction mixture was poured into a saturated sodium bicarbonate aqueous solution (100 mL), the organic phase was washed with saturated brine (100 mL x 3), the organic phase was dried, and concentrated to obtain an oily substance. 50 mL of tetrahydrofuran was added to the obtained oily substance, and the mixture was rapidly stirred for 30 minutes. The mixture was filtered, and the filtrate was rotary-dried to obtain oily substance I-80b (4.5 g, yield: 68%). LCMS (ESI) [M+1] + = 180.1.

[0199] Step 2 I-33a (5g, 21.1 mmol) and THF (20 mL) were added to a 100 mL three-necked flask, purged three times with nitrogen gas, and the temperature was controlled to 0°C. Isopropyl magnesium chloride (12.66 mL, 25.31 mmol) was slowly added dropwise. After the addition was complete, the mixture was allowed to return to room temperature and react for 3 hours. Then, a solution of I-80b (4g, 22.16 mmol) in THF (5 mL) was slowly added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for 1 hour with stirring. After the reaction was complete, the reaction solution was poured into a saturated aqueous solution of ammonium chloride (100 mL), extracted with ethyl acetate (50 mL x 2), washed with saturated brine (50 mL x 3), dried the ethyl acetate phase, filtered, concentrated, and the residue was purified by column chromatography to obtain I-80c (3.5 g, yield: 60%). 1 H NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 8.4, 1.7 Hz, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 3.58 (t, J = 6.0 Hz, 2H), 2.98 (t, J = 6.7 Hz, 2H), 1.96 - 1.82 (m, 4H).

[0200] Step 3 I-80c (3g, 10.84 mmol), THF (50 mL), and R-tert-butylsulfenamide (1.71 g, 14.09 mmol) were added to a 100 mL necked flask. While stirring, tetraethyl titanate (7.42 g, 32.52 mmol) was added, and the mixture was reacted at 50°C for 16 hours with stirring. After the reaction was complete, the reaction mixture was diluted with THF (200 mL), and saturated saline (10 mL) was added dropwise while rapidly stirring to quench the mixture. After the dropwise addition was complete, the mixture was stirred for 30 minutes, filtered, the filtrate was separated, rinsed with THF (100 mL), the organic phase was dried, filtered, concentrated, and the residue was purified by column chromatography to obtain I-80d (3g, yield: 72.8%). 1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 3.64 (t, J = 6.5 Hz, 2H), 3.30 - 3.13 (m, 2H), 1.79 (ddd, J = 13.4, 7.5, 4.3 Hz, 2H), 1.64 (p, J = 7.6 Hz, 2H), 1.23 (s, 9H). LCMS (ESI) [M+1] + = 380.2.

[0201] Step 4 A 100 mL three-necked flask was sealed and purged three times with nitrogen gas. DIBAL-H (19.75 mL, 19.75 mmol) was added, the temperature was lowered to -78°C, and a solution of I-80d (3 g, 7.9 mmol) in THF (20 mL) was slowly added dropwise. After the addition was complete, the mixture was kept warm at -78°C and stirred for 1 hour. After the reaction was complete, 5 mL of methanol was added dropwise to quench the reaction mixture. The reaction solution was poured into an aqueous solution of potassium sodium tartrate (14.5 g, 69.13 mmol) (100 mL), ethyl acetate (100 mL) was added, and the mixture was rapidly stirred for 3 hours. The mixture was then separated, the ethyl acetate phase was washed with saturated brine (50 mL x 3), the ethyl acetate phase was dried, filtered, and concentrated to obtain I-80e (3 g, crude product). 1 H NMR (400 MHz, DMSO-d6) δ 7.49 (d, J = 1.6 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.23 (dd, J = 8.3, 1.6 Hz, 1H), 5.65 (d, J = 9.1 Hz, 1H), 4.20 (td, J = 8.6, 6.1 Hz, 1H), 3.62 (t, J = 6.5 Hz, 2H), 1.86 - 1.59 (m, 4H), 1.50 (td, J = 14.9, 14.2, 6.3 Hz, 1H), 1.31 (ddd, J = 14.4, 7.3, 3.1Hz, 1H), 1.14 (s, 9H). LCMS (ESI) [M+1] + = 382.2.

[0202] Step 5 I-80e (3g, 7.82 mmol), THF (30 mL), and 18-crown-6 (1.03 g, 3.91 mmol) were added to a 100 mL three-necked flask. The flask was purged three times with nitrogen gas, and the temperature was controlled to 0°C. Sodium hydride (950 mg, 23.69 mmol, 60%) was added in several batches. After adding the sodium hydride, the mixture was allowed to return to room temperature and react for 2 hours. After the reaction was complete, the reaction mixture was poured into a saturated ammonium chloride aqueous solution (100 mL), extracted with ethyl acetate (50 mL x 2), washed with saturated saline solution (50 mL x 3), dried, filtered, and concentrated to obtain I-80f (2.8 g, crude product). LCMS (ESI) [M+1] + = 346.1.

[0203] Step 6 I-80f (2.8 g, 8.11 mmol) and methanol (10 mL) were added to a 100 mL necked flask, and hydrochloric acid / methanol solution (6 mL, 4 mol / L) was added. The mixture was reacted at room temperature for 1 hour with stirring. After the reaction was complete, the reaction mixture was rotated dry, ethyl acetate (10 mL) and petroleum ether (20 mL) were added, the mixture was stirred for 30 minutes, filtered, and the filtered cake was dried to obtain I-80g (1.8 g, 3-step yield: 82%, HCl salt). 1 H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.37 (s, 1H), 7.79 (d, J = 1.5 Hz, 1H), 7.53 - 7.39 (m, 2H), 4.26 (d, J = 10.6 Hz, 1H), 3.34 - 3.27 (m, 1H), 2.99 (t, J = 12.8 Hz, 1H), 1.96 - 1.82 (m, 4H), 1.81 - 1.54 (m, 2H). LCMS (ESI) [M+1] + = 242.2.

[0204] Step 7 I-1f (60 mg, 0.23 mmol), I-80 g (72 mg, 0.30 mmol, HCl), NMI (57 mg, 0.69 mmol), and DMAC (3 mL) were mixed, cooled to 0°C, and TCFH (97 mg, 0.35 mmol) was added. After adding the TCFH, the mixture was reacted at 25°C for 1 hour. The complete reaction was monitored by LC-MS, and I-80 (51 mg, 46%) was obtained by separation by reverse-phase preparative chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.31 (s, 1H), 8.22 (s, 1H), 7.54 (d, J = 11.1 Hz, 1H), 7.44 - 7.34 (m, 2H), 7.21 (d, J = 8.5 Hz, LCMS (ESI) [M+1] + = 484.3.

[0205] Example I-109 [ka] I-109a (50 mg, 0.22 mmol), I-33f (62 mg, 0.22 mmol), NMI (54 mg, 0.45 mmol), and DMAC (3 mL) were mixed, cooled to 0°C, and TCFH (74 mg, 0.26 mmol) was added. The mixture was then reacted at 25°C for 1 hour. The complete reaction was monitored by LC-MS, and the mixture was separated by reverse-phase preparative chromatography to obtain I-109 (44 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 7.84 (s, 1H), 7.53 (s, 1H), 7.40 (d, J = 26.1 Hz, 2H), 7.07 (s, 2H), 5.65 (s, 1H), 5.37 (t, J = LCMS (ESI) [M+1]+ = 457.3.

[0206] Example I-111 [ka] I-37g (200mg, 0.66 mmol), I-80g (185mg, 0.67 mmol), and TEA (240mg, 2.38 mmol) were dissolved in DMAC (3 mL), cooled to 0°C, and TBTU (250 mg, 0.79 mmol) was added. The mixture was then reacted at room temperature for 16 hours. Complete reaction was monitored by LC-MS, the reaction solution was diluted with water, extracted with ethyl acetate, washed five times with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain I-111 (31.6 mg, 10%). ESI (m / z) = 467.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.35 (d, J = 1.4 Hz, 2H), 7.43 - 7.37 (m, 2H), 7.31 - 7.23 (m, 3H), 5.75 (s, 1H), 4.41 (s, 3H), 4.07 (s, 2H), 2.92 (s, 2H), 2.41 (d, J = 14.4 Hz, 1H), 1.95 (d, J = 15.3 Hz, 1H), 1.66 (d, J = 14.6 Hz, 2H).

[0207] Example I-114 [ka]

[0208] Step 1 Compound I-114a (5390 mg, 26.93 mmol) was added to dichloromethane (100 mL), cooled to 0°C, and a solution of liquid bromine (4303.89 mg, 26.93 mmol) in dichloromethane (10 mL) was slowly added dropwise. The reaction mixture was allowed to react under a nitrogen gas atmosphere at room temperature for 16 hours with stirring, and LC-MS confirmed that the starting materials had reacted completely. The reaction mixture was washed with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, the organic phase was further washed with saturated brine, then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 90 / 10) to obtain a white solid I-114b (4500 mg, yield 59.87%).

[0209] Step 2 Compound I-114c (1440 mg, 7.19 mmol) and sodium bicarbonate (1812.1 mg, 21.57 mmol) were added to dioxane / H2O (100 mL, 3 / 1), cooled to 0°C, and Fmoc-Cl (2790.08 mg, 10.78 mmol) was slowly added. The mixture was purged three times with nitrogen gas, and the reaction was carried out at room temperature under a nitrogen atmosphere with stirring for 16 hours. LC-MS confirmed that the starting materials had reacted completely. The reaction mixture was washed with water, extracted with ethyl acetate, and the organic phase was further washed with saturated brine. The mixture was then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 90 / 10) to obtain a white solid I-114d (2500 mg, yield 82.29%). MS Calcd.: 422.1; MS Found: 323.0 (M+1-100).

[0210] Step 3 I-114d (2300 mg, 5.44 mmol) was added to a mixed solution of EA (20 mL) and dioxane / HCl (4 M) (10 mL), and the reaction was carried out at 25°C for 4 hours with stirring. LC-MS showed that the starting materials had reacted completely, and the reaction mixture was concentrated under reduced pressure to obtain a white solid I-114e (1570 mg, yield 80.36%). MS Calcd.: 322.1; MS Found: 323.1 (M+1).

[0211] Step 4 Compound I-114e (643.04 mg, 1.79 mmol), compound I-114b (500 mg, 1.79 mmol), and triethylamine (725.29 mg, 7.16 mmol) were added to dichloromethane (20 mL), purged three times with nitrogen gas, and the reaction mixture was allowed to react under a nitrogen atmosphere with stirring for 16 hours. LC-MS confirmed that the starting materials had reacted completely. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA=50 / 50) to obtain yellow solid I-114f (600 mg, yield 64.32%). MS Calcd.: 520.1; MS Found: 521.0 (M+1).

[0212] Step 5 Compound I-114f (400 mg, 0.76 mmol) and sodium carbonate (244.36 mg, 2.30 mmol) were added to methanol (15 mL), the mixture was purged three times with nitrogen gas, the reaction mixture was heated to 50°C and reacted with stirring under a nitrogen gas atmosphere for 2 hours, LC-MS showed that the starting materials had reacted completely, the reaction mixture was cooled to room temperature, filtered, and the filtrate was used directly in the next reaction.

[0213] Step 6 The filtrate from step 5 was cooled in an ice bath, NaBH4 (58.04 mg, 1.53 mmol) was added, and the reaction mixture was allowed to proceed at 20°C for 2 hours with stirring. LC-MS confirmed that the starting materials had reacted completely. After quenching the reaction mixture with water, it was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM / MeOH = 80 / 20, 0.5% NH3, H2O) to obtain the yellow solid I-114h (180 mg). MS Calcd.: 282.1; MS Found: 283.0 (M+1).

[0214] Step 7 Compounds I-114h (180 mg, 0.63 mmol), I-114i (218.95 mg, 0.63 mmol), TCFH (214.73 mg, 0.76 mmol), and NMI (130.9 mg, 1.59 mmol) were added to DMF (15 mL), purged with nitrogen gas, and the reaction mixture was allowed to react at room temperature for 16 hours with stirring. The mixture was then quenched with H2O (30 mL), extracted with EA (30 mL), washed with saturated NaCl solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA = 50 / 50) to obtain yellow solid I-114j (280 mg, yield 72.26%). MS Calcd.: 607.1; MS Found: 608.0 (M+1).

[0215] Step 8 Compound I-114j (280 mg, 0.46 mmol) was added to a mixed solution of EA (10 mL) and dioxane / HCl (4 M) (10 mL) and reacted with stirring at 25°C for 8 hours. LC-MS confirmed that the starting materials had reacted completely. After cooling the reaction mixture, it was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography to obtain I-114 (130 mg, yield 55.58%). 1H NMR (400 MHz, DMSO-d6): δ 8.85 (s, 1 H), 8.34 (s, 1 H), 8.23 ​​(s, 1 H), 7.46 (s, 3 H), 7.33-7.26 m, 2 H), 5.53-5.50 (m, 1 H), 4.36 (s, 3 MS Calcd.: 507.1; MS Found: 508.1 (M+1).

[0216] Example I-112 [ka]

[0217] Step 1 Compound I-112a (1.0 g, 4.46 mmol), cyclopropylamine (0.28 g, 4.91 mmol), and potassium carbonate (1.23 g, 8.92 mmol) were added to DMF (20 mL). The reaction mixture was stirred at 80°C for 18 hours under nitrogen gas protection, and LC-MS confirmed that the starting materials had reacted completely. After cooling the reaction mixture, it was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM / MeOH / NH3.H2O=10 / 1 / 0.1%) to obtain a yellow oily substance I-112b (0.4 g, yield 44.8%). 1 H NMR (400 MHz, DMSO_d6): δ 6.50 (brs, 1H), 2.83-2.78 (m, 2H), 2.42-2.39 (m, 2H), 1.88-1.85 (m, 2H), 1.11 (s, 9H), 0.17-0.13 (m, 2H), 0.01-(-0.03) (m, 2H).

[0218] Step 2 Compound I-112b (400 mg, 1.99 mmol), compound I-114b (557.29 mg, 1.99 mmol), and potassium carbonate (549.24 mg, 3.98 mmol) were added to DMF (15 mL). The reaction mixture was stirred at 20°C for 4 hours under nitrogen gas protection. TLC confirmed that the starting materials had reacted completely. Water was added to the reaction to quench the mixture, and the reaction was extracted with EA (30 mL x 3). The organic phase was washed with saturated NaCl solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 4:1) to obtain a yellow oily substance I-112c (280 mg, yield 35.17%). MS Calcd.: 398.17; MS Found: 399.5 (M+1).

[0219] Step 3 Compound I-112c (280 mg, 0.70 mmol) was added to a mixed solution of dioxane (10 mL) and dioxane / HCl (4 M) (10 mL), and the reaction was carried out at room temperature for 4 hours with stirring. LC-MS confirmed that the starting materials had reacted completely. After cooling the reaction mixture, it was concentrated under reduced pressure to obtain a grayish-white solid I-112d (260 mg, crude product). MS Calcd.: 280.1; MS Found: 281.0 (M+1).

[0220] Step 4 Compound I-112d (322 mg, 1.15 mmol) was added to MeOH (20 mL), and then NaBH4 (130.4 mg, 3.45 mmol) was added in an ice bath. The reaction mixture was allowed to proceed at 20°C for 2 hours with stirring. LC-MS showed that the starting materials had reacted completely. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with water and DCM. The organic phase was washed with saturated NaCl solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound I-112e (180 mg, yield 55.5%), a yellow solid. MS Calcd.: 282.1; MS Found: 283.0 (M+1)

[0221] Step 5 Compounds I-112e (160 mg, 0.57 mmol), I-112f (251.35 mg, 0.57 mmol), TCFH (190.85 mg, 0.68 mmol), and NMI (160.19 mg, 1.42 mmol) were added to DMF (10 mL), purged with nitrogen gas, and the reaction mixture was allowed to react at room temperature for 4 hours with stirring. The mixture was quenched with H2O (30 mL), extracted with EA (10 mL x 3), washed with saturated NaCl solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (DCM / MeOH = 50 / 1) to obtain yellow solid I-112 g (350 mg, yield 87.25%). MS Calcd.: 707.2; MS Found: 708.0 (M+1)

[0222] Step 6 Compound I-112 g (300 mg, 0.42 mmol) was added to a mixed solution of dioxane (10 mL) and dioxane / HCl (4 M) (10 mL), and the reaction was carried out at 30°C for 5 hours with stirring. LC-MS showed that the starting materials had reacted completely. After cooling the reaction mixture, it was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography-mass spectrometry to obtain I-112 (65 mg, yield 30.2%). 1 H NMR (400 MHz, DMSO_d6): δ 8.85 (s, 1 H), 8.39 (s, 1 H), 8.35 (s, 1 H), 7.48-7.36 (m, 3 H), 7.21-7.20 (m, 2 H), 5.83 (brs, 1 H), 4.48 (brs, 3 H), 3.48-3.34 (m, 2 H), 2.82-2.77 (m, 2 H), 2.74-2.67 (m, 1 H), 2.40-2.33 (m, 1 H), 1.71-1.66 (m, 1 H), 0.49-0.44 (m, 2 H), 0.42-0.34 (m, 2 H). MS Calcd.: 507.18; MS Found: 508.1 (M+1).

[0223] Example I-113 [ka] Referring to the synthesis method of Example I-112, I-113 was synthesized by using I-113a instead of cyclopropylamine in step 1. 1 H NMR (400 MHz, DMSO-d6): δ 8.85 (s, 1 H), 8.36 (d, J=10.8 Hz, 2 H), 7.48-7.15 (m, 5 H), 5.81-5.84 (m, 1 H), 4.44 (brs, 3 H), 3.86-3.39 (m, 2 H), 3.11-2.59 (m, 4 H), 1.23-0.98 (m, 3 H), 0.46-0.33 (m, 4 H). MS Calcd.: 521.2; MS Found: 522.1 (M+1).

[0224] Examples I-112(PEAK1) and I-112(PEAK2) [ka] I-112 was purified by preparative SFC (IG, Hex:EtOH:DEA=50:50:0.3, 25 mL / min, 254 nm) to obtain I-112 (PEAK1, Rt=19.53 min) and I-112 (PEAK2, Rt=25.859 min).

[0225] I-112 (PEAK 1): 1 H NMR (400 MHz, DMSO_d6): δ 8.85 (s, 1 H), 8.39 (s, 1 H), 8.35 (s, 1 H), 7.48-7.36 (m, 3 H), 7.21-7.20 (m, 2 H), 5.83 (brs, 1 H), 4.48 (brs, 3 H), 3.48-3.34 (m, 2 H), 2.82-2.77 (m, 2 H), 2.74-2.67 (m, 1 H), 2.40-2.33 (m, 1 H), 1.71-1.66 (m, 1 H), 0.49-0.44 (m, 2 H), 0.42-0.34 (m, 2 H). MS Calcd.: 507.18; MS Found: 508.1 (M+1). I-112 (PEAK 2): 1 H NMR (400 MHz, DMSO_d6): δ 8.85 (s, 1 H), 8.39 (s, 1 H), 8.35 (s, 1 H), 7.48-7.36 (m, 3 H), 7.21-7.20 (m, 2 H), 5.83 (brs, 1 H), 4.48 (brs, 3 H), 3.48-3.34 (m, 2 H), 2.82-2.77 (m, 2 H), 2.74-2.67 (m, 1 H), 2.40-2.33 (m, 1 H), 1.71-1.66 (m, 1 H), 0.49-0.44 (m, 2 H), 0.42-0.34 (m, 2 H). MS Calcd.: 507.18; MS Found: 508.1 (M+1).

[0226] Examples I-113(PEAK1) and I-113(PEAK2) [ka] I-113 was purified by preparative SFC (IE, Hex:IPA:DEA=40:60:0.3, 25 mL / min, 254 nm) to obtain I-113 (PEAK 1, Rt=16.56 min) and I-113 (PEAK 2, Rt=26.21 min).

[0227] I-113 (PEAK 1): 1 H NMR (400 MHz, DMSO-d6): δ 8.85 (s, 1 H), 8.36 (d, J=10.8 Hz, 2 H), 7.48-7.15 (m, 5 H), 5.81-5.84 (m, 1 H), 4.44 (brs, 3 H), 3.86-3.39 (m, 2 H), 3.11-2.59 (m, 4 H), 1.23-0.98 (m, 3 H), 0.46-0.33 (m, 4 H). MS Calcd.: 521.2; MS Found: 522.1 (M+1). I-113 (PEAK 2): 1H NMR (400 MHz, DMSO-d6): δ 8.85 (s, 1 H), 8.36 (d, J=10.8 Hz, 2 H), 7.48-7.15 (m, 5 H), 5.81-5.84 (m, 1 H), 4.44 (brs, 3 H), 3.86-3.39 (m, 2 H), 3.11-2.59 (m, 4 H), 1.23-0.98 (m, 3 H), 0.46-0.33 (m, 4 H). MS Calcd.: 521.2; MS Found: 522.1 (M+1).

[0228] Biological Tests Experimental Example 1. Compound Activity Test After preparing the compounds in a 10 mM mother liquor with DMSO, nine concentration gradients (initial concentration 10 μM, diluted 1:5) were prepared using a buffer (50 mM Tris-HCl pH 8.5, 5 mM MgCl2, 4 mM DTT, 0.01% Triton X-100, 0.1 M NaCl, 0.5% DMSO). 5 μL of each gradient was added to each well. SAM, polypeptide, and MTA were prepared in buffer with final concentrations of 1 μM, 1 μM, and 2 μM, respectively. A total of 5 μL of each was added to each well, while an MTA-free control group was simultaneously prepared. The final concentration of PRMT5 protein was 25 nM, and 5 μL was added to each well. The mixture was incubated at 37°C for 2 hours. Subsequently, 2.5 μL of stop buffer A, 2.5 μL of 8X MT detection mixture (final concentration 1X), and a mixture of 24 μg / mL AMP2 / GMP2 antibody (final concentration 3 μg / mL) were added, and the mixtures were incubated at room temperature for 1.5 hours. FP (Ex 633, Em 647) was detected. Simultaneously, a negative control well (Blank) without protein and a positive control well (DMSO) without compound were prepared. Each experiment consisted of three independent replicates.

[0229] Data Processing: The values ​​for each group were statistically analyzed, and the inhibition rate was calculated according to the formula: Inhibition Percentage (%inh) in the compound well = [1 - (ave Blank - Cpd well) / (ave Blank - ave DMSO control)] × 100. Note: ave represents the mean value, and Cpd represents the value in the compound-doped well. Using GraphPad Prism 7.0 software, an S-type dose-inhibition curve was plotted using a nonlinear regression model, and IC was calculated. 50 The values ​​were fitted and calculated, and the results are shown in Table 1.

[0230] [Table 2]

[0231] Experimental Example 2. Compound Activity Test at the Cellular Level Growth inhibition Using CCK8, the compounds in this application are human colon cancer cell lines HCT-116 and HCT-116-MTAP. - / - Antiproliferative activity against (MTAP-deficient) and human lung adenocarcinoma cells A549 was evaluated. Normal-growing cells were taken, digested with pancreatin cell digestate, centrifuged, counted, and seeded at a suitable cell density in a 96-well plate (2000 cells / well), with 100 μL of compound in each well. The drug was administered the day after cell seeding, with different concentrations of the compound added to each well. Three parallel wells were set up at each concentration point, and a corresponding DMSO-negative controlled group was also established. Eight days after drug treatment, CCK8 solution was added to each well and incubated at 37°C for a set period (until the OD450 of the solvent group reached 1.0 or higher). The absorption at 450 nm was read using a plate reader, and the inhibition rate was calculated. 50 The values ​​were obtained by fitting using GraphPad Prism 7.0 software.

[0232] [Table 3]

[0233] SDMA inhibition detection HCT-116 and HCT-116-MTAP during their logarithmic growth phase. - / - A549 cells were taken, digested with pancreatin cell digestate, centrifuged, counted, and seeded at a suitable cell density in a 96-well plate (2000 cells / well), with 100 μL of medium in each well, and the wells were sealed with an appropriate amount of PBS. The following day, the cells were treated with compounds at different concentrations (initial concentration 10 μM, diluted 5-fold to create a 9-concentration gradient), and after 96 hours, the medium was aspirated and washed twice with 100 μL of PBS. Subsequently, the cells were fixed with 4% paraformaldehyde and incubated at room temperature for 20 minutes. The fixative was discarded and the cells were washed with PBS. 150 μL of a special blocking solution (containing 1% Triton-100) was added to each well, and the cells were blocked at room temperature for 2 hours, after which excess blocking solution was washed away with PBS. Anti-SDMA (CST) was diluted at a ratio of 1:2000 with a blocking solution containing 0.033% Triton-100, and a blank control group was established. The mixture was incubated overnight at 4°C. The following day, each group was washed twice with 1X PBST, and Anti-rabbit-IgG (H+L) (CST) and DRAQ5 (Thermofisher) were diluted in appropriate ratios (secondary antibody: 1:2000, DRAQ5: 1:10000) with 0.033% Triton-100 blocking solution. The mixture was incubated at room temperature for 2 hours. After washing twice with 1X PBST and once with PBS, fluorescence signals at 700 nm and 800 nm were detected using a Li-COR Odyssey two-color near-infrared laser imager. The inhibition rate was calculated, and the EC (Emission Control Value) was calculated. 50 The values ​​were obtained by fitting using GraphPad Prism 7.0 software.

[0234] [Table 4]

[0235] Experimental Example 3. Pharmacokinetic Studies of Compounds Pharmacokinetic studies in mice Eighteen male Balb / c mice aged 6-8 weeks were randomly divided into two groups (Group IV and Group PO). Animals in Group IV were administered 2 mg / kg of the corresponding compound via the tail vein, while animals in Group PO were administered 10 mg / kg or 100 mg / kg of the corresponding compound via intragastric administration. Animals in Group IV were allowed free feeding and watering, while animals in Group PO were fasted overnight before administration, fed 4 hours after administration, and allowed free watering throughout the entire study period. Plasma samples were collected at 0.083 (Group IV only), 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. Approximately 100 μL of blood was collected from the animal's orbit into a 1.5 mL anticoagulant centrifuge tube, centrifuged at 8000 rpm at 4°C for 10 minutes, and the upper layer plasma sample was pipetteed into an EP tube. Plasma samples were stored in a -80°C refrigerator until sample analysis. From drug concentration-time data, pharmacokinetic parameters including peak concentration Cmax, time to peak Tmax, clearance CL, steady-state apparent volume of distribution Vss, area under the drug-time curve AUC, efflux half-life t1 / 2, and bioavailability were calculated. Data below the 80% lower limit of quantification were not included in the calculation of pharmacokinetic parameters. [Table 5]

[0236] [Table 6]

[0237] Control compound A and control compound B were obtained by manufacturing according to the method described in patent application WO 2022132914 A1.

[0238] Pharmacokinetic studies in rats In this experiment, the pharmacokinetic behavior of compounds in SD rats after administration by intravenous injection (IV) and intragastric administration (PO) was investigated.

[0239] On the day of administration, the actual body weight of the rats was weighed, and the administration volume was calculated. Three rats were used in each group, and two groups were tested for each compound: one group received a single intravenous injection, and the other group received a single intragastric injection. Whole blood samples were collected using the jugular vein sampling method at predetermined times (0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration). Immediately after blood sample collection, the samples were transferred to commercially available sample tubes tagged with K2-EDTA (0.85-1.15 mg), and then centrifuged (3200 × g, 4°C, 10 minutes) to obtain plasma. The plasma was transferred to a pre-cooled centrifuge tube, rapidly frozen with dry ice, and then stored in an ultra-low temperature refrigerator at -60°C or below until LC-MS / MS analysis was performed.

[0240] Plasma concentrations were measured by LC-MS / MS. Plasma drug concentration data for compounds were processed using a non-compartmental model with WinNonlin Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software. Relevant pharmacokinetic parameters were calculated using a linear log-trapezoidal model. [Table 7]

[0241] [Table 8]

[0242] Experimental Example 4. Pharmacodynamic Study of Compounds Human colon cancer HCT-116-MTAP - / - Cells were cultured in vitro in a monolayer medium using McCoy 5A medium (HyClone) containing 10% fetal bovine serum (BI) and 1% penicillin streptomycin (Biyuntian), and incubated at 37°C in a 5% CO2 incubator. They were subcultured with pancreatin 2-3 times per week. When cell saturation reached 80%-90%, cells were collected, counted, and inoculated. 5 × 10⁶ 6 HCT-116-MTAP (0.1 mL) - / -Cells were subcutaneously inoculated into the right posterior dorsal region of each mouse. Approximately 15 days after cell inoculation, the average tumor volume was 172 mm². 3 The animals were randomly divided into groups and administered the drug (each group consisted of 6 animals, divided into a treatment group and a control group). The day of group division was designated as day d0, and administration began on day 1 via intragastric injection. The drug was administered once daily at a dose of 10 mL / kg, with the control group receiving a solvent control. Tumor volume was measured 2-3 times per week, weighed simultaneously, and the data was recorded. Surface signs of the mice were observed and recorded daily. After the experiment, the tumors were removed, weighed, photographed, and recorded.

[0243] Tumor volume calculation formula: Tumor volume (mm 3 ) = 1 / 2 × (a × b 2 (Note: a represents the major axis, and b represents the minor axis.) Relative tumor inhibition rate (TGI%) = (1 - tumor weight in the treatment group / tumor weight in the control group) × 100% [Table 9]

[0244] Human non-small cell lung cancer (NCI-H838) cells were cultured in a monolayer in vitro using McCoy 5A medium (HyClone) containing 10% fetal bovine serum (BI) and 1% penicillin streptomycin (Biyuntian), in an incubator at 37°C and 5% CO2. The cells were subcultured with pancreatin 2-3 times per week. When cell saturation reached 80%-90%, cells were collected, counted, and inoculated. (5 × 10⁶ cells) 6 NCI-H838 cells (0.1 mL) were subcutaneously inoculated into the right posterior dorsal region of each mouse. Approximately 29 days after cell inoculation, the average tumor volume was 156 mm². 3 The animals were randomly divided into groups and administered the drug (each group consisted of 6 animals, divided into a treatment group and a control group). The day of group division was designated as day d0, and administration began on day 1 via intragastric injection. The drug was administered once daily at a dose of 10 mL / kg, with the control group receiving a solvent control. Tumor volume was measured 2-3 times per week, weighed simultaneously, and the data was recorded. Surface signs of the mice were observed and recorded daily. After the experiment, the tumors were removed, weighed, photographed, and recorded.

[0245] Tumor volume calculation formula: Tumor volume (mm 3 ) = 1 / 2 × (a × b 2 (Note: a represents the major axis, and b represents the minor axis.) Relative tumor inhibition rate (TGI%) = (1 - tumor weight in the treatment group / tumor weight in the control group) × 100% [Table 10]

[0246] Experimental Example 5. Effect of compounds on hERG potassium ion channels HEK293 cells were cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg / mL of G418 at a culture temperature of 37°C and a CO2 concentration of 5%. TM After digestion with Express, the cell density was reduced to 2 × 10⁻⁶. 6 After adjusting to cells / mL, the cells were gently mixed for 15-20 minutes in a room temperature equilibrium shaker, then placed on the instrument for patch clamp detection. The culture medium of the prepared cells was replaced with extracellular fluid. Intracellular and extracellular fluids were aspirated from the liquid pool and added to the intracellular fluid pool, cell pool, and test material pool on the QPlate tip, respectively. The voltage stimulation of the hERG potassium current of all cells was recorded using whole-cell patch clamp, and the test data was collected and stored using Qpatch. The compound was diluted 3-fold from 30 μM, establishing 6 concentration points, and two doses were set for each drug concentration, with a time of at least 5 minutes. The current of each cell detected in the compound-free extracellular fluid was used as the self-control group, and detection was repeated twice independently using at least two cells for each concentration. All electrophysiological tests were performed at room temperature.

[0247] In the data analysis, first, the current after action and the blank control current at each drug concentration were standardized.

number

number

[0248] The mean value and standard error were calculated for each concentration, and the half-inhibitory concentration of each compound was also calculated.

[0249]

number

[0250] Experimental Example 6. Study on the inhibitory effect of compounds on human liver microsomal CYP450 enzymes. 1) Preparation of buffer solution: Stock solution A (9.5 mL) of 100 mM K-Buffer was mixed with stock solution B (40.5 mL), the total volume was adjusted to 500 mL with ultrapure water, and the buffer solution was titrated to pH 7.4 with KOH or H3PO4. Raw material A (1M potassium dihydrogen phosphate): 136.5g potassium dihydrogen phosphate in 1L of water, Stock solution B (1M potassium dihydrogen phosphate): 174.2g of potassium dihydrogen phosphate in 1L of water. 2) Preparation of the test substance The test substance powder was prepared into a stock solution of a certain concentration using DMSO or another organic solvent, and then further diluted with a suitable organic solvent. 3) In vitro incubation The in vitro incubation system for liver microsomes used in CYP450 enzyme metabolic phenotyping studies involves adding redox coenzymes to manufactured liver microsomes, followed by enzyme-specific selective inhibitors, and performing biochemical reactions under conditions that simulate physiological temperature and environment. 4) Detection of prototype drugs or metabolites LC-MS / MS is used to measure the concentration of the prototype drug or its metabolites in the incubation liquid, and IC 50 The value was calculated. [Table 12]

[0251] Experimental Example 7. Brain / blood drug concentration ratio and tumor tissue / blood drug concentration ratio in mice. Human lung cancer PC-9 cells were cultured in a monolayer in vitro using 1640 medium (HyClone) containing 10% fetal bovine serum (BI) and 1% penicillin streptomycin (Biyuntian), in an incubator at 37°C and 5% CO2. The cells were subcultured with pancreatin 2-3 times per week. When cell saturation reached 80%-90%, cells were collected, counted, and inoculated. 5 × 10⁶ cells were used. 6 PC-9 cells (0.2 mL, 1:1 gel addition) were subcutaneously inoculated into the right posterior dorsal subcutaneous tissue of Balb / c-nude female mice, and the average tumor volume was 500 mm². 3Once sufficient conditions were met, the mice were used in subsequent PK and tissue distribution experiments. On the day of administration, the actual body weight of the mice was weighed, and the administration volume was calculated. Nine mice were administered the compound as a single intravenous injection or intragastric administration. Whole blood samples were collected at predetermined times using the orbital blood collection method. Immediately after blood sample collection, the samples were transferred to commercially available sample tubes tagged with K2-EDTA (0.85-1.15 mg), and then centrifuged (3200 × g, 4°C, 10 minutes) to obtain plasma. The plasma was transferred to a pre-cooled centrifuge tube, rapidly frozen with dry ice, and then stored in an ultra-low temperature refrigerator below -60°C until LC-MS / MS analysis was performed. After euthanizing the animals with CO2 at predetermined times, tumor and brain tissues were collected, rapidly frozen with liquid nitrogen, and then stored in an ultra-low temperature refrigerator below -60°C until LC-MS / MS analysis was performed. 20 μL of plasma sample or brain / tumor tissue homogenate was taken and added to 80 μL of internal standard solution (50 ng / mL propafenone acetonitrile solution). The plate was sealed at 165°C using a film sealing device, shaken for 10 mins with a microoscillator (maximum vibration speed), and centrifuged at 4000 rpm for 20 mins using a low-speed benchtop centrifuge. 10 μL of the supernatant was pipetteed and added to 90 μL of acetonitrile, and after homogeneous mixing by vortexing, the plate was sealed at 165°C using a film sealing device, and after homogeneous mixing by vortexing, 1 μL of the supernatant was taken and performed LC-MS / MS analysis.

[0252] Data processing: At the same time point, the ratio of drug concentration in mouse brain / blood = drug concentration in brain tissue / drug concentration in plasma. At the same time point, the ratio of drug concentration in tumor tissue / blood drug concentration in mice = drug concentration in tumor tissue / drug concentration in plasma. The experimental results obtained are shown in the table below: [Table 13]

[0253] As is clear from the results in the table above, the compound of this application has very high drug distribution in the brain and in tumor tissue, and can be applied to the prevention and treatment of brain tumors.

[0254] In addition to those described herein, various modifications of the present invention based on the foregoing will be obvious to those skilled in the art. Such modifications are also intended to be included within the scope of the appended claims. Every reference cited herein (including all patents, patent applications, journal articles, books and any other disclosures) is incorporated herein by reference as a whole.

Claims

1. Equation (I): 【Chemistry 1】 (I) [In the formula, Ring A is C ３～１０ Hydrocarbon ring, 3-10 membered heterocycle, C ６～１０ It is an aromatic ring or a 5-14 membered heteroaromatic ring. Ring B is a benzene ring, X is CR Ｘ or N, Y is CR Ｙ or N, Z is CR Ｚ or N, R Ｘ 、R Ｙ 、R Ｚ 、R １ 、R ２ 、R ３ 、R ４ 、R ５ and R ６ each independently represents H, halogen, -OH, -NH ２ , -CN, -NO ２ , C １～６ alkyl group, deuterated C １～６ alkyl group, C ２～６ alkenyl group, C ２～６ alkynyl group, C ３～６ cyclic hydrocarbon group, 3- to 10-membered heterocyclyl group, C ６～１０ aryl group, 5- to 14-membered heteroaryl group, C ６～１２ aralkyl group, -C(=O)R ａ , -OC(=O)R ａ , -C(=O)OR ａ , -OR ａ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ａ R ｂ , -NR ａ R ｂ , -C(=O)NR ａ R ｂ , -NR ａ -C(=O)R ｂ , -NR ａ -C(=O)OR ｂ , -NR ａ -S(=O) ２ -R ｂ , -NR ａ -C(=O)-NR ａ R ｂ , -C １～６ alkylene-OR ａ , -C １～６ alkylene-NR ａ R ｂ and -O-C １～６ alkylene-NR ａ R ｂ is selected from, Or, R １ and R ２ They can optionally be linked together with the base C ３～１０ Hydrocarbon ring, 3-10 membered heterocycle, C ６～１０ Constituting an aromatic ring or a 5-14 membered heteroaromatic ring, and / or R ３ and R ４ These, together with the groups to which they are linked, optionally form a 3- to 10-membered complex ring. R ａ and R ｂ Each time they appear, H and C appear independently. １～６ alkyl group, C ３～１０ Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, C ６～１０ Aryl group, 5-14 membered heteroaryl group and C ６～１２ Selected from aralkyl groups, The alkyl group, alkylene group, alkenyl group, alkynyl group, cyclic hydrocarbon group, hydrocarbon ring, heterosilyl group, heterocyclic ring, aryl group, aromatic ring, heteroaryl group, heteroaromatic ring, and aralkyl group, each time they appear, are each optionally halogen, -OH, =O, -NH ２ , -CN, -NO ２ , C １～６ alkyl group, C ３～６ cyclic hydrocarbon group, 3- to 10-membered heterosilyl group, C ６～１０ aryl group, 5- to 14-membered heteroaryl group, C ６～１２ aralkyl group, -C(=O)R ｃ , -OC(=O)R ｃ , -C(=O)OR ｃ , -OR ｃ , -SR ｃ , -S(=O)R ｃ , -S(=O) ２ R ｃ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -C(=O)NR ｃ R ｄ , -NR ｃ -C(=O)R ｄ , -NR ｃ -C(=O)OR ｄ , -NR ｃ -S(=O) ２ -R ｄ , -NR ｃ , -NR-C(=O)-NR ｃ R ｄ , -C １～６ alkylene-OR ｃ , -C １～６ alkylene-NR ｃ R ｄ and -O-C １～６ alkylene-NR ｃ R ｄ and are substituted with one or more substituents independently selected from, and the alkyl group, cyclic hydrocarbon group, heterosilyl group, aryl group, heteroaryl group, and aralkyl group are further optionally halogen, -OH, =O, -C(=O)O-tert-butyl group, -NH ２ , -CN, -NO ２ , C １～６ alkyl group, C １～６ Haloalkyl group, C ３～６ Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, C ６～１０ Aryl group, 5-14 membered heteroaryl group, C ６～１２ Aralkyl group, -O-C １～６ Alkyl and -C １～６ Alkylene-OC １～６ Substituted with one or more substituents independently selected from the alkyl group, R ｃ and R ｄ Each time they appear, H and C appear independently. １～６ alkyl group, C ３～１０ Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, C ６～１０ Aryl group, 5-14 membered heteroaryl group and C ６～１２ Selected from aralkyl groups, the alkyl group, cyclic hydrocarbon group, heterocyclyl group, aryl group, heteroaryl group and aralkyl group may be further optionally halogen, -OH, =O, -C(=O)O-tert-butyl group, -NH ２ -CN, -NO ２ , C １～６ alkyl group, C １～６ Haloalkyl group, C ３～６ Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, C ６～１０ Aryl group, 5-14 membered heteroaryl group, C ６～１２ Aralkyl group and -C １～６ Alkylene-OC １～６ Substituted with one or more substituents independently selected from the alkyl group, and m and n are each an independent integer of 1, 2, 3, or 4, preferably an integer of 1, 2, or 3. Compounds having the structure of the same, or pharmaceutically acceptable salts, esters, stereoisomers, atropisomers, tautomers, crystalline polymorphs, solvates, metabolites, isotope-labeled compounds, or prodrugs thereof.

2. R Ｘ , R Ｙ and R Ｚ However, each is independently H, halogen, -CN, and C. １～６ Alkyl, halo C １～６ Alkyl and -O-(C １～６ Selected from alkyl groups, Preferably, R Ｘ , R Ｙ and R Ｚ However, each is independently selected from H, F, Cl, -CN, methyl group, trifluoromethyl group, and methoxy group. The compound described in claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof.

3. X is CH or C-CH ３ And, Y is CR Ｙ Or N, where R Ｙ H, halogen, -CN, C １～６ Alkyl, halo C １～６ Alkyl and -O-(C １～６ Selected from alkyl groups, preferably selected from H, F, Cl, -CN, methyl group, trifluoromethyl group and methoxy group, and Z is CH or N. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof.

4. R １ and R ２ However, each is independently H, halogen, and C １～６ Alkyl and deuterated C １～６ Selected from alkyl groups, Preferably, R １ and R ２ However, each is independently H, Cl, Br, I, methyl group, and -CD. ３ and selected from the ethyl group, Or, R １ and R ２ However, along with the bases that connect them, C can be optionally selected. ５～６ It constitutes a hydrocarbon ring, a 5-6 membered heterocycle, or a 5-6 membered heteroaromatic ring, preferably R １ and R ２ They are optionally linked together with the base to which they connect. 【Chemistry 2】 Constitutes, A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof. 【Request Item 5】 【Chemistry 3】 【Chemistry 4】 Selected from, A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof.

6. Ring A is a 5-6 membered heterocycle or a 5-6 membered heteroaromatic ring, preferably ring A is an oxygen-containing 5-membered heterocycle (for example, a 5-membered heterocycle containing one or two oxygen atoms), preferably ring A 【Transformation 5】 And, Preferably, 【Transformation 6】 but 【Transformation 7】 That is, A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof.

7. R ３ and R ４ However, H and C are independent of each other. １～６ alkyl group, C ３～６ Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, -C １～６ Alkylene-OH and -C １～６ Alkylene-OC １～６ Selected from alkyl groups, the alkylene group, alkyl group, cyclic hydrocarbon group and heterocyclyl group are optionally further C ３～６ Substituted with a cyclic hydrocarbon group, a 3-10 membered heterocyclyl group, or a 5-6 membered heteroaryl group, wherein the cyclic hydrocarbon group, heterocyclyl group, or heteroaryl group may be further optionally accompanied by one or more C11s. １～６ Substituted with an alkyl group, Preferably, R ３ and R ４ However, each is independently H, methyl group, ethyl group, isopropyl group, cyclopropyl group, 【Transformation 8】 Selected from, Or, R ３ and R ４ However, along with the base that connects them, optionally, 【Chemistry 9】 The base selected from A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof. 【Request Item 8】 【Chemistry 10】 but, 【Chemistry 11】 【Chemistry 12】 Selected from, A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof.

9. The above compound has the following structure 【Chemistry 13】 [In the formula, Ring C is C ５～６ Selected from hydrocarbon rings, 5-6 membered heterocycles, and 5-6 membered heteroaromatic rings, Ring D is a 3- to 10-membered heterocyclic ring. R ７ and R ８ Each time they appear, H and C appear independently. １～６ Alkyl and C ３～６ Selected from cyclic hydrocarbon groups, p and q are each independently integers of 1 or 2, and Each of the remaining groups is as defined in any one of claims 1 to 8. Having, A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof.

10. The aforementioned compound, 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 Selected from, A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof, in an effective amount for prevention or treatment, and a pharmaceutically acceptable carrier.

12. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, or the pharmaceutical composition according to claim 11, wherein the drug is used to prevent or treat cancer (preferably MTAP-deficient cancers, such as pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck cancer, head and neck squamous cell carcinoma, lymphoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, skin cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma).

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