Aminopyridine compound, preparation method therefor, pharmaceutical composition comprising same, and use thereof

Abstract

Provided in the present invention are an aminopyridine compound, a preparation method therefor, a pharmaceutical composition comprising same, and the use thereof. Specifically, the compound has the structure as shown in formula (I), can synergistically inhibit PRMT5 with MTA, and can be used for preparing a drug for treating MTAP- / --related cancers.

Description

An aminopyridine compound, its preparation method, pharmaceutical composition containing the same and its application Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and more specifically, to an aminopyridine compound that can be used as a PRMT5 inhibitor synergistic with MTA for the treatment of MTAP. - / - Cancer-related drugs. Background Art

[0002] Protein arginine N-methyltransferases (PRMTs) are classified into type I, type II, and type III based on the type of methylarginine produced. Type I primarily catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to the ω-amino nitrogen of the guanidine group of L-arginine in proteins, generating monomethylarginine (MMA) and a second methyl group to the same ω-amino nitrogen of the guanidine group, generating asymmetric dimethylarginine (aDMA). Type II primarily catalyzes the production of MMA and the transfer of a second methyl group to a different ω-amino nitrogen, generating symmetric dimethylarginine (sDMA). Type III exclusively catalyzes the production of MMA. PRMT5, a type II protein arginine methyltransferase, plays an important role in regulating cellular processes, including DNA repair, cell cycle progression, transcriptional regulation, and RNA splicing. Upregulation of PRMT5 can lead to a variety of cancers, including liver cancer, breast cancer, skin cancer, pancreatic cancer, head and neck cancer, colorectal cancer, lung cancer, gastric cancer, esophageal cancer, kidney cancer, bladder cancer, urethral cancer, prostate cancer, testicular cancer, uterine cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, bile duct cancer, multiple myeloma, spinal neurofibromas, astrocytomas, gliomas, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, and sarcoma.

[0003] Methylthioadenosine phosphorylase (MTAP) is located near the p16 / CDKN2a gene and is co-deleted with p16 / CDKN2a in approximately 15% of human cancers. This co-deletion leads to poor prognosis in malignant tumors and a lack of effective molecularly targeted therapies. MTAP is a methylthioadenosine (MTA) metabolizing enzyme, catalyzing the conversion of MTA to adenosine and 5-methylthioribose-1-phosphate. In tumor cells, MTAP deficiency leads to the accumulation of MTA. Due to its structural similarity to SAM, MTA can competitively inhibit PRMT5, forming a PRMT5-MTA complex. Small molecule inhibitors designed based on this complex can selectively kill tumor cells with minimal effects on normal cells, thereby improving drug safety.

[0004] "We believe that in MTAP-deficient cancers, MTA-synergistic inhibition of PRMT5 activity will provide therapeutic benefits across a wide range of cancers. The current lack of effective molecularly targeted therapies necessitates the development of novel MTA-synergistic PRMT5 inhibitors that can inhibit PRMT5 activity in the presence of elevated MTA concentrations for the treatment of MTAP-deficient cancers."

[0005] Summary of the Invention

[0006] The purpose of the present invention is to provide a more efficient and druggable MTA-synergistic PRMT5 inhibitor.

[0007] In a first aspect, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form, or combination thereof.

[0008] in,

[0009] R 1 、R 2 Each is independently hydrogen, halogen, cyano, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, 3-6 membered cycloalkyl, 3-6 membered halocycloalkyl, 3-6 membered heterocyclyl, C1-C3 alkoxy, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, C1-C6 alkyl- S-, -S(O)2-C1-C6 alkyl, -S(O)-C1-C6 alkyl, -S(O)2NH2, -S(O)2NH(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -C(O)H, -C(O)-C1-C6 alkyl, -C(O)-3-6 cycloalkyl, -C(O)-3-6 membered heterocyclyl, -C(O)O-C1-C6 alkyl, -CONR 1a R 1b (where R 1a and R 1b is H, D, C1-C3 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl), -SF5, -P(O)(C1-C3 alkyl)2; wherein the alkyl, cycloalkyl and heterocyclyl may be optionally further substituted by one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, C1-C3 alkyl;

[0010] Ring A is an optionally substituted 5-7 membered heterocyclic group, an optionally substituted benzene ring or an optionally substituted 5-7 membered heteroaromatic ring; the substitution refers to the substitution of one or more R A Replace; each R Aindependently selected from hydrogen, deuterium, C1-C4 alkyl, halogenated C1-C4 alkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, oxo, halogen, C1-C4 alkoxy, hydroxyl and amino;

[0011] R 3 for

[0012] L 1 is absent, C1-C3 alkylene or C1-C3 haloalkylene;

[0013] n is the number of methylene groups, and n is selected from 0, 1, 2, 3, and 4;

[0014] R 4 is an optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, an optionally substituted C3-C12 carbocyclyl, an optionally substituted C3-C12 heterocyclyl, an optionally substituted 6-10 membered aromatic ring group or an optionally substituted 5-10 membered aromatic heterocyclyl; the substitution refers to substitution by one or more R;

[0015] R 5 is an optionally substituted C1-C6 alkyl, an optionally substituted C3-C12 carbocyclyl, an optionally substituted C3-C12 heterocyclyl, an optionally substituted 6-10 membered aromatic ring, an optionally substituted 5-10 membered heteroaromatic ring, -NR a R b 、-OR a or -SR a ; Each R a and R b Each is independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted C3-C6 heterocyclyl, optionally substituted 6-10 membered aromatic ring or optionally substituted 5-10 membered aromatic heterocycle; the substitution refers to substitution by one or more R;

[0016] Each R 6 Each is independently hydrogen, halogen, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl, C3-C4 halocycloalkyl, C1-C3 alkoxy, -NH2, -NH(C1-C3 alkyl) or -N(C1-C3 alkyl)2;

[0017] m is R 6 The number of m is selected from 0, 1, 2, 3, and 4;

[0018] R 7 、R 8 are each independently hydrogen, deuterium, C1-C3 alkyl, C1-C3 haloalkyl, 3-4 membered cycloalkyl or 3-4 membered halocycloalkyl; or R 7 、R 8Form a 3-5 membered carbocyclic ring with the carbon atom to which it is attached;

[0019] Each R is independently selected from: H, deuterium, halogen, cyano, amino, hydroxyl, nitro, oxo Thio (= S), -SF5, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, -OC2-C6 alkenyl, -O cycloalkyl, -O heterocyclyl, -O-aryl, -O-heteroaryl, -N(optionally substituted C1-C6 alkyl) 2, -NH(optionally substituted C1-C6 alkyl), -N(optionally substituted C1-C6 alkyl)(optionally substituted C1-C6 alkylphenyl), -NH(optionally substituted C1-C6 alkylphenyl), -N(C1-C6 alkyl)(aryl), -N(C1-C6 alkyl)(heteroaryl), -NH(aryl), -NH(heteroaryl), -P(O)(C1-C3 alkyl) 2, optionally substituted C1-C6 alkyl-S-, -S(O) 2-optionally substituted C1-C6 alkyl -C6 alkyl, -S(O)-optionally substituted C1-C6 alkyl, -S(O)2-optionally substituted phenyl, -S(O)2NH2, -S(O)2NH(optionally substituted C1-C6 alkyl), -S(O)2NH(optionally substituted phenyl), -NHS(O)2(optionally substituted C1-C6 alkyl), -NHS(O)2(optionally substituted phenyl), optionally substituted C3-C16 carbocyclyl, optionally substituted 4-16 membered heterocyclyl, optionally substituted C6-C16 aryl or optionally substituted 5-16 membered heteroaryl; or any two adjacent R and the atoms to which they are attached form an optionally substituted 4-8 membered heterocyclyl or an optionally substituted C3-C8 membered carbocyclyl; wherein the substitution in R refers to substitution by one or more groups selected from the group consisting of H, deuterium, halogen, cyano, amino, hydroxyl, nitro, oxo Thio (= S), -SF5, -P(O)(C1-C3 alkyl)2, R'-substituted or unsubstituted C1-C6 alkyl, R'-substituted or unsubstituted C1-C6 alkoxy, R'-substituted or unsubstituted C1-C6 alkylsulfone, R'-substituted or unsubstituted C3-C16 carbocyclyl, R'-substituted or unsubstituted 4-16 membered heterocyclyl, R'-substituted or unsubstituted C6-C16 aryl, R'-substituted or unsubstituted 5-16 membered heteroaryl, -NH(R'-substituted or unsubstituted C1-C6 alkyl), -N(R'-substituted or unsubstituted C1-C6 alkyl)2, -CH2-NH(R'-substituted or unsubstituted C1-C6 alkyl ) and -CH2-N(R' substituted or unsubstituted C1-C6 alkyl)2, wherein R' is selected from one or more groups of the following groups: H, halogen, deuterium (D), halogen, -OH, nitro, amino, oxo (=O), mercapto, cyano, -CD3, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and 4-8 membered heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl is optionally further substituted with one or more substituents selected from the following groups: H, deuterium, C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, oxo (=O), -N H2, -N(R" substituted or unsubstituted C1-C6 alkyl)2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkylphenyl), -NH(C1-C6 alkylphenyl), -N(C1-C6 alkyl)(aryl), -NH(aryl), C3-C8 cycloalkyl, 4-8 membered heterocyclic group, C1-C4 haloalkyl-, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, cyano, nitro, -C(O)-OH, -C(O)OC1-C6 alkyl, -CON(C1-C6 alkyl)2, -CONH(C1 -C6 alkyl), -CONH2, -NHC(O)(C1-C6 alkyl), -NH(C1-C6 alkyl)C(O)(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2(phenyl), -SO2(C1-C6 haloalkyl), -SO2NH2, -SO2NH(C1-C6 alkyl), -SO2NH(phenyl), -NHSO2(C1-C6 alkyl), -NHSO2(phenyl), -NHSO2(C1-C6 haloalkyl) or -C1-C6 alkyl-NH2, wherein R" is selected from one or more groups of the following groups: H, halogen, cyano, amino, hydroxyl, oxo C1-C6 alkyl and C1-C6 alkoxy;

[0020] Indicates the attachment position of the group.

[0021] In some embodiments,

[0022] Ring A is selected from the group consisting of an optionally substituted benzene ring, an optionally substituted pyridine, an optionally substituted thiophene, an optionally substituted pyrrole, an optionally substituted furan, an optionally substituted imidazole, an optionally substituted pyrazole, and an optionally substituted thiazole; preferably, Ring A is an optionally substituted pyrrole; the substitution refers to the substitution of one or more R A Replace; each R A Independently selected from hydrogen, deuterium, C1-C4 alkyl, halogenated C1-C4 alkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, oxo, halogen, C1-C4 alkoxy, hydroxyl and amino.

[0023] In some embodiments,

[0024] R 1 is hydrogen, halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, 3-4 membered cycloalkyl, -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2;

[0025] R 2 It is hydrogen, halogen, cyano, or C1-C3 alkyl.

[0026] In some embodiments,

[0027] L 1 is absent or methylene;

[0028] n is selected from 1 and 2;

[0029] R 4 is an optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, an optionally substituted C3-C8 carbocyclyl, an optionally substituted C3-C8 heterocyclyl, an optionally substituted benzene ring or an optionally substituted 5-7 membered aromatic heterocyclyl; the substitution refers to substitution by one or more R;

[0030] R 5 is an optionally substituted C1-C6 alkyl, an optionally substituted C3-C8 carbocyclyl, an optionally substituted C3-C8 heterocyclyl or -NR a R b ; Each R a and R b Each is independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted C3-C6 heterocyclyl, optionally substituted 6-10 membered aromatic ring or optionally substituted 5-10 membered aromatic heterocycle; the substitution refers to substitution by one or more R;

[0031] R is defined as in claim 1.

[0032] In some embodiments, the compound is selected from the group consisting of:

[0033] In a second aspect of the present invention, a pharmaceutical composition is provided, comprising:

[0034] (1) a therapeutically effective amount of one or more of the compound according to the first aspect of the present invention, or its pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, cis-trans isomers, solvates, polymorphs and deuterated forms as an active ingredient; and

[0035] (2) Optional pharmaceutically acceptable carrier.

[0036] In the third aspect of the present invention, there is provided a compound according to the first aspect of the present invention, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph or deuterated compound thereof, or a pharmaceutical composition according to the second aspect of the present invention for use in the preparation of a pharmaceutical composition for preventing or treating MTAP. - / - Use in medicine for treating related cancers.

[0037] In some embodiments, the cancer is selected from the group consisting of liver cancer, breast cancer, skin cancer, pancreatic cancer, head and neck cancer, intestinal cancer, lung cancer, stomach cancer, esophageal cancer, kidney cancer, bladder cancer, urethral cancer, prostate cancer, testicular cancer, uterine cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, bile duct cancer, multiple myeloma, spinal neurofibroma, astrocytoma, glioma, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, and sarcoma.

[0038] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0039] After extensive and in-depth research, the inventors unexpectedly developed an aminopyridine compound that can effectively inhibit PRMT5 synergistically with MTA, which can be used to prepare a drug for treating MTAP. - / - On this basis, the present invention was completed.

[0040] Terminology

[0041] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0042] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0043] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0044] Group Definition

[0045] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy and pharmacological methods, are used. Unless otherwise specified, the terms used herein in the descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceuticals and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for use of the kit can be utilized, or reactions and purifications can be carried out in accordance with methods well known in the art or the description of the present invention. The above techniques and methods can generally be implemented according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0046] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0047] The section headings used herein are for organizational purposes only and should not be construed as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety.

[0048] Certain chemical groups defined herein are preceded by a simplified notation to indicate the total number of carbon atoms present in the group. For example, a C1-C6 alkyl group refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the simplified notation does not include carbons that may be present in substituents of the group.

[0049] In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0050] In this application, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0051] "Hydroxy" refers to an -OH group.

[0052] "Hydroxyalkyl" refers to an alkyl group, as defined below, substituted with a hydroxy (-OH) group.

[0053] "Carbonyl" refers to a -C(=O)- group.

[0054] "Nitro" refers to -NO2.

[0055] "Cyano" refers to -CN.

[0056] "Amino" refers to -NH2.

[0057] "Substituted amino" refers to an amino group substituted with one or two alkyl groups, alkylcarbonyl groups, arylalkyl groups, heteroarylalkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkylamido, arylalkylamino, heteroarylalkylamino.

[0058] "Carboxyl" refers to -COOH.

[0059] In the present application, as a group or part of other groups (for example, as used in groups such as halogen-substituted alkyl), the term "alkyl" refers to a fully saturated straight or branched hydrocarbon chain radical consisting only of carbon atoms and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and connected to the rest of the molecule by one or more single bonds, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl. For the purposes of the present invention, the term "alkyl" preferably refers to an alkyl group containing 1 to 6 carbon atoms.

[0060] In this application, the term "alkenyl" as a group or part of another group means a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule by one or more single bonds, such as but not limited to ethenyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, etc.

[0061] As used herein, the term "alkynyl" as a group or as part of another group refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule by one or more single bonds, such as, but not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0062] In the present application, the term "carbocycle" as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon atoms and hydrogen atoms, which may include a fused ring system, a bridged ring system or a spirocyclic system, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms (i.e., C3-C6), and which is a saturated or unsaturated ring (i.e., cycloalkyl, cycloalkenyl, etc.) and may be connected to the rest of the molecule through one or more single bonds via any suitable carbon atom. Unless otherwise specified in this specification, the carbon atoms in the carbocycle group may be optionally oxidized. Examples of carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, 2,3-dihydroindanyl, octahydro-4,7-methylene-1H-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, 1H-indenyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocyclohepten-5, 5,6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl, 1,2,3,4-tetrahydro-naphthyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, 1H-indenyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocyclohepten-5, 1,2,3,4-tetrahydro-naphthyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, 1H-indenyl, 6,7,8,9,10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl and octahydro-2,5-methylene-pentalenyl, etc.

[0063] In the present application, the term "cycloalkyl" as a group or part of other groups refers to the above-mentioned fully saturated carbon ring (group), typical cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, etc.

[0064] In the present application, the term "cycloalkenyl" as a group or a part of other groups refers to a partially unsaturated carbon ring (group). Typical cycloalkenyl groups include but are not limited to cyclobutenyl, cyclopentenyl, cyclohexenyl, etc.

[0065] In the present application, the term "heterocyclic ring (base)" as a group or part of another group means a stable 3- to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. Unless otherwise specified in this specification, the heterocyclic group can be a monocyclic, bicyclic, tricyclic or more ring system, which can include a fused ring system, a bridged ring system or a spirocyclic system; the nitrogen, carbon or sulfur atoms in the heterocyclic group can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclic group can be partially or fully saturated. The heterocyclic group can be connected to the rest of the molecule via a carbon atom or a heteroatom and by one or more single bonds. In a heterocyclic group containing a fused ring, one or more rings can be an aryl or heteroaryl group as defined below, provided that the point of connection to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, the heterocyclic group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2-azabicyclo[2.2.2]octanyl, 2,7-diaza-spiro[3.5]nonan-7-yl, 2-oxa-6-aza-spiro[3.3]heptan-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxolane, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimido, and the like.

[0066] In this application, the term "aryl" as a group or part of another group means a conjugated hydrocarbon ring system radical having 6 to 18 carbon atoms (preferably having 6 to 10 carbon atoms, i.e., C6-C10 aryl). For the purposes of the present invention, an aryl group can be a monocyclic, bicyclic, tricyclic, or polycyclic ring system, and can also be fused to a carbocyclic or heterocyclic group as defined above, provided that the aryl group is connected to the rest of the molecule through one or more single bonds via atoms on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like.

[0067] In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted by an aryl group as defined above.

[0068] In this application, the term "heteroaryl" as a group or part of another group means a 5- to 16-membered conjugated ring system having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specified in this specification, the heteroaryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused to a carbocyclic or heterocyclic group as defined above, provided that the heteroaryl group is connected to the rest of the molecule through one or more single bonds via atoms in the heteroaromatic ring. The nitrogen, carbon or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atom may be optionally quaternized. For the purposes of the present invention, heteroaryl is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5- to 10-membered aromatic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolyl, isoquinolyl, naphthazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothiophenyl, oxatriol, oxazolyl, cinnolinyl, quinazolinyl, phenylthio, indolizinyl, o-phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridinyl, [1,2,4]triazolo[4,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine, etc.

[0069] As used herein, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above.

[0070] In this application, the term "absent" means that the two sides of the group defined above are directly connected by a chemical bond. For example, "ABC in which B is absent" means "AC".

[0071] In this application, in Indicates the attachment position of the group R.

[0072] In this application, unless otherwise specified in the claims, "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both cases where the event or circumstance occurs and cases where it does not occur. For example, "optionally substituted aryl" means that the hydrogen atoms on the aryl group may or may not be substituted, and the description includes both substituted and unsubstituted aryl groups. For example, in the absence of explicit listing of substituents, the terms "optionally substituted", "substituted" or "substituted by" as used herein mean that one or more hydrogen atoms on a given atom or group are independently replaced by one or more, for example 1, 2, 3 or 4, substituents independently selected from the group consisting of: deuterium (D), halogen, -OH, oxo (=O), mercapto, cyano, -CD3, -C1-C6 alkyl (preferably -C1-3 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl (preferably C3-C8 cycloalkyl), aryl, heterocyclyl (preferably 3-8 membered heterocyclyl), heteroaryl, aryl-C1-C6 alkyl-, heteroaryl-C1-C6 alkyl-, C1-C6 haloalkyl-, -OC1-C6 alkyl (preferably -OC1-C3 alkyl), -OC2-C6 alkenyl, -O cycloalkyl, -O heterocyclyl, -O aryl -C1-C6 alkylphenyl, -C1-C6 alkyl-OH (preferably -C1-C4 alkyl-OH), -C1-C6 alkyl-SH, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1-C6 haloalkyl, -NH2, -C1-C6 alkyl-NH2 (preferably -C1-C3 alkyl-NH2), -N(C1-C6 alkyl)2 (preferably -N(C1-C3 alkyl)2), -NH(C1-C6 alkyl) (preferably -NH(C1-C3 alkyl)), -N(C1-C6 alkyl)(C1-C6 alkylphenyl), -NH(C1-C6 alkylphenyl), -N(C1-C6 alkyl)(aryl), -NH(aryl), nitro, -C(O)-OH, -C(O)OC1-C6 alkyl (preferably -C(O)OC1-C3 alkyl), -CONR i R ii (where R i and R iiis H, D and C1-6 alkyl, preferably C1-3 alkyl), -NHC(O)(C1-C6 alkyl), -NHC(O)(phenyl), -N(C1-C6 alkyl)C(O)(C1-C6 alkyl), -N(C1-C6 alkyl)C(O)(phenyl), -C(O)C1-C6 alkyl, -C(O)heteroaryl (preferably -C(O)-5-7 membered heteroaryl), -C(O)C1-C6 alkylphenyl, -C(O)C1-C6 haloalkyl, -OC(O)C1-C6 alkyl (preferably -O C(O)C1-C3 alkyl), -S(O)2-C1-C6 alkyl, -S(O)-C1-C6 alkyl, -S(O)2-phenyl, -S(O)2-C1-C6 haloalkyl, -S(O)2NH2, -S(O)2NH(C1-C6 alkyl), -S(O)2NH(phenyl), -NHS(O)2(C1-C6 alkyl), -NHS(O)2(phenyl) and -NHS(O)2(C1-C6 haloalkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, aromatic Each of the heteroaryl, heterocyclyl and heteroaryl groups is optionally further substituted by one or more substituents selected from the group consisting of halogen, -OH, oxo (=O), -NH2, cycloalkyl, 3-8 membered heterocyclyl, C1-C4 alkyl, C1-C4 haloalkyl-, -OC1-C4 alkyl, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, cyano, nitro, -C(O)-OH, -C(O)OC1-C6 alkyl, -CON(C1-C6 alkyl)2, -CONH(C1-C6 alkyl), -CONH2, -NHC(O)(C1-C6 alkyl), -NH(C1-C6 alkyl)C(O)(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2(phenyl), -SO2(C1-C6 haloalkyl), -SO2NH2, -SO2NH(C1-C6 alkyl), -SO2NH(phenyl), -NHSO2(C1-C6 alkyl), -NHSO2(phenyl) and -NHSO2(C1-C6 haloalkyl). When an atom or group is substituted with multiple substituents, the substituents may be the same or different. As used herein, the terms "moiety," "structural moiety," "chemical moiety," "group," and "chemical group" refer to a specific fragment or functional group in a molecule. A chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule.

[0073] In the present invention, (C1-C4 alkyl)2amino represents an amine substituted with two C1-C4 alkyl groups, for example, wait.

[0074] In the present invention, "plurality" refers to 2, 3 or 4.

[0075] Active ingredient

[0076] As used herein, "compound of the present invention" or "active ingredient" refers to the compound represented by Formula I, and also includes pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, cis-trans isomers, solvates, polymorphs, deuterated forms, or combinations thereof.

[0077] "Stereoisomers" refer to compounds composed of the same atoms, bonded by the same bonds, but having different three-dimensional structures. The present invention is intended to encompass various stereoisomers and mixtures thereof.

[0078] When the compounds of the present invention contain olefinic double bonds, and unless specified otherwise, it is intended that the compounds of the present invention include both E- and Z- geometric isomers.

[0079] "Tautomers" refer to isomers formed when a proton is shifted from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present invention are intended to be encompassed within the scope of the present invention.

[0080] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral carbon atom may be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the present invention may be prepared using racemates, diastereomers, or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0081] Conventional techniques for preparing / isolating individual isomers include chiral synthesis from appropriate optically pure precursors, or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography, see, for example, Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; A.M. Stalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3: 341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5. sup. TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128.

[0082] In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0083] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without the side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, and naphthalene disulfonate. These salts can be prepared by methods known in the art.

[0084] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. The salt derived from organic base includes but is not limited to following salt: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

[0085] Pharmaceutical compositions and methods of administration

[0086] As used herein, a "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, thereby facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0087] The compounds of general formula (I) can be used in combination with other drugs known to treat or improve similar conditions. When administered in combination, the original drug's administration method and dosage can remain unchanged, while the compound of formula I is taken simultaneously or subsequently. When the compound of formula I is taken simultaneously with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of formula I can be preferably used. Drug combination also includes taking the compound of formula I and one or more other known drugs during overlapping time periods. When the compound of formula I is used in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage of each drug taken alone.

[0088] The drugs or active ingredients that can be used in combination with the compounds of general formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, etc.), CD20 antibodies (such as rituximab, ibrutinib, etc.), KRAS inhibitors (such as AMG510, etc.), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocatinib), EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, osimertinib, etc.), VEGFR inhibitors (such as sorafenib, pazopanib, regorafenib, cabozantinib, sunitinib, etc.), PI3K inhibitors (such as dactolisib, Ta selisib, etc.), BTK inhibitors (such as Ibrutinib, Tilabutinib, Acalabrutinib, Zanubrutinib, Vecabuzinib, etc.), HDAC inhibitors (such as Vorinostat, Fimepinostat, Givinostat, Tucidinostat, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib, etc.), ERK inhibitors (such as BVD523, HH2710, etc.), mTOR inhibitors (such as Visusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068), SOS1 inhibitors (such as BI1701963, etc.), PRMT1 inhibitors, MAT2A inhibitors or a combination thereof.

[0089] As used herein, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to a subject without causing an adverse biological response or interacting in an adverse manner with any components contained in the composition.

[0090] In this application, "pharmaceutically acceptable carrier" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.

[0091] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0092] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0093] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0094] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0095] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0096] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0097] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0098] The term "tumor" as used herein includes, but is not limited to, lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdoid tumor, synovial sarcoma, endometrioma, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, glioma, bile duct cancer, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, and bladder cancer. As used herein, the terms "preventive," "prevention," and "prevention" include reducing the likelihood of a patient developing or worsening a disease or condition.

[0099] As used herein, the term "treatment" and other similar synonyms include the following meanings:

[0100] (i) preventing a disease or condition from occurring in a mammal, particularly where such mammal is susceptible to the disease or condition but has not yet been diagnosed as having the disease or condition;

[0101] (ii) inhibiting the disease or condition, i.e., curbing its development;

[0102] (iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

[0103] (iv) Alleviate the symptoms of the disease or condition.

[0104] As used herein, the terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to an amount of at least one agent or compound sufficient to provide some relief to some degree from one or more symptoms of the disease or condition being treated. This can result in a reduction and / or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system. For example, a therapeutically effective amount is the amount of a composition comprising a compound disclosed herein that provides a clinically significant alleviation of symptoms. Techniques such as dose escalation studies can be used to determine the effective amount appropriate for any individual case.

[0105] As used herein, the terms "administer," "administer," "dosing," and the like refer to methods by which a compound or composition can be delivered to the desired site for biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injections or infusions), topical administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used for the compounds and methods described herein, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

[0106] As used herein, the terms "pharmaceutical combination," "drug combination," "combination therapy," "administration of another therapy," "administration of another therapeutic agent," and the like refer to a pharmaceutical therapy obtained by mixing or combining more than one active ingredient, and include both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that at least one compound described herein and at least one synergistic agent are administered to a patient simultaneously as a single entity or single dosage form. The term "non-fixed combination" means that at least one compound described herein and at least one synergistic agent are administered to a patient simultaneously, in combination, or sequentially at variable intervals as separate entities. This also applies to cocktail therapies, e.g., administration of three or more active ingredients.

[0107] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0108] Compared with the prior art, the present invention has the following beneficial effects:

[0109] (1) The present invention provides a novel compound as shown in Formula I or a pharmaceutically acceptable salt thereof;

[0110] (2) The compounds of the present invention can synergistically inhibit PRMT5 with MTA, and can be used to prepare therapeutic agents for PRMT5. - / - Cancer-related drugs.

[0111] The technical solution of the present invention is further described below by way of specific embodiments. It should be understood by those skilled in the art that the embodiments are merely to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0112] In the following examples, the experimental methods without specific conditions are generally carried out under conventional conditions or the conditions recommended by the manufacturers. Unless otherwise specified, percentages and parts are by weight.

[0113] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.

[0114] In each embodiment, 1 H NMR spectra were recorded on a BRUKER AVANCE NEO 400 MHz nuclear magnetic resonance instrument, and chemical shifts are expressed in δ (ppm). Liquid chromatography-mass spectrometry (LCMS) spectra were recorded on Shimadzu LC-20AD, SIL-20A, CTO-20AC, SPD-M20A, CBM-20A, and LCMS-2020 mass spectrometers. Preparative HPLC separations were performed using a Gilson-281 liquid chromatograph.

[0115] Example

[0116] 1. Preparation of Intermediate A

[0117] The synthetic route of intermediate A is as follows:

[0118] (1) To a dichloromethane solution (50.0 mL) of compound A-1 (5.00 g, 22.8 mmol, hydrochloride) was added triethylamine (2.76 g, 27.3 mmol, 3.80 mL) and magnesium sulfate (27.4 g, 228 mmol). Benzaldehyde (2.42 g, 22.8 mmol, 2.30 mL) was then added. The reaction mixture was stirred under nitrogen for 25 min for 8 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain compound A-2.

[0119] MS-ESI[M+H] + , calculated value 272, measured value 272.

[0120] (2) Potassium carbonate (9.45 g, 68.3 mmol) and methyl acrylate (6.31 g, 73.3 mmol, 6.60 mL) were added to a solution of compound A-2 (6.18 g, 22.8 mmol) in acetonitrile (60.0 mL). The reaction mixture was stirred at 25°C for 5 hours under nitrogen protection. Water (60.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (300 mL × 3). The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 20:1) to obtain compound A-3.

[0121] MS-ESI[M+H] + , calculated value 358, measured value 358.

[0122] 1 H NMR(400MHz, CDCl3)δ8.13(s,1H),7.78(dd,J=7.6,1.6Hz,2H),7.37-7.50(m,5H),6.90-6.99(m, 2H), 3.68 (s, 3H), 3.50 (s, 3H), 2.50-2.56 (m, 2H), 2.29-2.39 (m, 1H), 2.22 (dd, J = 10, 6.0Hz, 1H).

[0123] (3) Compound A-3 (3.39 g, 9.49 mmol) was placed in a reaction flask and stirred at 120°C under nitrogen for 12 hours. The reaction solution was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 30:1) to obtain compound A.

[0124] 1 H NMR (400MHz, CDCl3) δ7.37 (td, J = 8.0, 6.0 Hz, 1H), 6.99-7.23 (m, 3H), 3.78 (s, 3H), 3.04 (ddd, J = 12.4, 8.4, 6.4Hz, 1H), 2.26-2.52 (m, 3H).

[0125] The second synthetic route of intermediate A is as follows:

[0126] 2. Preparation of intermediates B, C, D, and F

[0127] The preparation of intermediates B, C, D, D refers to intermediate A

[0128] 3. Preparation of intermediate G

[0129] (1) To a solution of compound G-1 (12.5 g, 87.6 mmol) in acetonitrile (100 mL) was added N-bromosuccinimide (15.6 g, 87.6 mmol). The reaction mixture was stirred at 25°C for 1 hour under nitrogen protection. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 4:1) to obtain compound G-2.

[0130] (2) Compound G-3 (10.7 g, 121 mmol, 8.59 mL), triethylamine (18.1 g, 178 mmol, 24.9 mL), palladium acetate (2.01 g, 8.94 mmol), and triphenylphosphine (2.13 g, 8.13 mmol) were added to a solution of compound 1-2 (9.00 g, 40.64 mmol) in dioxane (100 mL). The reaction mixture was stirred under nitrogen for 12 hours. Aqueous sodium hydroxide solution (50.0 mL, 2 mol / L) was added to the reaction mixture, and the mixture was washed with methyl tert-butyl ether (200 mL). The organic phase was extracted with aqueous sodium hydroxide solution (30.0 mL, 2 mol / L). The combined aqueous phases were acidified with dilute hydrochloric acid until a brown solid precipitated, and filtered to obtain compound G-4.

[0131] MS-ESI[M+H] + , calculated value 211, measured value 211.

[0132] (3) To a solution of compound G-4 (15.0 g, 71.2 mmol) in methanol (200 mL) was added sulfuric acid (6.99 g, 71.22 mmol, 3.80 mL). The reaction mixture was stirred at 80°C for 12 hours under nitrogen. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 4:1) to obtain compound G-5.

[0133] MS-ESI[M+H] + , calculated value 225, measured value 225.

[0134] 1 H NMR (400MHz, CDCl3) δ8.85-9.13(m,1H),7.63(s,1H),3.98(s,3H),2.51(s,3H).

[0135] (4) To a solution of compound G-5 (1.00 g, 4.45 mmol) in tetrahydrofuran (15.0 mL) was added potassium bis(trimethylsilyl)amide (5.34 mL, 1 mol / L). The reaction mixture was stirred at 5°C for 0.5 h under nitrogen protection. 2-(Trimethylsilyl)ethoxymethyl chloride (890 mg, 5.34 mmol, 945 μL) was added and continued to stir at 5°C for 1 h under nitrogen protection. Aqueous ammonium chloride solution (20.0 mL) was added to the reaction mixture and extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 4:1) to obtain compound G-6.

[0136] MS-ESI[M+H] + , calculated value 355, measured value 355.

[0137] (5) To a solution of compound G-6 (1.20 g, 3.38 mmol) in dichloromethane (25.0 mL) was added diisopropylaluminum hydride (7.44 mL, 1 mol / L). The reaction mixture was stirred at 0°C for 0.5 h under nitrogen protection. Aqueous sodium hydroxide solution (30.0 mL, 2 mol / L) was added to the reaction mixture, which was extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound G.

[0138] 4. Preparation of Intermediate H

[0139] (1) To a solution of compound H-1 (25.0 g, 118 mmol) in dioxane (200 mL) were added tert-butyl carbamate (15.3 g, 130.68 mmol), cesium carbonate (77.4 g, 237 mmol), tris(dibenzylideneacetone)dipalladium (4.35 g, 4.75 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (4.12 g, 7.13 mmol). The reaction mixture was stirred at 80°C under nitrogen for 12 hours, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 10:1) to obtain compound H-2.

[0140] MS-ESI[M+H] + , calculated value 247, measured value 247.

[0141] (2) To a solution of compound H-2 (23.0 g, 93.24 mmol) in dichloromethane (10.0 mL) was added trifluoroacetic acid (15.3 g, 134 mmol, 10.0 mL). The reaction mixture was stirred at 50°C for 24 hours under nitrogen. At 0°C, an aqueous sodium carbonate solution was added to the reaction mixture to adjust the pH to 7. The mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound H-3.

[0142] MS-ESI[M+H] + , calculated value 147, measured value 147.

[0143] 1 H NMR (400MHz, CDCl3) δ7.70 (d, J = 2.4Hz, 1H), 6.82 (dd, J = 9.6, 2.4Hz, 1H), 3.09-3.39 (m, 2H).

[0144] (3) To a solution of compound H-3 (5.80 g, 39.5 mmol) in acetonitrile (10.0 mL) was added N-bromosuccinimide (7.04 g, 39.5 mmol). The reaction mixture was stirred under nitrogen at 25°C for 1 hour. Water (20.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50.0 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 20:1) to obtain compound H-4.

[0145] MS-ESI[M+H] + , calculated value 227, measured value 227.

[0146] (4) To a solution of compound H-4 (8.00 g, 35.4 mmol) in dioxane (100 mL) were added pyruvic acid (9.37 g, 106 mmol, 7.50 mL), triethylamine (10.7 g, 106 mmol, 14.8 mL), palladium acetate (796 mg, 3.55 mmol), and triphenylphosphine (1.86 g, 7.10 mmol). The reaction mixture was stirred at 110 °C for 12 h under nitrogen protection. Aqueous sodium hydroxide solution (50.0 mL, 2 mol / L) was added to the reaction mixture, and the mixture was washed with methyl tert-butyl ether (200 mL). The organic phase was extracted with aqueous sodium hydroxide solution (30.0 mL, 2 mol / L). The combined aqueous phases were acidified with dilute hydrochloric acid until a brown solid precipitated, which was then filtered to obtain compound H-5.

[0147] MS-ESI[M+H] + , calculated value 215, measured value 215.

[0148] (5) To a solution of compound H-5 (9.40 g, 43.8 mmol) in methanol (100 mL) was added sulfuric acid (8.59 g, 87.6 mmol, 4.67 mL) at 0°C. The reaction mixture was stirred at 80°C for 12 hours under nitrogen protection. At 0°C, an aqueous sodium carbonate solution was added to the reaction mixture to adjust the pH to 7, followed by addition of water (100 mL). The mixture was extracted with dichloromethane (100 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 6:1) to obtain compound H-6.

[0149] MS-ESI[M+H] + , calculated value 229, measured value 229.

[0150] (6) To a solution of compound H-6 (3.60 g, 15.75 mmol) in tetrahydrofuran (30.0 mL) was added potassium bis(trimethylsilyl)amide (28.3 mL, 1 mol / L). The reaction solution was stirred at 0°C for 0.5 h under nitrogen protection. 2-(Trimethylsilyl)ethoxymethyl chloride (5.25 g, 31.5 mmol, 5.57 mL) was added and the mixture was stirred for 1 h under nitrogen protection. Aqueous ammonium chloride solution (50.0 mL) was added to the reaction solution and extracted with ethyl acetate (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 4:1) to obtain compound H.

[0151] MS-ESI[M+H] + , calculated value 359, measured value 359.

[0152] 5. Preparation of Intermediate I

[0153] The preparation of intermediate I refers to intermediate H, and the last step is to use diisopropylaluminum deuteride instead of diisopropylaluminum hydride

[0154] 5. Preparation of Intermediate J

[0155] The preparation of intermediate J refers to intermediate G, and the last step is to use diisopropylaluminum deuteride instead of diisopropylaluminum hydride

[0156] 6. Preparation of Intermediate K

[0157] Intermediate K was prepared by referring to Intermediate G, using 5-amino-2,3-dichloropyridine as the starting material.

[0158] 7. Preparation of Intermediate L

[0159] Intermediate L was prepared by referring to Intermediate G, using 5-amino-2,3-dichloropyridine as the starting material and replacing diisopropylaluminum hydride with diisopropyldeuterated aluminum in the last step.

[0160] 8. Preparation of intermediate M

[0161] (1) To a solution of compound M-1 (2.00 g, 9.80 mmol) in N,N-dimethylformamide (20.0 mL) were added triethylamine (1.98 g, 19.6 mmol, 2.73 mL) and methyl thioacetate (1.27 g, 11.9 mmol, 1.09 mL). The reaction mixture was stirred at 100°C under nitrogen for 4 hours. Water (200 mL) was added to the reaction mixture, and the mixture was filtered to obtain compound M-2.

[0162] MS-ESI[M+H] + , calculated value 274, measured value 274.

[0163] 1 H NMR (400MHz, CDCl3) δ8.15 (s, 1H), 8.05 (d, J = 8.4Hz, 1H), 7.52 (d, J = 8.4Hz, 1H), 3.99 (s, 3H).

[0164] (2) To a solution of compound M-2 (1.00 g, 3.67 mmol) in dichloromethane (10.0 mL) was added diisopropylaluminum hydride (7.35 mL, 1 mol / L). The reaction mixture was stirred at 0°C for 1 hour under nitrogen protection. Aqueous sodium hydroxide solution (0.35 mL, 15%) and water (10.0 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound M.

[0165] MS-ESI[M+H] + , calculated value 246, measured value 246.

[0166] 9. Preparation of Intermediate N

[0167] To a solution of compound N-1 (800 mg, 3.74 mmol) in tetrahydrofuran (15.0 mL) at 0°C was added borane tetrahydrofuran (11.2 mL, 1 mol / L). The reaction mixture was stirred at 25°C under nitrogen for 12 hours. Methanol (15 mL) and water (10.0 mL) were added to the reaction mixture, which was then extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 5:1) to obtain compound N.

[0168] MS-ESI[M+H] + , calculated value 200, measured value 200.

[0169] Example 1 Synthesis of Compound 1

[0170] (1) To a solution of compound G (300 mg, 917 μmol) in dichloromethane (10.0 mL) was added thionyl chloride (327 mg, 2.75 mmol, 199 μL). The reaction mixture was stirred under nitrogen at 25°C for 1 hour. Aqueous sodium bicarbonate solution (5.0 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-1.

[0171] (2) To a solution of compound 1-1 (300 mg, 868 μmol) in N,N-dimethylformamide (5.0 mL) was added cesium carbonate (849 mg, 2.61 mmol) and compound F (200 mg, 912 μmol). The reaction mixture was stirred at 60°C for 2 hours under nitrogen. Water (10.0 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 1:1) to obtain compound 1-2.

[0172] MS-ESI[M+H] + , calculated value 530, measured value 530.

[0173] 1H NMR (400MHz, CDCl3) δ7.50(s,1H),7.15-7.26(m,5H),6.00(s,1H),5.39(s,2H),4.50-4.89(m,2H),3.61(s,3H),3.44(t,J=8.0Hz ,2H),2.89(ddd,J=13.2,7.6,5.6Hz,1H),2.55(s,2H),2.46(s,3H),2.33-2.43(m,1H),0.85(td,J=8.0,2.4Hz,2H),0.06(s,9H).

[0174] (3) Benzophenone imine (68.6 mg, 378 μmol, 63.5 μL), sodium tert-butoxide (36.3 mg, 378 μmol), tris(dibenzylideneacetone)dipalladium (17.3 mg, 18.9 μmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (2.13 g, 8.13 mmol), and potassium iodide (157 mg, 946 μmol) were added to a toluene (2.0 mL) solution of compound 1-2 (100 mg, 189 μmol). The reaction mixture was stirred at 120°C under nitrogen for 12 hours, filtered, and concentrated under reduced pressure. The crude product was separated by preparative liquid chromatography to obtain compound 1-3.

[0175] MS-ESI[M+H] + , calculated value 659, measured value 659.

[0176] (4) To a solution of compound 1-3 (40.0 mg, 80.8 μmol) in dichloromethane (3.0 mL) were added diisopropylethylamine (31.3 mg, 242 μmol, 42.2 μL) and N,N,Nmg,-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (46. mg, 121 μmol), and the mixture was stirred at room temperature for 25 minutes. 3,3-Difluoroazetidine hydrochloride (12.5 mg, 97.0 μmol) was then added, and the reaction mixture was stirred at 25°C under nitrogen for 5 hours. Water (10.0 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 16:1) to obtain compound 1-4.

[0177] MS-ESI[M+H] + , calculated value 570, measured value 570.

[0178] (5) Trifluoroacetic acid (200 μL) was added to a solution of compound 1-4 (5.00 mg, 8.78 μmol) in dichloromethane (1.0 mL) at 0.5 °C. The reaction mixture was stirred for 1 hour at 25 °C under nitrogen. Potassium carbonate was added to the reaction mixture and stirring continued for 2 hours. The mixture was filtered and concentrated under reduced pressure. The crude product was separated by preparative HPLC (Xtimate C18, 150 mm × 40 mm 10 μm, A: water (formic acid); B: acetonitrile, 0%-30%: 25 min) to obtain the formate salt of compound 1.

[0179] MS-ESI[M+H] + , calculated value 440, measured value 440.

[0180] 1 H NMR(400MHz,MeOD)δ7.63(s,1H),7.27-7.48(m,5H),5.53(s,1H),4.80(s,1H),4.33-4.63(m,3H ), 4.28 (d, J = 16.4Hz, 1H), 3.52-3.71 (m, 1H), 2.85-2.97 (m, 1H), 2.54-2.79 (m, 3H), 2.22 (s, 3H).

[0181] Example 2 Synthesis of Compound 2

[0182] Synthesize Reference Example 1, using cyclopropylamine to replace 3,3-difluoroazetidine hydrochloride to obtain compound 2. MS-ESI [M+H] + , calculated value 404, measured value 404.

[0183] 1 H NMR(400MHz,MeOD)δ7.31-7.34(m,6H),5.58(s,1H),4.38-4.56(m,2H),2.63-2. 73(m,3H),2.54-2.56(m,2H),2.20(s,3H),0.63-0.68(m,2H),0.34-0.38(m,2H).

[0184] Example 3 Synthesis of Compound 3

[0185] Synthesize Reference Example 1, use Intermediate A to replace Compound 1-9 to obtain Compound 3. MS-ESI [M+H] + , calculated value 458, measured value 458.

[0186] 1H NMR(400MHz,MeOD)δ7.54(s,1H),7.35-7.37(m,1H),7.16-7.24(m,2H),7.03-7.04(m,1 H),5.55(s,1H),4.28-4.57(m,5H),3.71-3.72(m,1H),2.59-2.87(m,4H),2.22(s,3H).

[0187] Example 4 Synthesis of Compound 4

[0188] (1) Synthesis of Compound 1-1: Referring to Example 1, to a solution of Compound 1-1 (809 mg, 2.11 mmol) in N,N-dimethylformamide (15.0 mL), cesium carbonate (2.06 g, 6.32 mmol) and Compound A (500 mg, 2.11 mmol) were added. The reaction mixture was stirred at 60°C for 2 hours under nitrogen protection. Water (10.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 4:1) to obtain Compound 4-1.

[0189] MS-ESI[M+H] + , calculated value 546, measured value 546.

[0190] (2) To a solution of compound 4-1 (500 mg, 590 μmol) in toluene (10.0 mL) was added p-methoxybenzylamine (162 mg, 1.18 mmol), cesium carbonate (384 mg, 1.18 mmol), tris(dibenzylideneacetone)dipalladium (54.0 mg, 59.0 μmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (73.4 mg, 118 μmol). The reaction mixture was stirred at 120°C under nitrogen for 12 hours, filtered, and concentrated under reduced pressure. Water (10.0 mL) was added, and the mixture was extracted with ethyl acetate (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound 4-2.

[0191] MS-ESI[M+H] + , calculated value 647, measured value 647.

[0192] (3) To a solution of compound 4-2 (353 mg, 546 μmol) in tetrahydrofuran (2.00 mL) were added water (0.5 mL), methanol (1.00 mL), and lithium hydroxide monohydrate (183 mg, 4.37 mmol), and the reaction mixture was stirred at 25°C for 8 hours. The reaction mixture was concentrated under reduced pressure, water (5.0 mL) was added, the pH was adjusted to 3-4 with dilute hydrochloric acid, and the mixture was extracted with dichloromethane (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 4-3.

[0193] MS-ESI[M+H] + , calculated value 633, measured value 633.

[0194] (4) Compound 4-3 (300 mg, 474 μmol) and N,N,Ng,′,-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (270 mg, 711 μmol) were added to a solution of compound 4-4 (633 mg, 4.74 mmol, hydrochloride) in pyridine (4.0 mL). The reaction mixture was stirred for 12 hours under nitrogen. Water (20.0 mL) was added to the reaction mixture and extracted with ethyl acetate (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 0:1) to obtain compound 4-5.

[0195] (5) Trifluoroacetic acid (1.0 mL) was added to compound 4-5 (50.0 mg, 70.2 μmol) at 0.5 °C. The reaction mixture was stirred for 2 h at 25 °C under nitrogen protection. After concentration under reduced pressure, methanol (1.00 mL) and aqueous ammonia (910 mg, 7.79 mmol, 1.00 mL, 30%) were added and stirring continued for 4 h. Water (10.0 mL) was added to the reaction mixture and extracted with ethyl acetate (20.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative HPLC (Xtimate C18, 150 mm × 40 mm 10 μm, A: water (formic acid); B: acetonitrile, 0%-38%: 25 min) to obtain the formate salt of compound 4.

[0196] MS-ESI[M+H] + , calculated value 462, measured value 462.

[0197] (6) The formate salt of compound 4 was separated by chiral supercritical fluid chromatography to give compounds 4-P1 and 4-P2.

[0198] Separation conditions: Chromatographic column model: CHIRALPAK IG; Chromatographic column specifications: 250×30mm ID, 10μm; Injection volume: 10.0μL; Mobile phase: A: carbon dioxide, B: ethanol (0.1% ammonia water), B%: 50% elution for 3.5 minutes; Detection wavelength: 254nm; Column temperature: 35℃.

[0199] The retention time of compound 4-P1 was 1.481 minutes, and the ee value was 100%.

[0200] MS-ESI[M+H] + , calculated value 462, measured value 462.

[0201] 1 H NMR(400MHz,MeOD)δ7.22-7.42(m,1H),7.32(td,J=8.0,6.0Hz,1H),7.16(dd,J=8.0,0.8 Hz,1H),7.10(dt,J=10.4,2.0Hz,1H),7.01(td,J=8.0,2.4Hz,1H),5.51(s,1H),4.78(br d,J=16.1Hz,1H),4.29(d,J=16.1Hz,1H),4.02(s,2H),3.88(d,J=9.6Hz,1H),3.20(br d,J=9.6Hz,1H),2.65-2.79(m,2H),2.52-2.63(m,2H),2.20(s,3H),1.97-2.16(m,4H),1.70-1.83(m,2H).

[0202] The retention time of compound 4-P2 was 2.059 minutes, and the ee value was 100%.

[0203] MS-ESI[M+H] + , calculated value 462, measured value 462.

[0204] 1H NMR(400MHz,MeOD)δ7.28-7.35(m,2H),7.15(d,J=8.0Hz,1H),7.09(dt,J=10.0,2.0Hz,1H) ,6.97-7.04(m,1H),5.45(s,1H),4.74(s,1H),4.29(d,J=16.0Hz,1H),4.01(s,2H),3.85(br d,J=9.6Hz,1H),3.41(d,J=9.6Hz,1H),2.64-2.79(m,2H),2.54-2.62(m,2H),2.18(s,3H),1.99(br s,4H),1.65-1.83(m,2H).

[0205] Example 5-23 Synthesis of Compound 5-23

[0206] The preparation of compound 5-23 was carried out according to Example 4, except that the corresponding amine was used to replace 4-4, and compound 1-9 was used to replace intermediate A, and chiral resolution was not performed.

[0207] Example 24 Synthesis of Compound 24

[0208] Synthesize Reference Example 4, use Intermediate C to replace Compound A to obtain Compound 24. MS-ESI [M+H] + , calculated value 476, measured value 476.

[0209] 1 H NMR(400MHz,MeOD)δ7.61(s,1H),7.33-7.38(m,1H),7.19-7.24(m,2H),5.61(s,1H),4 .44-4.48(m,4H),4.27(d,J=16.4Hz,1H),3.66(s,1H),2.59-2.81(m,4H),2.24(s,3H).

[0210] Example 25 Synthesis of Compound 25

[0211] Synthesize Reference Example 4, use Intermediate B to replace Compound A to obtain Compound 25. MS-ESI [M+H] + , calculated value 458, measured value 458.

[0212] 1H NMR(400MHz,MeOD)δ7.34-7.37(m,2H),7.28(s,1H),7.18-7.20(m,1H),7.00-7.03(m,1H),5.57( s,1H),4.55-4.79(m,2H),4.23-4.29(m,3H),3.80-3.90(m,1H),2.61-2.77(m,4H),2.17(s,3H).

[0213] Example 26 Synthesis of Compound 26

[0214] Synthesize Reference Example 4, use Intermediate D to replace Compound A to obtain Compound 25. MS-ESI [M+H] + , calculated value 476, measured value 476.

[0215] 1 H NMR(400MHz,MeOD)δ7.61(s,1H),7.05-7.08(m,2H),6.85-6.89(m,1H),5.68(s,1H),4 .86-4.93(m,1H),4.2-4.48(m,4H),3.81-3.84(s,1H),2.60-2.81(m,4H),2.17(s,3H).

[0216] Example 27 Synthesis of Compound 1-P1 and Compound 1-P2

[0217] Compound 1 was separated by chiral supercritical fluid chromatography to give compounds 1-P1 and 1-P2.

[0218] Separation conditions: Chromatographic column model: Chiralpak IH-3; Chromatographic column specifications: 50×4.6mm ID, 3μm; Injection volume: 10μL; Mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 20%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 20% fixed concentration elution for 1 minute; Detection wavelength: 254nm; Column temperature: 40℃.

[0219] The retention time of compound 1-P1 was 0.934 minutes, and the ee value was 99.628%.

[0220] MS-ESI[M+H] + , calculated value 440, measured value 440.

[0221] 1H NMR(400MHz,MeOD)δ7.40-7.42(m,2H),7.34-7.36(m,3H),7.27(s,1H),5.35(s,1H), 4.58-4.67(m,2H),4.41-4.44(m,2H),4.26(d,J=8.0Hz,1H),3.66(s,1H),2.57-2.89(m,4H),2.17(s,3H).

[0222] The retention time of compound 1-P2 was 1.335 minutes, and the ee value was 98.29%.

[0223] MS-ESI[M+H] + , calculated value 440, measured value 440.

[0224] 1 H NMR (400MHz, MeOD) δ7.34-7.43(m,6H),5.43(s,1H),4.60(s,2H),4.39(s,2H),4.30(d,J=8.0Hz,1H),3.66(s,1H),2.58-2.90(m,4H),2.20(s,3H).

[0225] Example 28 Synthesis of Compound 3-P1 and Compound 3-P2

[0226] Compound 3 was separated by chiral supercritical fluid chromatography to give compounds 3-P1 and 3-P2.

[0227] Separation conditions: chromatographic column model: Chiralpak IC-3; chromatographic column specifications: 50×4.6mm ID, 3μm; injection volume: 10μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 40% fixed concentration elution for 7 minutes; detection wavelength: 254nm; column temperature: 40℃.

[0228] The retention time of compound 3-P1 was 2.888 minutes and the ee value was 99.80%.

[0229] MS-ESI[M+H] + , calculated value 458, measured value 458.

[0230] 1 H NMR (400MHz, MeOD) δ7.30-7.35(m,2H),7.02-7.23(m,3H),5.44(s,1H),4.27-4.44(m,5H),3.67-3.79(m,1H),2.57-2.81(m,4H),2.17(s,3H).

[0231] The retention time of compound 3-P2 was 4.069 minutes and the ee value was 99.46%.

[0232] MS-ESI[M+H] + , calculated value 458, measured value 458.

[0233] 1 H NMR (400MHz, MeOD) δ7.29-7.35(m,2H),7.02-7.22(m,3H),5.43(s,1H),4.27-4.47(m,5H),3.67-3.79(m,1H),2.59-2.81(m,4H),2.18(s,3H).

[0234] Example 29 Synthesis of Compound 7-P1 and Compound 7-P2

[0235] Compound 7 was separated by chiral supercritical fluid chromatography to give compounds 7-P1 and 7-P2.

[0236] Separation conditions: Chromatographic column model: Chiralpak AS-3; Chromatographic column specifications: 50×4.6mm ID, 3μm; Injection volume: 10μL; Mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 5%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 5% fixed concentration elution for 0.5 minutes; Detection wavelength: 254nm; Column temperature: 40℃.

[0237] The retention time of compound 7-P1 was 1.530 minutes, and the ee value was 99.82%.

[0238] MS-ESI[M+H] + , calculated value 418, measured value 418.

[0239] 1 H NMR (400MHz, MeOD) δ7.27-7.28(m,6H),5.18(s,1H),4.79-4.80(m,1H),4.02-4.06(m,1H),2.50-3.03(m,8H),2.17(s,3H),0.71-0.88(m,4H).

[0240] The retention time of compound 7-P2 was 1.968 minutes, and the ee value was 99.20%.

[0241] MS-ESI[M+H] + , calculated value 418, measured value 418.

[0242] 1 H NMR (400MHz, MeOD) δ7.27-7.28(m,6H),5.18(s,1H),4.81-4.82(m,1H),4.02-4.06(m,1H),2.51-2.97(m,8H),2.17(s,3H),0.71-0.88(m,4H).

[0243] Example 30 Synthesis of Compound 8-P1 and Compound 8-P2

[0244] Compound 8 was separated by chiral supercritical fluid chromatography to give compounds 8-P1 and 8-P2.

[0245] Separation conditions: Chromatographic column model: Chiralpak AD-3; Chromatographic column specifications: 50×4.6mm ID, 3μm; Injection volume: 10μL; Mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 5%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 5% fixed concentration elution for 0.5 minutes; Detection wavelength: 254nm; Column temperature: 40℃.

[0246] The retention time of compound 8-P1 was 1.695 minutes, and the ee value was 100%.

[0247] MS-ESI[M+H] + , calculated value 472, measured value 472.

[0248] 1 H NMR(400MHz,MeOD)δ7.27-7.41(m,6H),5.33-5.40(m,1H),4.74-4.80(m,2 H),4.01-4.30(m,4H),3.65-3.83(m,1H),2.54-2.88(m,4H),2.17(s,3H).

[0249] The retention time of compound 8-P2 was 2.366 minutes, and the ee value was 99.32%.

[0250] MS-ESI[M+H] + , calculated value 472, measured value 472.

[0251] 1 H NMR(400MHz,MeOD)δ7.29-7.41(m,6H),5.34-5.40(m,1H),4.74-4.81(m,2 H),4.01-4.30(m,4H),3.62-3.83(m,1H),2.52-2.88(m,4H),2.17(s,3H).

[0252] Examples 31-35 Synthesis of Compounds 31-P1, 31-P2 to 35-P1, 35-P2

[0253] The preparation of compounds 31-P1, 31-P2 to 35-P1, 35-P2 was carried out according to Example 4, using the corresponding amine in place of 4-4.

[0254] Example 36 Synthesis of Compound 9-P1 and Compound 9-P2

[0255] Compound 9 was separated by chiral high performance liquid chromatography to give compounds 9-P1 and 9-P2.

[0256] Separation conditions: chromatographic column model: ChiralPAK IE-3; chromatographic column specifications: 100×4.6mm ID, 3μm; injection volume: 10μL; mobile phase: A: cyclohexane, B: ethanol and acetonitrile (0.1% diethylamine), B%: 70% fixed concentration elution for 10 minutes; detection wavelength: 254nm; column temperature: 40℃.

[0257] The retention time of compound 9-P1 was 3.804 minutes, and the ee value was 99.88%.

[0258] MS-ESI[M+H] + , calculated value 444, measured value 444.

[0259] 1 H NMR (400MHz, CDCl3) δ9.20 (br s, 1H), 7.31-7.39 (m, 3H), 7.21-7.24 (m, 3H), 5.45 (s, 1H), 4.59 (d, J = 15.6Hz, 1H), 4.19-4.36 (m, 3H), 4.06 (br d,J=6.0Hz,2H),3.69(br d,J=9.2Hz,1H),3.47(br d,J=9.2Hz,1H),2.55-2.59(m,4H),2.20(s,3H),2.01-2.15(m,5H).

[0260] The retention time of compound 9-P2 was 4.625 minutes, and the ee value was 95.20%.

[0261] MS-ESI[M+H] + , calculated value 444, measured value 444.

[0262] 1H NMR (400MHz, CDCl3) δ9.20 (br s,1H),7.33-7.39(m,3H),7.21-7.25(m,3H),5.45(s,1H),4.59(d,J=15.6Hz,1H),4.20-4.34(m,3H),4.01-4.11(m,2H),3.69(br d,J=9.2Hz,1H),3.43-3.51(m,1H),2.55-2.60(m,4H),2.19-2.21(m,3H),2.05-2.15(m,2H),2.03(s,3H).

[0263] Example 37 Synthesis of Compound 14-P1 and Compound 14-P2

[0264] Compound 14 was separated by chiral supercritical fluid chromatography to give compounds 14-P1 and 14-P2.

[0265] Separation conditions: chromatographic column model: Chiralpak AD-3; chromatographic column specifications: 50×4.6mm ID, 3μm; injection volume: 10μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 40% fixed concentration elution for 3 minutes; detection wavelength: 254nm; column temperature: 40℃.

[0266] The retention time of compound 14-P1 was 0.768 min and the ee value was 99.64%.

[0267] MS-ESI[M+H] + , calculated value 454, measured value 454.

[0268] 1 H NMR (400MHz, CDCl3) δ9.11(br s,1H),7.34-7.45(m,3H),7.23(br d,J=4.0Hz,3H),5.21(br d,J=14.2Hz,1H),4.69(br d,J=5.6Hz,1H),4.43-4.62(m,2H),4.03-4.09(m,1H),3.87-3.94(m,1H),3.29-3.44(m,1H),3.06-3 .21(m,1H),2.77-2.88(m,1H),2.59-2.71(m,2H),2.44-2.56(m,1H),2.31-2.40(m,1H),2.18(s,4H).

[0269] The retention time of compound 14-P2 was 1.345 minutes, and the ee value was 97.98%.

[0270] MS-ESI[M+H] + , calculated value 454, measured value 454.

[0271] 1 H NMR(400MHz, CDCl3)δ9.14(br s,1H),7.35-7.43(m,3H),7.21-7.24(m,3H),5.22(br d,J=14.4Hz,1H),4.51-4.73(m,3H),4.02-4.08(m,1H),3.87-3.93(m,1H),3.29-3.45(m,1H ),3.09-3.21(m,1H),2.77-2.89(m,1H),2.60-2.69(m,2H),2.41-2.58(m,3H),2.18(s,3H).

[0272] Example 38 Synthesis of Compound 19-P1 and Compound 19-P2

[0273] Compound 19 was separated by chiral supercritical fluid chromatography to give compounds 19-P1 and 19-P2.

[0274] Separation conditions: chromatographic column model: Chiralpak AD-3; chromatographic column specifications: 50×4.6mm ID, 3μm; injection volume: 10μL; mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 40% fixed concentration elution for 3 minutes; detection wavelength: 254nm; column temperature: 40℃.

[0275] The retention time of compound 19-P1 was 1.054 minutes, and the ee value was 100%.

[0276] MS-ESI[M+H] + , calculated value 432, measured value 432.

[0277] 1H NMR (400MHz, CDCl3) δ9.13(br s,1H),7.29-7.40(m,3H),7.11-7.22(m,3H),5.01-5.11(m,1H),4.75(d,J=15.6Hz,1H),4.29(br s,2H),3.91(br d,J=15.6Hz,2H),3.07(s,2H),2.77-2.93(m,1H),2.54-2.65(m,3H),2.35-2.47(m,1H),2.25(br d,J=10.4Hz,1H),2.18(s,3H),2.09-2.15(m,1H),1.96-2.05(m,2H),1.56-1.67(m,1H).

[0278] Compound 19-P2 had a retention time of 2.077 minutes and an ee value of 98.96%.

[0279] MS-ESI[M+H] + , calculated value 432, measured value 432.

[0280] 1 H NMR (400MHz, CDCl3) δ9.16 (br s, 1H), 7.29-7.40 (m, 3H), 7.12-7.23 (m, 3H), 5.04-5.11 (m, 1H), 4.74 (d, J = 15.6Hz, 1H), 4.41 (br s,2H),3.85-3.99(m,2H),3.07(s,2H),2.78-2.91(m,1H),2.54-2.65(m,3H),2.41(ddd,J=12.8,8.8,4.0Hz,1H),2.25(br d,J=10.4Hz,1H),2.18(s,3H),2.09-2.14(m,3H),1.97-2.04(m,1H).

[0281] Example 39 Synthesis of Compound 22-P1 and Compound 22-P2

[0282] Compound 22 was separated by chiral supercritical fluid chromatography to give compounds 22-P1 and 22-P2.

[0283] Separation conditions: Chromatographic column model: Chiralpak IH-3; Chromatographic column specifications: 50×4.6mm ID, 3μm; Injection volume: 10μL; Mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 5%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1.5 minutes, 5% fixed concentration elution for 1 minute; Detection wavelength: 254nm; Column temperature: 40℃.

[0284] The retention time of compound 22-P1 was 1.551 minutes, and the ee value was 100%.

[0285] MS-ESI[M+H] + , calculated value 446, measured value 446.

[0286] 1 H NMR (400MHz, CDCl3) δ9.26 (br s,1H),7.31-7.40(m,3H),7.19-7.25(m,3H),5.13(s,1H),4.48-4.78(m,3H),3.96(d,J=15.6Hz,1H),3.4 6-3.66(m,2H),2.99(s,1H),2.71-2.86(m,2H),2.57-2.65(m,5H),2.45-2.55(m,1H),2.07-2.20(m,7H).

[0287] The retention time of compound 22-P2 was 1.944 minutes, and the ee value was 98.00%.

[0288] MS-ESI[M+H] + , calculated value 446, measured value 446.

[0289] 1 H NMR (400MHz, CDCl3) δ9.26 (br s,1H),7.31-7.40(m,3H),7.19-7.25(m,3H),5.13(s,1H),4.48-4.78(m,3H),3.96(d,J=15.6Hz,1H),3.4 6-3.66(m,2H),2.99(s,1H),2.71-2.86(m,2H),2.57-2.65(m,5H),2.45-2.55(m,1H),2.07-2.20(m,7H).

[0290] Example 40 Synthesis of Compound 40

[0291] (1) To a solution of compound H (1.40 g, 4.23 mmol) in dichloromethane (20.0 mL) was added thionyl chloride (1.51 g, 12.7 mmol, 922 μL). The reaction mixture was stirred under nitrogen at 25°C for 1 hour. Aqueous sodium bicarbonate solution (50.0 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 40-1.

[0292] (2) To a solution of compound 40-1 (1.47 g, 4.22 mmol) in N,N-dimethylformamide (30.0 mL) was added cesium carbonate (2.75 g, 8.43 mmol) and intermediate A (1.00 g, 4.22 mmol). The reaction mixture was stirred at 60°C for 1 hour under nitrogen protection. Water (50.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 4:1) to obtain compound 40-2.

[0293] MS-ESI[M+H] + , calculated value 550, measured value 550.

[0294] 1 H NMR (400MHz, CDCl3) δ7.48 (d, J = 8.8Hz, 1H), 7.19-7.26 (m, 1H), 6.88-7.01 (m, 3H), 6.03 (s, 1H), 5.35-5.49 (m, 2H), 4.61 -4.84(m,2H),3.65(s,3H),3.49(t,J=8.0Hz,2H),2.86-2.93(m,2H),2.51-2.60(m,2H),0.86-0.96(m,2H),0.03(s,9H).

[0295] (3) To a toluene (30.0 mL) solution of compound 40-2 (1.70 g, 3.09 mmol) was added 2,4-dimethoxybenzylamine (1.03 g, 6.18 mmol, 928 μL), cesium carbonate (2.01 g, 6.18 mmol), tris(dibenzylideneacetone)dipalladium (283 mg, 309 μmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (384 mg, 618 μmol). The reaction mixture was stirred at 120°C under nitrogen for 12 hours. Water (50.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound 40-3.

[0296] MS-ESI[M+H] + , calculated value 681, measured value 681.

[0297] (4) To a solution of compound 40-3 (1.90 g, 2.79 mmol) in tetrahydrofuran (30.0 mL) was added lithium hydroxide monohydrate (10.0 mL, 2 mol / L). The reaction mixture was stirred at 25°C under nitrogen for 12 hours. Aqueous hydrochloric acid was added to the reaction mixture at 0°C to adjust the pH to 7. The mixture was extracted with dichloromethane (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 40-4.

[0298] MS-ESI[M+H] + , calculated value 667, measured value 667.

[0299] (5) To a solution of compound 40-4 (300 mg, 449 μmol) in dichloromethane (8.0 mL) were added diisopropylethylamine (407 mg, 3.15 mmol, 548 μL) and N,N,Nmg,′,-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (256 mg, 674 μmol). The mixture was stirred at room temperature for 25 minutes, followed by the addition of methylcyclopropylamine hydrochloride (242 mg, 2.25 mmol). The reaction mixture was stirred under nitrogen for 24 hours. Water (30.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 10:1) to obtain compound 40-5.

[0300] MS-ESI[M+H] + , calculated value 720, measured value 720.

[0301] (6) Trifluoroacetic acid (10 μL) was added to a solution of compound 40-5 (100 mg, 138 μmol) in dichloromethane (1.0 mL) at 0.6 °C. The reaction mixture was stirred at 25 °C for 1 hour under nitrogen protection. Methanol (1.0 mL) and aqueous ammonia (1.37 g, 11.6 mmol, 1.50 mL) were added to the reaction mixture and stirred at 40 °C for 0.5 hour under nitrogen protection. Water (50.0 mL) was added to the reaction mixture and extracted with ethyl acetate (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative HPLC (Xtimate C18, 200 mm × 40 mm 7 μm, A: water (formic acid); B: acetonitrile, 0%-32%: 25 min) to obtain the formate salt of compound 40.

[0302] MS-ESI[M+H] +, calculated value 440, measured value 440.

[0303] (7) The formate salt of compound 40 was separated by chiral supercritical fluid chromatography to give compounds 40-P1 and 40-P2.

[0304] Separation conditions: Chromatographic column model: CHIRALPAK AS; Chromatographic column specifications: 250×30mm ID, 10μm; Injection volume: 10.0μL; Mobile phase: A: carbon dioxide, B: ethanol (0.1% ammonia water), B%: 50% elution for 3.0 minutes; Detection wavelength: 254nm; Column temperature: 35℃.

[0305] Compound 40-P1 had a retention time of 1.157 minutes and an ee value of 99.30%.

[0306] MS-ESI[M+H] + , calculated value 440, measured value 440.

[0307] 1 H NMR(400MHz,MeOD)δ7.24-7.32(m,2H),7.01-7.17(m,2H),6.90-7.00(m,1H),5.28(s,1H),4.92(s,1H),4.06(br d,J=15.6Hz,1H),2.83-2.98(m,2H),2.68-2.77(m,1H),2.58(s,3H),2. 51-2.55(m,1H),1.27-1.34(m,1H),0.78-0.93(m,3H),0.64-0.75(m,1H)

[0308] Compound 40-P2 had a retention time of 1.731 minutes and an ee value of 98.58%.

[0309] MS-ESI[M+H] + , calculated value 440, measured value 440.

[0310] 1 H NMR(400MHz,MeOD)δ7.22-7.34(m,2H),7.01-7.16(m,2H),6.92-7.00(m,1H),5.28(s,1H),4.92(s,1H),3.98-4.17(m,1H),2. 82-3.00(m,2H),2.68-2.78(m,1H),2.58(s,3H),2.47-2.55(m,1H),1.27-1.35(m,1H),0.74-0.94(m,3H),0.65-0.74(m,1H).

[0311] Examples 41-47 Synthesis of Compounds 41-P1, 41-P2 to 47-P1, 47-P2

[0312] The preparation of compounds 41-P1, 41-P2 to 47-P1, 47-P2 was carried out by referring to Example 40, using the corresponding amine in place of methylcyclopropylamine.

[0313] Example 48 Synthesis of Compound 48

[0314] (1) Synthesis of Compound 40-9 Reference Example 40. To a solution of compound 40-9 (660 mg, 1.89 mmol) in N,N-dimethylformamide (10.0 mL) was added cesium carbonate (1.54 g, 4.72 mmol) and intermediate F (414 mg, 1.89 mmol) at 60°C. The reaction mixture was stirred for 3 hours under nitrogen. Water (50.0 mL) was added to the reaction mixture, which was extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 1:1) to obtain compound 48-1.

[0315] MS-ESI[M+H] + , calculated value 532, measured value 532.

[0316] (2) To a solution of compound 48-1 (750 mg, 1.41 mmol) in toluene (10.0 mL) were added 2,4-dimethoxybenzylamine (471 mg, 2.82 mmol, 423 μL), cesium carbonate (918 mg, 2.82 mmol), tris(dibenzylideneacetone)dipalladium (129 mg, 140 μmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (175 mg, 281 μmol). The reaction mixture was stirred at 120°C under nitrogen for 12 hours. Water (50.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound 48-2.

[0317] MS-ESI[M+H] + , calculated value 663, measured value 663.

[0318] (3) To a solution of compound 48-2 (900 mg, 1.36 mmol) in tetrahydrofuran (9.0 mL) was added lithium hydroxide monohydrate (3.0 mL, 2 mol / L). The reaction mixture was stirred at 30°C under nitrogen for 12 hours. Aqueous hydrochloric acid was added to the reaction mixture at 0°C to adjust the pH to 7. The mixture was extracted with ethyl acetate (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 48-3.

[0319] MS-ESI[M+H] + , calculated value 650, measured value 650.

[0320] (4) To a solution of compound 48-3 (300 mg, 462 μmol) in N,N-dimethylformamide (5.0 mL) were added diisopropylethylamine (298 mg, 2.31 mmol, 402 μL) and N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (263 mg, 693 μmol). The mixture was stirred at room temperature for 25 minutes, followed by the addition of methylcyclobutylamine hydrochloride (281 mg, 2.31 mmol). The reaction mixture was stirred for 2 hours under nitrogen. Water (30.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / tetrahydrofuran = 1:0 to 2:1) to obtain compound 48-4.

[0321] MS-ESI[M+H] + , calculated value 716, measured value 716.

[0322] (5) Trifluoroacetic acid (1.0 mL) was added to a solution of compound 48-4 (220 mg, 307 μmol) in dichloromethane (3.0 mL) at 0.5 °C. The reaction mixture was stirred at 25 °C for 1 hour under nitrogen protection. Methanol (1.0 mL) and aqueous ammonia (0.91 g, 7.78 mmol, 1.0 mL) were added to the reaction mixture and stirred at 30 °C for 2 hours under nitrogen protection. Water (50.0 mL) was added to the reaction mixture and extracted with ethyl acetate (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative HPLC (Xtimate C18, 200 mm × 40 mm 7 μm, A: water (formic acid); B: acetonitrile, 0%-38%: 25 min) to obtain the formate salt of compound 48.

[0323] MS-ESI[M+H] + , calculated value 436, measured value 436.

[0324] (6) The formate salt of compound 48 was separated by chiral supercritical fluid chromatography to give compounds 48-P1 and 48-P2.

[0325] Separation conditions: Chromatographic column model: CHIRALPAK AS-3; Chromatographic column specifications: 50×4.6mm ID, 3μm; Injection volume: 10.0μL; Mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), B%: 20%-40% gradient elution for 1.5 minutes, 40% fixed concentration elution for 1 minute, 20% fixed concentration elution for 0.5 minutes; Detection wavelength: 254nm; Column temperature: 35℃.

[0326] Compound 48-P1 had a retention time of 0.765 min and an ee value of 99.10%.

[0327] MS-ESI[M+H] + , calculated value 436, measured value 436.

[0328] 1 H NMR (400MHz, CDCl3) δ9.35(br s,1H),7.32-7.38(m,3H),7.15-7.21(m,3H),5.12-5.20(m,1H),4.71(d,J=15.6Hz,1H),4.45(br d,J=2.4Hz,2H),3.88-3.92(m,1H),3.08(s,3H),2.84-2.92(m,1H),2.62(br s,1H),2.58(s,1H),2.43(ddd,J=13.2,9.2,4.0Hz,1H),2.26(br d,J=10.0Hz,1H),2.16(br d,J=10.4Hz,1H),2.02(br d,J=6.8Hz,1H),1.74-1.81(m,1H),1.61(br d,J=11.2Hz,1H),1.43-1.53(m,1H),1.28(br d,J=13.2Hz,1H)

[0329] The retention time of compound 48-P2 was 1.548 minutes, and the ee value was 99.74%.

[0330] MS-ESI[M+H] + , calculated value 436, measured value 436.

[0331] 1H NMR (400MHz, CDCl3) δ9.31 (br s, 1H), 7.24-7.30 (m, 3H), 7.07-7.14 (m, 3H), 5.08 (s, 1H), 4.62 (d, J = 15.6Hz, 1H), 4.45 (br s, 2H), 3.83 (br s,1H),3.00(s,3H),2.75-2.84(m,1H),2.55(br d,J=5.2Hz,1H),2.51(s,1H),2.32-2.38(m,1H),2.13-2.19(m,1H),2.07(s,1H),1.92-1.96(m,1H),1.66-1.74(m,1H),1.53(br d,J=10.0Hz,1H),1.37-1.44(m,1H),1.22-1.27(m,1H).

[0332] Examples 49-51 Synthesis of Compounds 49-P1, 49-P2 to 51-P1, 51-P2

[0333] The preparation of compounds 49-P1, 49-P2 to 51-P1, 51-P2 was carried out by referring to Example 48, using the corresponding amine in place of methylcyclobutylamine.

[0334] Example 52 Synthesis of Compound 52

[0335] Reference Example 48 was synthesized by using Intermediate I instead of Intermediate H to obtain compounds 52-P1 and 52-P2.

[0336] Example 53 Synthesis of Compound 53

[0337] Reference Example 52 was synthesized by using deuterated methylcyclobutylamine instead of methylcyclobutylamine to obtain compounds 53-P1 and 53-P2.

[0338] Example 54 Synthesis of Compound 54

[0339] Reference Example 40 was synthesized by using Intermediate I instead of Intermediate H to obtain compounds 54-P1 and 54-P2.

[0340] Example 55 Synthesis of Compound 55

[0341] Reference Example 54 was synthesized by using deuterated methylcyclobutylamine in place of methylcyclobutylamine to obtain Compound 55.

[0342] MS-ESI[M+H] + , calculated value 459, measured value 459.

[0343] 1 H NMR: (CDCl3, 400MHz) δ8.41 (s, 1H), 7.29-7.37 (m, 2H), 7.06-7.14 (m, 1H), 6.91-7.01 (m, 1H), 6.85 (br d,J=9.6Hz,1H),5.26-5.38(m,1H),3.77-3.99(m,1H),2.78-2.86(m,1H),2.61-2.67(m,2H), 2.37-2.51(m,1H),2.12-2.29(m,3H),1.98-2.08(m,1H),1.57-1.89(m,2H),1.52(br d,J=4.0Hz,1H),1.30-1.42(m,1H).

[0344] Examples 56-59 Synthesis of Compounds 56 to 59

[0345] Compounds 56 to 59 were prepared by referring to Example 4, using the corresponding amine in place of 4-4.

[0346] Examples 60-62 Synthesis of Compounds 60 to 62

[0347] The preparation of compounds 60- to 62 was carried out according to Example 4, using the corresponding tert-butyloxycarbonyl-protected amine in place of 4-4.

[0348] Example 63 Synthesis of Compound 63

[0349] Synthesize Reference Example 4, using Intermediate J instead of Intermediate G to obtain compounds 63-P1 and 63-P2.

[0350] Example 64 Synthesis of Compound 64

[0351] (1) To a solution of compound K (200 mg, 579 μmol) in dichloromethane (4.0 mL) was added thionyl chloride (343 mg, 2.88 mmol). The reaction mixture was stirred under nitrogen for 0.5 h. Aqueous sodium bicarbonate solution (50.0 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 64-1.

[0352] MS-ESI[M+H]+ , calculated value 367, measured value 367.

[0353] (2) To a solution of compound 64-1 (200 mg, 547 μmol) in N,N-dimethylformamide (2.0 mL) was added cesium carbonate (534 mg, 1.64 mmol) and intermediate A (130 mg, 547 μmol). The reaction mixture was stirred at 50°C for 2 hours under nitrogen. Water (10.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 2:1) to obtain compound 64-2.

[0354] MS-ESI[M+H] + , calculated value 566, measured value 566.

[0355] (3) To a solution of compound 64-2 (130 mg, 229 μmol) in toluene (5.0 mL) were added 2,4-dimethoxybenzylamine (95.9 mg, 574 μmol), cesium carbonate (150 mg, 459 μmol), tris(dibenzylideneacetone)dipalladium (21.0 mg, 22.9 μmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (28.6 mg, 45.9 μmol). The reaction mixture was stirred at 120°C under nitrogen for 3 hours. Water (50.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound 64-3.

[0356] MS-ESI[M+H] + , calculated value 697, measured value 697.

[0357] (4) To a solution of compound 64-3 (130 mg, 186 μmol) in tetrahydrofuran (2.0 mL) was added lithium hydroxide monohydrate (39.1 mg, 932 μmol). The reaction mixture was stirred under nitrogen at 25°C for 12 hours. Aqueous hydrochloric acid was added to the reaction mixture at 0°C to adjust the pH to 7. The mixture was extracted with dichloromethane (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 64-4.

[0358] (5) To a solution of compound 64-4 (100 mg, 146 μmol) in N,N-dimethylformamide (2.0 mL) were added diisopropylethylamine (75.7 mg, 585 μmol) and N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (83.5 mg, 220 μmol). The mixture was stirred at room temperature for 25 minutes, followed by the addition of compound 64-5 (47.3 mg, 293 μmol). The reaction mixture was stirred for 3 hours under nitrogen. Water (30.0 mL) was added to the reaction mixture, which was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative HPLC (Xtimate C18, 200 mm × 40 mm 7 μm, A: water (formic acid); B: acetonitrile, 0%-18%: 25 minutes) to obtain compound 64-6.

[0359] MS-ESI[M+H] + , calculated value 790, measured value 790.

[0360] (5) Trifluoroacetic acid (500 μL) was added to a solution of compound 64-6 (28.0 mg, 35.4 μmol) in dichloromethane (1.0 mL) at 0.5 °C. The reaction mixture was stirred at 25 °C for 1 hour under nitrogen protection. Methanol (1.0 mL) and aqueous ammonia (1.0 mL) were added to the reaction mixture and stirred at 25 °C for 8 hours under nitrogen protection. Water (50.0 mL) was added to the reaction mixture and extracted with ethyl acetate (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative HPLC (Xtimate C18, 200 mm × 40 mm 7 μm, A: water (formic acid); B: acetonitrile, 40%-50%: 25 min) to obtain the formate salt of compound 64.

[0361] MS-ESI[M+H] + , calculated value 510, measured value 510.

[0362] 1 H NMR(400MHz, CDCl3)δ9.11-9.31(m,1H),7.47(br s,1H),7.33-7.43(m,1H),7.03-7.18(m,2H),6.93-7.02(m,1H),5.49-5.58(m,1H),4.58-4.62(m,2 H),4.22-4.31(m,2H),3.77-3.97(m,1H),3.57-3.72(m,1H),3.03-3.32(m,1H),2.51-2.69(m,4H).

[0363] Example 65 Synthesis of Compounds 65, 93, and 94

[0364] The preparation of compounds 65, 93, and 94 was carried out by referring to Example 64, using the corresponding amine in place of 64-5.

[0365] Examples 66-74 Synthesis of Compounds 66-P1, 66-P2 to 74-P1, 74-P2

[0366] The preparation of compounds 66-P1, 66-P2 to 74-P1, 74-P2 was carried out by referring to Example 64, using the corresponding amine in place of compound 64-5, and performing chiral separation.

[0367] Examples 75-76 Synthesis of Compounds 75-P1, 75-P2 to 76-P1, 76-P2

[0368] The preparation of compounds 75-P1, 75-P2 to 76-P1, 76-P2 was carried out by referring to Example 64, using the corresponding tert-butyloxycarbonyl-protected amine in place of compound 64-5, and performing chiral separation.

[0369] Example 77 Synthesis of Compound 77

[0370] (1) Synthesis of Compound 64-1: Refer to Example 64. To a solution of compound 64-1 (1.14 g, 5.19 mmol) in N,N-dimethylformamide (25.0 mL) was added cesium carbonate (1.54 g, 4.72 mmol) and intermediate F (1.90 g, 5.19 mmol). The reaction mixture was stirred under nitrogen for 2 hours. Water (50.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound 77-1.

[0371] MS-ESI[M+H] + , calculated value 548, measured value 548.

[0372] 1H NMR(400MHz, CDCl3)δ7.75(s,1H),7.27-7.30(m,1H),7.23-7.27(m,2H),7 .16-7.21(m,2H),6.01(s,1H),5.38(s,2H),4.71-4.82(m,1H),4.54-4.66( m,1H),3.66(s,3H),3.45(t,J=8.4Hz,2H),2.90(ddd,J=12.8,8.0,4.8Hz,1 H),2.51-2.59(m,2H),2.36-2.48(m,1H),0.85-0.88(m,2H),-0.04(s,9H).

[0373] (2) To a solution of compound 77-1 (1.98 g, 3.61 mmol) in toluene (20.0 mL) were added 2,4-dimethoxybenzylamine (1.51 g, 9.02 mmol), cesium carbonate (2.35 g, 7.22 mmol), tris(dibenzylideneacetone)dipalladium (331 mg, 361 μmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (450 mg, 722 μmol). The reaction mixture was stirred at 120°C for 3 hours under nitrogen protection. Water (50.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound 77-2.

[0374] MS-ESI[M+H] + , calculated value 679, measured value 679.

[0375] 1H NMR (400MHz, CDCl3) δ7.43-7.53(m,1H),7.28-7.33(m,3H),7.16-7.23(m,2H) ,6.49(d,J=2.4Hz,1H),6.42-6.47(m,1H),6.05(s,1H),5.31(s,2H),5.23(br t,J=5.6Hz,1H),5.19(s,1H),4.80(d,J=16.0Hz,1H),4.62(dd,J=5.6,2.0Hz,2H),4.53(d,J=16.0Hz,1H),3.86(s,3H),3.81(s,3H),3.57( s,3H),3.39(t,J=8.0Hz,2H),2.92(dt,J=13.2,6.4Hz,1H),2.49-2.60(m,2H),2.29-2.37(m,1H),0.78-0.88(m,2H),-0.11--0.01(m,9H).

[0376] (3) To a solution of compound 77-2 (2.50 g, 3.68 mmol) in tetrahydrofuran (16.0 mL) was added lithium hydroxide monohydrate (1.08 g, 25.8 mmol). The reaction mixture was stirred at 25°C under nitrogen for 4 hours. Aqueous hydrochloric acid was added to the reaction mixture at 0°C to adjust the pH to 7. The mixture was extracted with ethyl acetate (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 77-3.

[0377] MS-ESI[M+H] + , calculated value 665, measured value 665.

[0378] 1 H NMR (400MHz, CDCl3) δ7.46(s,1H),7.34(d,J=7.2Hz,2H),7.16-7.27(m,4H),6.47(d,J=2.4Hz,1H),6.35-6.40(m,2H),5.31-5.33(m,2H),5.15 (d,J=12.0Hz,1H),4.93(d,J=16.0Hz,1H),4.55(s,3H),3.83(s,3H),3. 79(s,3H),3.37(t,J=8.0Hz,2H),2.96-3.06(m,1H),2.44-2.71(m,2H), 2.22-2.35(m,1H),0.77-0.85(m,2H),-0.08(s,9H).

[0379] (4) To a solution of compound 77-3 (160 mg, 241 μmol) in N,N-dimethylformamide (4.0 mL) were added diisopropylethylamine (218 mg, 1.68 mmol) and N,N,Nm,N,-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (137 mg, 361 μmol), and the mixture was stirred at room temperature for 25 minutes. Methylcyclobutylamine hydrochloride (146 mg, 1.20 mmol) was then added, and the reaction mixture was stirred for 2 hours under nitrogen. Water (30.0 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane / methanol = 1:0 to 30:1) to obtain compound 77-4.

[0380] MS-ESI[M+H] + , calculated value 732, measured value 732.

[0381] (5) Trifluoroacetic acid (1.0 mL) was added to a solution of compound 77-4 (190 mg, 259 μmol) in dichloromethane (1.0 mL) at 0.5 °C. The reaction mixture was stirred at 25 °C for 1 hour under nitrogen protection. Methanol (1.0 mL) and ammonia water (0.91 g, 7.78 mmol, 1.00 mL) were added to the reaction mixture and stirred at 30 °C for 8 hours under nitrogen protection. Water (50.0 mL) was added to the reaction mixture and extracted with ethyl acetate (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative high performance liquid chromatography (Xtimate C18, 200 mm × 40 mm 7 μm, A: water (ammonia water); B: acetonitrile, 18%-58%: 25 min) to obtain compound 77.

[0382] MS-ESI[M+H] + , calculated value 452, measured value 452.

[0383] (7) Compound 77 was separated by chiral supercritical fluid chromatography to give compounds 77-P1 and 77-P2.

[0384] Examples 78-81 Synthesis of Compounds 78-P1, 78-P2 to 81-P1, 81-P2

[0385] The preparation of compounds 78-P1, 78-P2 to 81-P1, 81-P2 was carried out by referring to Example 77, using the corresponding amine in place of methylcyclobutylamine.

[0386] Example 82 Synthesis of Compound 82

[0387] The preparation of compound 82 was carried out by referring to Example 77, using the corresponding tert-butyloxycarbonyl-protected amine in place of methylcyclobutylamine.

[0388] Example 83 Synthesis of Compound 83

[0389] Reference Example 77 was synthesized by using Intermediate I instead of Intermediate H to obtain compounds 83-P1 and 83-P2.

[0390] Example 84 Synthesis of Compound 84

[0391] Reference Example 83 was synthesized by using deuterated methylcyclobutylamine instead of methylcyclobutylamine to obtain compounds 84-P1 and 84-P2.

[0392] Example 85 Synthesis of Compound 85

[0393] Reference Example 85 was synthesized by using 2-azaspiro[3.3]heptane instead of methylcyclobutylamine to give compounds 85-P1 and 85-P2.

[0394] Example 86 Synthesis of Compound 86

[0395] Reference Example 85 was synthesized by using Intermediate I instead of Intermediate H to obtain compounds 86-P1 and 86-P2.

[0396] Examples 87-89 Synthesis of Compounds 87-P1, 87-P2 to 89-P1, 89-P2

[0397] Compounds 87-P1, 87-P2 to 89-P1, 89-P2 were prepared by referring to Example 86, using the corresponding amine in place of 2-azaspiro[3.3]heptane.

[0398] Example 90 Synthesis of Compound 90

[0399] (1) Compound 90-2 (538 mg, 6.27 mmol), potassium phosphate (2.56 g, 12.1 mmol), palladium acetate (108 mg, 482 μmol), and tricyclohexylphosphine (946 mg, 3.37 mmol, 1.09 mL) were added to a toluene (15 mL) solution of compound 90-1 (1.00 g, 4.82 mmol). The reaction mixture was stirred at 120°C under nitrogen for 12 hours. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 0:1) to obtain compound 90-3.

[0400] MS-ESI[M+H] + , calculated value 169, measured value 169.

[0401] 1 H NMR (400MHz, CDCl3) δ7.67 (d, J = 2.8 Hz, 1H), 6.56 (d, J = 2.8 Hz, 1H), 2.05-2.14 (m, 1H), 0.99-1.07 (m, 2H), 0.60-0.68 (m, 2H).

[0402] (2) To a solution of compound 90-3 (500 mg, 2.97 mmol) in acetonitrile (10.0 mL) was added N-bromosuccinimide (528 mg, 2.97 mmol) at 0.2 °C. The reaction mixture was stirred for 1 hour under nitrogen. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 0:1) to obtain compound 90-4.

[0403] MS-ESI[M+H] + , calculated value 249, measured value 249.

[0404] 1 H NMR (400MHz, CDCl3) δ6.58 (s, 1H), 4.02 (br s, 2H), 2.05 (tt, J = 8.4, 5.3Hz, 1H), 1.01-1.08 (m, 2H), 0.60-0.67 (m, 2H).

[0405] (3) To a solution of compound 90-4 (550 mg, 2.22 mmol) in dioxane (8.0 mL) were added pyruvic acid (587 mg, 6.67 mmol), triethylamine (967 mg, 9.55 mmol, 1.33 mL), palladium acetate (99.8 mg, 444 μmol), and triphenylphosphine (117 mg, 444 μmol). The reaction mixture was stirred at 100°C under nitrogen for 12 hours. Aqueous sodium hydroxide solution (50.0 mL, 2 mol / L) was added to the reaction mixture, which was washed with methyl tert-butyl ether (200 mL). The organic phase was extracted with aqueous sodium hydroxide solution (30.0 mL, 2 mol / L). The combined aqueous phases were acidified with dilute hydrochloric acid until a brown solid precipitated, which was then filtered to obtain compound 90-5.

[0406] MS-ESI[M+H] + , calculated value 237, measured value 237.

[0407] 1 H NMR (400MHz, CDCl3) δ11.97(br s,1H),7.45(s,1H),7.01(s,1H),2.15(tt,J=8.4,5.2Hz,1H),1.01-1.07(m,2H),0.67-0.72(m,2H).

[0408] (4) To a solution of compound 90-5 (470 mg, 1.99 mmol) in methanol (5.0 mL) was added sulfuric acid (584 mg, 5.96 mmol, 318 μL). The reaction mixture was stirred under nitrogen for 12 hours. Aqueous sodium bicarbonate solution was added to the reaction mixture to adjust the pH to 8, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 6:1) to obtain compound 90-6.

[0409] MS-ESI[M+H] + , calculated value 251, measured value 251.

[0410] (5) Potassium bis(trimethylsilyl)amide (1.6 mL, 1 mol / L) was added to a solution of compound 90-6 (200 mg, 798 μmol) in tetrahydrofuran (3.0 mL) at 0.5 °C. The reaction mixture was stirred at 5 °C for 0.5 h under nitrogen protection. 2-(Trimethylsilyl)ethoxymethyl chloride (200 mg, 1.20 mmol, 212 μL) was added and continued to stir at 5 °C for 1 h under nitrogen protection. Aqueous ammonium chloride solution (20.0 mL) was added to the reaction mixture and extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 6:1) to obtain compound 90-7.

[0411] MS-ESI[M+H] + , calculated value 381, measured value 381.

[0412] (6) To a solution of compound 90-7 (195 mg, 512 μmol) in dichloromethane (4.0 mL) was added diisobutylaluminum hydride (1.28 mL, 1 mol / L). The reaction mixture was stirred at 25°C under nitrogen for 0.5 h. Aqueous hydrochloric acid (5.0 mL, 1 mol / L) was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound 90-8.

[0413] (7) To a solution of compound 90-8 (170 mg, 482 μmol) in dichloromethane (2.0 mL) was added thionyl chloride (115 mg, 963 μmol, 70.1 μL). The reaction mixture was stirred under nitrogen at 25°C for 0.5 h. Aqueous sodium bicarbonate solution (50.0 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 90-9.

[0414] MS-ESI[M+H] + , calculated value 371, measured value 371.

[0415] (8) To a solution of compound 90-9 (173 mg, 466 μmol) in N,N-dimethylformamide (3.0 mL) was added cesium carbonate (455 mg, 1.40 mmol) and intermediate F (102 mg, 466 μmol). The reaction mixture was stirred at 60°C for 2 hours under nitrogen. Water (10.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 2:1) to obtain compound 90-10.

[0416] MS-ESI[M+H] + , calculated value 554, measured value 554.

[0417] (9) To a solution of compound 90-10 (80.0 mg, 144 μmol) in toluene (5.0 mL) were added 2,4-dimethoxybenzylamine (48.3 mg, 289 μmol, 43.4 μL), cesium carbonate (94.1 mg, 289 μmol), tris(dibenzylideneacetone)dipalladium (13.2 mg, 14.4 μmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (18.0 mg, 29.0 μmol). The reaction mixture was stirred at 120°C under nitrogen for 16 hours. Water (50.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound 90-11.

[0418] MS-ESI[M+H] + , calculated value 685, measured value 685.

[0419] (10) To a solution of compound 90-11 (67.0 mg, 97.8 μmol) in tetrahydrofuran (1.5 mL) was added lithium hydroxide monohydrate (2 mol / L, 0.50 mL). The reaction mixture was stirred under nitrogen at 25°C for 12 hours. Aqueous hydrochloric acid was added to the reaction mixture at 0°C to adjust the pH to 7. The mixture was extracted with dichloromethane (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 90-12.

[0420] MS-ESI[M+H] + , calculated value 671, measured value 671.

[0421] (11) To a solution of compound 90-12 (70.0 mg, 104 μmol) in N,N-dimethylformamide (2.0 mL) were added diisopropylethylamine (12.7 mg, 104 μmol) and N,N,N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (59.5 mg, 157 μmol). The mixture was stirred at room temperature for 25 minutes, followed by the addition of methylcyclobutylamine (47.3 mg, 293 μmol). The reaction mixture was stirred for 3 hours under nitrogen. Water (30.0 mL) was added to the reaction mixture, which was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / tetrahydrofuran = 1:0 to 30:1) to obtain compound 90-13.

[0422] MS-ESI[M+H] + , calculated value 738, measured value 738.

[0423] (11) Trifluoroacetic acid (500 μL) was added to a solution of compound 90-13 (80.0 mg, 108 μmol) in dichloromethane (3.0 mL) at 0.1 °C. The reaction mixture was stirred at 25 °C for 1 hour under nitrogen protection. Methanol (1.0 mL) and aqueous ammonia (1.0 mL) were added to the reaction mixture and stirred at 25 °C for 8 hours under nitrogen protection. Water (50.0 mL) was added to the reaction mixture and extracted with ethyl acetate (50.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative HPLC (F-Prepulite XP tC, 200 mm × 40 mm 7 μm, A: water (formic acid); B: acetonitrile, 0%-40%: 25 min) to obtain the formate salt of compound 90.

[0424] MS-ESI[M+H] + , calculated value 458, measured value 458.

[0425] 1 H NMR (400MHz, CDCl3) δ8.75(s,1H),7.40-7.44(m,2H),7.34-7.38(m,2H),7.12-7.17(m,2H),6.90-7.03(m,1H),5.30-5.35(m,1H),4.58(br d,J=15.6Hz,1H),3.90-3.94(m,1H),3.07(s,3H),2.83-2.93(m,1H),2.61-2.65(m,1H),2.58-2.60(m,1H),2.43( ddd,J=13.2,8.8,4.4Hz,1H),2.22-2.27(m,1H),2.11-2.18(m,1H),1.96-2.08(m,1H),1.59-1.70(m,2H),1.48(br s,1H),1.27-1.36(m,1H),0.96-1.00(m,2H),0.57-0.60(m,2H).

[0426] Example 91 Synthesis of Compound 91

[0427] Compound 91 was prepared by referring to Example 77, using Intermediate M instead of Intermediate K, and without chiral resolution.

[0428] Example 92 Synthesis of Compound 92

[0429] Compound 92 was prepared by referring to Example 77, using Intermediate N instead of Intermediate K, and without chiral resolution.

[0430] Example 95 Synthesis of Compound 95

[0431] Compound 71 (150 mg, 0.33 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborane (151.02 mg, 0.98 mmol) were dissolved in water (0.3 mL) and dioxane (3 mL). Cesium carbonate (266.23 mg, 0.82 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (138.97 mg, 0.16 mmol) were added to the reaction solution, which was then stirred at 110°C under nitrogen for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was stripped of the solvent under reduced pressure. Purification by column chromatography (dichloromethane:methanol=10:1) gave Compound 95.

[0432] MS-ESI[M+H] + , calculated value 451, measured value 451.

[0433] 1 H NMR (400MHz, CDCl3) δ9.66-9.43(m,1H),7.59-7.48(m,1H),7.40-7.31(m,1H),7.16-7.08(m,1H),7.05-6.87(m,2H),6.75 -6.64(m,1H),5.68-5.59(m,1H),5.48-5.14(m,4H),4.80-4.67(m,1H),4.12-4.00(m,1H),2.67(m,5H),1.05-0.82(m,4H).

[0434] Example 96 Synthesis of Compound 96

[0435] Compound 95 (25 mg, 0.06 mmol) was dissolved in methanol (2 mL), and palladium on carbon (20 mg, 0.19 mmol, 10%) was added to the reaction mixture. The reaction mixture was stirred at 25°C for 3 hours under a 15 psi hydrogen atmosphere. After monitoring the reaction completion, the reaction mixture was filtered through a filter, and the solvent was removed from the filtrate under reduced pressure to obtain the crude product. The crude product was then purified by high-performance liquid chromatography (Waters-Xbridge-C18, 250 mm × 19 mm 10 μm, A: water (10 mM NH4HCO3 / H2O); B: acetonitrile, 80%-50%-80%: 0-11.3-17.4 (min)) to obtain compound 96.

[0436] MS-ESI[M+H] + , calculated value 453, measured value 453.

[0437] 1 H NMR(400MHz, CDCl3)δ9.25(s,1H),7.32-7.27(m,2H),7.16-7.07(m,1H),7.06-6.86(m,2H),5.49-5.17(m,2H),4.80(d,J=16Hz,1H) ,4.60(s,2H),4.05(d,J=16Hz,1H),3.00-2.72(m,2H),2.58-2.47(m,4H),1.28-1.27(m,3H),1.00-0.86(m,2H),0.79-0.66(m,2H).

[0438] Biological Experiment Examples

[0439] I.HCT116 MTAP - / - and HCT 116 wt Cell proliferation inhibitory activity

[0440] Experimental Principle: HCT116 MTAP - / - Cellular MTAP is deficient and MTA levels are elevated; HCT 116 wt These two cell lines were used to determine whether the compounds exhibited synergistic MTA inhibitory activity.

[0441] Experimental materials: HCT116 MTAP - / - and HCT 116 wtCells were purchased from Horizon; CellTiter-Glo reagent was purchased from Promega (catalog number G7571); RPMI-1640 was purchased from ATCC (catalog number 30-2001); fetal bovine serum (FBS) was purchased from EXCELL (catalog number FND500); penicillin-streptomycin was purchased from Gibco (catalog number 15140-122); 0.25% trypsin-ethylenediaminetetraacetic acid digestion solution (Trypsin-EDTA) was purchased from Gibco (catalog number 25200-072); dimethyl sulfoxide (DMSO) was purchased from Sigma (catalog number D2650); 96-well plates were purchased from Corning (catalog number 3610); incubator was purchased from NuAire (model NU-5700E); inverted microscope was purchased from Nikon (model TS-100); and automatic cell counter was purchased from Life technologies (model Countess). II); the microplate reader was purchased from PerkinElmer (model: Envision); and the data processing software was GraphPad Prism 5.0.

[0442] Test method: HCT116 MTAP in the logarithmic growth phase - / - or HCT116 wt The cells were resuspended in growth medium (RPMI-1640 + 10% FBS) and diluted to the target density (5000 / mL). 100 μL of the cell suspension was seeded into a 96-well plate per well; the suspension was incubated overnight in a 2% incubator at 37°C. The culture medium served as the background control. The cells were starved with 80 μL of serum-free culture medium for 4 hours. The test compound was dissolved in DMSO and prepared into a stock solution with a concentration of 10 mmol / L. The stock solution was first diluted to 2 mmol / L (200X) with DMSO, and then diluted 3-fold for a total of 10 concentrations. 3 μL of the above solution of each concentration was taken and diluted with 297 μL of growth medium (2X). Then 80 μL / well was added to the 96-well plate seeded with cells. The cells with the test compound were placed in a 37°C, 5% CO2 incubator and incubated for 120 hours. The 96-well plate was balanced at room temperature, 40 μL of CellTiter-Glo reagent was added to each well, mixed on a vortexer for 2 minutes, and incubated at room temperature for 60 minutes. The luminescence value was read using an EnVision microplate reader, and the IC value of the compound was calculated using GraphPad Prism 5.0 software. 50 The results are shown in Table 2. A represents IC 50 <100nM, B represents 100nM <IC 50 <1μM, C represents 1μM <IC 50 <10μM, D represents IC 50>10μM.

[0443] Table 2

[0444] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form or a combination thereof, in, R 1 , R 2 Each is independently hydrogen, halogen, cyano, hydroxyl, C1-C3 alkyl, C1-C3 haloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, C2-C4 haloalkynyl, 3-6 membered cycloalkyl, 3-6 membered halocycloalkyl, 3-6 membered heterocyclyl, C1-C3 alkoxy, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, C1-C6 alkyl- S-, -S(O)2-C1-C6 alkyl, -S(O)-C1-C6 alkyl, -S(O)2NH2, -S(O)2NH(C1-C6 alkyl), -NHS(O)2(C1-C6 alkyl), -C(O)H, -C(O)-C1-C6 alkyl, -C(O)-3-6 cycloalkyl, -C(O)-3-6 membered heterocyclyl, -C(O)O-C1-C6 alkyl, -CONR 1a R 1b (where R 1a and R 1b is H, D, C1-C3 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl), -SF5, -P(O)(C1-C3 alkyl)2; wherein the alkyl, cycloalkyl and heterocyclyl may be further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, C1-C3 alkyl; Ring A is an optionally substituted 5-7 membered heterocyclic group, an optionally substituted benzene ring or an optionally substituted 5-7 membered heteroaromatic ring; the substitution refers to the substitution of one or more R A Replace; each R A independently selected from hydrogen, deuterium, C1-C4 alkyl, halogenated C1-C4 alkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, oxo, halogen, C1-C4 alkoxy, hydroxyl and amino; R 3 for L 1 is absent, C1-C3 alkylene or C1-C3 haloalkylene; n is the number of methylene groups, and n is selected from 0, 1, 2, 3, and 4; R 4 is an optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, an optionally substituted C3-C12 carbocyclyl, an optionally substituted C3-C12 heterocyclyl, an optionally substituted 6-10 membered aromatic ring group or an optionally substituted 5-10 membered aromatic heterocyclyl; the substitution refers to substitution by one or more R; R 5 is an optionally substituted C1-C6 alkyl, an optionally substituted C3-C12 carbocyclic group, an optionally substituted C3-C12 heterocyclic group, an optionally substituted 6-10 membered aromatic ring, an optionally substituted 5-10 membered heteroaromatic ring, -NR a R b 、-OR a or -SR a ; Each R a and R b Each is independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted C3-C6 heterocyclyl, optionally substituted 6-10 aromatic ring or optionally substituted 5-10 membered aromatic heterocycle; the substitution refers to substitution by one or more R; Each R 6 Each is independently hydrogen, halogen, hydroxy, C1-C3 alkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl, C3-C4 halocycloalkyl, C1-C3 alkoxy, -NH2, -NH(C1-C3 alkyl) or -N(C1-C3 alkyl)2; m is R 6 The number of , m is selected from 0, 1, 2, 3, 4; R 7 , R 8 are each independently hydrogen, deuterium, C1-C3 alkyl, C1-C3 haloalkyl, 3-4 membered cycloalkyl or 3-4 membered halocycloalkyl; or R 7 , R 8 It forms a 3-5 membered carbocyclic ring with the carbon atom it is connected to; Each R is independently selected from: H, deuterium, halogen, cyano, amino, hydroxyl, nitro, oxo thio(=S), —SF5, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, —OC2-C6 alkenyl, —O cycloalkyl, —O heterocyclyl, —O-aryl, —O-heteroaryl, —N(optionally substituted C1-C6 alkyl)2, —NH(optionally substituted C1-C6 alkyl), —N(optionally substituted C1-C6 alkyl)(optionally substituted C1-C6 alkylphenyl), —NH(optionally substituted C1-C6 alkylphenyl), —N(C1-C6 alkyl)(aryl), —N(C1-C6 alkyl)(heteroaryl), —NH(aryl), —NH(heteroaryl), —P(O)(C1-C3 alkyl)2, optionally substituted C1-C6 alkyl-S—, —S(O)2-optionally substituted C1-C6 alkyl The invention further comprises the following: -S(O)-optionally substituted C1-C6 alkyl, -S(O)-optionally substituted C1-C6 alkyl, -S(O)-optionally substituted phenyl, -S(O)2NH2, -S(O)2NH(optionally substituted C1-C6 alkyl), -S(O)2NH(optionally substituted phenyl), -NHS(O)2(optionally substituted C1-C6 alkyl), -NHS(O)2(optionally substituted phenyl), optionally substituted C3-C16 carbocyclyl, optionally substituted 4-16 membered heterocyclyl, optionally substituted C6-C16 aryl or optionally substituted 5-16 membered heteroaryl; or any two adjacent R and the atoms connected thereto form an optionally substituted 4-8 membered heterocyclyl or an optionally substituted C3-C8 membered carbocyclyl; wherein the substitution in R refers to substitution by one or more groups selected from the group consisting of: H, deuterium, halogen, cyano, amino, hydroxyl, nitro, oxo Thio (= S), -SF5, -P(O)(C1-C3 alkyl)2, R' substituted or unsubstituted C1-C6 alkyl, R' substituted or unsubstituted C1-C6 alkoxy, R' substituted or unsubstituted C1-C6 alkylsulfone, R' substituted or unsubstituted C3-C16 carbocyclyl, R' substituted or unsubstituted 4-16 membered heterocyclyl, R' substituted or unsubstituted C6-C16 aryl, R' substituted or unsubstituted 5-16 membered heteroaryl, -NH(R' substituted or unsubstituted C1-C6 alkyl), -N(R' substituted or unsubstituted C1-C6 alkyl)2, -CH2-NH(R' substituted or unsubstituted C1-C6 alkyl ) and -CH2-N(R' substituted or unsubstituted C1-C6 alkyl)2, wherein R' is selected from one or more groups of the following groups: H, halogen, deuterium (D), halogen, -OH, nitro, amino, oxo (=O), mercapto, cyano, -CD3, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and 4-8 membered heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl is optionally further substituted with one or more substituents selected from the following: H, deuterium, C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, oxo (=O), -N H2, -N(R" substituted or unsubstituted C1-C6 alkyl)2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkylphenyl), -NH(C1-C6 alkylphenyl), -N(C1-C6 alkyl)(aryl), -NH(aryl), C3-C8 cycloalkyl, 4-8 membered heterocyclyl, C1-C4 haloalkyl-, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, cyano, nitro, -C(O)-OH, -C(O)OC1-C6 alkyl, -CON(C1-C6 alkyl)2, -CONH(C1-C8 cycloalkyl), -C6 alkyl), -CONH2, -NHC(O)(C1-C6 alkyl), -NH(C1-C6 alkyl)C(O)(C1-C6 alkyl), -SO2(C1-C6 alkyl), -SO2(phenyl), -SO2(C1-C6 haloalkyl), -SO2NH2, -SO2NH(C1-C6 alkyl), -SO2NH(phenyl), -NHSO2(C1-C6 alkyl), -NHSO2(phenyl), -NHSO2(C1-C6 haloalkyl) or -C1-C6 alkyl-NH2, wherein R" is selected from one or more groups of the following group: H, halogen, cyano, amino, hydroxyl, oxo C1-C6 alkyl and C1-C6 alkoxy; Indicates the attachment position of the group.

2. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form or a combination thereof, characterized in that: Ring A is selected from the group consisting of an optionally substituted benzene ring, an optionally substituted pyridine, an optionally substituted thiophene, an optionally substituted pyrrole, an optionally substituted furan, an optionally substituted imidazole, an optionally substituted pyrazole and an optionally substituted thiazole; preferably, Ring A is an optionally substituted pyrrole; the substitution refers to the substitution of one or more R A Replace; each R A Independently selected from hydrogen, deuterium, C1-C4 alkyl, halogenated C1-C4 alkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, oxo, halogen, C1-C4 alkoxy, hydroxyl and amino.

3. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form or a combination thereof, characterized in that: R 1 is hydrogen, halogen, cyano, C1-C3 alkyl, C1-C3 haloalkyl, 3-4 membered cycloalkyl, -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2; R 2 It is hydrogen, halogen, cyano, C1-C3 alkyl.

4. [Corrected 28.06.2024 in accordance with Rule 26] A compound as claimed in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form or a combination thereof, characterized in that: L 1 is absent or methylene; n is selected from 1 and 2; R 4 is an optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, an optionally substituted C3-C8 carbocyclyl, an optionally substituted C3-C8 heterocyclyl, an optionally substituted benzene ring or an optionally substituted 5-7 membered aromatic heterocyclyl; the substitution refers to substitution by one or more R; R 5 is an optionally substituted C1-C6 alkyl, an optionally substituted C3-C8 carbocyclic group, an optionally substituted C3-C8 heterocyclic group or -NR a R b ; Each R a and R b Each is independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted C3-C6 heterocyclyl, optionally substituted 6-10 aromatic ring or optionally substituted 5-10 membered aromatic heterocycle; the substitution refers to substitution by one or more R; R is as defined in claim 1.

5. [Corrected 28.06.2024 in accordance with Rule 26] A compound as claimed in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, deuterated form or a combination thereof, characterized in that: The compound is selected from the group consisting of:

6. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: (1) a therapeutically effective amount of one or more selected from the group consisting of the compound described in any one of claims 1 to 5, and pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, cis-trans isomers, solvates, polymorphs and deuterated substances thereof as an active ingredient; and (2) Optional pharmaceutically acceptable carrier.

7. The compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph or deuterated substance or the pharmaceutical composition according to claim 6 for use in the preparation of a pharmaceutical composition for preventing or treating MTAP - / - Use in medicine for treating related cancers.

8. The use according to claim 7, characterized in that The cancer is selected from the group consisting of liver cancer, breast cancer, skin cancer, pancreatic cancer, head and neck cancer, intestinal cancer, lung cancer, gastric cancer, esophageal cancer, kidney cancer, bladder cancer, urethral cancer, prostate cancer, testicular cancer, uterine cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, bile duct cancer, multiple myeloma, spinal neurofibroma, astrocytoma, glioma, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and sarcoma.

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