Pyrazolopyrimidine compounds and salts, solvates, compositions and uses thereof

Abstract

The present invention relates to pyrazolopyrimidine methotransferase 2a inhibitors and methods for their preparation. In particular, the compounds of the invention have the structure of Formula I, wherein the various groups and substituents are as described in the specification. Methods for the preparation of the compounds and their use in the treatment of cell proliferative diseases, particularly cancer, are also disclosed.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of biological medicine, in particular to a class of pyrazolopyrimidine metabolic enzyme methionine adenosyltransferase 2a (MAT2A) inhibitors and a preparation method thereof, which have good enzyme activity and tumor cell proliferation inhibition effect on MAT2A. BACKGROUND

[0002] The methionine thioadenosine phosphorylase (MTAP) gene is located near the CDKN2A tumor suppressor and is co-encoded with CDKN2A in about 15% of cancers, resulting in reduced tumor treatment effect, but there is currently no effective molecular targeted therapy. MAT2A plays an important role in the metabolism and epigenetics of tumors, and it produces the methyl donor S-adenosyl methionine (SAM). Studies have shown that the depletion of MAT2A using RNA interference can lead to the treatment of cancers caused by MTAP deletion. The explanation for this is that when the MTAP gene is deleted, its metabolite 5'-methylthioadenosine (MTA) accumulates, thereby inhibiting the activity of type II arginine methyltransferase PRMT5, which utilizes SAM, and the catalytic activity of the PRMT5 enzyme is more easily inhibited further by the reduction of SAM levels. MAT2A inhibitors effectively reduce the level of SAM in cells by blocking the de novo biosynthesis of SAM. Using pharmacological inhibitors of MAT2A, researchers have verified MAT2A as a synthetic lethal target in MTAP-deleted cancers, demonstrating the inhibition of cancer cell proliferation in vitro and tumor growth in vivo. The biological consequences of MAT2A inhibition of MTAP-deleted cancer cells are described, including genotype-selective effects on intracellular PRMT5 activity and mRNA splicing, ultimately leading to cell cycle defects and reduced proliferation. Therefore, targeting MAT2A to treat MTAP-deleted cancers is a successful application of synthetic lethality and a potential treatment that can treat a large number of cyclin-dependent kinase inhibitor 2A (CDKN2A) / MTAP site deletion patients. Although targeting MAT2A is beneficial in cancers caused by MTAP deletion, it has been challenging to design effective MAT2A inhibitors.

[0003] Currently, there is no drug on the market targeting this target, and it is urgent to develop a new type of MAT2A inhibitor with excellent cell and in vivo activity and strong stability. SUMMARY

[0004] The present application aims to provide a compound having MAT2A inhibitory activity and a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, a pharmaceutical composition comprising the compound, and the compounds in the preparation of a medicament for treating cell proliferative diseases, particularly cancer, and other diseases related to MAT2A activity.

[0005] In a first aspect of the present application, a compound represented by Formula I, or an isomer, a pharmaceutically acceptable salt thereof,

[0006]

[0007] wherein,

[0008] X is selected from -CR A R B R C , NR A R B , OR A , SR A , CN, F, or X and R1 together with the carbon atom to which they are attached form a substituted or unsubstituted 5-7 membered carbocyclic or heterocyclic ring, spiro, bridged or fused ring, and the substituted or unsubstituted 5-7 membered carbocyclic or heterocyclic ring, spiro, bridged or fused ring contains 0 or 0 or more (1, 2, 3) heteroatoms;

[0009] R1, R2 are each independently selected from H, halogen, -CR A R B R C , -NR C R D , -OR C , -SR C , -L1-L2-L3-R E , carbonyl, ester, carboxyl, nitro, cyano, carbamoyl, halogenformyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C5-C12 heterocyclyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C6-C10 heteroaryl, or R1 and R2 together with the carbon atom to which they are attached form a substituted or unsubstituted 5-7 membered carbocyclic or heterocyclic ring, spiro, bridged or fused ring, and the substituted or unsubstituted 5-7 membered carbocyclic or heterocyclic ring, spiro, bridged or fused ring optionally contains 0 or 0 or more (1, 2, 3) heteroatoms;

[0010] L1 is selected from the group consisting of nothing, C1-C4 alkylene, C2-C4 alkenylene, C5-C7 heteroaryl-;

[0011] L2 is selected from the group consisting of nothing, -C5-C7heteroaryl-, -C(=O)-, -O-S(O) 0-2 -, -O-C(=O)-, -C(=O)-NH-, -O-C(=O)-NR F -, -(OCH2CH2) p -O-C(=O)-NR F -, -(OCH2CH2) p -O-C(=O)-, wherein R F is H or C1-C3alkyl;

[0012] L3is selected from the group consisting of null, C1-C8alkylene, C1-C8haloalkylene, -(CH2CH2O) q -;

[0013] R3, R4are each independently selected from R A , 5-7 membered carbocycle or 5-7 membered heterocycle;

[0014] R A , R B , R C , R D are each independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6alkoxy, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C4-C12heterocyclyl, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted C5-C12heteroaryl, spirocycle, bridged cycle, fused cycle, C1-C6silyl, keto, carbonyl, ester, alkoxycarbonyl, aryloxycarbonyl, carboxyl, hydroxyl, amino, cyano, carbamoyl, halogenformyl, isocyano, isocyanate, isothiocyanate, hydroxyl, nitro, or halogen;

[0015] R E is selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C4alkoxy, C2-C6alkenyl, C2-C6alkynyl, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted C5-C8heteroaryl, ester, carboxyl, hydroxyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C4-C12heterocyclyl, -NH2, -NR’R”;

[0016] R’, R” are each independently selected from H, C1-C4alkyl, C1-C4alkoxy, or R’, R” together with their adjacent nitrogen atom form a substituted or unsubstituted 4-12 membered ring (oxidizable), spirocycle, bridged cycle, or fused cycle, and said substituted or unsubstituted 4-12 membered ring, spirocycle, bridged cycle, or fused cycle optionally contains 0 or more than 0 (1, 2, 3) heteroatoms;

[0017] p, q are each independently selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0018] Unless specifically indicated, the term "substituted" means substituted with one or more (e.g. 2, 3, 4, 5, 6, etc.) substituents selected from the group consisting of carboxyl, halogen, C1-C6alkoxy, halogenated C1-C6alkoxy, hydroxyl, C1-C6alkylhydroxyl, C3-C8cycloalkyl, halogenated C3-C8cycloalkyl, methylsulfone, -S(=O)2NH2, oxo (=O), -CN, hydroxyl, -NH2, C1-C6amino, C1-C6amido (-C(=O)-N(R')2or -NH-C(=O)(R'), R' being H or C1-C5alkyl), or a substituted or unsubstituted group selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, C6-C10aryl, C3-C8cycloalkyl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O. 10 aryl, -(CH2)-C6-C 10 aryl, -(CH2)-(5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O), and said substituents are selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkoxy, oxo, -CN, -OH, C6-C 10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O.

[0019] In another preferred embodiment, X is selected from -NR A R B , -NH2, -OH, -SH, -CN, wherein R A , R B As described in the first aspect of the present application (preferably R A , R B are each independently selected from the group consisting of H, hydroxyl.

[0020] In another preferred embodiment, X is -OH.

[0021] In another preferred embodiment, when X is -OH, the compound of formula I has the structure of formulae IIa and IIb in tautomeric form:

[0022]

[0023] wherein R1, R2, R3, R4are as described in the first aspect of the present application.

[0024] In another preferred embodiment, X and R1together with the carbon atom to which they are attached form a substituted or unsubstituted 5-7 membered carbocyclic or heterocyclic ring, and said substituted or unsubstituted 5-7 membered carbocyclic or heterocyclic ring contains 0 or more than 0 (1, 2, 3) heteroatoms.

[0025] In another preferred embodiment, the compound has the structure of Formula III:

[0026]

[0027] wherein R2, R3, R4are as described in the first aspect of the application;

[0028] A ring is a substituted or unsubstituted 5-7 membered carbocyclic or heterocyclic ring, and the substituted or unsubstituted 5-7 membered carbocyclic or heterocyclic ring contains 0 or 0 or more (1, 2, 3) heteroatoms.

[0029] In another preferred embodiment, R2is selected from -NR C R D , wherein R C , R D As described in the first aspect of the application, preferably R C , R D are each independently selected from H, C5-C7heteroaryl.

[0030] In another preferred embodiment, R1and R2together with the carbon atom to which they are attached form a substituted or unsubstituted 5-7 membered carbocyclic or heterocyclic ring, spiro ring, bridged ring or fused ring, and the substituted or unsubstituted 5-7 membered carbocyclic or heterocyclic ring, spiro ring, bridged ring or fused ring optionally contains 0 or 0 or more (1, 2, 3) heteroatoms.

[0031] In another preferred embodiment, the carbon atom or heteroatom of the substituted or unsubstituted 5-7 membered carbocyclic or heterocyclic ring, spiro ring, bridged ring or fused ring can be oxidized (e.g., =O).

[0032] In another preferred embodiment, the compound has the structure of Formula IV:

[0033]

[0034] wherein X, R3, R4are as described herein;

[0035] B ring is a substituted or unsubstituted 5-7 membered carbocyclic or heterocyclic ring, and the substituted or unsubstituted 5-7 membered carbocyclic or heterocyclic ring contains 0 or 0 or more (1, 2, 3) heteroatoms.

[0036] In another preferred embodiment, when A ring is a substituted 5-7 membered carbocyclic or heterocyclic ring, and the substituted 5-7 membered carbocyclic or heterocyclic ring contains a heteroatom, the substituent is substituted on the heteroatom.

[0037] In another preferred embodiment, R1is selected from -L1-L2-L3-R E , substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl.

[0038] In another preferred embodiment, the compound has the structure of Formula V:

[0039]

[0040] wherein L1, L2, L3, R E as described herein.

[0041] In another preferred embodiment, L1is selected from the group consisting of C1-C4alkylene,

[0042] In another preferred embodiment, L2is selected from the group consisting of no, C5-C7heteroaryl-, -C(=0)-, -0-S(0) 0-2 -, -0-C(=0)-, -C(=0)-NH-, -0-C(=0)-NH-, -0-C(=0)-N(C1-C3alkyl)-.

[0043] In another preferred embodiment, R E is selected from the group consisting of H, hydroxyl, C1-C6alkyl, C1-C4alkoxy, C2-C4alkenyl, C2-C4alkynyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C4-C12heterocyclyl, -NH2, -NR’R”.

[0044] In another preferred embodiment, R E is selected from the group consisting of H, substituted or unsubstituted C1-C4alkyl, hydroxyl, substituted or unsubstituted C1-C4alkoxy, substituted or unsubstituted C4-C12heterocyclyl, substituted or unsubstituted C5-C12heteroaryl.

[0045] In another preferred embodiment, R E is selected from the group consisting of H, hydroxyl, C1-C4alkoxy, -NR’R”.

[0046] In another preferred embodiment, L1is no or C1-C2alkylene or C2-C4alkenylene, L2is L3is no.

[0047] In another preferred embodiment, R E is C1-C3alkoxy or C5-C7heteroaryl.

[0048] In another preferred embodiment, L1is C1-C2alkylene, L2is selected from -C(=0)-, and L3is no or C1-C2alkyl.

[0049] In another preferred embodiment, R Eselected from the group consisting of hydroxy, C1-C4alkoxy, -NR'R" (preferably -NR'R"), wherein R', R" together with the nitrogen atom to which they are attached form a substituted or unsubstituted 4-12 membered ring, spiro ring, bridged ring or fused ring, and said substituted or unsubstituted 4-12 membered ring, spiro ring, bridged ring or fused ring optionally contains 0 or 0 or more (1, 2, 3, 4) heteroatoms.

[0050] In another preferred embodiment, R E is selected from the group consisting of:

[0051]

[0052] In another preferred embodiment, L1is C1-C2alkylene, L2is -C(=O)-NH-, L3is C1-C8alkylene, C1-C8haloalkylene, -(CH2CH2O) q -.

[0053] In another preferred embodiment, R E is selected from the group consisting of hydroxy, C1-C4alkoxy.

[0054] In another preferred embodiment, the compound of formula I has the structure of formula VI, VII or VIII:

[0055]

[0056] wherein Y is O, X, R2, R3, R4, L3, R E , R F as described herein.

[0057] In another preferred embodiment, L1is L2is -O-S(O) 0-2 - or -O-C(=O)-, L3is null.

[0058] In another preferred embodiment, R E is selected from the group consisting of -NH2, -NR'R".

[0059] In another preferred embodiment, L1is L2is -O-C(=O)-NR F -, -(OCH2CH2) p -O-C(=O)-NR F - or -(OCH2CH2) p -O-C(=O)-, L3is C1-C8alkylene, C1-C8haloalkylene, -(CH2CH2O) q - wherein R F is H or C1-C3alkyl.

[0060] In another preferred embodiment, L3 is C1-C3 alkylene or C1-C3 haloalkylene.

[0061] In another preferred embodiment, R E is selected from the group consisting of C1-C4 alkoxy, hydroxy, C2-C6 alkynyl, -NH2, -NR'R".

[0062] In another preferred embodiment, q is an integer from 1 to 7 (1, 2, 3, 4, 5, 6, 7).

[0063] In another preferred embodiment, p is an integer from 1 to 3 (1, 2, 3).

[0064] In another preferred embodiment, the compound of formula I has the structure shown in formula VI-1, VII-1, or VIII-1:

[0065]

[0066] wherein Y is O, OR A R A and R B may be linked to form a ring;

[0067] X, R2, R3, R4, R A , R B as described herein.

[0068] In another preferred embodiment, R3 and R4 are each independently selected from a 5-7 membered carbocyclic ring or a 5-7 membered heterocyclic ring, preferably a 5-7 membered carbocyclic ring.

[0069] In another preferred embodiment, R3 is a 5-7 (5, 6, 7) membered carbocyclic ring; and R4 is a 5-7 (5, 6, 7) membered aromatic ring.

[0070] In another preferred embodiment, the substitution means being substituted with one or more (e.g., 2, 3, 4, etc.) substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, C1-C4 alkylhydroxy, C3-C8 cycloalkyl.

[0071] In another preferred embodiment, X, R1, R2, R3, and R4 are each independently the corresponding group in the compounds S1-S52 prepared in the Examples.

[0072] In another preferred embodiment, the compound of formula I is selected from the compounds shown in the following table:

[0073]

[0074]

[0075]

[0076]

[0077]

[0078] In a second aspect of the present application, there is provided a pharmaceutical composition comprising:

[0079] (i) one or more therapeutically effective amount of a compound according to the first aspect of the present application, or an isomer, a pharmaceutically acceptable salt thereof; and

[0080] (ii) a pharmaceutically acceptable carrier.

[0081] In another preferred embodiment, the pharmaceutical composition is for use in the prevention and / or treatment of a disease associated with methionine adenosyltransferase 2a.

[0082] In another preferred embodiment, the disease is selected from the group consisting of solid tumor, hematological tumor.

[0083] In another preferred embodiment, the solid tumor is selected from the group consisting of colon cancer, non-small cell lung cancer, gastric cancer, esophageal and bladder cancer, liver cancer, breast cancer, skin cancer, pancreatic cancer, head and neck cancer, intestinal cancer, lung cancer, kidney cancer, urethral cancer, prostate cancer, testicular cancer, uterine cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, cholangiocarcinoma, multiple myeloma, spinal neurofibroma, astrocytoma, glioma, sarcoma.

[0084] In another preferred embodiment, the hematological tumor is selected from the group consisting of leukemia, lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma.

[0085] In a third aspect of the present application, there is provided use of a compound according to the first aspect of the present application, or an isomer, a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to the second aspect of the present application, for the manufacture of a medicament for the prevention and / or treatment of a disease associated with methionine adenosyltransferase 2a, wherein the disease associated with methionine adenosyltransferase 2a is selected from the group consisting of solid tumor, hematological tumor.

[0086] In another preferred embodiment, the solid tumor is selected from the group consisting of colon cancer, non-small cell lung cancer, gastric cancer, esophageal and bladder cancer, liver cancer, breast cancer, skin cancer, pancreatic cancer, head and neck cancer, intestinal cancer, lung cancer, kidney cancer, urethral cancer, prostate cancer, testicular cancer, uterine cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, cholangiocarcinoma, multiple myeloma, spinal neurofibroma, astrocytoma, glioma, sarcoma.

[0087] In another preferred embodiment, the hematological tumor is selected from the group consisting of leukemia, lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma.

[0088] In a fourth aspect of the present application, there is provided a method for preventing and / or treating a disease associated with methionine adenosyltransferase 2a, comprising the step of administering to a subject in need thereof a compound of the first aspect of the present application, or an isomer, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the second aspect of the present application.

[0089] In another preferred embodiment, the subject is a mammal, preferably a human.

[0090] It should be understood that, within the scope of the present application, each of the technical features of the present application described above and each of the technical features specifically described hereinafter (e.g. in the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they will not be listed one by one here. DETAILED DESCRIPTION

[0091] The present inventors have made, through long-term and in-depth research, a compound of formula I which has a simple structure, is easy to synthesize and is metabolically stable, and the compound has an excellent inhibitory effect on the metabolic enzyme methionine adenosyltransferase 2a, especially an excellent selective inhibitory effect on HAP1 cells of MTAP - / - , thereby achieving the treatment of cell proliferative diseases, especially cancer, and other diseases associated with the activity of MAT2A. On this basis, the present inventors have completed the present application.

[0092] TERMS

[0093] Unless otherwise defined, 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 application belongs.

[0094] As used herein, the term "about," when used in reference to a particular recited numerical value, means that the value can vary from the recited value by not more than 1%. For example, as used herein, the expression "about 100" includes all values between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0095] As used herein, the term "comprising" or "including" can be open, semi-closed or closed. In other words, the term also includes "consisting essentially of" or "consisting of".

[0096] In the present application, the halogen is F, Cl, Br or I.

[0097] In the present application, the term "C1-C6" means having 1, 2, 3, 4, 5 or 6 carbon atoms, "C1-C8" means having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and so on. "5-6 membered" means having 5-6 ring atoms, and so on.

[0098] In the present application, the term "alkyl" denotes a saturated linear or branched hydrocarbon moiety, for example the term "Ci-C8alkyl" refers to a straight chain or branched alkyl group having 1 to 8 carbon atoms, including without limitation methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, and hexyl groups, and the like; preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and t-butyl groups.

[0099] In the present application, the term "alkylene" refers to a straight chain or branched alkane having two bonds that are substituted, for example Ci-C4alkylene denotes a straight chain or branched Ci-C4alkane having two bonds that are substituted, for example methylene, ethylene, n-propylene, i-propylene, butylene, and the like.

[0100] In the present application, the term "alkoxy" denotes an -0-(Ci-C6alkyl) group. For example the term "Ci-C4alkoxy" refers to a straight chain or branched alkoxy group having 1 to 4 carbon atoms, including without limitation methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups, and the like.

[0101] In the present application, the term "alkenyl" denotes a straight chain or branched hydrocarbon group containing at least one double bond, for example the term "C2-C6alkenyl" refers to a straight chain or branched alkenyl group having 2 to 6 carbon atoms containing one double bond, including without limitation ethenyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl groups, and the like.

[0102] In the present application, the term "alkenylene" refers to a straight chain or branched alkene having two bonds that are substituted. The alkenes can include mono-alkenes and di-alkenes, for example conjugated di-alkenes. For example C2-C6alkenylene denotes a straight chain or branched C2-C6alkene having two bonds that are substituted, for example ethenylene, n-propenylene, i-propenylene, butenylene, 1,3-butadienylene, and the like.

[0103] In the present application, the term "alkynyl" refers to a straight chain or branched alkynyl group containing one triple bond, including without limitation ethynyl, propynyl, butynyl, isobutynyl, pentynyl, and hexynyl groups, and the like.

[0104] In the present application, the term "cycloalkyl" denotes a saturated cyclic hydrocarbon moiety, for example the term "C3-C8cycloalkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring, including without limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl groups, and the like. The terms "C3-C6cycloalkyl", and "C5-C6cycloalkyl" have similar meanings.

[0105] In the present application, the term "heterocyclyl" denotes a stable non-aromatic ring moiety consisting of carbon atoms and from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Unless specifically indicated otherwise in the specification, a heterocyclyl group can be a monocyclic, bicyclic, tricyclic or more ring ring system, which can include fused ring systems, bridged ring systems or spirocyclic ring systems; a nitrogen, carbon or sulfur atom in a heterocyclyl group can optionally be oxidized (e.g., =0); a nitrogen atom can optionally be quaternized; a heterocyclyl group can be partially or fully saturated. A heterocyclyl group can be attached to the remainder of the molecule via a carbon atom or a heteroatom and by a single bond. In a heterocyclyl group comprising fused rings, one or more of the rings can be an aryl or heteroaryl group as defined below, provided that the point of attachment to the remainder of the molecule is a non-aromatic ring atom. Examples of heterocyclyl groups include, but are not limited to: tetrahydropyrrolyl, morpholinyl, piperazinyl, piperidinyl, thiomorpholinyl, 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, dioxolanyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolinyl, octahydroisoindolinyl, pyrrolidinyl, pyrazolidinyl, phthalimido, and the like.

[0106] In the present application, the term "aryl" denotes a hydrocarbon group comprising one or more aromatic rings. For example, the term "C6-C10 aryl" refers to an aromatic ring group having from 6 to 10 carbon atoms in the ring, which does not contain heteroatoms, such as phenyl, naphthyl, and the like.

[0107] In the present application, the term "heteroaryl" denotes an aromatic ring group comprising at least one (e.g., 1, 2, 3) ring internal heteroatom (e.g., N, O, or S), such as furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, triazolyl, tetrazolyl, and the like.

[0108] Unless otherwise indicated, the alkyl, haloalkyl, alkoxy, alkyl sulfide, cycloalkyl, heterocyclyl, and aryl groups described herein are substituted and unsubstituted groups. Possible substituents on the alkyl, haloalkyl, alkoxy, alkyl sulfide, cycloalkyl, heterocyclyl, and aryl groups include, but are not limited to, hydroxy, amino, nitro, nitrile, halogen, C1-C6alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C20cycloalkyl, C3-C20cycloalkenyl, C1-C20heterocycloalkyl, C1-C20heterocycloalkenyl, C1-C6alkoxy, aryl, heteroaryl, heteroaryloxy, C1-C10alkylamino, C1-C20dialkylamino, arylamino, diarylamino, C1-C10alkylsulfonamido, arylsulfonamido, C1-C10alkylimino, C1-C10alkylsulfinylimino, arylsulfinylimino, thiol, C1-C10alkylthio, C1-C10alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, guanidino, ureido, cyano, acyl, thioacyl, acyloxy, carboxy, and carboxylate. In another aspect, the cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl groups can also be fused to one another.

[0109] In the present application, the substituents are single or multiple substituents, and the multiple substituents are di-, tri-, tetra-, or penta-substituents. The di-substituents mean two substituents, and the like.

[0110] As used herein, the term "solvate" means a complex of a specific ratio of a compound of the present application and a molecule of a solvent.

[0111] Salt Form

[0112] As used herein, the term "pharmaceutically acceptable salt" means a salt of a compound of the present application with an acid or a base suitable for use in medicine. The pharmaceutically acceptable salts include inorganic salts and organic salts. One preferred class of salts is the salts of the compounds of the present application with acids. The pharmaceutically acceptable salts of the compounds represented by Formula I include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, and the like; organic acid salts such as formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, and the like; alkylsulfonate salts such as methanesulfonate, ethanesulfonate, and the like; arylsulfonate salts such as benzenesulfonate, p-toluenesulfonate, and the like.

[0113] Another preferred salt is a salt of a compound of the present application with a base, for example, an alkali metal salt (for example, a sodium or potassium salt), an alkaline earth metal salt (for example, a magnesium or calcium salt), an ammonium salt (for example, a lower alkylammonium salt and other pharmaceutically acceptable amine salts), for example, a methylamine salt, an ethylamine salt, a propylamine salt, a dimethylamine salt, a trimethylamine salt, a diethylamine salt, a triethylamine salt, a t-butylamine salt, an ethylenediamine salt, a hydroxyethylamine salt, a dihydroxyethylamine salt, a trihydroxyethylamine salt, and an amine salt formed by morpholine, piperazine, lysine, respectively.

[0114] The term "solvate" means a compound of the present application coordinated with solvent molecules in a specific ratio to form a complex. The pharmaceutically acceptable solvate of the compound represented by the general formula I includes, without limitation, a solvate of the compound represented by the general formula I with water, ethanol, isopropanol, diethyl ether, acetone, and the like. The "hydrate" means a complex formed by coordination of the compound of the present application with water.

[0115] Pharmaceutical composition and administration method

[0116] The present application also provides a pharmaceutical composition comprising:

[0117] (i) one or more therapeutically effective amount of a compound represented by the general formula I, or an isomer, a prodrug, a solvate, a hydrate thereof, or a pharmaceutically acceptable salt thereof; and

[0118] (ii) a pharmaceutically acceptable carrier.

[0119] Since the compound of the present application has excellent anti-tumor activity, the compound of the present application and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and a pharmaceutical composition containing the compound of the present application as a main active ingredient can be used for the treatment, prevention, and alleviation of diseases associated with tumors.

[0120] The pharmaceutical composition of the present application comprises a safe and effective amount of the compound of the present application or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. The "safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The therapeutically effective amount is determined according to the age, condition, course of treatment, and the like of the subject. Generally, the pharmaceutical composition contains 1-2000 mg of the compound of the present application per dose, more preferably, 10-1000 mg of the compound of the present application per dose. Preferably, the "one dose" is one capsule or tablet.

[0121] The term "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler substances or gel materials, which are suitable for human use and which are of sufficient purity and sufficiently low toxicity. By "compatible" it is meant that the components of the composition are capable of being commingled with the compounds of the application, and with each other, in the dosage form with no interaction that significantly affects the efficacy of the compounds. Examples of suitable pharmaceutically acceptable carriers are sugars (e.g., dextrose, sucrose, lactose, etc.), starches (e.g., corn starch, potato starch, etc.), cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween), wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

[0122] The mode of administration of the compounds or pharmaceutical compositions of the present application is not narrowly critical and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0123] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or with such other ingredients as binders, (a) fillers or extenders, e.g., starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, e.g., hydroxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, e.g., glycerol; (d) disintegrating agents, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, e.g., paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof; and (h) coloring agents. In the case of capsules, tablets, and pills, the dosage forms also can comprise buffering agents.

[0124] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They can optionally contain opacifying agents, and can also be of a composition that they release the active compound or compounds in a certain part of the digestive tract. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0125] Liquid dosage forms for oral administration include pharmaceutically- acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, and the like, citric acids, and / or sodium benzoate, and / or sorbic acid, and / or flavoring agents.

[0126] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0127] Suspensions, in addition to the active compounds, can contain suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and agar-agar, and the like.

[0128] Compositions for parenteral injection can contain physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.

[0129] Dosage forms of the compounds of the present application for topical administration include ointments, powders, sprays, and inhalers. The active compound is admixed under sterile conditions with physiologically acceptable carriers and any preservatives, buffers, or propellants as can be required.

[0130] The aminobenzimidazole derivatives of the above Formula I and pharmaceutically acceptable salts thereof in the present application can be administered alone or in combination with other pharmaceutically acceptable therapeutic agents.

[0131] The therapeutic methods of the present application can be used alone or in combination with other therapeutic procedures or therapeutic agents.

[0132] The pharmaceutical compositions are used in a safe and effective amount of the compounds of the present application for a mammal (e.g., human) in need of treatment, wherein the amount administered is a pharmaceutically effective amount, and for a 60 kg body weight human, the daily amount is usually 1-2000 mg, preferably 50-1000 mg. Of course, the specific dose will also take into account the route of administration, the patient's health status, and the like, which are all within the skill of a skilled practitioner.

[0133] The main advantages of the present application include:

[0134] (1) The compounds are easy to synthesize and simple to operate;

[0135] (2) The compound has excellent inhibitory effect on MAT2A, thereby achieving effective treatment of cell proliferation diseases, especially cancer;

[0136] (3) The compound has an effect on MTAP - / - It showed good selective inhibitory effect on HAP1 cells, compared with MTAP + / + Compared to cells, IC 50 The difference in multiples is 8 times.

[0137] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0138] 1 H-NMR and 13 C-NMR 1 H-NMR and 13 C-NMR was determined using a Bruke 400, 500, 600, or 700 instrument; all starting materials and reagents used were commercially available; all solvents were redistilled before use; and all anhydrous solvents were dried according to standard methods; unless otherwise specified, all reactions were carried out under nitrogen protection and monitored by TLC; post-processing included washing with saturated sodium chloride aqueous solution and drying with anhydrous sodium sulfate; unless otherwise specified, the products were purified using silica gel (200-300 mesh) column chromatography; the silica gel (200-300 mesh) was produced by Qingdao Ocean Chemical Plant, and the GF-254 thin-layer silica gel plates were produced by Yantai Jiangyou Silica Gel Development Co., Ltd.

[0139] Example 1. Preparation of the compound

[0140] The following preparation examples exemplarily demonstrate the preparation of compounds of formula I of the present invention, each compound being represented by S1 to S52.

[0141] 1. Preparation of compound S1:

[0142]

[0143] Compound 1-1 (956 mg, 4 mmol), 1-2 (1.97 g, 2 eq) were added into a microwave tube, followed by adding anhydrous ethanol (8 mL), 20% NaOEt in ethanol (4 mL) successively. After microwave reaction at 130 °C for 80 min, the reaction was detected by TLC. The starting material was completely reacted. After drying by rotary evaporation, Et2O / NH4Cl (aq) was added and ultrasonic was applied. A large amount of solid was precipitated. After suction filtration, the filter cake was dissolved in EA / 1M HCl (aq). The organic phase was dried over anhydrous sodium sulfate. After drying by rotary evaporation, compound 1-3 crude product was obtained without further purification, which was directly used in the next step.

[0144] Compound 1-3 was dissolved in MeOH / H2O = 3:1 (20 mL). LiOH (10 eq) was added. After stirring at room temperature overnight, the reaction was detected by TLC. The starting material was completely reacted. After removing methanol by concentration, the residual liquid was poured into 12M HCl (aq). A large amount of solid was precipitated. After suction filtration, the filter cake was dried to obtain compound 1-4 (790 mg).

[0145] Compound 1-4 (6.31 g) was dissolved in POCl3 (10 mL). After stirring at 110 °C overnight, the reaction was detected by TLC. The starting material was completely reacted. After concentration, methanol was added and stirred for 5 min. After drying by rotary evaporation, EA / Na2CO3 (aq) was added for extraction. The organic phase was dried over anhydrous sodium sulfate. After drying by rotary evaporation, column chromatography was performed to obtain compound 1-5 (2.97 g).

[0146] Compound 1-4 (2.97 g) was dissolved in dichloromethane (30 mL). After stirring at -20 °C, 30% NaOMe in methanol (7.97 mL) was added. After 10 min, the reaction was detected by TLC. The starting material was completely reacted. After quenching the reaction by adding water, DCM was added for extraction. The organic phase was dried over anhydrous sodium sulfate. After drying by rotary evaporation, column chromatography was performed to obtain compound 1-6 (2.75 g).

[0147] Compound 1-6 (2.75 g) was dissolved in dioxane (20 mL) under argon protection. Compound 2-aminopyridine (954.5 mg, 1.5 eq), Pd(OAc)2 (298.8 mg, 0.2 eq), Xant-phos (780.5 mg, 0.2 eq), K2CO3 (3.70 g, 4 eq) were added successively. After stirring at 120 °C for 60 min, the reaction was detected by TLC. The starting material was completely reacted. After concentration, it was dissolved in 4M HCl in dioxane solution. After stirring at room temperature overnight, drying by rotary evaporation, EA / NaHCO3 (aq) was added for extraction. The organic phase was dried over anhydrous sodium sulfate. After drying by rotary evaporation, column chromatography was performed to obtain compound S1 (1.12 g). 1H NMR (700 MHz, Chloroform-d) δ 13.02 (s, 1H), 8.57 (d, J = 8.6 Hz, 1H), 8.38 (dd, J = 5.1, 1.9 Hz, 1H), 7.96 (m, 1H), 7.90 - 7.83 (m, 2H), 7.44 - 7.39 (m, 2H), 7.39 - 7.35 (m, 1H), 7.34 (m, 1H), 6.03 (tt, J = 3.7, 1.7 Hz, 1H), 3.82 (s, 2H), 2.34 (m, 2H), 2.10 (m, 2H), 1.80 - 1.69 (m, 4H).

[0148] 2. Preparation of compound S2

[0149]

[0150] The synthesis method of compound 2-2 is the same as that of compound 1-3.

[0151] Compound 2-2 (500 mg) was dissolved in dichloromethane (10 mL), 1M BCl3 solution in dichloromethane (3.39 mL, 3eq) was added under stirring at 0°C, the reaction was continued at this temperature for 30 minutes, TLC detection showed that the raw material was completely reacted, the reaction was quenched by adding saturated NH4Cl (aq), DCM extraction, the organic phase was dried with anhydrous sodium sulfate, and the compound 2-3 was obtained after rotary evaporation. The crude product was directly used in the next step without further purification.

[0152] Compound 2-3 (235 mg) was dissolved in POCl3 (10 mL) and stirred at 110°C overnight, TLC detection showed that the raw material was completely reacted, concentrated, EA / Na2CO3 (aq) was added for extraction, the organic phase was dried with anhydrous sodium sulfate, and the compound 2-4 (152 mg) was obtained after column chromatography.

[0153] Compound p-methoxybenzylamine (60.8 mg, 1.2eq) was dissolved in tetrahydrofuran (5 mL), 60% NaH (29.7 mg, 2eq) was added under stirring at 0°C, the reaction was continued until no gas bubbles were generated, compound 2-4 (150 mg) was dissolved in tetrahydrofuran (3 mL) and added dropwise to the reaction solution, the reaction was continued at room temperature for 30 minutes after the dropwise addition was completed, TLC detection showed that the raw material was completely reacted, the reaction was quenched by adding saturated NH4Cl (aq), DCM extraction, the organic phase was dried with anhydrous sodium sulfate, and the compound 2-5 (146 mg) was obtained after column chromatography.

[0154] Compound 2-5 (146 mg) was dissolved in dioxane (10 mL) under argon protection, compound 2-amino pyridine (44.3 mg, 1.5 eq), Pd(OAc)2(13.9 mg, 0.2 eq), Xant-phos (36.3 mg, 0.2 eq), K2CO3(171.6 mg, 4 eq) were added to the solution successively, the reaction was stirred at 120 °C for 60 min, TLC detection showed that the starting material was completely reacted, and then it was dissolved in trifluoroacetic acid (5 mL), stirred at 80 °C overnight, TLC detection showed that the starting material was completely reacted, concentrated, rotary dried, extracted with EA / NaHCO3(aq), the organic phase was dried over anhydrous sodium sulfate, rotary dried, and column chromatography to obtain compound S2 (52 mg). 1 HNMR (500 MHz, chloroform-d) δ 8.98 (s, 1H), 8.34 (dd, J = 5.0, 1.3 Hz, 1H), 7.62 (td, J = 4.9, 4.3, 1.9 Hz, 2H), 7.55 (td, J = 8.1, 1.3 Hz, 1H), 7.42 (dp, J = 3.3, 2.0 Hz, 3H), 6.98 (ddd, J = 7.8, 4.9, 0.9 Hz, 1H), 6.59 - 6.54 (m, 1H), 5.98 - 5.93 (m, 1H), 3.91 (t, J = 7.3 Hz, 2H), 3.38 (t, J = 7.3 Hz, 2H), 2.03 - 1.93 (m, 4H), 1.65 - 1.57 (m, 4H).

[0155] 3. Preparation of compound S3

[0156]

[0157] The synthesis of compound S3 was the same as that of compound S1. 1 H NMR (400 MHz, chloroform-d) δ 8.75 (d, J = 8.5 Hz, 1H), 8.20 (dd, J = 5.0, 1.8 Hz, 1H), 7.69 (m, 1H), 7.43 - 7.36 (m, 2H), 7.34 - 7.29 (m, 2H), 7.18 - 7.04 (m, 5H), 6.94 (dd, J = 7.2, 5.0 Hz, 1H), 5.93 - 5.89 (m, 1H), 3.91 (s, 3H), 2.34 (d, J = 17.4 Hz, 1H), 2.19 (d, J = 5.1 Hz, 2H), 2.08 (d, J = 17.4 Hz, 1H), 1.69 (p, J = 9.3, 8.6 Hz, 4H).

[0158] 4. Preparation of compound S4

[0159]

[0160] The synthesis of compound S4 follows the same procedure as for compound S1. 1 H NMR (400 MHz, Chloroform-d) δ 8.84 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 5.0 Hz, 1H), 7.88 - 7.79 (m, 2H), 7.67 (t, J = 7.8 Hz, 1H), 7.48 - 7.33 (m, 4H), 7.11 (d, J = 8.4 Hz, 2H), 6.88 (t, J = 6.2 Hz, 1H), 5.97 (d, J = 4.2 Hz, 1H), 5.34 (s, 2H), 3.89 (s, 2H), 2.40 (s, 2H), 2.24 (d, J = 5.5 Hz, 2H), 1.84 - 1.70 (m, 4H).

[0161] 5. Preparation of compound S5

[0162]

[0163] The synthesis of compound S5 follows the same procedure as for compound S1. 1 H NMR (500 MHz, Chloroform-d) δ 8.98 (s, 1H), 8.28 (dd, J = 4.9, 1.2 Hz, 1H), 7.66 - 7.61 (m, 2H), 7.48 (td, J = 8.0, 1.3 Hz, 1H), 7.42 (ddt, J = 6.1, 4.2, 2.5 Hz, 5H), 7.01 - 6.93 (m, 3H), 6.56 (dd, J = 8.1, 1.0 Hz, 1H), 5.90 (dd, J = 6.6, 5.4 Hz, 1H), 3.80 (s, 3H), 2.20 (s, 1H), 2.02 - 1.93 (m, 4H), 1.65 - 1.56 (m, 4H).

[0164] 6. Preparation of compound S6

[0165]

[0166] The synthesis of compound S6 follows the same procedure as for compound S1. 1 H NMR (500 MHz, Chloroform-d) δ 8.98 (s, 1H), 8.29 (dd, J = 4.9, 1.2 Hz, 1H), 7.69 - 7.61 (m, 2H), 7.53 - 7.40 (m, 6H), 7.00 - 6.94 (m, 3H), 6.56 (dd, J = 8.1, 0.9 Hz, 1H), 5.98 (dd, J = 6.6, 5.4 Hz, 1H), 3.80 (s, 3H), 2.02 - 1.94 (m, 4H), 1.64 - 1.58 (m, 4H).

[0167] 7. Preparation of compound S7

[0168]

[0169] The synthesis of compound S7 follows the procedure for compound S1. 1 H NMR (500 MHz, Chloroform-d) δ 8.98 (s, 1H), 8.35 (dd, J = 5.0, 1.3 Hz, 1H), 7.99 (s, 1H), 7.63 (ddq, J = 6.8, 4.6, 2.8, 2.2 Hz, 2H), 7.58 (td, J = 8.0, 1.3 Hz, 1H), 7.42 (dp, J = 3.2, 2.0 Hz, 3H), 6.98 (ddd, J = 8.0, 5.0, 0.9 Hz, 1H), 6.74 (dd, J = 16.8, 10.0 Hz, 1H), 6.58 - 6.53 (m, 1H), 6.14 - 6.09 (m, 1H), 5.63 (dd, J = 13.7, 10.1 Hz, 1H), 5.33 (dd, J = 16.8, 13.8 Hz, 1H), 2.02 - 1.93 (m, 4H), 1.64 - 1.57 (m, 4H).

[0170] 8. Preparation of compound S8

[0171]

[0172] The synthesis of compound S8 follows the procedure for compound S1. 1 H NMR (700 MHz, Chloroform-d + Methanol-d4) δ 8.09 (t, J = 3.3 Hz, 1H), 7.79 (d, J = 7.7 Hz, 2H), 7.61 - 7.56 (m, 1H), 7.36 (q, J = 5.2, 2.9 Hz, 2H), 7.31 (dd, J = 8.7, 5.8 Hz, 1H), 7.25 - 7.20 (m, 2H), 6.97 - 6.90 (m, 1H), 6.82 - 6.75 (m, 2H), 6.63 (d, J = 8.5 Hz, 1H), 5.98 (d, J = 4.4 Hz, 1H), 4.00 (d, J = 6.2 Hz, 2H), 3.71 (d, J = 2.6 Hz, 3H), 2.29 (m, 2H), 2.09 - 2.00 (m, 2H), 1.75 - 1.62 (m, 4H).

[0173] 9. Preparation of compound S9

[0174]

[0175] The synthesis of compound S9 follows the procedure for compound S1. 1H NMR (500 MHz, Chloroform-d) δ 8.98 (s, 1H), 8.34 (dd, J = 4.9, 1.2 Hz, 1H), 7.99 (s, 1H), 7.65 - 7.56 (m, 3H), 7.46 - 7.39 (m, 3H), 7.27 (t, J = 7.5 Hz, 1H), 7.04 - 6.89 (m, 4H), 6.56 (dd, J = 8.1, 1.0 Hz, 1H), 5.94 (dd, J = 6.6, 5.4 Hz, 1H), 3.90 (d, J = 1.2 Hz, 2H), 3.71 (s, 3H), 2.04 - 1.92 (m, 4H), 1.65 - 1.57 (m, 4H).

[0176] 10. Preparation of compound S10

[0177]

[0178] The synthesis of compound S10 follows the same steps as for compound S1. 1 H NMR (500 MHz, Chloroform-d) δ 8.98 (s, 1H), 8.71 (d, J = 1.2 Hz, 1H), 8.50 (dd, J = 4.9, 1.2 Hz, 1H), 8.39 (dd, J = 5.0, 1.3 Hz, 1H), 7.99 (s, 1H), 7.76 (dt, J = 8.0, 1.4 Hz, 1H), 7.66 - 7.59 (m, 2H), 7.56 (td, J = 8.0, 1.2 Hz, 1H), 7.46 - 7.39 (m, 3H), 7.26 (dd, J = 8.0, 5.0 Hz, 1H), 6.98 (ddd, J = 8.0, 4.9, 0.9 Hz, 1H), 6.56 (dd, J = 8.2, 1.0 Hz, 1H), 5.89 (dd, J = 6.6, 5.4 Hz, 1H), 3.90 (s, 2H), 2.02 - 1.91 (m, 4H), 1.66 - 1.55 (m, 4H).

[0179] 11. Preparation of compound S11

[0180]

[0181] The synthesis of compound S11 follows the same steps as for compound S1. 1H NMR (500 MHz, Chloroform-d) δ 8.98 (s, 1H), 8.60 (d, J = 1.3 Hz, 1H), 8.55 (dd, J = 5.0, 1.3 Hz, 1H), 8.36 (dd, J = 4.9, 1.2 Hz, 1H), 7.99 (s, 1H), 7.65 - 7.56 (m, 4H), 7.42 (dp, J = 3.3, 2.0 Hz, 3H), 7.32 (dd, J = 8.0, 5.0 Hz, 1H), 6.98 (ddd, J = 8.0, 4.9, 0.9 Hz, 1H), 6.56 (dd, J = 8.0, 1.0 Hz, 1H), 5.92 (tt, J = 6.2, 1.1 Hz, 1H), 2.88 (s, 4H), 2.03 - 1.91 (m, 4H), 1.65 - 1.57 (m, 4H).

[0182] 12. Preparation of compound S12

[0183]

[0184] The synthesis of compound S12 follows the same procedure as for compound S1. 1 H NMR (500 MHz, Chloroform-d) δ 8.98 (s, 1H), 8.86 (d, J = 1.2 Hz, 1H), 8.62 (dd, J = 4.9, 1.2 Hz, 1H), 8.51 (dd, J = 4.9, 1.2 Hz, 1H), 8.03 (dt, J = 8.0, 1.4 Hz, 1H), 7.99 (s, 1H), 7.64 (dq, J = 6.1, 1.9 Hz, 2H), 7.58 (td, J = 8.1, 1.3 Hz, 1H), 7.53 (dd, J = 8.0, 5.0 Hz, 1H), 7.47 - 7.39 (m, 3H), 6.98 (ddd, J = 8.0, 4.9, 0.9 Hz, 1H), 6.83 (s, 2H), 6.59 - 6.54 (m, 1H), 6.19 - 6.12 (m, 1H), 2.03 - 1.92 (m, 4H), 1.65 - 1.57 (m, 4H).

[0185] 13. Preparation of compound S13

[0186]

[0187] Compound 1-6 (2.75 g) was dissolved in dioxane (20 mL) under argon protection, compound 2-aminopyridine (954.5 mg, 1.5 eq), Pd(OAc)2(298.8 mg, 0.2 eq), Xant-phos (780.5 mg, 0.2 eq), K2CO3(3.70 g, 4 eq) were added to the solution successively, the reaction was stirred at 120 °C for 60 min, TLC detection showed that the starting material was completely reacted, and then it was dissolved in 4 M HC1 in dioxane solution, stirred at room temperature overnight, rotary evaporation, extracted with EA / NaHC03(aq), the organic phase was dried over anhydrous sodium sulfate, rotary evaporation and column chromatography to give compound S13 (1.77 g). 1 H NMR (700 MHz, Chloroform-d + Methanol-d4) δ 14.66 (s, 1H), 9.22 (s, 1H), 8.05 (dd, J = 5.2, 1.8 Hz, 1H), 7.83 - 7.77 (m, 2H), 7.54 (ddd, J = 8.8, 7.3, 1.9 Hz, 1H), 7.44 - 7.33 (m, 4H), 6.94 (d, J = 8.3 Hz, 1H), 6.76 (dd, J = 7.2, 5.0 Hz, 1H), 5.94 (tt, J = 3.7, 1.7 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 2H), 2.35 (dq, J = 6.4, 3.2 Hz, 2H), 2.05 (tt, J = 5.9, 2.4 Hz, 2H), 1.79 - 1.68 (m, 4H).

[0188] 14. Preparation of compound S14

[0189]

[0190] The synthesis of compound S14 was the same as that of compound 1-4. 1 H NMR (500 MHz, Chloroform-d) δ 8.98 (s, 1H), 8.39 (dd, J = 4.9, 1.2 Hz, 1H), 7.99 (s, 1H), 7.64 - 7.58 (m, 2H), 7.53 (td, J = 8.0, 1.2 Hz, 1H), 7.42 (dp, J = 3.3, 2.0 Hz, 3H), 6.98 (ddd, J = 7.9, 4.9, 0.9 Hz, 1H), 6.56 (dd, J = 8.2, 1.0 Hz, 1H), 6.12 - 6.05 (m, 1H), 3.92 (s, 2H), 2.04 - 1.92 (m, 4H), 1.67 - 1.55 (m, 4H).

[0191] 15. Preparation of compound S15

[0192]

[0193] Compound S13 (60 mg), 15-1 (60 mg), Na2CO3(60 mg) were dissolved in dry tert-butanol (3 mL), stirred at 90 °C overnight, TLC detected the reaction, the raw material completely reacted, concentrated, rotary dried and column chromatography to give compound S15 (12 mg). 1 H NMR (700 MHz, Chloroform-d) δ 14.57 (s, 1H), 10.68 (s, 1H), 8.18 (d, J = 5.0 Hz, 1H), 7.88 (d, J = 7.6 Hz, 2H), 7.72 (t, J = 7.9 Hz, 1H), 7.40 (t, J = 7.5 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 7.01 (t, J = 6.3 Hz, 1H), 6.03 (d, J = 4.5 Hz, 1H), 4.04 (d, J = 4.8 Hz, 2H), 3.85 (s, 2H), 3.67 (t, J = 4.7 Hz, 2H), 3.64 (d, J = 5.1 Hz, 2H), 3.61 (d, J = 5.2 Hz, 2H), 2.37 - 2.31 (m, 2H), 2.11 (d, J = 5.8 Hz, 2H), 1.75 (dp, J = 23.3, 5.4 Hz, 4H).

[0194] 16. Preparation of compound S16

[0195]

[0196] The synthesis of compound S16 was the same as compound S15. 1 H NMR (700 MHz, Chloroform-d) δ 14.57 (s, 1H), 10.68 (s, 1H), 8.18 (d, J = 5.0 Hz, 1H), 7.88 (d, J = 7.6 Hz, 2H), 7.72 (t, J = 7.9 Hz, 1H), 7.40 (t, J = 7.5 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 7.01 (t, J = 6.3 Hz, 1H), 6.03 (d, J = 4.5 Hz, 1H), 4.04 (d, J = 4.8 Hz, 2H), 3.85 (s, 2H), 3.67 (t, J = 4.7 Hz, 2H), 3.64 (d, J = 5.1 Hz, 2H), 3.61 (d, J = 5.2 Hz, 2H), 2.37 - 2.31 (m, 2H), 2.11 (d, J = 5.8 Hz, 2H), 1.75 (dp, J = 23.3, 5.4 Hz, 4H).

[0197] 17. Preparation of compound S17

[0198]

[0199] The synthesis of compound S17 follows that of compound S15. 1 H NMR (700 MHz, Methanol-d4) δ 7.96 (s, 1H), 7.78 - 7.65 (m, 2H), 7.57 (s, 1H), 7.42 (dt, J = 16.5, 7.5 Hz, 3H), 6.88 (d, J = 69.0 Hz, 2H), 5.83 (s, 1H), 4.53 - 4.28 (m, 2H), 3.61 (m, 5H), 3.22 - 2.73 (m, 5H), 2.27 (s, 2H), 1.97 (s, 2H), 1.69 (d, J = 32.8 Hz, 4H).

[0200] 18, Preparation of compound S18

[0201]

[0202] The synthesis of compound S18 follows that of compound S15. 1 H NMR (700 MHz, Chloroform-d + Methanol-d4) δ 8.09 (d, J = 5.0 Hz, 1H), 7.73 (d, J = 7.3 Hz, 2H), 7.64 (t, J = 7.6 Hz, 1H), 7.36 (t, J = 7.4 Hz, 2H), 7.31 (dd, J = 8.1, 5.5 Hz, 1H), 7.01 (dd, J = 8.2, 4.8 Hz, 1H), 6.92 (dd, J = 7.3, 5.0 Hz, 1H), 5.98 - 5.93 (m, 1H), 4.18 (dq, J = 21.6, 5.0 Hz, 2H), 4.06 (dd, J = 11.4, 5.7 Hz, 1H), 3.79 (dd, J = 11.4, 5.6 Hz, 1H), 3.73 (dd, J = 14.6, 5.9 Hz, 1H), 3.63 (d, J = 14.4 Hz, 1H), 3.55 (dd, J = 12.9, 5.7 Hz, 1H), 3.41 (dd, J = 12.9, 4.5 Hz, 1H), 2.28 (dq, J = 6.8, 3.5 Hz, 2H), 2.06 - 1.95 (m, 2H), 1.68 (dq, J = 31.1, 5.4 Hz, 4H).

[0203] 19, Preparation of compound S19

[0204]

[0205] The synthesis of compound S19 follows that of compound S15. 1H NMR (500 MHz, chloroform-d) δ 8.98 (s, 1H), 8.28 (dd, J = 5.1, 1.3 Hz, 1H), 7.99 (s, 1H), 7.65 - 7.53 (m, 3H), 7.46 - 7.38 (m, 3H), 6.98 (ddd, J = 8.0, 4.9, 0.9 Hz, 1H), 6.56 (dd, J = 8.1, 1.0 Hz, 1H), 6.07 - 6.01 (m, 1H), 4.43 (d, J = 12.2 Hz, 1H), 4.20 (dt, J = 11.5, 7.0 Hz, 1H), 4.12 (dd, J = 11.5, 6.9 Hz, 1H), 3.98 - 3.85 (m, 3H), 3.64 (td, J = 12.2, 11.7, 6.9 Hz, 2H), 3.33 (dd, J = 12.5, 7.0 Hz, 1H), 3.25 (dt, J = 12.4, 7.1 Hz, 1H), 3.13 - 2.99 (m, 2H), 2.73 - 2.57 (m, 2H), 2.50 - 2.43 (m, 1H), 2.41 - 2.26 (m, 3H), 2.19 - 2.11 (m, 1H), 1.81 (dddd, J = 18.2, 16.7, 8.2, 3.7, 2.2 Hz, 2H), 1.70 - 1.53 (m, 2H).

[0206] 20. Preparation of compound S20

[0207]

[0208] The synthesis of compound S20 is carried out according to the procedure described for compound S15. 1H NMR (500 MHz, Chloroform-d) δ 8.98 (s, 1H), 8.28 (dd, J = 5.0, 1.3 Hz, 1H), 7.99 (s, 1H), 7.62 - 7.52 (m, 3H), 7.45 - 7.39 (m, 3H), 6.98 (ddd, J = 7.8, 4.9, 0.9 Hz, 1H), 6.56 (dd, J = 8.2, 1.0 Hz, 1H), 6.06 (dp, J = 4.1, 1.2 Hz, 1H), 4.89 (dd, J = 11.3, 7.0 Hz, 1H), 4.81 (p, J = 6.9 Hz, 1H), 4.63 - 4.53 (m, 2H), 4.26 (dddd, J = 20.3, 12.4, 3.1, 1.3 Hz, 2H), 4.00 (dd, J = 12.5, 6.9 Hz, 1H), 3.85 (d, J = 12.2 Hz, 1H), 3.34 (td, J = 12.4, 3.0 Hz, 1H), 3.24 (dd, J = 12.4, 6.9 Hz, 1H), 2.91 (td, J = 12.2, 3.1 Hz, 1H), 2.66 - 2.54 (m, 1H), 2.35 - 2.19 (m, 3H), 1.88 - 1.72 (m, 2H), 1.72 - 1.53 (m, 2H).

[0209] 21. Preparation of compound S21

[0210]

[0211] The synthesis of compound S21 follows the same procedure as for compound S15. 1 H NMR (500 MHz, Chloroform-d) δ 8.97 (d, J = 15.0 Hz, 2H), 8.73 (s, 1H), 8.46 (dd, J = 5.0, 1.2 Hz, 1H), 7.99 (s, 1H), 7.64 - 7.52 (m, 3H), 7.46 - 7.39 (m, 3H), 6.98 (ddd, J = 8.0, 4.9, 0.9 Hz, 1H), 6.58 - 6.53 (m, 1H), 6.09 - 6.02 (m, 1H), 4.71 (s, 2H), 3.62 (t, J = 5.5 Hz, 2H), 3.52 (s, 2H), 2.82 (t, J = 5.5 Hz, 2H), 2.03 - 1.92 (m, 4H), 1.65 - 1.57 (m, 4H).

[0212] 22. Preparation of compound S22

[0213]

[0214] The synthesis of compound S22 follows the same procedure as for compound S15. 1H NMR (500 MHz, Chloroform-d) δ 8.98 (s, 1H), 8.31 (dd, J = 4.9, 1.2 Hz, 1H), 7.99 (s, 1H), 7.62 (ddq, J = 6.7, 4.5, 2.8, 2.3 Hz, 2H), 7.60 - 7.52 (m, 2H), 7.45 - 7.40 (m, 3H), 7.01 - 6.95 (m, 2H), 6.59 - 6.53 (m, 1H), 5.81 (dd, J = 6.6, 5.5 Hz, 1H), 4.66 (s, 2H), 4.23 (t, J = 5.3 Hz, 2H), 3.72 (t, J = 5.3 Hz, 2H), 3.52 (s, 2H), 2.03 - 1.93 (m, 4H), 1.65 - 1.57 (m, 4H).

[0215] 23. Preparation of compound S23

[0216]

[0217] The synthesis of S23 follows that of compound S15. 1 H NMR (700 MHz, Chloroform-d) δ 14.58 (s, 1H), 10.92 (s, 1H), 8.14 (d, J = 5.1 Hz, 1H), 7.86 (d, J = 7.6 Hz, 2H), 7.68 (t, J = 7.8 Hz, 1H), 7.37 (dt, J = 33.1, 7.4 Hz, 3H), 7.03 (d, J = 8.4 Hz, 1H), 7.01 - 6.93 (m, 1H), 6.02 (d, J = 4.1 Hz, 1H), 4.33 (d, J = 11.2 Hz, 1H), 3.94 - 3.83 (m, 2H), 3.78 (d, J = 12.2 Hz, 1H), 3.61 (d, J = 14.3 Hz, 1H), 3.55 (dd, J = 11.5, 6.6 Hz, 1H), 3.43 (td, J = 11.8, 5.8 Hz, 2H), 2.40 - 2.30 (m, 2H), 2.10 (d, J = 6.9 Hz, 2H), 1.74 (dt, J = 26.6, 5.7 Hz, 4H), 1.54 (ddd, J = 35.1, 7.6, 3.8 Hz, 2H), 0.87 (q, J = 6.0, 5.0 Hz, 1H).

[0218] 24. Preparation of compound S24

[0219]

[0220] The synthesis of S24 follows that of compound S15. 1H NMR (700 MHz, Chloroform-d) δ 14.79 (s, 1H), 11.41 (s, 1H), 8.69 (d, J = 5.5 Hz, 1H), 8.13 (d, J = 5.0 Hz, 1H), 7.79 (d, J = 7.5 Hz, 2H), 7.68 (t, J = 7.8 Hz, 1H), 7.40 (t, J = 7.5 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.97 (dd, J = 7.1, 5.3 Hz, 1H), 6.01 (d, J = 4.0 Hz, 1H), 4.98 (s, 1H), 3.80 (d, J = 10.5 Hz, 4H), 3.48 (q, J = 5.1 Hz, 2H), 2.33 (dt, J = 7.3, 3.4 Hz, 2H), 2.12 - 2.02 (m, 2H), 1.73 (dq, J = 30.8, 5.3 Hz, 4H).

[0221] 25. Preparation of compound S25

[0222]

[0223] The synthesis of compound S25 follows the same procedure as for compound S15. 1 H NMR (700 MHz, Chloroform-d) δ 14.79 (s, 1H), 11.41 (s, 1H), 8.69 (d, J = 5.5 Hz, 1H), 8.13 (d, J = 5.0 Hz, 1H), 7.79 (d, J = 7.5 Hz, 2H), 7.68 (t, J = 7.8 Hz, 1H), 7.40 (t, J = 7.5 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.97 (dd, J = 7.1, 5.3 Hz, 1H), 6.01 (d, J = 4.0 Hz, 1H), 4.98 (s, 1H), 3.80 (d, J = 10.5 Hz, 4H), 3.48 (q, J = 5.1 Hz, 2H), 2.33 (dt, J = 7.3, 3.4 Hz, 2H), 2.12 - 2.02 (m, 2H), 1.73 (dq, J = 30.8, 5.3 Hz, 4H).

[0224] 26. Preparation of compound S26

[0225]

[0226] The synthesis of compound S26 follows the same procedure as for compound S15. 1H NMR (400 MHz, Chloroform-d + Methanol-d4) δ 8.14 (d, J = 5.0 Hz, 1H), 7.79 (d, J = 7.3 Hz, 2H), 7.75 - 7.66 (m, 1H), 7.36 (dt, J = 11.4, 6.7 Hz, 3H), 7.08 (d, J = 8.4 Hz, 1H), 6.99 (dd, J = 7.3, 5.2 Hz, 1H), 5.99 (d, J = 4.2 Hz, 1H), 3.78 (t, J = 4.4 Hz, 2H), 3.59 (d, J = 11.2 Hz, 10H), 3.39 (t, J = 5.2 Hz, 2H), 2.35 - 2.29 (m, 2H), 2.04 (d, J = 5.3 Hz, 2H), 1.71 (q, J = 8.5, 7.5 Hz, 4H).

[0227] 27. Preparation of compound S27

[0228]

[0229] The synthesis of compound S27 follows the same procedure as for compound S15. 1 H NMR (400 MHz, Chloroform-d + Methanol-d4) δ 8.14 (d, J = 5.0 Hz, 1H), 7.79 (d, J = 7.3 Hz, 2H), 7.75 - 7.66 (m, 1H), 7.36 (dt, J = 11.4, 6.7 Hz, 3H), 7.08 (d, J = 8.4 Hz, 1H), 6.99 (dd, J = 7.3, 5.2 Hz, 1H), 5.99 (d, J = 4.2 Hz, 1H), 3.78 (t, J = 4.4 Hz, 2H), 3.59 (d, J = 11.2 Hz, 10H), 3.39 (t, J = 5.2 Hz, 2H), 2.35 - 2.29 (m, 2H), 2.04 (d, J = 5.3 Hz, 2H), 1.71 (q, J = 8.5, 7.5 Hz, 4H).

[0230] 28. Preparation of compound S28

[0231]

[0232] The synthesis of compound S28 follows the same procedure as for compound S15. 1H NMR (700 MHz, Chloroform-d) δ 8.17 (dt, J = 4.9, 2.2 Hz, 1H), 7.73 (t, J = 8.1 Hz, 1H), 7.71 - 7.66 (m, 2H), 7.43 - 7.35 (m, 3H), 7.11 (d, J = 8.3 Hz, 1H), 7.01 (dd, J = 7.1, 5.2 Hz, 1H), 6.02 (d, J = 3.7 Hz, 1H), 4.45 - 4.38 (m, 4H), 3.97 - 3.90 (m, 4H), 2.33 (dq, J = 6.5, 3.3 Hz, 2H), 2.06 - 2.01 (m, 2H), 1.77 - 1.69 (m, 4H).

[0233] 29. Preparation of compound S29

[0234]

[0235] The synthesis of compound S29 follows the same procedure as for compound S15. 1 H NMR (700 MHz, Chloroform-d) δ 8.17 (dt, J = 4.9, 2.2 Hz, 1H), 7.73 (t, J = 8.1 Hz, 1H), 7.71 - 7.66 (m, 2H), 7.43 - 7.35 (m, 3H), 7.11 (d, J = 8.3 Hz, 1H), 7.01 (dd, J = 7.1, 5.2 Hz, 1H), 6.02 (d, J = 3.7 Hz, 1H), 4.45 - 4.38 (m, 4H), 3.97 - 3.90 (m, 4H), 2.33 (dq, J = 6.5, 3.3 Hz, 2H), 2.06 - 2.01 (m, 2H), 1.77 - 1.69 (m, 4H).

[0236] 30. Preparation of compound S30

[0237]

[0238] The synthesis of compound S30 follows the same procedure as for compound S15. 1H NMR (700 MHz, Chloroform-d + Methanol-d4) δ 8.13 (dt, J = 5.4, 2.7 Hz, 1H), 7.81 - 7.75 (m, 2H), 7.72 - 7.66 (m, 1H), 7.40 - 7.30 (m, 3H), 7.07 (dd, J = 8.8, 3.4 Hz, 1H), 6.99 (dt, J = 8.1, 4.0 Hz, 1H), 5.99 (d, J = 4.4 Hz, 1H), 4.25 (ddt, J = 48.4, 8.6, 4.3 Hz, 1H), 3.65 (ddq, J = 33.9, 14.6, 3.0 Hz, 1H), 3.56 (tdd, J = 14.5, 13.1, 11.6, 3.9 Hz, 2H), 3.38 - 3.27 (m, 1H), 2.30 (dq, J = 7.2, 3.6 Hz, 2H), 2.07 - 1.99 (m, 2H), 1.77 - 1.62 (m, 4H), 1.20 (d, J = 7.6 Hz, 7H).

[0239] 31. Preparation of compound S31

[0240]

[0241] The synthesis of compound S31 follows the same steps as for compound S15. 1 H NMR (700 MHz, Chloroform-d) δ 14.73 (d, J = 3.5 Hz, 1H), 10.86 (d, J = 3.4 Hz, 1H), 8.29 (t, J = 5.9 Hz, 1H), 8.15 (d, J = 4.8 Hz, 1H), 7.87 - 7.78 (m, 2H), 7.73 - 7.65 (m, 1H), 7.44 - 7.31 (m, 3H), 7.08 (dd, J = 8.4, 3.3 Hz, 1H), 6.98 (q, J = 5.1, 3.9 Hz, 1H), 6.02 (d, J = 4.1 Hz, 1H), 3.72 (d, J = 3.3 Hz, 2H), 3.35 (d, J = 3.4 Hz, 2H), 3.25 (t, J = 4.6 Hz, 2H), 2.34 (dt, J = 7.2, 3.7 Hz, 3H), 2.08 (d, J = 8.3 Hz, 2H), 1.74 (dq, J = 29.0, 5.3 Hz, 4H), 0.43 (dt, J = 21.2, 5.5 Hz, 4H).

[0242] 32. Preparation of compound S32

[0243]

[0244] The synthesis of compound S32 follows the same steps as for compound S15. 1H NMR (700 MHz, Chloroform-d) δ 14.53 (s, 1H), 10.69 (s, 1H), 8.15 (dd, J = 5.2, 1.7 Hz, 1H), 7.89 - 7.84 (m, 2H), 7.68 (td, J = 7.9, 7.5, 1.8 Hz, 1H), 7.39 (t, J = 7.4 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.15 (t, J = 6.1 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.97 (dd, J = 7.2, 5.1 Hz, 1H), 6.03 - 6.01 (m, 1H), 3.65 (s, 2H), 3.33 (s, 3H), 3.15 (d, J = 6.0 Hz, 2H), 3.11 (s, 2H), 2.34 (dq, J = 6.4, 3.3 Hz, 2H), 2.09 (tt, J = 6.1, 2.7 Hz, 2H), 1.79 - 1.70 (m, 4H).

[0245] 33. Preparation of compound S33

[0246]

[0247] The synthesis of compound S33 follows the same steps as for compound S15. 1 H NMR (700 MHz, Chloroform-d) δ 14.66 (s, 1H), 10.83 (s, 1H), 8.17 (d, J = 5.0 Hz, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.75 - 7.69 (m, 1H), 7.64 - 7.56 (m, 1H), 7.43 - 7.33 (m, 3H), 7.10 (d, J = 8.4 Hz, 1H), 7.00 (dd, J = 7.3, 5.1 Hz, 1H), 6.03 (td, J = 3.9, 1.9 Hz, 1H), 3.66 (t, J = 6.3 Hz, 2H), 3.61 (s, 2H), 3.22 (q, J = 6.5 Hz, 2H), 2.34 (dq, J = 6.2, 3.2 Hz, 2H), 2.13 - 2.06 (m, 2H), 1.80 - 1.68 (m, 5H), 1.55 (dt, J = 13.2, 6.6 Hz, 4H), 1.39 (dq, J = 8.4, 5.0 Hz, 4H).

[0248] 34. Preparation of compound S34

[0249]

[0250] The synthesis of compound S34 follows the same steps as for compound S15. 1H NMR (400 MHz, Chloroform-d + Methanol-d4) δ 8.18 (t, J = 5.7 Hz, 1H), 8.13 (dd, J = 5.2, 1.8 Hz, 1H), 7.77 (dt, J = 6.2, 1.6 Hz, 2H), 7.70 (ddd, J = 8.8, 7.3, 1.9 Hz, 1H), 7.40 - 7.29 (m, 3H), 7.08 (d, J = 8.4 Hz, 1H), 6.98 (dd, J = 7.3, 5.2 Hz, 1H), 5.99 (dt, J = 4.0, 2.2 Hz, 1H), 3.56 - 3.47 (m, 4H), 3.13 (q, J = 7.0 Hz, 2H), 2.30 (p, J = 4.7, 4.0 Hz, 2H), 2.02 (q, J = 4.7, 3.9 Hz, 2H), 1.76 - 1.63 (m, 4H), 1.46 (q, J = 6.9 Hz, 4H), 1.27 (s, 6H).

[0251] 35. Preparation of compound S35

[0252]

[0253] Compound 35-1 (95 mg), pyridine (47.5 mg) were dissolved in anhydrous DMF (3 mL), compound 35-2 (46.2 mg) was added at 0 °C, and the mixture was stirred at room temperature overnight. TLC detection showed that the reaction was complete. The mixture was concentrated and dried, and column chromatography was performed to obtain compound S35 (13 mg). 1 H NMR (500 MHz, Chloroform-d) δ 8.31 (dd, J = 4.9, 1.2 Hz, 1H), 7.70 - 7.62 (m, 2H), 7.54 (td, J = 8.1, 1.3 Hz, 1H), 7.46 - 7.38 (m, 3H), 7.16 - 7.04 (m, 4H), 7.04 - 6.90 (m, 2H), 6.02 (t, J = 6.2 Hz, 1H), 4.34 (s, 1H), 4.16 (s, 2H), 2.04 - 1.91 (m, 4H), 1.66 - 1.55 (m, 4H).

[0254] 36. Preparation of compound S36

[0255]

[0256] Compound 35-1 (95 mg), 36-1 (80.6 mg), DIPEA (77.5 mg) were dissolved in anhydrous THF (6 mL) and stirred at room temperature overnight. TLC was used to monitor the reaction and the starting material was completely consumed. 0.4 M NH3 in dioxane (2 mL) was added to the reaction and stirred at room temperature for 30 minutes. TLC was used to monitor the reaction and the starting material was completely consumed. The reaction was concentrated and dried in vacuo and purified by column chromatography to give compound S35 (15 mg). 1 H NMR (500 MHz, Chloroform-d) δ 8.30 (dd, J = 5.0, 1.3 Hz, 1H), 7.69 - 7.61 (m, 2H), 7.46 - 7.39 (m, 4H), 7.12 (d, J = 7.5 Hz, 2H), 7.01 - 6.93 (m, 4H), 5.97 (t, J = 6.0 Hz, 1H), 4.86 (s, 2H), 2.05 - 1.91 (m, 4H), 1.67 - 1.56 (m, 4H).

[0257] 37. Preparation of compound S37

[0258]

[0259] The synthesis of compound S37 followed the procedure of compound S36. 1 H NMR (500 MHz, Chloroform-d) δ 8.30 (dd, J = 5.0, 1.3 Hz, 1H), 7.69 - 7.61 (m, 2H), 7.46 - 7.39 (m, 4H), 7.12 (d, J = 7.5 Hz, 2H), 7.01 - 6.93 (m, 4H), 5.97 (t, J = 6.0 Hz, 1H), 4.86 (s, 2H), 2.05 - 1.91 (m, 4H), 1.67 - 1.56 (m, 4H).

[0260] 38. Preparation of compound S38

[0261]

[0262] The synthesis of compound S38 followed the procedure of compound S36. 1H NMR (500 MHz, Chloroform-d) δ 8.30 (dd, J = 5.0, 1.3 Hz, 1H), 7.69 - 7.61 (m, 2H), 7.47 - 7.39 (m, 4H), 7.12 (d, J = 7.5 Hz, 2H), 7.01 - 6.92 (m, 4H), 5.97 (dd, J = 6.6, 5.4 Hz, 1H), 4.31 (ddd, J = 25.1, 11.2, 4.7 Hz, 2H), 4.11 (ddd, J = 25.2, 11.2, 1.0 Hz, 2H), 3.61 (dd, J = 25.2, 5.0 Hz, 2H), 2.26 (t, J = 5.0 Hz, 1H), 2.04 - 1.92 (m, 4H), 1.67 - 1.56 (m, 4H).

[0263] 39. Preparation of compound S39

[0264]

[0265] The synthesis of compound S39 follows the same procedure as for compound S36. 1 H NMR (500 MHz, Chloroform-d) δ 8.30 (dd, J = 5.0, 1.3 Hz, 1H), 7.69 - 7.61 (m, 2H), 7.47 - 7.39 (m, 4H), 7.12 (d, J = 7.5 Hz, 2H), 7.01 - 6.92 (m, 4H), 5.97 (dd, J = 6.6, 5.4 Hz, 1H), 4.31 (ddd, J = 25.1, 11.2, 4.7 Hz, 2H), 4.11 (ddd, J = 25.2, 11.2, 1.0 Hz, 2H), 3.61 (dd, J = 25.2, 5.0 Hz, 2H), 2.26 (t, J = 5.0 Hz, 1H), 2.04 - 1.92 (m, 4H), 1.67 - 1.56 (m, 4H).

[0266] 40. Preparation of compound S40

[0267]

[0268] The synthesis of compound S40 follows the same procedure as for compound S36. 1 H NMR (500 MHz, Chloroform-d) δ 8.30 (dd, J = 5.0, 1.3 Hz, 1H), 7.69 - 7.61 (m, 2H), 7.47 - 7.39 (m, 4H), 7.12 (d, J = 7.5 Hz, 2H), 7.01 - 6.92 (m, 4H), 5.97 (dd, J = 6.6, 5.4 Hz, 1H), 4.31 (ddd, J = 25.1, 11.2, 4.7 Hz, 2H), 4.11 (ddd, J = 25.2, 11.2, 1.0 Hz, 2H), 3.61 (dd, J = 25.2, 5.0 Hz, 2H), 2.26 (t, J = 5.0 Hz, 1H), 2.04 - 1.92 (m, 4H), 1.67 - 1.56 (m, 4H).

[0269] 41. Preparation of compound S41

[0270]

[0271] The synthesis of compound S41 follows the same procedure as compound S36. 1 H NMR (500 MHz, Chloroform-d) δ 8.31 (dd, J = 4.9, 1.3 Hz, 1H), 7.70 - 7.62 (m, 2H), 7.47 - 7.37 (m, 4H), 7.16 - 7.09 (m, 2H), 7.02 - 6.92 (m, 4H), 5.99 - 5.91 (m, 1H), 4.52 (s, 1H), 3.62 (t, J = 3.8 Hz, 2H), 3.60 - 3.55 (m, 2H), 3.24 (s, 3H), 2.05 - 1.92 (m, 4H), 1.65 - 1.55 (m, 4H), 1.36 (t, J = 4.9 Hz, 1H).

[0272] 42. Preparation of compound S42

[0273]

[0274] The synthesis of compound S42 follows the same procedure as compound S36. 1 H NMR (500 MHz, Chloroform-d) δ 8.31 (dd, J = 5.0, 1.2 Hz, 1H), 7.72 - 7.60 (m, 2H), 7.50 - 7.38 (m, 4H), 7.23 - 7.10 (m, 2H), 7.06 - 6.98 (m, 3H), 6.98 - 6.92 (m, 1H), 5.98 (dd, J = 6.6, 5.4 Hz, 1H), 5.34 (s, 1H), 4.39 (s, 1H), 3.74 (t, J = 4.1 Hz, 2H), 3.37 (s, 3H), 3.13 (t, J = 4.1 Hz, 2H), 2.06 - 1.90 (m, 4H), 1.66 - 1.56 (m, 4H).

[0275] 43. Preparation of compound S43

[0276]

[0277] The synthesis of compound S43 follows the same procedure as compound S36. 1H NMR (500 MHz, Chloroform-d) δ 8.31 (dd, J = 5.0, 1.2 Hz, 1H), 7.71 - 7.59 (m, 2H), 7.51 - 7.37 (m, 4H), 7.17 - 7.07 (m, 2H), 7.05 - 6.91 (m, 4H), 5.34 (s, 1H), 4.50 (s, 1H), 3.74 (t, J = 4.7 Hz, 4H), 3.54 (t, J = 5.2 Hz, 2H), 2.60 (t, J = 5.2 Hz, 2H), 2.51 (t, J = 4.7 Hz, 4H), 2.06 - 1.90 (m, 4H), 1.69 - 1.54 (m, 4H).

[0278] 44. Preparation of compound S44

[0279]

[0280] The synthesis of compound S44 follows the same procedure as compound S36. 1 H NMR (500 MHz, Chloroform-d) δ 8.31 (dd, J = 5.0, 1.2 Hz, 1H), 7.71 - 7.59 (m, 2H), 7.51 - 7.37 (m, 4H), 7.17 - 7.07 (m, 2H), 7.05 - 6.91 (m, 4H), 5.34 (s, 1H), 4.50 (s, 1H), 3.74 (t, J = 4.7 Hz, 4H), 3.54 (t, J = 5.2 Hz, 2H), 2.60 (t, J = 5.2 Hz, 2H), 2.51 (t, J = 4.7 Hz, 4H), 2.06 - 1.90 (m, 4H), 1.69 - 1.54 (m, 4H).

[0281] 45. Preparation of compound S45

[0282]

[0283] The synthesis of compound S45 follows the same procedure as compound S36. 1 H NMR (500 MHz, Chloroform-d) δ 8.31 (dd, J = 5.0, 1.2 Hz, 1H), 7.71 - 7.59 (m, 2H), 7.51 - 7.37 (m, 4H), 7.17 - 7.07 (m, 2H), 7.05 - 6.91 (m, 4H), 5.34 (s, 1H), 4.50 (s, 1H), 3.74 (t, J = 4.7 Hz, 4H), 3.54 (t, J = 5.2 Hz, 2H), 2.60 (t, J = 5.2 Hz, 2H), 2.51 (t, J = 4.7 Hz, 4H), 2.06 - 1.90 (m, 4H), 1.69 - 1.54 (m, 4H).

[0284] 46. Preparation of compound S46

[0285]

[0286] The synthesis of compound S46 follows the same procedure as compound S36. 1 H NMR (500 MHz, Chloroform-d) δ 8.31 (dd, J = 5.0, 1.3 Hz, 1H), 7.73 - 7.60 (m, 2H), 7.53 - 7.37 (m, 4H), 7.19 - 7.10 (m, 2H), 7.10 - 6.90 (m, 4H), 6.03 - 5.92 (m, 1H), 5.34 (s, 1H), 4.40 (s, 1H), 4.09 (td, J = 7.2, 5.0 Hz, 2H), 3.74 (t, J = 7.3 Hz, 2H), 3.60 (t, J = 7.2 Hz, 2H), 3.13 (t, J = 7.3 Hz, 2H), 2.07 - 1.89 (m, 5H), 1.69 - 1.56 (m, 4H).

[0287] 47. Preparation of compound S47

[0288]

[0289] The synthesis of compound S47 follows the same procedure as compound S36. 1 H NMR (500 MHz, Chloroform-d) δ 8.30 (dd, J = 5.0, 1.3 Hz, 1H), 7.69 - 7.61 (m, 2H), 7.47 - 7.37 (m, 4H), 7.11 (d, J = 7.5 Hz, 2H), 7.02 - 6.90 (m, 4H), 5.96 (td, J = 6.2, 1.2 Hz, 1H), 3.33 (td, J = 7.5, 5.0 Hz, 2H), 3.24 (t, J = 7.6 Hz, 2H), 2.05 - 1.91 (m, 4H), 1.69 - 1.55 (m, 6H), 1.43 - 1.24 (m, 7H).

[0290] 48. Preparation of compound S48

[0291]

[0292] The synthesis of compound S48 follows the same procedure as compound S36. 1H NMR (500 MHz, Chloroform-d) δ 8.30 (dd, J = 5.0, 1.2 Hz, 1H), 7.68 - 7.62 (m, 2H), 7.47 - 7.39 (m, 4H), 7.15 - 7.09 (m, 2H), 7.01 - 6.92 (m, 4H), 5.96 (ddd, J = 4.7, 2.4, 1.2 Hz, 1H), 5.34 (s, 1H), 4.57 (d, J = 7.1 Hz, 1H), 4.49 (s, 1H), 4.22 (q, J = 7.0 Hz, 1H), 4.08 - 3.91 (m, 2H), 3.49 - 3.39 (m, 2H), 3.29 (s, 3H), 3.23 (td, J = 7.0, 5.0 Hz, 1H), 3.08 (ddd, J = 19.6, 5.2, 1.9 Hz, 1H), 2.80 - 2.66 (m, 1H), 2.30 (dt, J = 18.2, 5.6 Hz, 1H), 2.26 - 2.16 (m, 2H), 2.16 - 2.06 (m, 2H), 2.04 - 1.96 (m, 2H), 1.89 (qdd, J = 12.6, 5.0, 2.7 Hz, 2H).

[0293] 49. Preparation of compound S49

[0294]

[0295] The synthesis of compound S49 follows the procedure for compound S36. 1 H NMR (700 MHz, CDCl3+CD3OD) δ 8.12 - 8.03 (m, 1H), 7.74 - 7.62 (m, 2H), 7.61 - 7.50 (m, 1H), 7.35 - 7.18 (m, 5H), 6.98 - 6.86 (m, 3H), 6.80 - 6.66 (m, 1H), 6.02 - 5.91 (m, 1H), 4.41 - 4.23 (m, 2H), 4.22 - 4.06 (m, 4H), 3.55 - 3.42 (m, 2H), 2.31 - 2.17 (m, 2H), 2.03 - 1.92 (m, 2H), 1.76 - 1.54 (m, 4H).

[0296] 50. Preparation of compound S50

[0297] The synthesis of compound S50 follows the procedure for compound S36. 1H NMR (400 MHz, CDC13 + CD3OD) δ 8.16 - 8.11 (m, 1H), 7.74 (d, J = 6.9 Hz, 2H), 7.64 - 7.55 (m, 1H), 7.36 - 7.27 (m, 5H), 7.00 - 6.93 (m, 3H), 6.88 (dd, J = 16.9, 8.3 Hz, 1H), 6.07 - 6.01 (m, 1H), 4.39 - 4.29 (m, 2H), 4.17 (t, J = 4.5 Hz, 2H), 3.64 (t, J = 5.6 Hz, 1H), 3.51 (t, J = 5.7 Hz, 1H), 3.30 (dt, J = 30.6, 5.7 Hz, 2H), 2.90 (s, 3H), 2.37 - 2.27 (m, 2H), 2.11 - 2.01 (m, 2H), 1.78 - 1.62 (m, 4H).

[0298] 51. Preparation of compound S51

[0299] The synthesis of compound S51 follows similar procedures to compound S36. 1 H NMR (700 MHz, CDC13 + CD3OD) δ 8.14 (d, J = 3.9 Hz, 1H), 7.76 (d, J = 7.4 Hz, 2H), 7.64 - 7.59 (m, 1H), 7.37 - 7.27 (m, 5H), 7.02 - 6.94 (m, 3H), 6.75 (d, J = 8.4 Hz, 1H), 6.06 - 6.01 (m, 1H), 4.37 (t, J = 4.6 Hz, 2H), 4.23 - 4.13 (m, 2H), 3.42 (t, J = 5.3 Hz, 2H), 3.34 - 3.26 (m, 5H), 2.35 - 2.27 (m, 2H), 2.11 - 2.03 (m, 2H), 1.77 - 1.64 (m, 4H).

[0300] 52. Preparation of compound S52

[0301] The synthesis of compound S52 follows similar procedures to compound S36. 1H NMR (700 MHz, CDC13) δ 14.86 (s, 1H), 8.20 (d, J = 5.0 Hz, 1H), 7.81 (d, J = 7.4 Hz, 2H), 7.62 - 7.55 (m, 1H), 7.48 - 7.37 (m, 2H), 7.37 - 7.28 (m, 3H), 6.98 (t, J = 6.1 Hz, 1H), 6.84 (s, 2H), 6.16 (s, 1H), 4.27 - 4.12 (m, 2H), 4.01 (s, 2H), 3.59 (d, J = 46.8 Hz, 4H), 3.39 (d, J = 33.8 Hz, 4H), 2.45 - 2.35 (m, 2H), 2.28 - 2.16 (m, 2H), 1.87 - 1.70 (m, 4H).

[0302] Example 2. Test of compounds to inhibit the activity of MAT2A enzyme at the molecular level

[0303] The MAT2A phosphate assay method was used to detect the inhibitory activity of the compound molecules on MAT2A. The experimental operation steps are as follows:

[0304] Enzyme reaction buffer: 50 mM Tris-HCl, 5 mM MgCl2, 100 mM KCl, 0.005% [w / v] BSA, pH 7.4, 1 mM DTT; 30 L reaction system was prepared in a 384-well plate, containing 1 ng / μL MAT2A enzyme, 160 μΜ substrate Lmethionine, 200 μΜ ATP and 1 M starting test compound; 2 duplicate holes were set for each group, and enzyme-free negative control and enzyme group control were set; incubated at room temperature for 1.5 h; phosphate-assay-kit-picolorlock (Abeam, product number ab270004) reagent was used for detection, and the chemiluminescence was read by enzyme-labeled instrument (Bioteck synergy H1) 623 nM;

[0305] The inhibition rate of the compound was calculated using the following formula:

[0306] Inhibition rate (%) = [(enzyme hole reading value - blank reading value) - (inhibitor reading value - blank reading value)] / (enzyme hole reading value - blank reading value) x 100%,

[0307] The half maximal inhibitory concentration IC50was calculated using GraphPad software 50 . The results are shown in Table 1.

[0308] Table 1: Inhibitory activity of some compounds on MAT2A enzyme in the example

[0309] Compound IC50 (nM) Compound IC50 (nM) S8 396.40 S42 59.01 S11 255.50 S43 86.30 S17 175.00 S44 168.50 S24 192.00 S45 71.39 S30 33.09 S46 84.44 S35 82.24 S48 50.19 S36 59.38 S49 116 S37 331.30 S50 104 S39 544.45 S51 143 S40 126.20 S52 147 S41 305.85 AG270 AG271 AG272 AG273 AG274 AG275 AG276 AG277 AG278 AG 53.63

[0310] Example 3. Assay of the compound's inhibitory activity on MAT2A enzyme at the cellular level

[0311] Using HAP1 and HAP1 / MTAP - / - (Near-haploid leukemia cell line) A pair of cells were treated with the compound for 72 hours, and the proliferative and growth-inhibiting activity of the compound was detected by the SRB method. The specific steps are as follows: HAP1 and HAP1 / MTAP cells in logarithmic growth phase... - / - Cells were seeded at an appropriate density into 96-well plates, 90 μL per well, and cultured overnight. Different concentrations of the compound were then added and incubated for 72 h, with a solvent control group (negative control) included. After 72 h of incubation, the effect of the compound on cell proliferation was detected using the SRB assay: The culture medium was discarded, and 100 μL / well of pre-chilled 10% trichloroacetic acid (TCA) was added. After fixation at 4°C for 1 hour, the cells were washed five times with distilled water and air-dried. 100 μL / well of SRB (4 mg / mL) solution prepared with 1% glacial acetic acid was added, and staining was performed at room temperature for 15 minutes. The supernatant was discarded, and the cells were washed five times with 1% acetic acid and air-dried. 150 μL / well of Tris (10 mM) solution was added, and the cells were incubated at room temperature for 15 minutes. Finally, the readings were taken using a SpectraMax 190 microplate reader at a wavelength of 560 nm.

[0312] Using AG 270 as the control compound, its structural formula is as follows:

[0313]

[0314] The inhibition rate (%) of the compound on tumor cell growth was calculated using the following formula:

[0315] Inhibition rate (%) = (OD control well - OD drug administration well) / OD control well × 100%

[0316] The results are shown in Table 2.

[0317] Table 2. Effects of some compounds in the examples on HAP1 / MTAP - / - (Near-haploid leukemia cell lines) Inhibition of cell proliferation activity by a single cell line (SI = HAP1 IC50) 50 / HAP1 / MTAP - / - IC 50 )

[0318]

[0319] *A refers to IC 50 ≤2μM, B refers to 2μM <IC 50 ≤10μM, C refers to IC 50 >10μM

[0320] Data test results show that the enzyme activity of S42 and its inhibitory effect on the proliferation of HAP1 cells of MTAP - / - are equivalent to positive compound AG270, but the selective inhibitory effect of S42 on HAP1 cells of MTAP - / - is better, and the IC + / + 50 fold difference compared with MTAP 50 cells, which indicates that the compound has better safety compared with AG270.

[0321] All documents mentioned in the present application are incorporated herein by reference as if each document were individually incorporated by reference. In addition, it is to be understood that the application can be carried out by specifically different embodiments and that each disclosed embodiment can be implemented with or without the corresponding benefits disclosed herein.

Claims

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein said compound having a structure of Formula VIII: X is -OH; R2 is R3 is R4 is R F R is H or C1-C3 alkyl; L3 is C1-C8 alkylene; R E selected from the group consisting of C1-C6alkyl, C1-C4alkoxy, hydroxy, substituted or unsubstituted C4-C12heterocyclyl; p is selected from the group consisting of 0, 1, 2; wherein said "substituted" means substituted with one or more substituents selected from the group consisting of C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxy, C1-C6 alkylhydroxy, -NH2; wherein the compound is not 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formula I, wherein said compound of Formula I has a structure of Formula IIa and IIb in tautomeric form: wherein R1, R2, R3, R4 are as described in claim 1.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formula I, wherein R E selected from the group consisting of: C1-C4alkoxy, hydroxy, substituted or unsubstituted C4-C12heterocyclyl, wherein said "substituted" means substituted with one or more substituents selected from the group consisting of: C1-C6alkoxy, hydroxy.

4. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R E is C1-C4alkoxy.

5. The compound of claim 3, or a pharmaceutically acceptable salt thereof, having Formula I, p is 0 or 1.

6. The compound of claim 1 of Formula I, or a pharmaceutically acceptable salt thereof, wherein L3 is C1-C3 alkylene.

7. The compound of claim 1 of Formula I, or a pharmaceutically acceptable salt thereof, wherein R E selected from the group consisting of:

8. A compound, or a pharmaceutically acceptable salt thereof, characterized in that, said compound is selected from the group consisting of:

9. A pharmaceutical composition, characterized by, comprising: (i) one or more therapeutically effective amount of a compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable carrier.

10. Use of a compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, characterized in that, for the preparation of a medicament for the prevention and / or treatment of a disease associated with methionine adenosyltransferase 2a, wherein said disease associated with methionine adenosyltransferase 2a is selected from the group consisting of solid tumors, blood tumors.

11. Use according to claim 10, characterized in that, said solid tumor is selected from the group consisting of colon cancer, non-small cell lung cancer, gastric cancer, esophageal cancer and bladder cancer, said blood tumor is selected from the group consisting of leukemia, lymphoma.

Images