ULK1 inhibitor, preparation method therefor and use thereof

Abstract

Provided are a ULK1 inhibitor, a preparation method therefor and a use thereof. Specifically, provided are a compound of formula 1 or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, a hydrate, an N-oxide, an isotope labeled compound, a metabolite, an ester or a prodrug thereof, wherein X1, X2, X3, R1, R2, R3, and R are as defined herein. Also provided are a pharmaceutical composition containing the compound, a treatment method using the compound, and a method for preparing the compound.

Description

ULK1 inhibitors and their preparation methods and uses

[0001] Citation of Related Applications

[0002] This application claims priority to Chinese patent application No. 202311138740.7 filed on September 1, 2023, the contents of which are incorporated by reference into this application in their entirety and for all purposes. Technical Field

[0003] The present invention relates to a novel ULK1 inhibitor, a pharmaceutical composition containing the same, a preparation method thereof and use thereof in preparing a medicament for ULK1-mediated diseases. Background Art

[0004] Autophagy is a central cellular mechanism for the elimination of damaged proteins, protein complexes, and organelles. This conserved process, in addition to being required for proper cellular and tissue homeostasis during embryonic development and in defense against pathogens, plays a crucial role in the cellular response to nutrient deprivation and other stresses. Defects in the autophagic pathway have been implicated in several human pathologies, including infectious diseases, neurodegenerative disorders, and cancer. Despite these highly conserved, fundamental cellular functions, the molecular and biochemical details of how different cargoes initiate autophagy, as well as the coordination of steps from autophagosome priming to eventual fusion with lysosomes, remain poorly understood.

[0005] Provided herein are inhibitors of Unc-51-like autophagy-activating kinase (ULK) proteins. In many cases, ULK1 and ULK2 are important proteins that regulate autophagy in mammalian cells. In some cases, ULK1 and ULK2 are activated by several upstream signals under conditions of nutrient deprivation, subsequently initiating autophagy. The requirement for ULK1 and ULK2 in the initiation of autophagy has been studied in the context of nutrient deprivation. Although ULK1 appears to be the most essential for autophagy, in some cases, ULK1 and ULK2 show a high degree of functional redundancy. The kinase domains of ULK1 and ULK2 share 78% sequence homology, suggesting that in some cases, ULK2 may compensate for the loss of ULK1. Therefore, only when both ULK1 and ULK2 are inhibited can nutrient-dependent autophagy be eliminated. However, in some cases, ULK1 inhibition alone is sufficient to provide therapeutic benefits, such as normalizing autophagy in any of the methods provided herein, or other beneficial results. While inhibition of ULK1 and ULK2 produces therapeutic benefits, such as tumor shrinkage, tumor cell death, or reduced tumor growth rate, there remains a need to provide new ULK1 inhibitors for the treatment of ULK1-mediated diseases.

[0006] SUMMARY OF THE INVENTION

[0007] In one aspect, the present invention provides a pyrimidine compound that has a specific inhibitory effect on ULK1, thereby having a good therapeutic effect on ULK1-mediated diseases. The compound is a compound of Formula 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, or prodrug thereof:

[0008] Wherein, X1 is CH or N; X2 is N or CR4; X3 is N or CR5;

[0009] R1 is selected from H, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl are each optionally substituted with one or more R6;

[0010] R2 is selected from H, halogen, cyano, nitro, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, R7O-, -SR7, -NR7R8, -NHCONR7R8, -NHCOR7, -CONR7R8 and -SO2R7, wherein the C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl are each optionally substituted with one or more R6;

[0011] R3 is selected from H, cyano, halogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl and C3-C 10 Cycloalkyl;

[0012] R4 is selected from H, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10aryl, 5-10 membered heteroaryl, R7O-, -NR7R8 and -NHCONR7R8, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl are each optionally substituted with one or more R6;

[0013] Alternatively, R2, R4 and the groups connected thereto together form a 3-12 membered monocyclic or spirocyclic heterocyclic ring, a C6-C 10 aromatic ring or 5-10 membered heteroaromatic ring, wherein the 3-12 membered monocyclic or spirocyclic heterocyclic ring, C6-C 10 The aromatic ring or 5-10 membered heteroaromatic ring is each substituted with one or more R6;

[0014] R5 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl;

[0015] Alternatively, R1, R5 and the group to which they are attached together form a 5-6 membered heterocyclic ring, a benzene ring or a 5-6 membered heteroaromatic ring;

[0016] R6 is independently selected from halogen, cyano, nitro, amino, -NHCO (C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl, wherein the C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl are each optionally substituted with one or more halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy;

[0017] R7 and R8 are each independently selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group and C6-C 10 Aryl, wherein the C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group or C6-C 10 each aryl group is optionally substituted with one or more R6;

[0018] Or R7, R8 and the groups connected thereto together form a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring;

[0019] R is selected from 3-12 membered heterocyclyl, 5-10 membered heteroaryl and -L-R9, wherein the 3-12 membered heterocyclyl or 5-10 membered heteroaryl are each optionally replaced by one or more R 10 replace;

[0020] L is -(L1) m -(L2) n -(L3) p -;

[0021] L1 is selected from -O-, -N(R 12 )-、-C(R 12 )(R 13 )-O-、-N(R 12 )CO- and -S-;

[0022] L2 is selected from C1-C6 alkylene, C1-C6 heteroalkylene, C3-C 10 Cycloalkylene and 3-10 membered heterocyclylene;

[0023] L3 is selected from -N(R 12 )-、-N(R 12 )C(O)- and -C(O)-;

[0024] m, n and p are each independently selected from 0, 1 and 2, and m, n and p are not 0 at the same time;

[0025] R9 is selected from C3-C 10 Cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclic group, the C3-C 10 Cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl are each optionally substituted by one or more R 14 replace;

[0026] R 10 Each independently selected from C1-C6 alkyl, oxo, 5-10 membered heteroaryl, 3-12 membered heterocyclic group, R 11 C(O)-、R 11 C(O)N(R 12 )- and -NR 12 R 13 wherein the C1-C6 alkyl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl are each optionally substituted by one or more R 15 replace;

[0027] R 11 Selected from C1-C6 alkyl and C3-C 10 Cycloalkyl;

[0028] R12 and R 13 Each independently selected from H, C1-C6 alkyl and C3-C 10 Cycloalkyl;

[0029] R 14 Each is independently selected from H, halogen, cyano, oxo, C1-C6 alkyl, C1-C6 alkoxy, -CONR 12 R 13 and R 11 C(O)-; and

[0030] R 15 Each independently selected from H, halogen, cyano, oxo, C1-C6 alkyl, C3-C 10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the C1-C6 alkyl, C3-C 10 The cycloalkyl or 3-12 membered heterocyclyl groups are each optionally substituted with one or more substituents selected from C1-C6 alkyl and oxo;

[0031] The conditions are:

[0032] (1) When R9 is C3-C 10 Cycloalkyl, C6-C 10 When it is an aryl group or a 5-10 membered heteroaryl group, n is not 0;

[0033] (2) When L is -(L1) m -(L2) n -(L3) p -, L1 is selected from -N(R 12 )-, m is 1, L2 is selected from C1-C6 alkylene, and when n is 1, L3 is not -N(R 12 )C(O)-;

[0034] (3) When L is -(L1) m -(L2) n -(L3) p -, L1 is selected from -N(R 12 )-, m is 1, L2 is selected from C1-C6 alkylene, n is 1, p is 0, and R9 is a 3-12 membered heterocyclic group, the 3-12 membered heterocyclic group is substituted by oxo; and

[0035] (4) When L is -(L1) m -(L2) n -(L3) p -, L1 is selected from -N(R 12 )-, m is 1, L2 is selected from C1-C6 alkylene, n is 1, p is 0, and R9 is a 5-10 membered heteroaryl, R2 is not morpholinyl.

[0036] In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0037] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, or prodrug thereof, or a pharmaceutical composition of the present invention for the preparation of a medicament for treating a ULK1-mediated disease in a subject in need thereof.

[0038] In another aspect, the present invention provides a method for treating a ULK1-mediated disease in a subject in need thereof, comprising administering to the subject a compound according to the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, or prodrug thereof, or a pharmaceutical composition of the present invention.

[0039] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, or prodrug thereof, or a pharmaceutical composition of the present invention, for use in treating a ULK1-mediated disease in a subject in need thereof.

[0040] In another aspect, the present invention provides a method for preparing the compound of the present invention, comprising the steps shown in the following synthetic route A or B:

[0041] Synthesis Route A

[0042] Synthesis Route B

[0043] wherein: R1, R2, R3, R, X1, X2, X3 are as defined above.

[0044] Detailed Description of the Invention

[0045] definition

[0046] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0047] As used herein, the terms "comprises," "comprising," "having," "containing," or "involving," and variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

[0048] As used herein, the term "alkyl" is defined as a straight-chain or branched saturated aliphatic hydrocarbon group. For example, as used herein, the term "C 1-6 The term "alkyl" refers to a straight-chain or branched group having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, isopentyl and isobutyl.

[0049] As used herein, the term "alkylene" refers to a straight-chain or branched divalent alkyl group.

[0050] As used herein, the term "alkenyl" refers to a straight-chain or branched aliphatic hydrocarbon group having one or more unsaturated double bonds. For example, as used herein, the term "C2-C6 alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-buten-1-yl, 3-buten-1-yl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 5-hexen-1-yl, 4-hexen-1-yl, 3-hexen-1-yl, 2-hexen-1-yl, 3-methyl-2-buten-1-yl, 3-methyl-3-penten-1-yl, 3-methyl-2-penten-1-yl, 4-methyl-3-penten-1-yl, 4-methyl-2-penten-1-yl, and 2-methyl-2-penten-1-yl, etc. Preferably, the alkenyl group has one double bond.

[0051] As used herein, the term "alkynyl" refers to a straight or branched aliphatic hydrocarbon group with one or more unsaturated triple bonds. For example, as used herein, the term "C2-C6 alkynyl" refers to an alkenyl group with 2 to 6 carbon atoms, such as ethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 2-butyn-1-yl, 3-butyn-1-yl, 2-pentyn-1-yl, 3-pentyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl, 4-hexyn-1-yl, 3-hexyn-1-yl and 2-hexyn-1-yl. Preferably, it has one triple bond.

[0052] As used herein, the term "alkoxy" refers to a group having an oxygen atom inserted into an alkyl group (as defined above) at any reasonable position, such as C 1-8 Alkoxy, C 1-6 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkoxy. C 1-6 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

[0053] As used herein, the term "halo" or "halogen" group is defined to include fluorine, chlorine, bromine, or iodine.

[0054] As used herein, the term "haloalkyl" refers to an alkyl group substituted by one or more (such as 1 to 3) the same or different halogen atoms. For example, the term "C 1-6 "Haloalkyl" refers to a haloalkyl group having 1 to 6 carbon atoms, for example, -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl or -CH2CH2CF3, etc.

[0055] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) hydroxy groups. For example, the term "C 1-6 The term "hydroxyalkyl" refers to a hydroxyalkyl group having 1 to 6 carbon atoms, for example, -CH2OH, -CH2CH2OH, etc.

[0056] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) amino groups. For example, the term "C 1-6 "Aminoalkyl" refers to an aminoalkyl group having 1 to 6 carbon atoms, for example, -CH2NH2, -CH2CH2NH2, etc.

[0057] As used herein, the term "heteroalkyl" refers to a group consisting of one or more groups independently selected from N, O, or S(O). q(where q is 0, 1 or 2) is a straight or branched alkyl group interrupted by a heteroatom. For example, the term "C 1-6 "Heteroalkyl" refers to a heteroalkyl group having 1 to 6 carbon atoms.

[0058] As used herein, the term "heteroalkylene" refers to a group consisting of one or more groups independently selected from N, O, or S(O). q (wherein q is 0, 1 or 2) is a straight or branched chain alkylene group interrupted by a heteroatom. For example, the term "C 1-6 "Heteroalkylene" refers to a heteroalkylene group having 1 to 6 carbon atoms.

[0059] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring, for example, a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring, including a spirocyclic, fused (parallel ring) or bridged (bridged ring) system, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decahydronaphthyl, etc. The cycloalkyl group has 3 to 15, for example 3 to 10 carbon atoms. For example, the term "C 3-10 "Cycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring having 3 to 10 ring carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0060] As used herein, the term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic (including spirocyclic, fused (paracyclic) or bridged (bridged) ring) group, for example, having 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and one or more (e.g., 1, 2, 3 or 4) independently selected from N, O or S (O) in the ring. q (wherein q is 0, 1 or 2) heteroatoms, such as 3-12 membered heterocyclyl, 3-10 membered heterocyclyl, 3-6 membered heterocyclyl, 5-6 membered heterocyclyl, etc. Representative examples of heterocyclyl include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, etc. As used herein, the term "nitrogen-containing heterocycle" refers to a heterocycle having at least one nitrogen atom in the ring and optionally other heteroatoms, including monocyclic or polycyclic (including spirocyclic, fused (parallel ring) or bridged (bridged ring) systems) heterocycles.

[0061] As used herein, the term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. For example, the term "C 6-10 Aryl" or "C 6-10 "Aromatic ring" refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl (ring) or naphthyl (ring).

[0062] As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic, bicyclic or tricyclic aromatic ring system containing at least one heteroatom selected from N, O and S, for example having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular containing 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and, in each case, may be benzo-fused. For example, examples of heteroaryl or heteroaromatic rings include, but are not limited to, thienyl (ring), furanyl (ring), pyrrolyl (ring), oxazolyl (ring), thiazolyl (ring), imidazolyl (ring), pyrazolyl (ring), isoxazolyl (ring), isothiazolyl (ring), oxadiazolyl (ring), triazolyl (ring), thiadiazolyl (ring), and the like, and benzo derivatives thereof; or pyridinyl (ring), pyridazinyl (ring), pyrimidinyl (ring), pyrazinyl (ring), triazinyl (ring), and the like, and benzo derivatives thereof.

[0063] The term "substituted" means that one or more (e.g., 1, 2, 3, or 4) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence in the current context is not exceeded and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0064] If a substituent is described as being "optionally substituted with," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, with independently selected substituents or unsubstituted. If a nitrogen of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected substituent or unsubstituted.

[0065] If a substituent is described as being "independently selected" from a group of groups, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0066] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10, where reasonable.

[0067] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0068] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0069] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of suitable isotopes for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., 2 H. 3 H, deuterium D, tritium T); carbon isotopes (such as 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 37 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioactive isotopes) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and easy to detect. 11 C. 18 F. 15 O and 13 N) substitution can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by methods analogous to those described in the accompanying schemes and / or examples and preparations by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent is isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6.

[0070] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers may occur. Specific individual molecules may also exist as geometric isomers (cis / trans).

[0071] Similarly, the compound of the present invention can exist as a mixture (commonly referred to as tautomer) of two or more structurally different forms in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imines-enamine tautomers, etc. It is understood that the scope of the present application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0072] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0073] It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0074] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0075] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0076] Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; AR Katritzky and AJ Boulton, Eds., Academic Press; and GWH Cheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

[0077] Also included within the scope of the present invention are metabolites of the compounds of the invention, i.e., substances formed in vivo upon administration of the compounds of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Thus, the present invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0078] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity, and when administered to the body or thereon, can be converted into the compounds of the present invention having the desired activity by, for example, hydrolytic cleavage. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compounds in vivo. Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E.B. Roche, ed., American Pharmaceutical Association). The prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)).

[0079] The present invention also encompasses compounds of the present invention that contain protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P.GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0080] The term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0081] Compound

[0082] One object of the present invention is to provide a compound of Formula 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, or prodrug thereof:

[0083] Wherein, X1 is CH or N; X2 is N or CR4; X3 is N or CR5;

[0084] R1 is selected from H, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl are each optionally substituted with one or more R6;

[0085] R2 is selected from H, halogen, cyano, nitro, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, R7O-, -SR7, -NR7R8, -NHCONR7R8, -NHCOR7, -CONR7R8 and -SO2R7, wherein said C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl are each optionally substituted with one or more R6;

[0086] R3 is selected from H, cyano, halogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl and C3-C 10 Cycloalkyl;

[0087] R4 is selected from H, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, R7O-, -NR7R8 and -NHCONR7R8, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10Aryl or 5-10 membered heteroaryl are each optionally substituted with one or more R6;

[0088] Alternatively, R2, R4 and the groups connected thereto together form a 3-12 membered monocyclic or spirocyclic heterocyclic ring, a C6-C 10 aromatic ring or 5-10 membered heteroaromatic ring, wherein the 3-12 membered monocyclic or spirocyclic heterocyclic ring, C6-C 10 The aromatic ring or 5-10 membered heteroaromatic ring is each substituted with one or more R6;

[0089] R5 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl;

[0090] Alternatively, R1, R5 and the group to which they are attached together form a 5-6 membered heterocyclic ring, a benzene ring or a 5-6 membered heteroaromatic ring;

[0091] R6 is independently selected from halogen, cyano, nitro, amino, -NHCO (C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl, wherein the C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl are each optionally substituted with one or more halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy;

[0092] R7 and R8 are each independently selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group and C6-C 10 Aryl, wherein the C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group or C6-C 10 each aryl group is optionally substituted with one or more R6;

[0093] Or R7, R8 and the groups connected thereto together form a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring;

[0094] R is selected from 3-12 membered heterocyclyl, 5-10 membered heteroaryl and -L-R9, wherein the 3-12 membered heterocyclyl or 5-10 membered heteroaryl are each optionally replaced by one or more R 10 replace;

[0095] L is -(L1) m -(L2) n-(L3) p -;

[0096] L1 is selected from -O-, -N(R 12 )-、-C(R 12 )(R 13 )-O-、-N(R 12 )CO- and -S-;

[0097] L2 is selected from C1-C6 alkylene, C1-C6 heteroalkylene, C3-C 10 Cycloalkylene and 3-10 membered heterocyclylene;

[0098] L3 is selected from -N(R 12 )-、-N(R 12 )C(O)- and -C(O)-;

[0099] m, n and p are each independently selected from 0, 1 and 2, and m, n and p are not 0 at the same time;

[0100] R9 is selected from C3-C 10 Cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclic group, the C3-C 10 Cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl are each optionally substituted by one or more R 14 replace;

[0101] R 10 Each independently selected from C1-C6 alkyl, oxo, 5-10 membered heteroaryl, 3-12 membered heterocyclic group, R 11 C(O)-、R 11 C(O)N(R 12 )- and -NR 12 R 13 wherein the C1-C6 alkyl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl are each optionally substituted by one or more R 15 replace;

[0102] R 11 Selected from C1-C6 alkyl and C3-C 10 Cycloalkyl;

[0103] R 12 and R 13 Each independently selected from H, C1-C6 alkyl and C3-C 10 Cycloalkyl;

[0104] R 14 Each is independently selected from H, halogen, cyano, oxo, C1-C6 alkyl, C1-C6 alkoxy, -CONR12 R 13 and R 11 C(O)-; and

[0105] R 15 Each independently selected from H, halogen, cyano, oxo, C1-C6 alkyl, C3-C 10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the C1-C6 alkyl, C3-C 10 The cycloalkyl or 3-12 membered heterocyclyl groups are each optionally substituted with one or more substituents selected from C1-C6 alkyl and oxo;

[0106] The conditions are:

[0107] (1) When R9 is C3-C 10 Cycloalkyl, C6-C 10 When it is an aryl group or a 5-10 membered heteroaryl group, n is not 0;

[0108] (2) When L is -(L1) m -(L2) n -(L3) p -, L1 is selected from -N(R 12 )-, m is 1, L2 is selected from C1-C6 alkylene, and when n is 1, L3 is not -N(R 12 )C(O)-;

[0109] (3) When L is -(L1) m -(L2) n -(L3) p -, L1 is selected from -N(R 12 )-, m is 1, L2 is selected from C1-C6 alkylene, n is 1, p is 0, and R9 is a 3-12 membered heterocyclic group, the 3-12 membered heterocyclic group is substituted by oxo; and

[0110] (4) When L is -(L1) m -(L2) n -(L3) p -, L1 is selected from -N(R 12 )-, m is 1, L2 is selected from C1-C6 alkylene, n is 1, p is 0, and R9 is a 5-10 membered heteroaryl, R2 is not morpholinyl.

[0111] According to some embodiments of the present invention, at most one of X1, X2, and X3 is N.

[0112] According to some embodiments of the invention, R1 is selected from H, C1-C6 alkoxy and C3-C6 cycloalkyl.

[0113] In some embodiments of the present invention, R1 is selected from the group consisting of H, cyclopropyl, and methoxy.

[0114] According to some embodiments of the invention, R5 is H.

[0115] According to some embodiments of the present invention, R1, R5 and the group to which they are attached together form a 5-6 membered heterocyclic ring.

[0116] In some embodiments of the present invention, R1, R5 and the group to which they are attached together form a 5-6 membered oxygen-containing heterocyclic ring.

[0117] In some embodiments of the present invention, Part of The wavy line Indicates the point of attachment of a group to the rest of the molecule.

[0118] According to some embodiments of the invention, R3 is selected from H and C1-C6 haloalkyl.

[0119] In some embodiments of the present invention, R3 is selected from C1-C6 haloalkyl.

[0120] In some embodiments of the present invention, R3 is selected from H and trifluoromethyl.

[0121] In some embodiments of the present invention, R3 is selected from trifluoromethyl.

[0122] According to some embodiments of the invention, R2 is selected from H, C2-C6 alkynyl, 3-10 membered monocyclic, spirocyclic or annelated heterocyclyl and R7O-, wherein the C2-C6 alkynyl or 3-10 membered monocyclic, spirocyclic or annelated heterocyclyl is each optionally substituted by 1 or 2 R6.

[0123] In some embodiments of the present invention, R2 is selected from C2-C6 alkynyl, 3-10 membered monocyclic, spirocyclic or annelated heterocyclyl and R7O-, wherein the C2-C6 alkynyl or 3-10 membered monocyclic, spirocyclic or annelated heterocyclyl is each optionally substituted by 1 or 2 R6.

[0124] In some embodiments of the present invention, R2 is selected from H, C2-C4 alkynyl, 3-6 membered monocyclic heterocyclyl, 7-10 membered spirocyclic or annelated heterocyclyl and R7O-, wherein said C2-C4 alkynyl, 3-6 membered monocyclic heterocyclyl, 7-10 membered spirocyclic or annelated heterocyclyl are each optionally substituted by 1 or 2 R6.

[0125] In some embodiments of the present invention, R6 is each independently selected from C1-C6 alkyl and 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl is optionally substituted with C1-C6 alkyl.

[0126] In some embodiments of the present invention, R7 is selected from C1-C6 alkyl and 5-6 membered heterocyclyl, wherein the C1-C6 alkyl is optionally substituted by a 3-6 membered heterocyclyl, and the 5-6 membered heterocyclyl and 3-6 membered heterocyclyl are each optionally substituted by C1-C6 alkyl.

[0127] In some embodiments of the present invention, R7 is selected from C1-C6 alkyl and 5-6 membered heterocyclyl, wherein the 5-6 membered heterocyclyl is optionally substituted with C1-C6 alkyl.

[0128] According to some embodiments of the present invention, R2 is selected from C2-C6 alkynyl, 3-10 membered monocyclic, spirocyclic or cyclic heterocyclyl and R7O-, wherein the C2-C6 alkynyl or 3-10 membered monocyclic, spirocyclic or cyclic heterocyclyl is each optionally substituted with 1 or 2 R6;

[0129] R6 are each independently selected from C1-C6 alkyl and 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl is optionally substituted with C1-C6 alkyl; and

[0130] R7 is selected from C1-C6 alkyl and 5-6 membered heterocyclyl, wherein the 5-6 membered heterocyclyl is optionally substituted by C1-C6 alkyl.

[0131] In some embodiments of the present invention, R2 is selected from H, The wavy line Indicates the point of attachment of a group to the rest of the molecule.

[0132] In some embodiments of the present invention, R2 is selected from The wavy line Indicates the point of attachment of a group to the rest of the molecule.

[0133] According to some embodiments of the present invention, R4 is selected from H, C1-C6 alkyl, -NR7R8 and -NHCONR7R8, wherein the C1-C6 alkyl is optionally substituted with a 3-6 membered heterocyclyl, R7 is selected from H, R8 is selected from C6-C 10 Aryl, wherein the C6-C 10 The aryl group is optionally substituted by amino, -NHCO(C1-C6 alkyl), or R7, R8 and the group to which they are attached together form a 5-6 membered heterocyclic ring.

[0134] In some embodiments of the present invention, H,

[0135] In some embodiments of the present invention, R4 is H.

[0136] According to some embodiments of the present invention, R2, R4 and the group to which they are attached together form a 6-12 membered nitrogen-containing monoheterocycle or nitrogen-containing spirocyclic heterocycle, each of which is optionally substituted by one or more R6.

[0137] In some embodiments of the present invention, R2, R4 and the groups to which they are attached together form a 6-12 membered nitrogen-containing monocyclic heterocycle or a nitrogen-containing spirocyclic heterocycle, and the 6-12 membered nitrogen-containing heterocycle is substituted by 1 or 2 C1-C6 alkyl groups.

[0138] In some embodiments of the present invention, R2, R4 and the group to which they are attached together form a 6-7 membered nitrogen-containing monocyclic heterocycle or a 7-12 membered nitrogen-containing spirocyclic heterocycle, and each of the 6-7 membered nitrogen-containing monocyclic heterocycle or the 7-12 membered nitrogen-containing spirocyclic heterocycle is substituted by 1 or 2 C1-C6 alkyl groups.

[0139] In some embodiments of the present invention, Part of The wavy line Indicates the point of attachment of a group to the rest of the molecule.

[0140] In some embodiments of the present invention, Part of The wavy line Indicates the point of attachment of a group to the rest of the molecule.

[0141] In some embodiments of the present invention, Part of The wavy line Indicates the point of attachment of a group to the rest of the molecule.

[0142] In some embodiments of the present invention, Part of

[0143] In some embodiments of the present invention, Part of

[0144] The present invention encompasses compounds of formula (1) obtained by any combination of the above preferred groups.

[0145] According to some embodiments of the present invention, the compound of the present invention is a compound of Formula 1A:

[0146] wherein R is as defined above for the compound of formula (1); Ring A is a 6-12 membered nitrogen-containing monocyclic heterocycle or a nitrogen-containing spirocyclic heterocycle; and R6 is a C1-C6 alkyl group.

[0147] According to some embodiments of the present invention, in the compound of Formula 1A, Part of

[0148] According to some embodiments of the present invention, in the compound of Formula 1A, Part of The wavy line Indicates the point of attachment of a group to the rest of the molecule.

[0149] According to some embodiments of the present invention, in the compound of Formula 1A, Part of

[0150] According to some embodiments of the present invention, the compound of the present invention is a compound of Formula 1B':

[0151] Among them, R1, R2, R4, R 10 As defined above for compounds of formula (1); Ring B is selected from 3-12 membered heterocyclyl and 5-10 membered heteroaryl; and r is selected from 0, 1 and 2.

[0152] In some embodiments of the present invention, in the compound of formula 1B' of the present invention, ring B is selected from a 3-12 membered heterocyclic group.

[0153] According to some embodiments of the present invention, the compound of the present invention is a compound of Formula 1B:

[0154] Among them, R1, R2 and R 10 As defined above for compounds of formula (1); Ring B is selected from 3-12 membered heterocyclyl and 5-10 membered heteroaryl; and r is selected from 0, 1 and 2.

[0155] In some embodiments of the present invention, in the compound of formula 1B of the present invention, ring B is selected from a 3-12 membered heterocyclic group.

[0156] According to some embodiments of the present invention, in the compound of formula 1B' or 1B, ring B is a 5-12 membered spiro heterocyclic group or a 5-12 membered bridged heterocyclic group, preferably a 7-12 membered spiro heterocyclic group or a 7-12 membered bridged heterocyclic group, preferably More preferably and

[0157] R 10 Each independently selected from C1-C6 alkyl, oxo, 3-6 membered heterocyclic group and -NR 12 R 13 , preferably, R 10 Each is independently selected from methyl, oxo, amino and morpholinyl.

[0158] According to some embodiments of the present invention, in the compound of formula 1B' or 1B, ring B is a 3-10 membered monocyclic heterocyclyl or a 5-10 membered heteroaryl, preferably a 4-7 membered monocyclic heterocyclyl or a 5-6 membered heteroaryl, more preferably an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, 1,4-diazepanyl or pyrazolyl group;

[0159] R 10 Each independently selected from C1-C6 alkyl, oxo, 5-6 membered heteroaryl, 5-7 membered heterocyclic group, R 11 C(O)- and R 11 C(O)NH-, wherein the C1-C6 alkyl, 5-6 membered heteroaryl or 5-7 membered heterocyclyl are each optionally substituted by 1-4 R 15 replace;

[0160] R 11 is a C4-C6 cycloalkyl group; and

[0161] R 15 are each independently selected from halogen, oxo, C1-C6 alkyl, C3-C6 cycloalkyl and 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl is each optionally substituted with one or more substituents selected from C1-C6 alkyl and oxo,

[0162] Preferably, ring B is a 3-10 membered monocyclic heterocyclic group, preferably a 4-7 membered monocyclic heterocyclic group, more preferably an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, 1,4-diazepanyl; preferably, R 10 Each independently selected from C1-C6 alkyl, oxo, 5-6 membered heteroaryl, 4-7 membered heterocyclic group, R 11 C(O)- and R 11 C(O)NH-, wherein the C1-C6 alkyl, 5-6 membered heteroaryl or 4-7 membered heterocyclyl are each optionally substituted by 1-4 R 15 replace.

[0163] Preferably, R 10Each is independently selected from C1-C6 alkyl, oxo, pyrazolyl, piperidinyl, pyrrolidinyl, azetidinyl, C4-C6 cycloalkyl-C(O)- and C4-C6 cycloalkyl-C(O)-NH-, wherein the azetidinyl, pyrrolidinyl or piperidinyl is each optionally substituted with 1-4 C1-C6 alkyl or oxo, the C1-C6 alkyl is optionally substituted with 1-4 substituents selected from fluoro and C3-C6 cycloalkyl, and the pyrazolyl is optionally substituted with 1-4 C1-C6 alkyl;

[0164] Preferably, R 10 Each is independently selected from C1-C6 alkyl, oxo, pyrazolyl, piperidinyl, pyrrolidinyl, azetidinyl, C4-C6 cycloalkyl-C(O)- and C4-C6 cycloalkyl-C(O)-NH-, wherein the azetidinyl, pyrrolidinyl or piperidinyl is each optionally substituted with 1-4 C1-C6 alkyl or oxo, and the C1-C6 alkyl is optionally substituted with 1-4 substituents selected from fluoro and C3-C6 cycloalkyl;

[0165] More preferably, R 10 Each is independently selected from methyl, oxo, pyrazolyl, piperidinyl, 3-methyl-1H-pyrazolyl, N-methylazetidinyl, N-methylpiperidinyl, cyclobutylcarbonyl, cyclobutylcarbonylamino, oxopyrrolidinyl, oxopiperidinyl, The wavy line It indicates the point of attachment of the group to the rest of the molecule;

[0166] More preferably, R 10 Each independently selected from methyl, oxo, pyrazolyl, piperidinyl, 3-methyl-1H-pyrazolyl, N-methylazetidinyl, N-methylpiperidinyl, cyclobutylcarbonyl, cyclobutylcarbonylamino, oxopyrrolidinyl, oxopiperidinyl and The wavy line Indicates the point of attachment of a group to the rest of the molecule.

[0167] According to some embodiments of the present invention, the compound of formula 1B is a compound of formula 1B-1, 1B-2, 1B-3, 1B-4, or 1B-5:

[0168] wherein R1 and R2 are as defined above for the compound of formula (1); t is selected from 0, 1, 2 and 3; u, v, w, x, y and z are each independently selected from 1, 2 and 3; Y is selected from -CH- and -N-; and r is selected from 1 and 2.

[0169] According to some embodiments of the present invention, the compound of the present invention is a compound of Formula 1B-A, 1B-B, 1B-C, 1B-D, 1B-E, 1B-F, or 1B-G:

[0170] According to some embodiments of the present invention, the compound of the present invention is a compound of Formula 1C:

[0171] wherein R1, R2, and R4 are as defined above for the compound of formula (1);

[0172] L is -(L1) m -(L2) n -(L3) p -;

[0173] L1 is selected from -O- and -N(R 12 )-, preferably selected from -O- and -NH-;

[0174] L2 is selected from C1-C6 alkylene and C3-C 10 Cycloalkylene, preferably selected from C1-C6 alkylene and C3-C6 cycloalkylene, more preferably selected from ethylene, propylene and cyclohexylene;

[0175] L3 is selected from -N(R 12 )-、-N(R 12 )C(O)- and -C(O)-, preferably selected from -NH-, -NHC(O)- and -C(O)-, preferably, when L3 is -NHC(O)-, the amino portion of the -NHC(O)- is connected to L2, and the carbonyl portion is connected to ring C;

[0176] m, n and p are each independently selected from 0 and 1, and m, n and p are not 0 at the same time;

[0177] Preferably, L is selected from -O-, -O-cyclohexylene-, -NH-cyclohexylene-, -O-propylene-, -NH-propylene-, -ethylene-, -ethylene-NHC(O)-, and -O-propylene-C(O)-;

[0178] Ring C is selected from C3-C 10 Cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclic group, preferably selected from C3-C6 cycloalkyl, C6-C 10 Aryl, 5-6 membered heteroaryl and 5-7 membered heterocyclyl, preferably selected from cyclobutyl, phenyl, pyrazolyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, morpholinyl, 1,3-oxazinyl, azepanyl, 1,4-oxaazepanyl and 5-azaspiro[2.5]octanyl;

[0179] R 14Each is independently selected from H, halogen, cyano, oxo, C1-C6 alkyl, C1-C6 alkoxy, -CONR 12 R 13 and R 11 C(O)-, preferably, R 14 Each is independently selected from H, fluoro, chloro, cyano, oxo, methyl, methoxy, -CONHCH3 and cyclobutyl-C(O)-; and s is selected from 0, 1 and 2.

[0180] According to some embodiments of the present invention, the compound of formula 1C is a compound of formula 1C-1, 1C-2, 1C-3, 1C-4 or IC-5:

[0181] wherein R1 and R2 are as defined above for the compound of formula (1);

[0182] X is selected from a bond, -O-, -S-, -NH- and -CH2-O-, preferably, X is selected from -O-, -S-, -NH- and -CH2-O-;

[0183] V is selected from -O-, -S-, -NR 12 -and-CHR 12 -;

[0184] R 12 Selected from H and C1-C6 alkyl;

[0185] h and l are each independently selected from 0, 1, 2 and 3;

[0186] i is selected from 0, 1 and 2; and

[0187] j and k are each independently selected from 1, 2 and 3.

[0188] According to some embodiments of the present invention, the compound of the present invention is a compound of Formula 1D:

[0189] Among them, R1, R2, R4, R 10 As defined above for the compound of formula (1);

[0190] Preferably, R 10 is selected from 3-12 membered heterocyclic groups, wherein the 3-12 membered heterocyclic groups are optionally substituted by one or more R 15 substituted; preferably, R 10 is selected from 4-7 membered heterocyclic groups, wherein the 4-7 membered heterocyclic groups are optionally substituted by one or more R 15 substituted; more preferably, R 10 is selected from 4-7 membered nitrogen-containing heterocyclic groups (e.g., piperidinyl), wherein the 4-7 membered nitrogen-containing heterocyclic groups are optionally substituted by one or more R15 replace;

[0191] Preferably, R 15 is selected from C1-C6 alkyl, more preferably, R 15 Selected from methyl.

[0192] According to some embodiments of the present invention, in the compound of the present invention, L is -(L1) m -(L2) n -(L3) p -*, where the bond marked with "*" is connected to R9;

[0193] L1 is selected from -O-, -N(R 12 )-、-C(R 12 )(R 13 )-O- and -N(R 12 )CO-;

[0194] L2 is selected from C1-C6 alkylene, C1-C6 heteroalkylene, C3-C 10 Cycloalkylene and 3-10 membered heterocyclylene;

[0195] L3 is selected from -N(R 12 )-、-N(R 12 )C(O)- and -C(O)-;

[0196] m, n and p are each independently selected from 0, 1 and 2, and m, n and p are not 0 at the same time;

[0197] Preferably, L1 is selected from -O-, -N(R 12 )-、#-C(R 12 )(R 13 )-O- and #-N(R 12 )CO-, where the bond marked with "#" is connected to

[0198] Preferably, L1 is selected from -O-, -N(R 12 )-;

[0199] Preferably, L2 is selected from C1-C6 alkylene, C1-C6 heteroalkylene, C3-C6 cycloalkylene and 3-6 membered heterocyclylene;

[0200] Preferably, L3 is selected from -N(R 12 )-、-N(R 12 )C(O)-$ and -C(O)-, wherein the bond identified by "$" is connected to R9;

[0201] Preferably, -(L1) m -(L2) n -(L3)p -* as a whole is selected from -L1-L2-*, -L1-, -L2-, -L1-L2-L3-*, -L1-L3-*, -L2-L3-*, wherein the bond identified by "*" is connected to R9;

[0202] Preferably, -(L1) m -(L2) n -(L3) p -* as a whole is selected from -L1-, -L2-, -L1-L2-*, -L1-L2-L3-*, -L2-L3-*;

[0203] Preferably, -(L1) m -(L2) n -(L3) p -* as a whole is selected from -L1-, -L1-L2-*, -L1-L2-L3-*;

[0204] More preferably, -(L1) m -(L2) n -(L3) p -* as a whole is selected from -L1-L2-*, -L1-L2-L3-*;

[0205] Preferably, -(L1) m -(L2) n -(L3) p -*as a whole is selected from -N(R 12 )-C3-C6 cycloalkylene-*, -N(R 12 )-、-N(R 12 )-3-6 membered heterocyclylene-C(O)-*、-N(R 12 )C(O)-*、-N(R 12 )-C1-C6 alkylene-*, -O-C3-C6 cycloalkylene-*, -O-, -O-3-6 membered heterocyclylene-C(O)-*, -O-C1-C6 alkylene-*, -O-C1-C6 alkylene-C(O)-*, -O-C1-C6 alkylene-N(R 12 )-*、-C1-C6 alkylene-、-C1-C6 alkylene-N(R 12 )-C(O)-*、-C(R 12 )(R 13 )-O-C1-C6 alkylene-*, wherein the bond marked with "*" is connected to R9;

[0206] Preferably, -(L1) m -(L2) n -(L3) p-* as a whole is selected from -O-, -O-C1-C6 alkylene-*, -O-C1-C6 alkylene-C(O)-*, -N(R 12 )-C3-C6 cycloalkylene-*, -N(R 12 )-3-6 membered heterocyclylene-C(O)-*、-N(R 12 )-C1-C6 alkylene-*, -N(R 12 )C(O)-*、-N(R 12 )-、-C1-C6 alkylene-N(R 12 )-C(O)-*, -C1-C6 alkylene-, -O-3-6 membered heterocyclylene-C(O)-*;

[0207] Preferably, -(L1) m -(L2) n -(L3) p -* as a whole is selected from -O-C1-C6 alkylene-*, -N(R 12 )-C1-C6 alkylene-*, -O-C1-C6 alkylene-C(O)-*, -N(R 12 )-C3-C6 cycloalkylene-*, -N(R 12 )-3-6 membered heterocyclylene-C(O)-*, -O-;

[0208] More preferably, -(L1) m -(L2) n -(L3) p -* as a whole is selected from -O-C1-C6 alkylene-*, -N(R 12 )-C1-C6 alkylene-*, -N(R 12 )-C3-C6 cycloalkylene-*, -N(R 12 )-3-6 membered heterocyclylene-C(O)-*.

[0209] According to some embodiments of the present invention, the compound of formula (1) of the present invention satisfies the condition:

[0210] (1) When R9 is optionally replaced by R 14 Substituted C3-C 10 Cycloalkyl, C6-C 10 When aryl or 5-10 membered heteroaryl, n is not 0; and / or

[0211] (2) When L is -(L1) m -(L2) n -(L3) p -, L1 is selected from -N(R 12 )-, m is 1, L2 is selected from C1-C6 alkylene, and when n is 1, L3 is not -N(R 12)C(O)-; and / or

[0212] (3) When L is -(L1) m -(L2) n -(L3) p -, L1 is selected from -N(R 12 )-, m is 1, L2 is selected from C1-C6 alkylene, n is 1, p is 0, R9 is R 14 substituted 3-12 membered heterocyclic group, and at least one R 14 When it is an oxo substituent, R2 is selected from a C2-C6 alkynyl group substituted by one or more R6, or R2, R4 and the group connected thereto together form a 7-12 membered spiro heterocycle substituted by one or more R6; and / or

[0213] (4) When L is -(L1) m -(L2) n -(L3) p -, L1 is selected from -N(R 12 )-, m is 1, L2 is selected from C1-C6 alkylene, n is 1, p is 0, and R9 is a 5-10 membered heteroaryl, R2 is not morpholinyl; and / or

[0214] (5) When L is -(L1) m -(L2) n -(L3) p -, L1 is selected from -N(R 12 )-, m is 1, n is 0, p is 0, and R9 is a 3-12 membered heterocyclic group, the 3-12 membered heterocyclic group is a monocyclic ring and is substituted by at least one oxo group.

[0215] The definitions of the various groups in the compounds of formula (1) according to the present invention also apply to compounds of formula 1A, 1, 1B-1, 1B-2, 1B-3, IB-4, IB-5, 1B-A, 1B-B, 1B-C, 1B-D, 1B-E, 1B-F, 1B-G, 1C, 1C-1, 1C-2, 1C-3, 1C-4, 1C-5 or 1D.

[0216] According to some embodiments of the invention, the compound of the invention is selected from the group consisting of:

[0217] Preparation method

[0218] Another object of the present invention is to provide a method for preparing the compound of the present invention, which comprises the steps shown in the following synthetic route A or B:

[0219] Synthesis Route A

[0220] Synthesis Route B

[0221] wherein: R1, R2, R3, R, X1, X2, X3 are as defined above.

[0222] Pharmaceutical composition

[0223] Another object of the present invention is to provide a pharmaceutical composition comprising an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0224] In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with the therapeutic agent and is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response or other problems or complications corresponding to a reasonable benefit / risk ratio within the scope of reasonable medical judgment.

[0225] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions or pharmaceutical formulations of this invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.

[0226] The pharmaceutical composition can be in the form of a solid preparation, a semisolid preparation, a liquid preparation, or a gaseous preparation. Examples of solid preparations include tablets, capsules, powders, granules, or suppositories, and examples of liquid preparations include solutions, suspensions, or injections. The composition can also be in the form of liposomes, microspheres, or other dosage forms. In particular, the pharmaceutical composition is in the form of a preparation suitable for oral administration.

[0227] When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and glucose and glycerol aqueous solutions can also be used as liquid carriers, particularly for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc. The composition can also optionally include a small amount of wetting agent, emulsifier or pH buffer. Oral formulations can include standard carriers, such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, saccharin sodium, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0228] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered by suitable routes, for example, by injection (such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

[0229] For these routes of administration, the pharmaceutical compositions of the present invention can be administered in suitable dosage forms, including but not limited to tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.

[0230] The content or dosage of the compound of the present invention in the pharmaceutical composition may be about 0.001 mg to about 1000 mg, suitably 0.001-100 mg, preferably 0.001-10 mg, more preferably 0.05-5 mg, particularly preferably 0.01-1 mg.

[0231] In some embodiments, the present invention provides a method for preparing a pharmaceutical composition of the present invention, comprising combining a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, or prodrug thereof with one or more pharmaceutically acceptable carriers.

[0232] Treatment methods and uses

[0233] Another object of the present invention is to provide a method for treating a ULK1-mediated disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, or prodrug thereof, or a pharmaceutical composition of the present invention.

[0234] Another object of the present invention is to provide a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, or prodrug thereof, or a pharmaceutical composition of the present invention for preparing a medicament for treating a ULK1-mediated disease in a subject in need thereof.

[0235] Another object of the present invention is to provide a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, or prodrug thereof, or a pharmaceutical composition of the present invention, for use in treating a ULK1-mediated disease in a subject in need thereof.

[0236] Another object of the present invention is to provide a method for preventing or treating ULK1-mediated related diseases, which comprises administering to an individual in need thereof a preventively or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention.

[0237] According to some embodiments of the invention, the ULK1-mediated disease is characterized by aberrant autophagy.

[0238] According to some embodiments of the invention, the abnormal autophagy is induced by a treatment.

[0239] According to some embodiments of the invention, the ULK1-mediated disease is cancer, such as lung cancer, breast cancer or pancreatic cancer, in particular, the lung cancer is non-small cell lung cancer, the breast cancer is triple-negative breast cancer, or the pancreatic cancer is pancreatic ductal adenocarcinoma.

[0240] According to some embodiments of the invention, the ULK1 -mediated disease is tuberous sclerosis complex (TSC) or lymphangioleiomyomatosis (LAM).

[0241] According to some embodiments of the invention, the compound is co-administered with an additional therapeutic agent.

[0242] According to some embodiments of the invention, the additional therapeutic agent is a standard of care therapy.

[0243] According to some embodiments of the invention, the standard of care therapy is an mTOR inhibitor, carboplatin, a MEK inhibitor, or a PARP inhibitor.

[0244] According to some embodiments of the invention, administering the compound or pharmaceutical composition of the invention degrades ATG13 in the subject.

[0245] As used herein, the term "effective amount" refers to an amount sufficient to achieve the desired prophylactic or therapeutic effect, for example, to achieve relief of one or more symptoms associated with the disease being treated.

[0246] The dosage regimen can be adjusted to provide the optimal desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It is to be noted that dosage values ​​can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition.

[0247] The amount of the compound of the present invention administered will depend on the severity of the individual, disease or the patient's condition, the speed of administration, the disposal of the compound and the judgment of the prescribing physician for treatment. Generally speaking, effective dose is about 0.0001 to about 50mg per kg body weight per day, for example, about 0.01 to about 10mg / kg / day (single or divided administration). For 70kg people, this will add up to about 0.007mg / day to about 3500mg / day, for example, about 0.7mg / day to about 700mg / day. In some cases, it can be enough to be not higher than the dosage level of the lower limit of the aforementioned range, and in other cases, it is still possible to adopt a larger dose in the case of not causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

[0248] As used herein, unless otherwise indicated, the terms "treat," ...

[0249] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.). Example

[0250] In order to make the purpose and technical scheme of the present invention clearer, the embodiments of the present invention are described in detail below in conjunction with embodiment.But those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.Unindicated specific conditions in the examples are all carried out according to the conditions of normal conditions or manufacturer's advice.Reagents used or instruments not indicated by manufacturer are all conventional products that can be obtained commercially.

[0251] Example

[0252] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0253] MS was measured using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid spectrometer / mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0254] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 liquid chromatographs.

[0255] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0256] High performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

[0257] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0258] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0259] The thin layer chromatography silica gel plate used was Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the silica gel plate used in thin layer chromatography (TLC) had a specification of 0.15 mm to 0.2 mm.

[0260] Silica gel column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0261] The average kinase inhibition rate and IC50 value were determined using a NovoStar microplate reader (BMG, Germany).

[0262] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0263] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0264] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0265] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0266] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate. The volume ratio of the solvents was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0267] Preparation of intermediate Int-1

[0268] 1) Step 1: To a solution of compound Int-1a (45 g, 204.55 mmol, Bid) and compound Int-1b (25 mL, 225.00 mmol, Bid) in N,N-dimethylformamide (400 mL) was added potassium carbonate (56.54 g, 409.09 mmol) with stirring at 25°C. The mixture was heated to 60°C and stirred for 18 hours under a nitrogen atmosphere. The reaction mixture was poured into water (500 mL), stirred for 10 minutes, and filtered. The filter cake was washed with water (50 mL x 4), dissolved in dichloromethane (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to yield compound Int-1c. MS m / z (ESI): 300.1 / 302.1 [M+1].

[0269] 2) Step 2: To a mixed solution of compound Int-1c (46 g, 153.25 mmol) and compound Int-1d (19.75 g, 229.88 mmol, Bid) in toluene (416 mL) and water (44 mL) at 25°C were added palladium acetate (3.44 g, 15.33 mmol), potassium phosphate (97.59 g, 459.75 mmol), and tricyclohexylphosphine (8.60 g, 30.65 mmol), respectively. The mixture was purged with nitrogen three times, heated to 100°C, and stirred for 18 hours. The mixture was concentrated under reduced pressure to obtain a crude product. Water (200 mL) was added to the mixture, and the mixture was extracted with dichloromethane (200 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: dichloromethane:methanol=0 to 10:1) to give compound Int-1e. MS m / z (ESI): 262.1 [M+1].

[0270] 3) Step 3: To a solution of compound Int-1e (30 g, 114.80 mmol) in methanol (200 mL) was added palladium on carbon (2 g, 18.79 mmol, 10% purity) at room temperature with stirring. The mixture was purged with hydrogen three times and stirred at 25°C for 18 hours. The mixture was filtered, the filter cake was washed with methanol (50 mL x 3), and the filtrate was concentrated under reduced pressure to yield compound Int-1f. MS m / z (ESI): 232.2 [M+1].

[0271] 4) Step 4: To a mixed solution of compound Int-1g (10 g, 46.30 mmol) in 1,2-dichloroethane (400 mL) and tert-butanol (50 mL) at 0°C under a nitrogen atmosphere was added zinc chloride (102 mL, 101.86 mmol). The mixture was stirred at 0°C for 1 hour. Triethylamine (7.1 mL, 50.93 mmol) and compound Int-1f (10.71 g, 46.30 mmol) were then added, and the resulting mixture was stirred at 0°C for 3 hours. The mixture was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: methanol:dichloromethane = 0 to 10%) to obtain compound Int-1. MS m / z (ESI): 412.2 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ10.01(s,1H),8.65–8.50(m,1H),7.12(t,J=9.0Hz,1H),6.81(dd,J=8.6,2.4Hz,1H),6.51(d,J=2.6Hz, 1H), 3.14–3.06 (m, 4H), 2.69 (s, 3H), 1.93–1.64 (m, 4H), 1.27 (dd, J = 17.4, 8.4Hz, 1H), 0.88–0.75 (m, 2H), 0.63 (q, J = 5.6Hz, 2H).

[0272] Example 1. Preparation of Compound 1

[0273] Step 1: Under a nitrogen atmosphere at 0°C, sodium hydride (2.42 g, 60.53 mmol, 60% purity) was added to a solution of compound 1a (5 g, 50.44 mmol, Bid) in N,N-dimethylformamide (50 mL). The mixture was stirred for 20 minutes, followed by the addition of compound 1b (14 mL, 60.53 mmol, Bid), and the mixture was naturally warmed to room temperature and stirred for 18 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (eluent: MeOH:DCM = 5% to 10%) to obtain compound 1c. 1 H NMR (400MHz, CDCl3): δ3.60 (t, J=6.2Hz, 2H), 3.40-3.32 (m, 2H), 3.25 (t, J=5. 2Hz, 2H), 2.31 (t, J = 6.0Hz, 2H), 1.79-1.68 (m, 6H), 0.84 (s, 9H), 0.00 (s, 6H).

[0274] Step 2: To a solution of compound 1c (5 g, 18.42 mmol) in tetrahydrofuran (50 mL) at 25°C was added TBAF (8.1 mL, 27.63 mmol) and stirred for 18 hours. The mixture was concentrated under reduced pressure to afford the crude product, which was purified by silica gel chromatography (eluent: MeOH:DCM = 3% to 10%) to afford compound 1d. MS m / z (ESI): 158.1 [M+1].

[0275] Step 3: To a solution of compound 1d (214.71 mg, 1.09 mmol) in tetrahydrofuran (5 mL) at 0°C under a nitrogen atmosphere was added sodium hydride (58.27 mg, 1.46 mmol, 60% purity). The mixture was stirred for 10 minutes, followed by the addition of compound Int-1 (300 mg, 0.73 mmol). The temperature was raised to 60°C and stirred for 5 hours. Water (3 mL) was added to the mixture, and the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10μm-19*250mm; mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile, gradient: 95% acetonitrile, flow rate: 20 mL / min) to afford compound 1. MS m / z (ESI): 533.3 [M+1]. 1 HNMR (400MHz, DMSO-d6): δ9.35-9.25(m,1H),8.39-8.28(m,1H),7.19-7.09(m,1H),6.77-6.71(m,1H),6.43(s,1H),4.45-4.11(m,2H),3.23-3. 14(m,2H),3.09(s,4H),2.51(s,2H),2.44(s,4H),2.22(s,3H),2.16(s, 2H), 1.95-1.80 (m, 3H), 1.67 (s, 4H), 0.81 (s, 2H), 0.60 (d, J = 3.7Hz, 2H).

[0276] Example 2. Preparation of Compound 2

[0277] Step 1: Compounds 2a (1 g, 3.15 mmol, Bid) and 2b (0.51 mL, 6.30 mmol, Bid) were dissolved in acetonitrile (30 mL). N,N-diisopropylethylamine (1.04 mL, 6.30 mmol) was added, and the reaction mixture was stirred at 70°C for 18 hours. The reaction mixture was concentrated to dryness, and the crude product was purified by silica gel column chromatography (eluent system: ethyl acetate:petroleum ether = 10:1 to 3:1) to obtain compound 2c. MS m / z (ESI): 304.2 [M+1].

[0278] Step 2: Dissolve compound 2c (100 mg, 0.33 mmol) in 5 mL of methanol, add palladium on carbon (35.07 mg, 0.03 mmol), and stir at 50°C for 4 hours. Filter the reaction mixture, wash the filter cake with methanol (5 mL x 3), and concentrate the filtrate to dryness to obtain compound 2d. MS m / z (ESI): 138.2 [M+1].

[0279] Step 3: Compound 2d (45 mg, 0.33 mmol) and compound Int-1 (122.81 mg, 0.30 mmol) were dissolved in 1 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (0.15 mL, 0.89 mmol) was added, and the mixture was stirred at 90°C for 1 hour. The reaction mixture was purified by HPLC (Gilson 306-1741, Shimadzu Shim-pack C18-5 μm-20 x 250 mm column; mobile phase: water (containing 0.05% HCl) and acetonitrile, gradient: acetonitrile 23% to 33%, flow rate: 20 mL / min) to afford compound 2. MS m / z (ESI): 513.4 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ11.34(s,1H),9.85(s,1H),8.42(s,1H),7.43(s,1H),6.88–6.74(m ,1H),6.57(d,J=3.2Hz,1H),6.06(dd,J=4.4,2.4Hz,1H),5.29(s,1H),4.68(d,J=10.2Hz,2H ),4.47(s,2H),3.74(s,2H),3.42(d,J=11.4Hz,2H),3.15(d,J=21.2Hz,4H),2.76(d,J=4.6H z,3H),2.22(dq,J=28.2,2.2Hz,3H),1.96(s,1H),0.92(d,J=8.0Hz,2H),0.74–0.58(m,2H).

[0280] Example 3. Preparation of Compound 3

[0281] To a solution of compound Int-1 (200 mg, 0.49 mmol) in N,N-dimethylformamide (3 mL) was added compound 3a (89.87 mg, 0.53 mmol, Bis-Phe) at room temperature. The mixture was heated to 100°C and stirred for 2 h. The mixture was cooled to room temperature. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10μm-19*250mm; mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile, gradient: 95% acetonitrile, flow rate: 25 mL / min) to afford compound 3. MS m / z (ESI): 544.3 [M+1]. 1 HNMR (400MHz, DMSO-d6): δ8.89(s,1H),8.29(s,1H),7.24-7.12(m,1H),6.76-6.68(m,1H),6.42(s,1H),3.41(s,8H),3.08 (m,4H),2.43(m,4H),2.21(s,3H),2.07(m,5H),1.96-1.83(m,2H),1.80-1.66(m,1H),0.80(m,2H),0.59(d,J=3.6Hz,2H).

[0282] Example 4. Preparation of Compound 4

[0283] Step 1: To a solution of compound 4a (1 g, 4.27 mmol, Bid) and triethylamine (1.8 mL, 12.80 mmol) in N,N-dimethylformamide (10 mL) at room temperature was added compound 4b (535.73 μL, 4.69 mmol, Bid) and stirred at room temperature for 18 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether:ethyl acetate = 10:1 to 1:2) to obtain compound 4c. MS m / z (ESI): 317.1 [M+1].

[0284] Step 2: To a solution of compound 4c (1.8 g, 5.69 mmol) and acetic acid (2 mL, 34.97 mmol) in methanol (20 mL) at room temperature was added palladium on carbon (0.13 g, 4.11 mmol). The mixture was replaced with hydrogen three times, heated to 50°C, stirred for 18 h, and filtered. The filter cake was washed with methanol (20 mL x 3), and the filtrate was concentrated under reduced pressure to provide compound 4d. MS m / z (ESI): 183.1 [M+1].

[0285] Step 3: To a solution of compound Int-1 (200 mg, 0.49 mmol) in N,N-dimethylformamide (3 mL) at 25°C, triethylamine (336.56 μL, 2.43 mmol) and compound 4d (139.09 mg, 0.53 mmol) were added, respectively. The mixture was heated to 100°C and stirred for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile, gradient: 95% acetonitrile, flow rate: 25 mL / min) to afford compound 4. MS m / z (ESI): 558.3 ​​[M+1]. 1 H NMR (400MHz, DMSO-d6): δ8.79(s,1H),8.26(s,1H),7.61-7.56(m,1H),7.25-7.17(m ,1H),6.74-6.68(m,1H),6.42(s,1H),3.96-3.87(m,2H),3.85-3.74(m,1H),3.07(m, 6H),2.97-2.90(m,1H),2.43(m,4H),2.21(s,3H),2.13-2.06(m,2H),2.00-1.83(m, 4H), 1.78-1.68 (m, 3H), 1.41-1.31 (m, 2H), 0.85-0.80 (m, 2H), 0.59 (d, J = 4.0Hz, 2H).

[0286] Example 5. Preparation of Compound 5

[0287] Compound 5a (60.97 mg, 0.53 mmol, Bid) and compound Int-1 (200 mg, 0.49 mmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (0.24 mL, 1.46 mmol) was added, and the mixture was stirred at 90°C for 1 hour. The reaction mixture was purified by HPLC (Gilson 306-1741, Waters Xbridge C18-10μm-19*250mm column; mobile phase: water (containing 10 mM sodium bicarbonate) and acetonitrile, gradient: acetonitrile 38%-68%, flow rate: 25 mL / min) to afford compound 5. MS m / z (ESI): 490.2 [M+1]. 1H NMR (400MHz, DMSO-d6): δ8.96 (s, 1H), 8.31 (s, 1H), 7.17 (d, J = 8.6Hz, 1H), 6. 72(dd,J=8.8,2.8Hz,1H),6.41(d,J=2.8Hz,1H),4.00(s,2H),3.72(s,2H),3. 35(s,2H),3.08(t,J=5.0Hz,4H),2.85(s,3H),2.43(t,J=5.0Hz,4H),2.21(s, 3H), 1.92 (ddd, J=8.4, 5.2, 3.2Hz, 1H), 0.86–0.78 (m, 2H), 0.63–0.56 (m, 2H).

[0288] Example 6. Preparation of Compound 6

[0289] Compound 6a (122.55 mg, 0.73 mmol, Bid) and compound Int-1 (300 mg, 0.73 mmol) were dissolved in N,N-dimethylformamide (3 mL). N,N-diisopropylethylamine (0.60 mL, 3.64 mmol) was added, and the mixture was stirred at 90°C for 1 hour. The reaction mixture was purified by HPLC (Gilson 306-1741, column: Puningtech-Pntulips-C18-5 μm-21.2*150 mm; mobile phase: water (containing 10 mM sodium bicarbonate) and acetonitrile, gradient: acetonitrile 50%-80%, flow rate: 20 mL / min) to obtain compound 6. MS m / z (ESI): 544.5 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ8.82(s,1H),8.27(s,1H),7.20(d,J=8.0Hz,1H),6.71(d d,J=8.8,2.8Hz,1H),6.42(d,J=4.0Hz,1H),4.12–3.95(m,3H),3.25(t,J=7.0Hz,2 H),3.07(t,J=5.0Hz,4H),2.96(s,2H),2.43(t,J=5.0Hz,4H),2.20(d,J=7.2Hz,5H ),1.94–1.84(m,3H),1.58(s,4H),0.85–0.78(m,2H),0.59(dd,J=5.2,1.9Hz,2H).

[0290] Example 7. Preparation of Compound 7

[0291] Compound Int-1 (300 mg, 0.73 mmol) and compound 7a (79.43 mg, 0.80 mmol, Bid) were dissolved in 1,4-dioxane (6 mL), and tris(dibenzylideneacetone)dipalladium (66.70 mg, 0.07 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (66.70 mg, 0.07 mmol) and cesium carbonate (711.98 mg, 2.19 mmol) were added and stirred at 110 ° C. under nitrogen atmosphere for 18 hours. The reaction mixture was purified by HPLC (Gilson 306-1741, Puningtech-Pntulips C18 5 μm, 21.2 x 150 mm column; mobile phase: water (containing 0.225% formic acid) and acetonitrile, gradient: acetonitrile 25% to 35%, flow rate: 15 mL / min) to afford compound 7. MS m / z (ESI): 475.1 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ9.41(s,1H),8.53(s,1H),8.15(s,1H),7.11(d,J=8 .6Hz,1H),6.76(dd,J=8.6,2.8Hz,1H),6.47(d,J=2.8Hz,1H),3.11(t,J=5.0 Hz,4H),2.68(t,J=2.0Hz,1H),2.47(d,J=4.0Hz,4H),2.25(s,3H),2.08(s,3 H), 1.90 (s, 2H), 1.73 (s, 2H), 0.82–0.76 (m, 2H), 0.60 (dd, J = 5.4, 2.0Hz, 2H).

[0292] Example 8. Preparation of Compound 8

[0293] Step 1: Dissolve compound 8a (1 g, 4.27 mmol, Bid) and triethylamine (0.89 mL, 6.40 mmol) in dichloromethane (20 mL). Add 8b (0.55 mL, 4.27 mmol) dropwise at 0°C and stir at room temperature for 18 hours. The reaction mixture was concentrated to yield compound 8c. MS m / z (ESI): 353.0 [M+1].

[0294] Step 2: Dissolve compound 8c (1.3 g, 3.68 mmol) in N,N-dimethylformamide (15 mL), add potassium tert-butoxide (7.37 mL, 7.37 mmol), and stir at room temperature for 3 hours. Dilute the reaction mixture with water (30 mL) and extract with ethyl acetate (30 mL x 3). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by silica gel column chromatography (eluent: methanol:dichloromethane = 10:1) to yield compound 8d. MS m / z (ESI): 317.3 [M+1].

[0295] Step 3: Dissolve compound 8d (460 mg, 1.45 mmol) in methanol (15 mL) and formic acid (1 mL). Add palladium on carbon (154.72 mg, 0.15 mmol). Stir under a hydrogen atmosphere at room temperature for 18 hours. Filter the reaction mixture, wash the filter cake with methanol (10 mL x 3), and concentrate the filtrate to yield compound 8e. MS m / z (ESI): 183.2 [M+1].

[0296] Step 4: Compound 8e (265 mg, 1.45 mmol) and compound Int-1 (598.80 mg, 1.45 mmol) were dissolved in N,N-dimethylformamide (6 mL). N,N-diisopropylethylamine (0.96 mL, 5.82 mmol) was added and stirred at 90°C for 1 hour. The reaction solution was purified by HPLC (Gilson 306-1741, Waters Xbridge C18-10 μm-19*250 mm column; mobile phase: water (containing 10 mM ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 39% to 69%, flow rate: 25 mL / min) to afford compound 8. MS m / z (ESI): 558.5 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ8.82(s,1H),8.26(s,1H),7.20(d,J=8.6Hz,1H),6.72(dd,J=8.6, 2.8Hz,1H),6.42(d,J=2.8Hz,1H),4.57–4.47(m,1H),4.07(d,J=13.2Hz,2H),3.09(d,J=6.4 Hz, 6H), 2.94 (t, J = 12.6Hz, 2H), 2.51-2.49 (m, 4H), 2.27–2.18 (m, 5H), 1.93 (s, 1H), 1.70–1. 61 (m, 6H), 1.50 (d, J = 12.0 Hz, 2H), 0.81 (dt, J = 8.4, 3.0 Hz, 2H), 0.59 (dt, J = 5.4, 2.8 Hz, 2H).

[0297] Example 9. Preparation of Compound 9

[0298] Step 1: To a solution of compound 9a (485.44 μL, 2.50 mmol, Bid) and triethylamine (1.1 mL, 7.49 mmol) in dichloromethane (5 mL) was added compound 9b (313.06 μL, 2.75 mmol, Bid) at room temperature and stirred at room temperature for 18 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 9c. MS m / z (ESI): 227.1 [M-56].

[0299] Step 2: To a solution of compound 9c (970 mg, 2.40 mmol) in 1,4-dioxane (10 mL) was added hydrochloric acid / 1,4-dioxane (5 mL, 4 M) and stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure to afford compound 9d. MS m / z (ESI): 183.2 [M+1].

[0300] Step 3: To a solution of compound Int-1 (300 mg, 0.73 mmol) in N,N-dimethylformamide (3 mL) were added triethylamine (504.84 μL, 3.64 mmol) and compound 9d. The mixture was heated to 100°C and stirred for 2 h. The mixture was concentrated under reduced pressure to yield a crude product. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: A: 10 mM ammonium bicarbonate / water B: acetonitrile, gradient: 95% acetonitrile, flow rate: 25 mL / min) to yield compound 9. MS m / z (ESI): 558.3 ​​[M+1]. 1 H NMR (400MHz, DMSO-d6): δ8.78(d,J=43.8Hz,1H),8.24(s,1H),7.16(d,J=8.3Hz ,1H),6.77-6.65(m,1H),6.43(dd,J=8.1,2.4Hz,1H),3.66(s,1H),3.54(s,3H) ,3.36(s,1H),3.32-3.22(m,4H),3.08(s,4H),2.45-2.36(m,4H),2.21(s,3H), 2.07-1.76(m,6H),1.63(d,J=9.8Hz,3H),0.87-0.76(m,2H),0.64-0.54(m,2H).

[0301] Example 10. Preparation of Compound 10

[0302] Step 1: Compound 10a (175 mg, 1.41 mol, Bid) was dissolved in methanol (6 mL). Platinum dioxide (50 mg, 0.22 mmol, Bid) was added. The reaction was stirred at room temperature under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered, the filter cake was washed with methanol (5 mL x 3), and the filtrate was concentrated under reduced pressure to obtain compound 10b. MS m / z (ESI): 129.2 [M+1].

[0303] Step 2: Compound 10b (180 mg, 0.7 mol) and compound Int-1 (289 mg, 0.7 mol) were dissolved in 5 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (0.35 mL, 2.11 mmol) was added, and the mixture was stirred at 100°C for 1 hour. The reaction solution was then separated and purified by HPLC (Waters-2545, column: Gemini-NX 80*40 mm, 3 μm; mobile phase: water (containing 0.01 mol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to obtain compound 10. MS m / z (ESI): 504.4 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ8.74(s,1H),8.09(s,1H),7.15(d,J=8.6Hz,1H),6.70(dd ,J=8.7,2.8Hz,1H),6.59(d,J=7.3Hz,1H),6.40(d,J=2.8Hz,1H),3.19(s,1H),3.0 7(t,J=4.9Hz,4H),2.78(s,3H),2.52(s,2H),2.50(s,2H),2.46(s,1H),2.44(t,J= 5.0Hz,4H),2.21(s,3H),1.97–1.88(m,2H),0.85–0.78(m,2H),0.62–0.54(m,2H).

[0304] Example 11. Preparation of Compound 11

[0305] Step 1: Dissolve compound 11a (500 mg, 2.50 mmol, Bid) in N,N-dimethylformamide (10 mL). Add sodium hydride (109.87 mg, 2.75 mmol) at 0°C and stir under a nitrogen atmosphere for 30 minutes. Dissolve iodomethane (0.16 mL, 2.62 mmol) in N,N-dimethylformamide (1 mL) and add dropwise to the reaction mixture. Stir at room temperature under a nitrogen atmosphere for 18 hours. Dilute the reaction mixture with water (30 mL) and extract with ethyl acetate (20 mL x 3). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 11b. MS m / z (ESI): 215.2 [M+1].

[0306] Step 2: Dissolve compound 11b (535 mg, 2.50 mmol) in dichloromethane (10 mL), add hydrochloric acid (10 mL, 40.00 mmol), and stir at room temperature for 18 hours. Concentrate the reaction mixture to obtain compound 11c. MS m / z (ESI): 115.1 [M+1].

[0307] Step 3: Compound 11c (316 mg, 2.30 mmol) and compound Int-1 (505.13 mg, 1.23 mmol) were dissolved in N,N-dimethylformamide (5 mL). N,N-diisopropylethylamine (1.02 mL, 6.15 mmol) was added and stirred at 90°C for 1 hour. The reaction solution was purified by HPLC (Gilson 306-1741, Waters-CORTECS-C18-2.7 μm-4.6*30 mm column; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 39% to 59%, flow rate: 20 mL / min) to afford compound 11. MS m / z (ESI): 490.4 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ8.64(s,1H),8.09(s,1H),7.11(d,J=8.6Hz,1H),6.89(d,J= 7.2Hz,1H),6.72(dd,J=8.6,2.8Hz,1H),6.44(d,J=2.8Hz,1H),4.44(s,1H),3.33-3.3 0(m,1H),3.08(t,J=5.0Hz,6H),2.60(s,2H),2.43(t,J=5.0Hz,4H),2.21(s,3H),2.0 8-2.03(m,2H),1.88(td,J=8.4,4.2Hz,1H),0.79(d,J=8.2Hz,2H),0.62–0.54(m,2H).

[0308] Example 12. Preparation of Compound 12

[0309] Step 1: To a solution of compound 12a (190.48 μL, 1.00 mmol, Bid) and TEA (415.27 μL, 3.00 mmol) in N,N-dimethylformamide (2 mL) at 25°C was added 5-chlorovaleryl chloride (154.80 μL, 1.20 mmol, Bid) and stirred for 18 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 12b. MS m / z (ESI): 319.2 [M+1].

[0310] Step 2: To a solution of compound 12b (370 mg, 1.16 mmol) in N,N-dimethylformamide (4 mL) at 25°C was added potassium tert-butoxide (2.3 mL, 2.32 mmol, 1 M) and stirred for 4 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 12c. MS m / z (ESI): 283.2 [M+1].

[0311] Step 3: To a solution of compound 12c (340 mg, 0.60 mmol) in 1,4-dioxane (4 mL) at 25°C was added 1,4-dioxane hydrochloride (2 mL, 4 M). The mixture was stirred for 18 h and concentrated under reduced pressure to afford compound 12d. MS m / z (ESI): 183.2 [M+1].

[0312] Step 4: To a solution of compound Int-1 (350 mg, 0.85 mmol) and compound 12d (340.77 mg, 0.93 mmol) in N,N-dimethylformamide (3 mL) at room temperature was added triethylamine (588.98 μL, 4.25 mmol). The mixture was heated to 100°C and stirred for 2 h. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: A: 10 mM ammonium bicarbonate / water: acetonitrile, gradient: 95% acetonitrile, flow rate: 20 mL / min) to obtain compound 12. MS m / z (ESI): 558.3 ​​[M+1]. 1H NMR (400MHz, DMSO-d6): δ8.53(s,1H),8.20(s,1H),7.34(s,1H),6.72(dd,J=8.6,2.8Hz,1H),6.44 (d,J=2.8Hz,1H),3.57(dd,J=11.6,7.0Hz,2H),3.49-3.35(m,2H),3.23(td,J=12.4,6.6Hz,4H),3. 06(t,J=5.0Hz,4H),2.43(t,J=4.8Hz,4H),2.20(d,J=4.6Hz,4H),1.98-1.90(m,2H),1.69(d,J=5. 0Hz, 4H), 1.61 (dd, J = 12.0, 7.6Hz, 1H), 1.23 (s, 2H), 0.86-0.79 (m, 2H), 0.58 (q, J = 5.0, 4.6Hz, 2H).

[0313] Example 13. Preparation of Compound 13

[0314] Step 1: To a solution of compound 13a (500 mg, 2.48 mmol, Bid) and triethylamine (378.79 μL, 2.73 mmol) in dichloromethane (5 mL) at 0°C was added methylsulfonyl chloride (211.48 μL, 2.73 mmol) and stirred for 2 hours. The mixture was poured into water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 13b. MS m / z (ESI): 280.1 [M+1].

[0315] Step 2: To a solution of compound 13c (215.69 μL, 2.68 mmol, Bid) in N,N-dimethylformamide (5 mL) at 0°C was added sodium hydride (154.33 mg, 3.86 mmol, 60%). The mixture was stirred for 10 minutes, followed by the addition of compound 13b (598.78 mg, 2.14 mmol). The temperature was raised to 50°C and stirred for 18 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 13d. MS m / z (ESI): 266.2 [M+1].

[0316] Step 3: To a solution of compound 13d (731 mg, 2.48 mmol) in 1,4-dioxane (5 mL) was added 1,4-dioxane hydrochloride (2 mL, 4 M) at 25°C and stirred for 3 h. The mixture was concentrated under reduced pressure to afford compound 13e. MS m / z (ESI): 166.2 [M+1].

[0317] Step 4: To a solution of compound Int-1 (500 mg, 1.21 mmol) and compound 13e (219.93 mg, 1.33 mmol) in N,N-dimethylformamide (5 mL) was added triethylamine (841.41 μL, 6.07 mmol) at room temperature. The mixture was heated to 100°C and stirred for 2 h. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile, gradient: 95% acetonitrile, flow rate: 25 mL / min) to obtain compound 13. MS m / z (ESI): 541.3 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ8.84(s,1H),8.30(s,1H),7.30(m,2H),6.74-6.65(m,1H),6.41(s,1H),5.99(s,1H),4.45-4.34(m,1 H),4.17-4.02(m,2H),3.07(s,4H),2.43(m,4H),2.29(s,3H),2.21(s,3H),1.90(d,J=27.8Hz,7H),0.84(m,2H),0.60(m,2H).

[0318] Example 14. Preparation of Compound 14

[0319] Step 1: To a solution of compound 14a (500 mg, 2.48 mmol, Bid) and triethylamine (379 mL, 2.73 mmol) in dichloromethane (5 mL) at 0°C was added methylsulfonyl chloride (212 μL, 2.73 mmol) and stirred for 2 hours. The mixture was poured into water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 14b. MS m / z (ESI): 280.1 [M+1].

[0320] Step 2: To a solution of compound 14c (141.84 μL, 2.94 mmol, Bid) in N,N-dimethylformamide (5 mL) at 0°C was added sodium hydride (169.21 mg, 4.23 mmol, 60% purity). The mixture was stirred for 10 minutes, followed by the addition of compound 14b (820 mg, 2.35 mmol). The temperature was raised to 50°C and stirred for 18 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product. This was purified by silica gel chromatography (eluent: MeOH:DCM = 5%-10%) to afford compound 14d. MS m / z (ESI): 252.2 [M+1].

[0321] Step 3: To a solution of compound 14d (304 mg, 1.21 mmol) in 1,4-dioxane (3 mL) was added 1,4-dioxane hydrochloride (6 mL, 4 M) at 25°C, stirred for 3 h, and concentrated under reduced pressure to afford compound 14e.

[0322] MS m / z(ESI):152.2[M+1].

[0323] Step 4: To a solution of compound Int-1 (400 mg, 0.97 mmol) and compound 14e (200 mg, 1.06 mmol) in N,N-dimethylformamide (5 mL) was added triethylamine (674 μL, 4.86 mmol) at room temperature. The mixture was heated to 100°C and stirred for 2 h. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile, gradient: 95% acetonitrile, flow rate: 20 mL / min) to obtain compound 14. MS m / z (ESI): 527.5 [M+1]. 1H NMR (400MHz, DMSO-d6): δ8.85(s,1H),8.29(s,1H),7.77(d,J=1.9Hz,1H),7.43(s,1H),7.2 5-7.17(m,1H),6.71(dd,J=8.7,2.7Hz,1H),6.41(d,J=2.6Hz,1H),6.23(d,J=4.0Hz,1H),4 .50-4.39(m,1H),4.07(dd,J=12.2,3.0Hz,2H),3.14-3.08(m,2H),3.06(d,J=9.6Hz,4H),2 .42(d,J=9.7Hz,4H),2.20(s,3H),2.06-1.87(m,5H),0.87-0.77(m,2H),0.63-0.56(m,2H).

[0324] Example 15. Preparation of Compound 15

[0325] Step 1: Compound 15a (600 mg, 2.77 mmol, Bid) was dissolved in 10 mL of N,N-dimethylformamide. Compound 15b (0.30 mL, 2.77 mmol, Bid) and triethylamine (0.42 mL, 3.04 mmol) were added at 0°C. The reaction mixture was stirred at 0°C for 10 minutes and then heated to 25°C for 5 hours. After the reaction, 10 mL of ice water was added to the reaction mixture, which was stirred at 0°C for 30 minutes. The mixture was then filtered and the filter cake was washed with ethyl acetate (20 mL). The mixture was extracted (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by HPLC (Phenomenex Gemini C18 column, 25 x 150 mm, 10 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% to 40%, flow rate: 30 mL / min) to obtain compound 15c. MS m / z(ESI):295.0[M+1]. 1 H NMR (400MHz, DMSO-d6): δ 8.67 (s, 1H), 4.15 (s, 2H), 3.93 (t, J = 5.4Hz, 2H), 3.44 (t, J = 5.4Hz, 2H), 2.88 (s, 3H).

[0326] Step 2: Compound 15c (132 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (2 mL). Compound 15d (79.95 mg, 0.49 mmol) and a solution of hydrochloric acid in dioxane (223.99 μL, 0.90 mmol, 4 M) were added. After stirring at 100°C for 4 hours, the reaction solution was concentrated, and the residue was purified by HPLC (Waters-SunFire-C18-10 μm-19*250 mm column; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient: acetonitrile 3% to 33%, flow rate: 25 mL / min) to afford compound 15-. MS m / z (ESI): 421.2 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ9.75(s,1H),8.43(s,1H),8.17(s,1H),7.53-7.51(m,1H),7.36-7.33(m,1H),6.98-6.95(m,1H),4.12(s,2H),3.85 -3.83(m,2H),3.47-3.44(m,4H),2.88(s,3H),2.83-2.80(m,2H),2.63-2.59(m,2H),2.35(s,3H).

[0327] Example 16. Preparation of Compound 16

[0328] Step 1: Dissolve compound 16a (1.0 g, 4.63 mmol, Bid) and compound 16b (0.81 mL, 9.26 mmol, Bid) in tetrahydrofuran (20 mL). Add triethylamine (0.64 mL, 4.63 mmol, Bid) and stir at 60°C for 2 hours. Dilute the reaction mixture with water (40 mL) and extract with ethyl acetate (20 mL x 3). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 16c. MS m / z (ESI): 223.2 [M+1].

[0329] Step 2: Dissolve compound 16c (1.05 g, 4.72 mmol) in methanol (40 mL), add 10% palladium on carbon (503 mg, 0.47 mmol), and stir at room temperature under a hydrogen atmosphere for 2 hours. Filter the reaction mixture, and concentrate the filtrate to obtain compound 16d. MS m / z (ESI): 193.1 [M+1].

[0330] Step 3: Compound 16d (146.81 mg, 0.76 mmol) and compound 15c (150 mg, 0.51 mmol) were dissolved in N,N-dimethylformamide (1 mL). 4M hydrochloric acid (0.38 mL, 1.53 mmol) was added, and the mixture was stirred at 100°C for 1 hour. The reaction solution was purified by HPLC (Waters-2545, column: Waters-SunFire-C18-10μm-19*250mm; mobile phase: water (containing 0.1% FA) and acetonitrile, gradient: acetonitrile 7% to 37%, flow rate: 25 mL / min) to obtain compound 16. MS m / z (ESI): 451.2 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ9.85(s,1H),8.45(s,1H),7.79(s,1H),7.50(d,J=8.2Hz,1H),7.24(t,J=7.8Hz,1H),6.95 (d,J=7.4Hz,1H),4.14(s,2H),3.87(s,2H),3.57(t,J=4.6Hz,4H),3.46(d,J=6.0Hz,4H),2.88(s,3H),2.37(s,4H).

[0331] Example 17. Preparation of Compound 17

[0332] Step 1: To a solution of compound 17a (25 g, 115.22 mmol, Bid) in tetrahydrofuran (250 mL) at 0°C under a nitrogen atmosphere was added zinc chloride solution (265 mL, 265.01 mmol, c = 1 M / L). The mixture was stirred at 0°C for 90 minutes, followed by the addition of sodium thiomethoxide (10.50 g, 149.79 mmol). The mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction solution was concentrated to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: ethyl acetate:petroleum ether = 2% to 5%) to obtain compound 17b. MS m / z (ESI): 228.97 [M+1]. 1 H NMR (400MHz, CDCl3): δ8.67 (s, 1H), 2.61 (s, 3H).

[0333] Step 2: To a solution of compound 17c (7 g, 60.80 mmol, Bid) and imidazole (8278.64 mg, 121.60 mmol) in N,N-dimethylformamide (80 mL) were added 4-(dimethylamino)pyridine (742.80 mg, 6.08 mmol) and chlorodimethyl(2-methylprop-2-yl)silane (15.8 mL, 91.20 mmol), respectively. The mixture was heated to 90°C and stirred for 2 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (70 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 17d. MS m / z (ESI): 230.15 [M+1].

[0334] Step 3: Under a nitrogen atmosphere at 0°C, sodium hydride (1.83 g, 60% purity, 45.77 mmol) was added to a solution of compound 17d (10 g, 30.51 mmol) in N,N-dimethylformamide (100 mL). The mixture was stirred at 0°C for 10 minutes, followed by the addition of iodomethane (2.85 mL, 45.77 mmol). The mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (80 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (eluent: dichloromethane-methanol = 4-6%) to obtain compound 17e. MS m / z (ESI): 244.17 [M+1].

[0335] Step 4: Tetrabutylammonium fluoride (5.7 mL, 19.47 mmol) was added to a solution of compound 17e (3.16 g, 12.98 mmol) in tetrahydrofuran (30 mL) at 25°C under a nitrogen atmosphere and stirred for 5 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: dichloromethane-methanol = 6-10%) to obtain compound 17f. MS m / z (ESI): 130.08 [M+1].

[0336] Step 5: Under a nitrogen atmosphere at 0°C, sodium hydride (325.18 mg, 60% purity, 8.13 mmol) was added to a solution of compound 17f (1 g, 5.42 mmol) in N,N-dimethylformamide (20 mL). The mixture was stirred at 0°C for 10 minutes, followed by the addition of compound 17b (2.85 mL, 45.77 mmol). The mixture was naturally warmed to room temperature and stirred for 18 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (eluent: dichloromethane-methanol = 7-9%) to yield compound 17g. MS m / z (ESI): 322.08 [M+1].

[0337] Step 6: Sulfonyl chloride (1.02 mL, 12.70 mmol) was added to a mixed solution of compound 17g (408 mg, 1.27 mmol) in dichloromethane (5 mL) and acetonitrile (5 mL) at 0°C and stirred at 0°C for 2 hours. The mixture was poured into water (10 mL), and the reaction mixture was adjusted to pH 8 with saturated sodium bicarbonate solution and extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide compound 17h. MS m / z (ESI): 310.05 [M+1].

[0338] Step 7: Trifluoroacetic acid (292.39 μL, 3.92 mmol) was added to a solution of compound 17h (270 mg, 0.78 mmol) and compound Int-1f (199.69 mg, 0.86 mmol) in isopropanol (5 mL) at 25°C. The mixture was heated to 40°C and stirred for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (column: Waters-SunFire-C18-10 μm-19*250 mm; mobile phase: A: 0.1% formic acid / water B: acetonitrile, gradient ratio: acetonitrile 54%:46%, flow rate: 25 mL / min) to obtain compound 17. MS m / z (ESI): 505.25 [M+1]. 1H NMR (400MHz, DMSO-d6): δ9.35(s,1H),8.35(s,1H),7.14(s,1H),6.74(s,1H ),6.43(s,1H),5.64-4.98(m,1H),3.25(d,J=23.0Hz,3H),3.13(s,4H),2.81 (s,3H),2.55(s,4H),2.38(d,J=19.5Hz,1H),2.30(s,3H),2.17-1.98(m,2H),1.91(t,J=6.3Hz,1H),0.86-0.78(m,2H),0.64-0.57(m,2H).

[0339] Example 18. Preparation of Compound 18

[0340] Step 1: To a 20 mL microwave tube, compound Int-1 (600 mg, 1.45 mmol), compound 18a (586 mg, 2.91 mmol), N-methylpyrrolidone (5 mL), and potassium tert-butoxide (327 mg, 2.91 mmol) were added at room temperature. The temperature was raised to 180°C and stirred for 1 hour. After completion, the reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product. Compound 18b was purified by silica gel chromatography (eluent: MeOH:DCM = 5% to 10%). MS m / z (ESI): 477.2 [M+1].

[0341] Step 2: To a solution of compound 18b (100 mg, 0.21 mmol) in dichloromethane (2 mL) at room temperature was added N,N-diisopropylethylamine (54 mg, 0.42 mmol). The temperature was lowered to 0°C, and compound 18c (32 mg, 0.27 mmol) was added. After stirring at 0°C for 3 hours, the reaction was complete. The crude product was purified by preparative HPLC (column: Bonnasil-BR-C18-10 μm-20*250 mm; mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile, gradient: acetonitrile 75% to 95%, flow rate: 20 mL / min) to yield compound 18. MS m / z (ESI): 559.3 [M+1]. 1H NMR (400MHz, DMSO-d6): δ8.82(s,1H),8.27(s,1H),7.20(s,1H),6.72(s,1H),6.44–6.36 (m,1H),4.90(d,J=4.8Hz,1H),3.77–3.54(m,2H),3.18–3.11(m,1H),3.10–3.03(m,4H),2 .69–2.65(m,1H),2.43–2.40(m,2H),2.34–2.31(m,1H),2.21(s,3H),2.13(s,4H),2.01– 1.75(m,6H),1.62–1.46(m,2H),1.30–1.16(m,1H),0.87–0.76(m,2H),0.62–0.54(m,2H).

[0342] Example 19. Preparation of Compound 19

[0343] Step 1: Dissolve compound 19a (500 mg, 1.81 mmol, Bid) in N,N-dimethylformamide (10 mL). Add sodium hydride (108.38 mg, 2.71 mmol) at 0°C and stir under a nitrogen atmosphere for 30 minutes. Then, dissolve iodomethane (0.12 mL, 1.99 mmol) in N,N-dimethylformamide (1 mL) and add dropwise to the reaction mixture. Stir at room temperature under a nitrogen atmosphere for 18 hours. Dilute the reaction mixture with water (30 mL) and extract with dichloromethane / methanol (5:1) (20 mL x 3). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 19b. MS m / z (ESI): 255.4 [M+1].

[0344] Step 2: Dissolve compound 19b (460 mg, 1.81 mmol) in 1,4-dioxane (6 mL), add hydrochloric acid (6 mL, 24.00 mmol), and stir at room temperature for 1 hour. Concentrate the reaction mixture to obtain compound 19c. MS m / z (ESI): 155.3 [M+1].

[0345] Step 3: Compound 19c (220 mg, 1.43 mmol) and compound Int-1 (533.98 mg, 1.30 mmol) were dissolved in N,N-dimethylformamide (5 mL). N,N-diisopropylethylamine (1.07 mL, 6.48 mmol) was added and stirred at 100°C for 1 hour. The reaction solution was purified by HPLC (Gilson 306-1741, Waters-CORTECS-C18-2.7 μm-4.6*30 mm column; mobile phase: water (containing 0.225% formic acid) and acetonitrile, gradient: acetonitrile 10%-20%, flow rate: 20 mL / min) to obtain compound 19. MS m / z (ESI): 530.2 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ8.78(s,1H),8.25(s,1H),7.22(s,1H),6.72(dd,J=8.6,2.8H z,1H),6.42(d,J=2.8Hz,1H),3.46-3.09(m,4H),3.08(t,J=4.8Hz,4H),2.56(d,J=6.9 Hz,2H),2.46–2.43(m,4H),2.40(s,2H),2.27(s,3H),2.22(s,3H),2.08(s,1H),1.63( t, J=6.9Hz, 2H), 1.53 (s, 4H), 0.82 (dd, J=8.2, 2.2Hz, 2H), 0.59 (dd, J=5.6, 2.0Hz, 2H).

[0346] Example 20. Preparation of Compound 20

[0347] Step 1: Dissolve compound Int-1 (300 mg, 0.73 mmol) and 20a (218.83 mg, 1.09 mmol, Bid) in N,N-dimethylformamide (1 mL). Add N,N-diisopropylethylamine (0.36 mL, 2.19 mmol) and stir at 100°C for 1 hour. Dilute the reaction mixture with water (30 mL) and extract with ethyl acetate (20 mL x 3). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by silica gel column chromatography (eluent: dichloromethane:methanol = 20:1) to yield compound 20b. MS m / z (ESI): 576.4 [M+1].

[0348] Step 2: Dissolve compound 20b (430 mg, 0.75 mmol) in a hydrochloric acid / 1,4-dioxane solution (8 mL, 4 M) and stir at room temperature for 1 hour. Concentrate the reaction mixture to obtain compound 20c. MS m / z (ESI): 476.3 [M+1].

[0349] Step 3: Compound 20c (360 mg, 0.76 mmol) and N,N-diisopropylethylamine (0.63 mL, 3.79 mmol) were dissolved in N,N-dimethylformamide (6 mL). Compound 20d (62.83 mg, 0.53 mmol) was added at 0°C, and the mixture was stirred at 0°C for 30 minutes. The reaction solution was purified by HPLC (Gilson 306-1741, Waters SunFire C18-10 μm-19*250 mm column; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient: acetonitrile 10%-40%, flow rate: 25 mL / min) to afford compound 20. MS m / z (ESI): 558.4 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ8.66(s,1H),8.07(s,1H),7.23(d,J=8.4Hz,1H),6.72(dd,J=8.8,2.8Hz,1H),6.42(d,J =2.8Hz,1H),6.37(d,J=7.6Hz,1H),4.35(d,J=13.0Hz,1H),3.66(d,J=13.6Hz,1H),3.32(p,J=8.6Hz,4H),3.07( t,J=5.0Hz,4H),2.44(t,J=5.0Hz,4H),2.21(s,3H),2.16(td,J=9.4,8.8,4.0Hz,2H),2.11–2.03(m,2H),1.96–1 .85(m,2H),1.78–1.68(m,3H),1.40(t,J=19.8Hz,2H),0.82(dt,J=8.6,3.0Hz,2H),0.59(td,J=5.8,3.8Hz,2H).

[0350] Example 21. Preparation of Compound 21

[0351] Step 1: To a solution of compound 21a (3.00 g, 21.26 mmol, Bid) and triethylamine (8.84 mL, 63.78 mmol) in dimethyl sulfoxide (30 mL) was added compound 21b (4.43 g, 21.26 mmol, Bid) at room temperature and reacted at 160°C for 8 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the crude product. The crude product was purified by silica gel chromatography (eluent: EtOAc:PE = 5% to 35%) to yield compound 21c. MS m / z (ESI): 330.3 [M+1].

[0352] Step 2: To a solution of compound 21c (1.10 g, 3.34 mmol) in methanol (15 mL) at room temperature were added palladium on carbon (40 mg, 0.33 mmol) and aqueous ammonia (1.38 mL, 10.02 mmol). After hydrogenation three times, the reaction mixture was stirred at room temperature under a hydrogen balloon for 18 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (eluent: EtOAc:PE = 5% to 60%) to obtain compound 21d. MS m / z (ESI): 300.2 [M+1].

[0353] Step 3: Compound 21d (200 mg, 0.67 mmol) was dissolved in dioxane (3 mL) at room temperature. Cesium carbonate (653 mg, 2.00 mmol), compound 15c (197 mg, 0.67 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (77 mg, 0.13 mmol, Bis(II)), and tris(dibenzylideneacetone)dipalladium (61 mg, 0.07 mol, Bis(II)) were added to the reaction mixture. The mixture was stirred at 100°C under nitrogen for 18 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel chromatography (eluent: MeOH:DCM = 0% to 10%) to obtain compound 21f. MS m / z (ESI): 558.2 [M+1].

[0354] Step 4: To a solution of compound 21f (240 mg, 1.21 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL) at room temperature and stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC (column: Waters-Xbridge-C18-10μm-19*250mm; mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile, gradient: 95% acetonitrile, flow rate: 20 mL / min) to obtain compound 21. MS m / z (ESI): 458.2 [M+1]. 1H NMR (400MHz, DMSO-d6): δ9.64(s,1H),8.40(s,1H),7.72(s,1H),7.48(d,J=8.9Hz,2H),7.00(d,J=8.9Hz,2H),6.84(t,J=7.9Hz,1H),6.30( s,1H),6.20(d,J=7.8Hz,1H),6.03(d,J=9.1Hz,1H),5.02(brs,2H),4.10(s,2H),3.82(t,J=5.2Hz,2H),3.44(t,J=5.2Hz,2H),2.87(s,3H).

[0355] Example 22. Preparation of Compound 22

[0356] Step 1: Dissolve compound 22a (0.33 mL, 3.05 mmol, Bid) in 3 mL of tetrahydrofuran at room temperature. Compound 22b (0.30 mL, 3.66 mmol, Bid) was then added and stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated to dryness to yield compound 22c. MS m / z (ESI): 236.1 [M+1].

[0357] Step 2: Under nitrogen, compound 22c (700 mg, 2.68 mmol, purity: 90%) was dissolved in 50% ethanol (8 mL). Iron powder (598.18 mg, 10.71 mmol, Bidex) and ammonium chloride (859.51 mg, 16.07 mmol, Bidex) were then added, and the mixture was stirred at 80°C for 3 hours. After completion of the reaction, the reaction solution was filtered and washed with dichloromethane (30 mL). The filtrate was concentrated to dryness, and the residue was purified by silica gel column chromatography with a gradient of methanol:dichloromethane = 2% to 3% to afford compound 22d. MS m / z (ESI): 206.1 [M+1].

[0358] Step 3: Compound 22d (100 mg, 0.49 mmol) was dissolved in N,N-dimethylformamide (2 mL). Compound 15c (143.55 mg, 0.49 mmol) and a solution of hydrochloric acid in dioxane (243.59 μL, 0.97 mmol, 4 M) were added. The mixture was stirred at 100°C for 3 hours. The reaction solution was concentrated under reduced pressure and purified by HPLC (column: Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: water (containing 10 mmol NH4HCO3) and acetonitrile, gradient ratio: acetonitrile 27%-57%, flow rate: 25 mL / min) to obtain compound 22. MS m / z (ESI): 464.2 [M+1]. 1H NMR (400MHz, DMSO-d6): δ9.82(s,1H),8.44(s,1H),8.12(s,1H),7.92(s,1H),7.21-7.11(m, 3H), 4.13 (s, 2H), 3.87 (t, J = 5.4Hz, 2H), 3.45-3.36 (m, 6H), 2.86 (s, 3H), 1.89-1.81 (m, 4H).

[0359] Example 23. Preparation of Compound 23

[0360] Step 1: To a solution of compound 23a (1000 mg, 2.89 mmol) in acetonitrile (5 mL) and dichloromethane (5 mL) at 0°C was added sulfonyl chloride (2332.84 μL, 28.87 mmol). The mixture was stirred at 0°C for 3 hours. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by reverse-phase HPLC (mobile phase: A: 0.1% formic acid / water; B: acetonitrile, gradient: 30-50% acetonitrile, flow rate: 25 mL / min) to obtain compound 23b. MS m / z (ESI): 335.1 [M+1].

[0361] Step 2: Compounds 23b (160 mg, 0.48 mmol, Bid) and 23c (170 mg, 0.96 mmol, Bid) were dissolved in N,N-dimethylformamide (2 mL). Hydrochloric acid (238.97 μL, 0.96 mmol, 4 M) was added and stirred at 100°C for 1 hour. After the reaction, the pH was adjusted to 8-9 with methanolic ammonia solution. The mixture was then purified by HPLC (Waters-Xbridge-C18-10 μm-19*250 mm column; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 29% to 59%, flow rate: 25 mL / min) to afford compound 23. MS m / z (ESI): 477.3 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ9.49(s,1H),8.32(s,1H),7.61-7.49(m,2H),6.89(d,J=9.2Hz,2H),3.76-3.70(m,4 H),3.58-3.44(m,4H),3.09-3.00(m,4H),2.46(t,J=5.6Hz,2H),2.33(s,2H),2.21(s,3H),1.66-1.54(m,6H).

[0362] Example 24. Preparation of Compound 24

[0363] Compound Int-1 (100 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (1 mL). Compound 24a (54.13 mg, 0.36 mmol, Bid) and N,N-diisopropylethylamine (201.17 μL, 1.21 mmol) were then added, respectively. The reaction mixture was stirred at 80°C for 1 hour. After completion of the reaction, the mixture was purified by HPLC (Waters-SunFire-C18-10 μm-19*250 mm column; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient: acetonitrile 2% to 32%, flow rate: 25 mL / min) to obtain compound 24. MS m / z (ESI): 488.4 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ8.63(s,1H),8.30(d,J=3.6Hz,1H),8.13(s,1H),6.73-6.70(m,1H),6.43(d,J=2.8Hz,1H),4.15(s,4H),3.33- 3.27(m,4H),3.07(t,J=5.2Hz,4H),2.43(t,J=5.2Hz,4H),2.23-2.16(m,6H),1.98-1.84(m,1H),0.85-0.78(m,2H),0.60-0.55(m,2H).

[0364] Example 25. Preparation of Compound 25

[0365] Compound Int-1 (100 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (1 mL). Compound 25a (36.77 μL, 0.29 mmol, Bid) and N,N-diisopropylethylamine (80.47 μL, 0.49 mmol) were then added, respectively, and stirred at 80°C for 2 hours. After completion of the reaction, the reaction solution was purified by HPLC (Waters-Xbridge-C18-10 μm-19*250 mm column; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 44% to 74%, flow rate: 25 mL / min) to obtain compound 25. MS m / z (ESI): 502.3 [M+1]. 1H NMR (400MHz, DMSO-d6): δ8.61(s,1H),8.13(s,1H),7.29(s,1H),6.73-6.70(m,1H),6.43(d,J=2.8Hz,1H),4.10-3.90(m,4H),3.09 -3.02(t,J=5.2Hz,4H),2.62(s,2H),2.45-2.37(m,6H),2.23-2.17(m,6H), 2.07-2.00(m,2H),1.95-1.88(m,1H),0.86-0.77(m,2H),0.61-0.53(m,2H).

[0366] Example 26. Preparation of Compound 26

[0367] Compound Int-1 (200 mg, 0.49 mmol) and compound 26a (74.91 mg, 0.53 mmol, Bid) were dissolved in N,N-dimethylformamide (1 mL). N,N-diisopropylethylamine (0.24 mL, 1.46 mmol) was added, and the mixture was stirred at 100°C for 1 hour. The reaction solution was purified by HPLC (Waters-2545, column: Waters-Xbridge-C18-10μm-19*250mm; mobile phase: water (containing 10 mM ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 49% to 79%, flow rate: 25 mL / min) to obtain compound 26. MS m / z (ESI): 516.4 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ8.58(s,1H),8.20(s,1H),7.29(s,1H),6.72(dd,J=8 .8,2.8Hz,1H),6.43(d,J=2.8Hz,1H),3.59–3.35(m,4H),3.07(t,J=5.0Hz,4H) ,2.55(dd,J=8.4,6.0Hz,2H),2.46–2.38(m,6H),2.21(s,6H),1.88(ddt,J=26 .4,13.8,6.4Hz,3H),1.75–1.64(m,2H),0.86–0.79(m,2H),0.62–0.56(m,2H).

[0368] Example 27. Preparation of Compound 27

[0369] Step 1: Compound Int-1 (2.00 g, 4.86 mmol) and 27a (2.05 mL, 9.71 mmol, Bis(II)) were dissolved in 1,4-dioxane (20 mL) and water (4 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.36 g, 0.49 mmol) and cesium carbonate (4.75 g, 14.57 mmol) were added, respectively. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 18 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (eluent system: dichloromethane:methanol = 50:1 to 20:1) to provide compound 27b. MS m / z (ESI): 448.4 [M+1].

[0370] Step 2: Compound 27b (2.06 g, 4.60 mmol) was dissolved in tetrahydrofuran (20 mL), and hydrochloric acid (40 mL, 1 M) was added. The mixture was stirred at room temperature for 18 hours. Saturated sodium bicarbonate solution was added to the reaction mixture to adjust the pH to 8. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (eluent system: dichloromethane:methanol = 20:1 to 10:1) to obtain compound 27c. MS m / z (ESI): 420.4 [M+1].

[0371] Step 3: Dissolve compound 27c (330 mg, 0.79 mmol) and ammonium acetate (485.14 mg, 6.29 mmol) in acetic acid (6 mL). Add sodium cyanoborohydride (98.88 mg, 1.57 mmol) and stir at room temperature for 1 hour. The reaction solution was purified by reverse-phase silica gel column chromatography (eluent: 30% acetonitrile and water) to obtain compound 27d. MS m / z (ESI): 421.4 [M+1].

[0372] Step 4: Compound 27d (60 mg, 0.14 mmol) and N,N-diisopropylethylamine (0.12 mL, 0.71 mmol) were dissolved in N,N-dimethylformamide (1 mL). Compound 27e (15.23 mg, 0.13 mmol, Bis-Phenyl) was added at 0°C and stirred for 30 minutes. The reaction mixture was purified by HPLC (Gilson 306-1741, Waters Xbridge C18-10 μm-19*250 mm column; mobile phase: water (containing 10 mM NH4HCO3) and acetonitrile, gradient: acetonitrile 38%-68%, flow rate: 25 mL / min) to afford compound 27 (3.09 mg). MS m / z (ESI): 503.3 [M+1]. 1H NMR (400MHz, DMSO-d6): δ9.36(s,1H),8.48(s,1H), 7.60(s,1H),7.15(s,1H),6.75-6.72(m,1H),6.44(d,J=2.8Hz,1H),3.33-3.20(m,2H),3.10(t,J=4.8Hz,4H),2.90-2.78(m,3H),2.44 (t,J=5.0Hz,4H),2.21(s,3H),2.06(d,J=9.8Hz,2H),1.98–1.83(m,4H),1.72(s,1H),0.82–0.77(m,2H),0.60(dd,J=5.2,1.8Hz,2H).

[0373] Example 28. Preparation of Compound 28

[0374] Step 1: Dissolve compound 27d (165 mg, 0.39 mmol) and triethylamine (109.09 μL, 0.78 mmol) in dichloromethane (3 mL). Add compound 28a (50.69 μL, 0.39 mmol, Bid) and stir at room temperature for 1 hour. Concentrate the reaction mixture to dryness to obtain compound 28b. MS m / z (ESI): 539.4 [M+1].

[0375] Step 2: Compound 28b (60 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (3 mL), and potassium tert-butoxide (131.77 mg, 1.17 mmol) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by HPLC (Gilson 306-1741, Waters Xbridge C18-10 μm-19*250 mm column; mobile phase: water (containing 10 mM NH4HCO3) and acetonitrile, gradient: acetonitrile 34%-64%, flow rate: 25 mL / min) to afford compound 28. MS m / z (ESI): 503.4 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ9.39(s,1H),8.48(s,1H),7.12(d,J=8.4Hz,1H),6.74(d,J=8.6Hz,1H),6.49–6.40(m,1H),3.58(s,2H),3.09(d,J=5 .4Hz,6H),2.87(s,2H),2.44(s,4H),2.22(s,3H),2.18–2.09(m,2H),1.90(s,1H),1.62(s,4H),0.79(d,J=8.0Hz,2H),0.60(d,J=5.0Hz,2H).

[0376] Example 29. Preparation of Compound 29

[0377] To a solution of compound 29a (91.90 mg, 0.73 mmol, Bid) in tetrahydrofuran (5 mL) at 0°C was added sodium hydride (38.85 mg, 0.97 mmol, 60% purity). The mixture was stirred for 10 minutes, followed by the addition of compound Int-1 (200 mg, 0.49 mmol). The temperature was raised to 60°C and stirred for 18 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10μm-19*250mm; mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile, gradient ratio: acetonitrile 95%, flow rate: 25 mL / min) to obtain compound 29. MS m / z(ESI):502.3[M+1]. 1 H NMR (400MHz, DMSO-d6): δ9.29(s,1H),8.35(s,1H),7.63(s,1H),7.43(s,1H) ,7.10(d,J=8.5Hz,1H),6.71(dd,J=8.7,2.7Hz,1H),6.41(d,J=2.8Hz,1H),6 .22(s,1H),4.18(s,4H),3.08(t,J=5.0Hz,4H),2.43(t,J=5.0Hz,4H),2.21( s,5H),1.88(t,J=5.2Hz,1H),0.82-0.74(m,2H),0.58(dt,J=5.4,3.0Hz,2H).

[0378] Example 30. Preparation of Compound 30

[0379] Step 1: Dissolve compound 30a (2.00 g, 29.38 mmol, Bid) and tetrabutylammonium sulfate (0.68 mL, 1.18 mmol, Bid) in acetonitrile (60 mL). Add sodium hydroxide (4.47 g, 111.64 mmol) and stir at room temperature for 30 minutes. Add compound 30b (4.58 g, 35.26 mmol, Bid) and stir at room temperature for 3 days. The reaction mixture was filtered, and the filter cake was washed with acetonitrile (20 mL x 3). The filtrate was concentrated to dryness to obtain compound 30c. MS m / z (ESI): 126.2 [M+1].

[0380] Step 2: Compound 30c (72.94 mg, 0.58 mmol) and Int-1 (200 mg, 0.49 mmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (0.24 mL, 1.46 mmol) was added and stirred at room temperature for 1 hour. The reaction solution was purified by HPLC (Gilson 306-1741, column: Bonnasil-HS-AK-C18-10 μm-20*250 mm; mobile phase: water (containing 10 mmol NaHCO₃) and acetonitrile, gradient: acetonitrile 50%-80%, flow rate: 20 mL / min) to afford compound 30. MS m / z (ESI): 501.4 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ8.58(s,1H),8.06(s,1H),7.61(s,1H),7.40(d,J=1.8Hz,1H), 7.24(d,J=8.8Hz,1H),6.97-6.96(m,1H),6.72-6.69(m,1H),6.43(d,J=2.8Hz,1H),6.20 -6.19(m,1H),3.97(s,2H),3.26(s,2H),3.06(t,J=5.0Hz,4H),2.42(t,J=5.0Hz,4H),2 .20(s,3H),2.02–1.86(m,3H),0.81(dd,J=8.4,2.0Hz,2H),0.57(dd,J=5.4,1.8Hz,2H).

[0381] Example 31. Preparation of Compound 31

[0382] Step 1: At 0°C under nitrogen, oxalyl chloride (489.51 μL, 5.71 mmol, Bid) was added to a solution of compound 31a (400 mg, 2.28 mmol) in dichloromethane (4 mL). The mixture was stirred at 25°C for 1 h. The reaction solution was concentrated under reduced pressure, and the solid was dissolved in tetrahydrofuran (4 mL). Sodium borohydride (863.7 mg, 22.83 mmol) was added, and the mixture was stirred at 20°C for 16 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 31b. MS m / z (ESI): 162.1 [M+1].

[0383] Step 2: At 0°C under nitrogen, compound 31b (70 mg, 0.43 mmol) was added to a tetrahydrofuran (2 mL) solution. Sodium hydride (34.74 mg, 0.87 mmol, 60%) was then added. The mixture was reacted at 0°C for 0.5 h. Compound Int-1 (178.85 mg, 0.43 mmol) was then added and stirred at 60°C for 16 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The crude product was purified by HPLC (Waters-Xbridge-C18-10μm-19*250mm column; mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile, gradient ratio: 95% acetonitrile, flow rate: 20 mL / min) to yield compound 31. MS m / z(ESI):537.4[M+1]. 1 HNMR (400MHz, DMSO-d6): δ9.27(s,1H),8.42–8.28(m,1H),7.78(d,J=7.6Hz,1H),7.63(t,J=7 .6Hz,1H),7.41(t,J=7.4Hz,2H),7.12(d,J=8.2Hz,1H),6.69(d,J=8.6Hz,1H),6.42(d,J=2.6H z,1H),4.31(s,2H),3.12–3.05(m,4H),2.95–2.80(m,2H),2.46–2.40(m,4H),2.21(s,3H),2. 12–1.95(m,2H),1.89(ddd,J=13.6,8.4,5.4Hz,1H),0.82–0.76(m,2H),0.58(q,J=5.8Hz,2H).

[0384] Example 32. Preparation of Compound 32

[0385] Step 1: Dissolve compound 32a (3.00 g, 13.93 mmol, Bidler) and p-toluenesulfonyl chloride (3.19 mL, 16.72 mmol) in dichloromethane (80 mL). Add 4-dimethylaminopyridine (0.85 g, 6.97 mmol, Bidler) and triethylamine (3.86 mL, 27.87 mmol), respectively, and stir at room temperature for 18 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (eluent system: dichloromethane:methanol = 20:1 to 5:1) to obtain compound 32b. MS m / z (ESI): 370.5 [M+1].

[0386] Step 2: Compound 32c (245.68 mg, 3.61 mmol, Bid) and compound 32b (2.0 g, 5.41 mmol) were dissolved in N,N-dimethylformamide (20 mL). Tetrabutylammonium bromide (116.34 mg, 0.36 mmol) and cesium carbonate (2.35 g, 7.22 mmol) were added, respectively, and stirred at 80°C for 18 hours. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography (eluent system: petroleum ether:tetrahydrofuran = 10:1 to 3:1) to obtain compound 32d. MS m / z (ESI): 266.2 [M+1].

[0387] Step 3: Dissolve compound 32d (200 mg, 0.75 mmol) in 4 mL of 4 M ethyl acetate hydrochloride solution and stir at room temperature for 1 hour. Concentrate the reaction mixture to dryness to obtain compound 32e. MS m / z (ESI): 166.0 [M+1].

[0388] Step 4: Compound 32e (124 mg, 0.75 mmol) and Int-1 (206.05 mg, 0.50 mmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (0.41 mL, 2.50 mmol) was added and stirred at 100°C for 1 hour. The reaction mixture was purified by HPLC (Gilson 306-1741, Waters Xbridge C18-10 μm-19*250 mm column; mobile phase: water (containing 10 mmol NaHCO₃) and acetonitrile, gradient: acetonitrile 37% to 67%, flow rate: 25 mL / min) to afford compound 32. MS m / z (ESI): 541.4 [M+1]. 1H NMR (400MHz, DMSO-d6): δ8.63(s,1H),8.08(s,1H),7.80(d,J=2.2Hz,1H),7.45(d,J=1.8Hz,1H), 7.25(s,1H),6.74-6.71(m,1H),6.44(d,J=2.8Hz,1H),6.26-6.25(m,1H),5.99(d,J=7.0Hz,1H), 4.26(s,1H),4.09(s,1H),3.08(t,J=5.0Hz,4H),2.44(t,J=5.0Hz,4H),2.21(s,3H),2.20–2.10( m,2H),1.97–1.91(m,1H),1.83–1.70(m,4H),1.66(s,2H),0.86–0.80(m,2H),0.62–0.57(m,2H).

[0389] Example 33. Preparation of Compound 33

[0390] Step 1: Under nitrogen, compound 33a (1.5 g, 10.21 mmol, Bid) was dissolved in tetrahydrofuran (20 mL). Compound 33b (0.65 g, 9.66 mmol, Bid), triphenylphosphine (2.68 g, 10.21 mmol), and diisopropyl azodicarboxylate (2.02 mL, 10.21 mmol) were then added in an ice bath. The reaction mixture was slowly warmed to room temperature and stirred for 18 hours. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 2%-5%) to yield compound 33c. MS m / z (ESI): 244.0 / 246.0 [M+1].

[0391] Step 2: Under nitrogen, compound 33c (650 mg, 2.66 mmol) was dissolved in 1,4-dioxane (10 mL). Compound 33d (1352.18 mg, 5.32 mmol, Bidex), potassium acetate (522.58 mg, 5.32 mmol), and DPPF palladium dichloride (38.96 mg, 0.05 mmol) were then added. The atmosphere was purged with nitrogen three times and stirred at 90°C for 18 hours. After completion of the reaction, the reaction mixture was filtered and washed with ethyl acetate (30 mL). The filtrate was concentrated to dryness, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 10% to 17%) gradient to afford compound 33e. MS m / z (ESI): 292.2 [M+1].

[0392] Step 3: Under nitrogen, compound Int-1 (141.44 mg, 0.34 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (0.5 mL). Compound 33e (5100 mg, 0.34 mmol), potassium carbonate (335.67 mg, 1.03 mmol), and DPPF palladium dichloride (25.13 mg, 0.03 mmol) were then added. The reaction mixture was purged with nitrogen three times and stirred at 100°C for 2 hours. After completion of the reaction, the reaction mixture was poured into water (15 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by high-performance liquid chromatography (HPLC column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm; mobile phase: water (containing 10 mmol NH4HCO3) and acetonitrile, gradient: 40% to 70% acetonitrile, flow rate: 25 mL / min) to obtain compound 33. MS m / z (ESI): 541.3 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ9.28(s,1H),8.56(s,1H),8.15(s,1H),7.88(s,1H) ,7.18(d,J=7.6Hz,1H),6.77(d,J=2.4Hz,1H),6.46(d,J=2.4Hz,1H),4.28-4 .22(m,1H),3.13-3.00(m,4H),2.84(d,J=10.8Hz,2H),2.47-2.41(m,4H),2. 21(d,J=8.4Hz,6H),2.07-1.87(m,7H),0.82-0.78(m,2H),0.62-0.59(m,2H).

[0393] Example 34. Preparation of Compound 34

[0394] Step 1: To a solution of compound 34b (377 mg, 2.40 mmol, Bid) in tetrahydrofuran (8 mL) at 0°C was added sodium hydride (95.9 mg, 2.40 mmol, 60% purity). The mixture was stirred for 30 minutes, followed by the addition of compound 34a (457 mg, 2.00 mmol). The temperature was raised to 60°C and stirred for 18 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product. Purification by silica gel chromatography (eluent: petroleum ether:ethyl acetate = 5:1 to 1:2) afforded compound 34c. MS m / z (ESI): 350.1 [M+1].

[0395] Step 2: To a solution of compound 34c (230 mg, 0.66 mmol) in acetonitrile (2 mL) and dichloromethane (2 mL) at 0°C was added sulfonyl chloride (888 mg, 6.58 mmol). The reaction mixture was stirred at 0°C for 2 hours. The mixture was poured into water (10 mL), adjusted to pH 7 with saturated sodium bicarbonate solution, and extracted with dichloromethane (5 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide compound 34d. MS m / z (ESI): 338.2 [M+1].

[0396] Step 3: Compound 34d (140 mg, 0.41 mmol) was dissolved in isopropanol (2 mL), followed by the addition of compound 34f (107.94 mg, 0.41 mmol) and trifluoroacetic acid (157.46 μL, 2.07 mmol), respectively. The mixture was stirred at 40°C for 18 hours. After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by HPLC (column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm; mobile phase: water (containing 10 mmol NH4HCO3) and acetonitrile, gradient ratio: acetonitrile 46% to 76%, flow rate: 25 mL / min) to afford compound 34. MS m / z (ESI): 562.3 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ9.37(s,1H),8.35(s,1H),7.17(d,J=8.6Hz,1H),6.73 -6.70(m,1H),6.41(d,J=2.8Hz,1H),4.27(s,2H),3.78(d,J=6.3Hz,2H),3.31( s,1H),3.17(s,2H),2.76(dt,J=11.6,3.2Hz,2H),2.19-2.10(m,5H),2.01-1.5 6(m,13H),1.28(dt,J=12.0,6.0Hz,2H),0.87-0.79(m,2H),0.64-0.56(m,2H).

[0397] Example 35. Preparation of Compound 35

[0398] To a solution of compound Int-1 (150 mg, 0.36 mmol) and compound 35a (73.01 mg, 0.47 mmol, Bid) in N,N-dimethylformamide (3 mL) was added triethylamine (252.42 μL, 1.82 mmol) at 25°C. The mixture was heated to 100°C and stirred for 2 hours. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: A: 0.1% formic acid / water; B: acetonitrile, gradient: 40-60% acetonitrile, flow rate: 25 mL / min) to obtain compound 35. MS m / z (ESI): 530.28 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ8.79-8.69(m,1H),8.32-8.21(m,1H),7.64-7.55(m,1H),7.23(d,J=4.7Hz,1H),6.73-6.70(m,1H),6.46 -6.36(m,1H),3.90(s,2H),3.49(dd,J=23.1,6.1Hz,1H),3.20-3.18(m,1H),3.13-3.02(m,6H),2.44(d,J=4.9Hz,4H),2.22(s,3H) ,2.00(t,J=6.7Hz,2H),1.95-1.87(m,1H),1.67(dd,J=18.8,7.8Hz,2H),1.44-1.34(m,2H),0.86-0.79(m,2H),0.63-0.56(m,2H).

[0399] Example 36. Preparation of Compound 36

[0400] Compound Int-1 (200 mg, 0.49 mmol) and compound 36a (102.96 mg, 0.58 mmol, Bid) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (0.40 mL, 2.43 mmol) was added, and the mixture was stirred at 100°C for 1 hour. The reaction solution was purified by HPLC (Gilson 306-1741, Waters Xbridge C18-10μm-19*250mm column; mobile phase: water (containing 10 mM NH4HCO3) and acetonitrile, gradient: acetonitrile 40% to 70%, flow rate: 25 mL / min) to obtain compound 36. MS m / z (ESI): 516.4 [M+1]. 1H NMR (400MHz, DMSO-d6): δ8.76(s,1H),8.24(s,1H),7.08(d,J=8.8Hz,1H),6.73- 6.71(m,1H),6.41(d,J=2.8Hz,1H),3.87(s,2H),3.06(d,J=5.4Hz,7H),2.53-2.4 9(m,2H),2.42(t,J=5.0Hz,4H),2.36–2.27(m,2H),2.20(s,3H),1.96–1.90(m,1 H),1.80(s,2H),1.24(s,2H),0.93(s,2H),0.83–0.77(m,2H),0.61–0.56(m,2H).

[0401] Example 37. Preparation of Compound 37

[0402] Step 1: Compound 37b (174.44 mg, 1.38 mmol, Bid) was dissolved in N,N-dimethylformamide (3 mL). Sodium hydride (50.69 μL, 60% purity, 0.39 mmol) was added at 0°C. After stirring at 0°C for 20 minutes, compound 37a (0.19 mL, 1.38 mmol, Bid) was added and stirred at room temperature for 18 hours. The reaction mixture was purified by HPLC (Gilson 306-1741, Waters Xbridge C18-10 μm-19*250 mm column; mobile phase: water (containing 10 mM NH4HCO3) and acetonitrile, gradient: acetonitrile 40%-70%, flow rate: 25 mL / min) to afford compound 37c. MS m / z (ESI): 307.0 [M+1].

[0403] Step 2: Compound 37c (100 mg, 0.33 mmol) and compound 37d (58.19 mg, 0.36 mmol, Bid) were dissolved in isopropanol (2 mL). Trifluoroacetic acid (0.12 mL, 1.63 mmol) was added, and the mixture was stirred at 40°C for 18 hours. The reaction mixture was purified by HPLC (Gilson 306-1741, Waters Xbridge C18-10 μm-19*250 mm column; mobile phase: water (containing 10 mM NH4HCO3) and acetonitrile, gradient: acetonitrile 33% to 63%, flow rate: 25 mL / min) to afford compound 37. MS m / z (ESI): 433.2 [M+1]. 1H NMR (400MHz, DMSO-d6): δ10.05(s,1H),8.51(s,1H),7.69(d,J=2.2Hz,1H) ,7.45-7.44(m,2H),7.39(d,J=8.4Hz,1H),6.97(d,J=8.2Hz,1H),6.24-6.2 3(m,1H),4.37(t,J=6.2Hz,2H),4.25(t,J=6.8Hz,2H),3.42(s,2H),2.77( t, J=5.8Hz, 2H), 2.56 (t, J=5.8Hz, 2H), 2.32 (s, 3H), 2.27 (q, J=6.4Hz, 2H).

[0404] Example 38. Preparation of Compound 38

[0405] Compound Int-1 (100 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (2 mL). Compound 38a (39.83 mg, 0.32 mmol, Bid) and N,N-diisopropylethylamine (80.47 μL, 0.49 mmol) were then added, stirring at 80°C for 1 hour. After completion of the reaction, the reaction solution was purified by HPLC (Waters-Xbridge-C18-10 μm-19*250 mm column; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: 45% to 75% acetonitrile, flow rate: 25 mL / min) to obtain compound 38. MS m / z (ESI): 502.4 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ8.58(s,1H),8.20(s,1H),7.29(s,1H),6.73-6.70(m,1H),6.43(d,J=2.8Hz,1H),3.57(s,2H),3.52-3.43(m,2H) ),3.11-3.01(m,8H),2.43(t,J=4.8Hz,4H),2.21(s,6H),1.99(t,J=6.8Hz,2H),1.95-1.89(m,1H),0.85-0.78(m,2H),0.61-0.56(m,2H).

[0406] Example 39. Preparation of Compound 39

[0407] To a solution of compound Int-1 (100 mg, 0.24 mmol) and compound 39a (40.85 mg, 0.29 mmol, Aikon) in acetonitrile (5 mL) was added triethylamine (100.97 μL, 0.73 mmol) at 25°C. The mixture was heated to 100°C and stirred for 18 hours. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: A: 0.1% formic acid / water; B: acetonitrile, gradient: 40-60% acetonitrile, flow rate: 25 mL / min) to obtain compound 39. MS m / z (ESI): 516.36 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ8.92(s,1H),8.30(s,1H),7.22(s,1H),6.74-6.70(m,1H),6.43(d,J=2.2Hz,1H),4.66-4.53(m,2H),3.53(d,J=6.0Hz, 1H),3.17(s,1H),3.08(d,J=9.6Hz,4H),2.71(s,3H),2.46-2.42(m,4H) ,2.21(s,3H),2.09-1.75(m,5H),0.84-0.78(m,2H),0.61-0.56(m,2H).

[0408] Example 40. Preparation of Compound 40

[0409] Step 1: At 25°C, a solution of compound Int-1f (6 g, 25.94 mmol) in formic acid (60 mL) was heated to 100°C and stirred for 18 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent: dichloromethane-methanol = 10% to 15%) to give compound 40f, MS m / z (ESI): 260.2 [M+1].

[0410] Step 2: To a solution of compound 40a (5.90 g, 25.8 mmol) and compound 40b (9.94 g, 30.9 mmol, Bismuth) in toluene (50 mL) was added tetrakistriphenylphosphine palladium (2.98 g, 2.58 mmol) at 0°C. The reaction mixture was stirred at 100°C for 18 hours. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluent: petroleum ether:ethyl acetate = 50:1-10:1) to afford compound 40c. MS m / z (ESI): 225.0 [M+1].

[0411] Step 3: To a solution of compound 40c (3.15 g, 14.05 mmol) in N,N-dimethylformamide (5 mL) at 0°C, tert-butyldimethylsilyl chloride (2.54 g, 16.86 mmol) and imidazole (1.91 g, 28.10 mmol) were added. The reaction was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel chromatography (eluent: petroleum ether:ethyl acetate = 50:1-10:1) to afford compound 40d. MS m / z (ESI): 339.1 [M+1].

[0412] Step 4: To a solution of compound 40d (1.0 g, 2.95 mmol) in dichloromethane (10 mL) at 0°C was added m-chloroperbenzoic acid (610 mg, 3.55 mmol). The reaction was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel chromatography (eluent: petroleum ether:ethyl acetate = 20:1 to 1:1) to afford compound 40e. MS m / z (ESI): 355.1 [M+1].

[0413] Step 5: To a solution of compound 40e (1.0 g, 4.1 mmol) in tetrahydrofuran (10 mL) at 0°C was added potassium bis(trimethylsilyl)amide (8.2 mL, 8.2 mmol, 1 M). The reaction was stirred at room temperature for 1 hour. Compound 40f (1.45 g, 4.1 mmol) was then added, and the reaction was stirred at room temperature for another 2 hours. The mixture was then concentrated under reduced pressure to yield the crude product, which was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 5%-100%) to yield compound 40g. MS m / z (ESI): 522.4 [M+1].

[0414] Step 6: To a solution of compound 40g (150 mg, 0.29 mmol) in ethyl acetate (2 mL) was added 4M hydrochloric acid / ethyl acetate (1 mL, 4.0 mmol) at 0°C. The reaction mixture was stirred at room temperature for 3 hours. The mixture was adjusted to pH 7 with sodium bicarbonate solution and extracted with dichloromethane (5 mL x 3). The combined organic phases were washed with saturated brine, dried, filtered, and concentrated to yield compound 40h. MS m / z (ESI): 408.2 [M+1].

[0415] Step 7: To a solution of compound 40h (80 mg, 0.20 mmol) in dichloromethane (2 mL) at 0°C, methanesulfonyl chloride (34 mg, 0.29 mmol) and triethylamine (60 mg, 0.59 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was poured into an aqueous solution (5 mL) and extracted with dichloromethane (5 mL x 3). The combined organic phases were washed with saturated brine, dried, filtered, and concentrated under reduced pressure to provide compound 40i. MS m / z (ESI): 486.2 [M+1].

[0416] Step 8: To a solution of compound 40i (80 mg, 0.16 mmol) and compound 40j (38 mg, 0.33 mmol, Bid) in tetrahydrofuran (2 mL) was added N,N-diisopropylethylamine (85 mg, 0.66 mmol) at room temperature. The mixture was heated to 60°C and stirred for 3 hours. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (column: Waters-SunFire-C18-10μm-19*250mm; mobile phase: A: 0.1% formic acid / water; B: acetonitrile, gradient: acetonitrile 10-40%, flow rate: 25 mL / min) to obtain compound 40. MS m / z (ESI): 504.2 [M+1]. 1 H NMR (400MHz, MeOD): δ8.48(s,1H),8.44(s,1H),7.41(d,J=8.6Hz,1H),6.85(dd,J=8.6,2.6Hz,1H),6.66(d,J=2.6Hz,1H),3.76(s,2H),3. 34–3.30(m,8H),3.14–3.09(m,4H),2.93(s,3H),2.90–2.85(m,2H),2 .72(s,3H),1.99–1.89(m,1H),0.97–0.83(m,2H),0.70–0.58(m,2H).

[0417] Example 41. Preparation of Compound 41

[0418] Step 1: Dissolve compound 41a (2 g, 9.04 mmol, Bid) and triethylamine (2.51 mL, 18.08 mmol, Bid) in dichloromethane (20 mL). Add methylsulfonyl chloride (1.04 mL, 6.30 mmol). Stir the reaction mixture at 0°C for 1 hour. Pour the reaction mixture into water (100 mL) and extract with dichloromethane (30 mL x 3). The combined organic phases are washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 41b.

[0419] Step 2: Dissolve compound 41c (820 mg, 10.02 mmol, Bid) in N,N-dimethylformamide (20 mL). Add sodium hydride (500 mg, 60% purity, 12.53 mmol) under ice-cooling and stir at 0°C for 0.5 hours. Add compound 41b (2.5 g, 8.35 mmol) to the reaction mixture, and stir at 60°C for 18 hours. The reaction mixture is quenched with saturated ammonium chloride solution and extracted with ethyl acetate (30 mL x 3). The combined organic phases are washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography and then by high-performance liquid chromatography (Gilson 306-1741, column: SW-8201-220g; mobile phase: water (containing 0.05% TFA) and acetonitrile, gradient: acetonitrile 23% to 33%, flow rate: 60 mL / min) to afford compound 41d. MS m / z (ESI): 286.2 [M+1].

[0420] Step 3: Dissolve compound 41d (400 mg, 1.40 mmol) in tetrahydrofuran (10 mL) and hydrochloric acid (0.5 mL). Add palladium on carbon (149.0 mg, 1.40 mmol). Stir under a hydrogen atmosphere at 25°C for 18 hours. The reaction mixture is filtered and concentrated under reduced pressure to yield compound 41e. MS m / z (ESI): 152.2 [M+1].

[0421] Step 4: Compound 41e (55.07 mg, 0.36 mmol) and compound Int-1 (150 mg, 0.36 mmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (0.05 mL, 0.36 mmol) was added, and the mixture was stirred at 100°C for 18 hours. The reaction mixture was purified by HPLC (Gilson 306-1741, Shimadzu Shim-pack C18-5 μm-20 x 250 mm column; mobile phase: water (containing 0.05% HCl) and acetonitrile, gradient: acetonitrile 23% to 33%, flow rate: 20 mL / min) to afford compound 41. MS m / z (ESI): 527.4 [M+1]. 1H NMR (400MHz, DMSO-d6): δ8.64(s,1H),8.23(s,1H),7.64(d,J=2.4Hz,1H),7.2 7(s,1H),6.71(dd,J=8.8,2.8Hz,1H),6.42(d,J=2.8Hz,1H),6.02(d,J=2.4Hz, 1H),5.00–4.86(m,1H),3.97–3.85(m,1H),3.86–3.75(m,1H),3.76–3.58(m,2H),3.07(t,J=4.8Hz,4H),2.47–2. 41(m,4H),2.37–2.30(m,2H),2.22(s,3H),2.14(s,3H),1.97–1.89(m,1H),0.86–0.77(m,2H),0.64–0.55(m,2H).

[0422] Example 42. Preparation of Compound 42

[0423] Step 1: To a solution of compound 42a (1.39 g, 14.0 mmol, Bid) in N,N-dimethylformamide (40 mL) at 0°C was added sodium hydride (1.05 g, 17.8 mmol, 60% purity). The mixture was stirred for 30 minutes, followed by the addition of compound 42b (5.00 g, 17.8 mmol, Bid). The reaction mixture was stirred at room temperature for 3 hours. The mixture was poured into water (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether:ethyl acetate = 5:1 to 1:1) to yield compound 42c. MS m / z (ESI): 258.1 [M+1].

[0424] Step 2: To a solution of compound 42c (200 mg, 0.78 mmol) in ethyl acetate (4 mL) was added 4 M hydrochloric acid / ethyl acetate (1 mL, 4.0 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was adjusted to pH 7 with sodium bicarbonate solution and extracted with dichloromethane (8 mL x 3). The combined organic phases were washed with saturated brine, dried, filtered, and concentrated under reduced pressure to yield compound 42d. MS m / z (ESI): 144.1 [M+1].

[0425] Step 3: To a solution of compound 42d (200 mg, 0.41 mmol) in tetrahydrofuran (5 mL) at 0°C was added sodium hydride (25 mg, 0.62 mmol, 60% purity). The mixture was stirred for 30 minutes, followed by the addition of compound 40i (88 mg, 0.62 mmol). The mixture was heated to 60°C and stirred for 18 hours. The mixture was concentrated under reduced pressure to afford the crude product. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10μm-19*250mm; mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile, gradient: 40-70% acetonitrile, flow rate: 25 mL / min) to afford compound 42. MS m / z (ESI): 533.4 [M+1]. 1 H NMR (400MHz, MeOD): δ8.49(s,1H),7.42(d,J=8.6Hz,1H),6.84(dd,J=8.6,2.8Hz, 1H),6.65(d,J=2.8Hz,1H),4.57(s,2H),3.80–3.63(m,2H),3.59–3.44(m,2H),3. 42–3.33(m,2H),3.22–3.12(m,4H),2.69–2.54(m,4H),2.35(s,3H),2.33–2.26(m ,2H),1.98–1.87(m,1H),1.80–1.69(m,4H),0.94–0.84(m,2H),0.67–0.58(m,2H).

[0426] Example 43. Preparation of Compound 43

[0427] To a solution of compound 21 (60 mg, 0.13 mmol) in dichloromethane (2 mL) was added triethylamine (40 mg, 0.39 mmol) at room temperature. Acetic anhydride (0.01 mL, 0.13 mmol) was then added dropwise under an ice bath. The mixture was allowed to react at room temperature for 2 hours. The mixture was concentrated under reduced pressure to afford a crude product. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10μm-19*250mm; mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile, gradient: 95% acetonitrile, flow rate: 20 mL / min) to afford compound 43. MS m / z (ESI): 500.2 [M+1]. 1H NMR (400MHz, DMSO-d6): δ9.77(s,1H),9.69(s,1H),8.41(s,1H),8.04(s,1H),7.52(d,J =8.8Hz,2H),7.44-7.38(m,1H),7.08(t,J=8.0Hz,1H),7.04(d,J=8.8Hz,2H),6.94(d,J=8.2Hz,1H),6.6 6(d,J=6.0Hz,1H),4.10(s,2H),3.83(t,J=5.0Hz,2H),3.44(t,J=5.0Hz,2H),2.87(s,3H),2.01(s,3H).

[0428] Example 44. Preparation of Compound 44

[0429] Step 1: At 0°C, under nitrogen, compound 44a (500 mg, 2.85 mmol, Bid) was added to anhydrous dichloromethane (5 mL), followed by 2-chloro-2-oxoacetyl chloride (611.88 μL, 7.14 mmol), and stirred at 25°C for 1 hour. The mixture was concentrated to dryness, the solid was dissolved in tetrahydrofuran (5 mL), and sodium borohydride (1.08 g, 28.54 mmol) was added. The mixture was stirred at 20°C for 16 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give compound 44b. MS m / z (ESI): 162.2 [M+1].

[0430] Step 2: At zero degrees Celsius, compound 44b (170 mg, 1.0 mmol) was added to a DCM (2 mL) solution. Thionyl chloride (382.48 μL, 5.27 mmol) and N,N-dimethylformamide (8.20 μL, 0.11 mmol) were then added, respectively. The mixture was stirred at 55°C for 3 hours. The mixture was concentrated to dryness to afford compound 44c. MS m / z (ESI): 180.5 [M+1].

[0431] Step 3: Compound 44c (80 mg, 0.45 mmol) was added to N,N-dimethylformamide (4 mL), followed by the addition of 1,3-isoindolinedione potassium salt (164.96 mg, 0.89 mmol, Bidler's), and stirred at 60°C for 16 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to yield compound 44d. MS m / z (ESI): 291.3 [M+1].

[0432] Step 4: Add 44d (90 mg, 0.31 mmol) to ethanol (2 mL), followed by hydrazine hydrate (0.18 mL, 3.10 mmol, 85%), and stir at 25°C for 2 hours. Concentrate the reaction mixture to dryness to afford compound 44e. MS m / z (ESI): 161.1 [M+1].

[0433] Step 5: To a mixture of compound Int-1 (77.12 mg, 0.19 mmol), 44e (30 mg, 0.19 mmol), and N,N-diisopropylethylamine (94.45 μL, 0.57 mmol) was added N,N-dimethylformamide (1 mL), and stirred at 100% CO for 1 hour. The reaction solution was purified by preparative HPLC (Phenomenex Gemini 150 mm*25 mm*25 mm*10 mm column (eluent: 30% to 60% (v / v) CH3CN and H2O with 0.025% NH4HCO3) to afford compound 44. MS m / z (ESI): 536.4 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ8.56(s,1H),8.06(s,1H),7.80–7.73(m,1H),7.64–7.55(m,1 H),7.42–7.35(m,1H),7.36–7.21(m,2H),7.02–6.95(m,1H),6.71–6.65(m,1H),6.47– 6.39(m,1H),3.41–3.33(m,2H),3.09–2.99(m,4H),2.69–2.62(m,2H),2.41(s,4H),2. 19(s,3H),1.96–1.89(m,1H),1.85–1.71(m,2H),0.85–0.78(m,2H),0.60–0.54(m,2H).

[0434] Example 45. Preparation of Compound 45

[0435] Step 1: To a solution of compound 45b (1.6 g, 18.37 mmol, Leyan) and compound 45a (5.74 g, 25.61 mmol, Bidex) in N,N-dimethylformamide (50 mL) was added potassium carbonate (8.85 g, 64.02 mmol) at approximately 25°C. The mixture was heated to 60°C and stirred for 48 hours. The mixture was poured into water (50 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the crude product. The crude product was purified by silica gel chromatography (eluent: dichloromethane-methanol = 4% to 10%) to yield compound 45c. MS m / z (ESI): 378.2 [M+1].

[0436] Step 2: To a solution of compound 45c (3.5 g, 9.27 mmol) in dichloromethane (60 mL) at approximately 0°C, triethylamine (3855.66 μL, 27.82 mmol) and chloroacetyl chloride 45d (884.92 μL, 11.13 mmol) were added, respectively. The mixture was stirred at 25°C for 18 hours. The mixture was poured into water (20 mL) and extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 45e. MS m / z (ESI): 454.2 [M+1].

[0437] Step 3: To a solution of compound 45e (2.5 g, 5.51 mmol) in dichloromethane (20 mL) was added hydrochloric acid / 1,4-dioxane (10 mL, 40.00 mmol, 4 mmol / L) at approximately 25°C. The mixture was stirred at 25°C for 3 hours. The mixture was concentrated under reduced pressure to afford compound 45f. MS m / z (ESI): 354.1 [M+1].

[0438] Step 4: To a solution of compound Int-1 (200 mg, 0.49 mmol) and compound 45f (368.21 mg, 0.73 mmol) in acetonitrile (5 mL) at approximately 25°C was added triethylamine (336.56 μL, 2.43 mmol). The mixture was heated to 90°C and stirred for 18 hours. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (0.1% aqueous ammonium bicarbonate-acetonitrile = 40-60%) to afford compound 45g. MS m / z (ESI): 693.3 [M+1].

[0439] Step 5: To a solution of compound 45g (20 mg, 0.03 mmol) in methanol (3 mL) at approximately 25°C, palladium on carbon (3.07 mg, 0.00 mmol, 10%) and acetic acid (0.3 mL, 5.25 mmol) were added. The mixture was replaced with hydrogen three times and stirred under a hydrogen atmosphere at 25°C for 6 hours. The mixture was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10μm-19*250mm; mobile phase: A: 10mM ammonium bicarbonate / water; B: acetonitrile, gradient ratio: 40-60% acetonitrile, flow rate: 25 mL / min) to obtain compound 45. MS m / z (ESI): 559.3 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ8.35(s,1H),7.80(d,J=8.6Hz,1H),7.33-7.27(m,1H),6.84(dd,J= 8.8,2.6Hz,1H),6.72(d,J=2.4Hz,1H),4.44-4.34(m,1H),4.30–4.20(m,2H),3.89-3.72(m, 2H),3.49-3.31(m,2H),3.25-3.07(m,6H),2.82-2.72(m,1H),2.63(d,J=9.4Hz,4H),2.60-2 .52(m,1H),2.39(s,3H),1.69(td,J=11.6,6.0Hz,5H),1.03-0.94(m,2H),0.70-0.64(m,2H).

[0440] Example 46. Preparation of Compound 46

[0441] Step 1: To a mixed solution of compound 46a (5.00 g, 22.73 mmol, Bid), cyclopropaneboronic acid (2.93 g, 34.09 mmol, Bid), and potassium phosphate (14.47 g, 68.18 mmol) in toluene (80 mL) and H₂O (16 mL) at approximately 25°C were added palladium acetate (0.51 g, 2.27 mmol) and tricyclohexylphosphine (0.64 g, 2.27 mmol), respectively. The mixture was purged with nitrogen three times, heated to 90°C, and stirred for 18 hours. After cooling to room temperature, the mixture was concentrated to obtain the crude product, which was purified by silica gel chromatography (eluent: ethyl acetate:petroleum ether = 15-25%) to afford compound 46b. MS m / z (ESI): 182.0 [M+1].

[0442] Step 2: To a solution of compound 46b (2 g, 11.04 mmol) in N,N-dimethylformamide (20 mL) at 0°C was added sodium hydride (0.66 g, 16.56 mmol, 60% purity). The mixture was stirred at 0°C for 15 minutes, followed by the addition of compound 46c (1213.73 μL, 11.04 mmol, Bid), and stirred at 25°C for 18 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the crude product. The crude product was purified by silica gel chromatography (eluent: methanol:dichloromethane = 1% to 8%) to yield compound 46d. MS m / z (ESI): 263.1 [M+1].

[0443] Step 3: To a solution of compound 46d (1 g, 3.81 mmol) in methanol (20 mL) at 25°C was added palladium on carbon (0.1 g, 0.94 mmol, 10%). The mixture was replaced with hydrogen three times and stirred under a hydrogen atmosphere at 25°C for 18 hours. The mixture was filtered, the filter cake was rinsed with methanol (20 mL x 3), and the filtrate was concentrated under reduced pressure to provide compound 46e. MS m / z (ESI): 233.2 [M+1].

[0444] Step 4: To a solution of compound 46e (123.82 mg, 0.53 mmol) and compound 34d (150 mg, 0.44 mmol) in isopropanol (5 mL) was added trifluoroacetic acid (165.49 μL, 2.22 mmol) at 25°C. The temperature was raised to 40°C and stirred for 18 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: A: 0.1% formic acid / water; B: acetonitrile, gradient: 40-60% acetonitrile, flow rate: 25 mL / min) to afford compound 46. MS m / z (ESI): 534.4 [M+1]. 1H NMR (400MHz, DMSO-d6): δ9.41(s,1H),8.35(s,1H),7.19(s,1H),6.68(dd,J=8.4,2.8Hz,1H),6.35(d,J=2.6Hz,1H ),4.90-4.84(m,1H),4.48-4.10(m,2H),3.17(dd,J=18.8,8.2Hz,2H),2.87-2.80(m,1H),2.76-2.65(m,2H),2.45 -2.39(m,1H),2.34-2.11(m,7H),1.94-1.75(m,4H),1.74-1.59(m,5H),0.87-0.80(m,2H),0.62-0.56(m,2H).

[0445] Example 47. Preparation of Compound 47

[0446] Step 1: To a solution of compound 47a (1.6 g, 18.37 mmol, Bid) and triethylamine (7.64 mL, 55.10 mmol) in dichloromethane (30 mL) at approximately 0°C was added compound 47b (4.15 g, 27.55 mmol, Bid) and stirred at 25°C for 2 hours. The mixture was poured into water (30 mL) and extracted with dichloromethane (30 mL x 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether:tetrahydrofuran = 5-30%) to yield compound 47c. MS m / z (ESI): 202.1 [M+1].

[0447] Step 2: To a solution of compound 47c (2 g, 9.94 mmol) in THF (20 mL) at approximately 25°C was added lithium borohydride (19.88 mL, 19.88 mmol, 1 mmol / L). The mixture was stirred at 25°C for 18 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether-tetrahydrofuran = 5% to 80%) to obtain compound 47d. MS m / z (ESI): 173.1 [M+1].

[0448] Step 3: To a solution of compound 47d (54.67 mg, 0.32 mmol) in tetrahydrofuran (5 mL) at approximately 0°C was added sodium hydride (19.42 mg, 0.49 mmol, 60% purity). The mixture was stirred at 0°C for 15 minutes, followed by the addition of compound Int-1 (100 mg, 0.24 mmol). The temperature was raised to 60°C and stirred for 18 hours. After cooling to room temperature, the mixture was quenched with water (3 mL) and concentrated under reduced pressure to afford the crude product. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10μm-19*250mm; mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile, gradient: 40-60% acetonitrile, flow rate: 25 mL / min) to afford compound 47. MS m / z (ESI): 549.3 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ9.31(s,1H),8.33(s,1H),7.12(s,1H),6.73(dd,J=8.6,2.6Hz,1H),6.42(d,J=2.6Hz,1H),4.52-4.10(m,2H),3.53(d, J=4.8Hz,4H),3.36(s,4H),3.13-3.04(m,4H),2.43(t,J=5.0Hz,6H),2. 21(s,3H),2.00-1.78(m,3H),0.80(d,J=8.8Hz,2H),0.63-0.56(m,2H).

[0449] Example 48. Preparation of Compound 48

[0450] To a solution of compound Int-1 (200 mg, 0.49 mmol) and compound 48a (81.72 mg, 0.58 mmol, Bid) in N,N-dimethylformamide (3 mL) was added triethylamine (336.56 μL, 2.43 mmol) at approximately 25°C. The mixture was heated to 100°C and stirred for 2 hours. After cooling to room temperature, the reaction solution was purified by preparative HPLC (column: Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile, gradient: 40-60% acetonitrile, flow rate: 25 mL / min) to afford compound 48. MS m / z (ESI): 516.3 [M+1]. 1H NMR (400MHz, DMSO-d6): δ8.59(s,1H),8.13(s,1H),7.27(s,1H),6.71(dd,J=8.8,2.6Hz,1H),6.43(s,1H),3.78(s,4H),3.07(d,J=9. 6Hz, 4H), 2.43 (d, J = 9.6Hz, 4H), 2.34-2.01 (m, 10H), 1.98-1.92 (m, 1H), 1.70 (t, J = 10.2Hz, 4H), 0.85-0.77 (m, 2H), 0.62-0.55 (m, 2H).

[0451] Example 49. Preparation of Compound 49

[0452] Step 1: Dissolve compound 49a (10 g, 57.08 mmol, Bid) and 1,2-dibromoethane (7.41 mL, 85.62 mmol) in aqueous sodium hydroxide (40 mL, 50%) and toluene (80 mL). Add tetrabutylammonium bromide (3.68 g, 11.42 mmol), and stir the reaction at room temperature for 1 hour. Pour the reaction solution into water (100 mL), dilute it, and extract it with ethyl acetate (50 mL x 3). The combined organic phases are washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The residue is purified by silica gel column chromatography (eluent system: petroleum ether:ethyl acetate = 10:1 to 4:1) to obtain compound 49b. MS m / z (ESI): 202.0 [M+1].

[0453] Step 2: Compound 49b (8.94 g, 44.43 mmol) was dissolved in methanol (80 mL), and Raney nickel (1.8 g, 30.67 mmol) was added. The reaction solution was replaced with hydrogen five times and stirred at room temperature under a hydrogen atmosphere for two days. The reaction solution was filtered, and the filter cake was washed with methanol (30 mL x 3). The filtrate was spin-dried to obtain compound 49c. MS m / z (ESI): 174.0 [M+1].

[0454] Step 3: Compound 49c (6.95 g, 40.12 mmol) was dissolved in concentrated sulfuric acid (120 mL). Potassium nitrate (4.46 g, 44.13 mmol) was added. The reaction mixture was stirred at 0°C for 5 minutes, then warmed to room temperature and stirred for 15 minutes. The reaction mixture was diluted with 1000 mL of water, filtered, and the filter cake was washed with water (200 mL) and dried to yield compound 49d. MS m / z (ESI): 219.0 [M+1].

[0455] Step 4: Dissolve boron trifluoride etherate (4.52 mL, 36.66 mmol) in tetrahydrofuran (20 mL). Add sodium borohydride (1.04 g, 27.50 mmol) to the reaction mixture at 0°C, warm to room temperature, and stir for 1 hour. Compound 49d (2 g, 9.17 mmol) is then dissolved in tetrahydrofuran (20 mL). Add the resulting mixture to the reaction mixture and stir at 70°C for 2 hours. Pour the reaction mixture into saturated ammonium chloride solution (100 mL) to quench the mixture. Adjust the pH to 7 with saturated sodium bicarbonate solution and extract with ethyl acetate (50 mL x 3). The combined organic phases are washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 49e. MS m / z (ESI): 205.2 [M+1].

[0456] Step 5: Compound 49e (0.5 g, 2.45 mmol) was dissolved in methanol (10 mL). Formaldehyde (1.82 mL, 24.48 mmol) and sodium triacetoxyborohydride (2.58 g, 12.24 mmol) were added at room temperature and allowed to react for 4 hours. The pH was adjusted to 7 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 49f. MS m / z (ESI): 219.2 [M+1].

[0457] Step 6: Compound 49f (0.5 g, 2.29 mmol) was dissolved in methanol (10 mL). Ammonium formate (1.44 g, 22.91 mmol) and 10% palladium on carbon (0.10 g, 0.09 mmol) were added at room temperature and reacted under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered, diluted with water (100 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 49g. MS m / z (ESI): 189.3 [M+1].

[0458] Step 7: Compound 49g (100 mg, 0.30 mmol) and compound 34d (61.32 mg, 0.33 mmol) were dissolved in isopropanol (5 mL). Trifluoroacetic acid (110.33 μL, 1.48 mmol) was added at room temperature and the mixture was reacted at 40°C for 18 hours. The reaction solution was purified by HPLC using a Gilson 306-1741 column (Waters SunFire C18-10 μm-19 x 250 mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient: acetonitrile 0% to 95%, flow rate: 20 mL / min) to afford compound 49. MS m / z (ESI): 490.5 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ10.04(s,1H),8.49(s,1H),7.44(dd,J=8.4,2.2Hz ,1H),7.39(s,1H),6.69(d,J=8.4Hz,1H),4.43(t,J=6.4Hz,2H),3.59(s,2H) ,3.39(d,J=7.0Hz,4H),3.24(t,J=5.6Hz,3H),2.46(d,J=2.0Hz,2H),2.18(t ,J=6.2Hz,2H),1.95(p,J=6.6Hz,2H),1.72–1.63(m,4H),0.92–0.82(m,4H).

[0459] Example 50. Preparation of Compound 50

[0460] Step 1: Under nitrogen, compound 50a (200 mg, 0.88 mmol, Bid) was dissolved in tetrahydrofuran (4 mL). Lithium aluminum hydride (1.41 mL, 3.53 mmol) was then added in an ice bath. The reaction solution was slowly warmed to room temperature and stirred for 16 hours. After completion, the reaction solution was quenched with sodium sulfate decahydrate. The mixture was then filtered and washed with tetrahydrofuran (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to yield compound 50b. MS m / z (ESI): 141.1 [M+1].

[0461] Step 2: Compound 50b (137.43 mg, 0.49 mmol, 50% purity) was dissolved in N,N-dimethylformamide (2 mL). Compound Int-1 (100 mg, 0.24 mmol) and N,N-diisopropylethylamine (120.70 μL, 0.73 mmol) were then added, respectively, and stirred at 80°C for 1 hour. The reaction mixture was purified by HPLC (column: Waters-CORTECS-C18-2.7 μm-4.6*30 mm; mobile phase: water (containing 10 mmol NH4HCO3) and acetonitrile, gradient: acetonitrile 46% to 76%, flow rate: 25 mL / min) to afford compound 50. MS m / z (ESI): 516.3 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ8.58(s,1H),8.13(s,1H),7.28(s,1H),6.71(dd,J=8.8,2.8Hz,1H),6.43(d,J=2.8Hz,1H),3.85-3.65(m,4H),3.07(t ,J=5.0Hz,4H),2.45-2.34(m,6H),2.21-2.14(m,7H),1.95-1.87(m,1H) ,1.63-1.41(m,4H),1.24(s,1H),0.84-0.76(m,2H),0.63-0.55(m,2H).

[0462] Example 51. Preparation of Compound 51

[0463] Compound Int-1 (100 mg, 0.24 mmol) and 51a (40.86 mg, 0.24 mmol, Bid) were dissolved in N,N-dimethylformamide (1 mL). N,N-diisopropylethylamine (62.64 mg, 0.49 mmol) was added to the reaction mixture and allowed to react at room temperature for 1 hour. The reaction mixture was purified by HPLC using a Gilson 306-1741 column (Waters SunFire C18-10μm-19*250mm; mobile phase: water (containing 10 mM ammonium bicarbonate) and acetonitrile, gradient: acetonitrile 5% to 60%, flow rate: 20 mL / min) to afford compound 51. MS m / z (ESI): 544.4 [M+1]. 1H NMR (400MHz, DMSO-d6): δ8.76(s,1H),8.24(s,1H),7.21(s,1H),6.71(dd,J=8.8,2.8Hz,1H),6.41(d,J=2.8Hz,1H),3.43(s,4H),3.08(t,J=4.8H z,4H),2.44(t,J=5.0Hz,6H),2.25(d,J=26.4Hz,7H),1.94-1.90(m,1H) ,1.47(d,J=27.2Hz,9H),0.86–0.78(m,2H),0.59(dt,J=5.4,2.8Hz,2H).

[0464] Example 52. Preparation of Compound 52

[0465] Step 1: To a solution of compound 52a (1 g, 4.67 mmol, Bid) in dichloromethane (8 mL) at 0°C was added 4-chlorobutyryl chloride (0.63 mL, 5.60 mmol). The mixture was then warmed to 25°C and stirred for 2 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to provide compound 52b. MS m / z (ESI): 319.8 [M+1].

[0466] Step 2: Compound 52b (500 mg, 1.57 mmol) and potassium tert-butoxide solution (4.71 mL, 4.71 mmol, C = 1 M) were dissolved in tetrahydrofuran (5 mL) at 25°C. The mixture was purged with N2 three times and stirred at 25°C under N2 for 2 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (eluent: PE:THF = 1:1 to 1:5) to obtain compound 52c. MS m / z (ESI): 283.3 [M+1].

[0467] Step 3: Compound 52c (300 mg, 1.06 mmol) and HCl (3 mL, 12.00 mmol, c = 4 M) were dissolved in tetrahydrofuran (5 mL) at 25°C and stirred under N₂ for 2 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate (20 mL x 3). The filtrate was concentrated to dryness under reduced pressure to yield compound 52d. MS m / z (ESI): 183.2 [M+1].

[0468] Step 4: Compound Int-1 (300 mg, 0.73 mmol) was dissolved in acetonitrile (6 mL), followed by the addition of compound 52d (455.20 mg, 0.87 mmol) and triethylamine (504.84 μL, 3.64 mmol). The mixture was stirred at 60°C for 18 hours. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: A: 0.1% ammonium bicarbonate / water; B: acetonitrile, gradient: 40-60% acetonitrile, flow rate: 25 mL / min) to obtain compound 52. MS m / z (ESI): 558.3 ​​[M+1]. 1 H NMR (400MHz, DMSO-d6): δ8.73(s,1H),8.11(s,1H),7.21(s,1H),6.71(dd,J=8.8,2.6Hz,1 H),6.42(d,J=2.6Hz,1H),5.56(d,J=6.4Hz,1H),4.21–3.96(m,1H),3.80(s,1H),3.36(s,2 H),3.07(t,J=5.0Hz,4H),2.43(t,J=5.0Hz,4H),2.20(d,J=3.8Hz,5H),1.91(q,J=7.4,7. 0Hz, 5H), 1.67–1.51 (m, 4H), 1.45 (t, J = 11.8Hz, 2H), 0.82-0.79 (m, 2H), 0.66–0.53 (m, 2H).

[0469] Example 53. Preparation of Compound 53

[0470] To a solution of compound 53a (82.40 mg, 0.53 mmol, Bid) in acetonitrile (4 mL) was added triethylamine (201.94 μl, 1.46 mmol) and then Int-1 (200 mg, 0.49 mmol). The mixture was stirred at 90°C under a nitrogen atmosphere for 1 hour. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (column: Waters-Xbridge-C18-10 μm-19*250 mm; mobile phase: A: 10 mM ammonium bicarbonate / water; B: acetonitrile, gradient ratio: 40-60% acetonitrile, flow rate: 25 mL / min) to obtain compound 53. MS m / z (ESI): 530.3 [M+1]. 1H NMR (400MHz, DMSO-d6): δ8.59(s,1H),8.20(s,1H),7.28(s,1H),6.71(dd,J=8 .8,2.8Hz,1H),6.43(d,J=2.8Hz,1H),3.58-3.50(m,2H),3.07(t,J=5.0Hz,4H ),2.47-2.32(m,7H),2.25-2.11(m,8H),1.96-1.90(m,1H),1.78-1.72(m,2H) ,1.53-1.46(m,4H),1.26-1.23(m,1H),0.85-0.79(m,2H),0.61-0.56(m,2H).

[0471] Example 54. Preparation of Compound 54

[0472] Step 1: Dissolve compound 54a (1 g, 4.64 mmol, Bid), triethylamine (1.29 mL, 9.29 mmol), and 4-dimethylaminopyridine (0.28 g, 2.32 mmol) in dichloromethane (10 mL). Add p-toluenesulfonyl chloride (1.06 mL, 5.57 mmol) and stir at room temperature for 18 hours. The reaction solution was concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography (eluent system: dichloromethane:methanol = 100:1 to 5:1) to obtain compound 54b. MS m / z (ESI): 370.5 [M+1].

[0473] Step 2: Compound 54b (1 g, 2.71 mmol) and compound 54c (0.18 g, 2.71 mmol, Bid) were dissolved in N,N-dimethylformamide (1 mL). Tetrabutylammonium bromide (0.09 g, 0.27 mmol) and cesium carbonate (1.76 g, 5.41 mmol) were added, and the mixture was stirred at 80°C under a nitrogen atmosphere for 18 hours. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent system: petroleum ether:dichloromethane = 10:1 to 3:1) to obtain compound 54d. MS m / z (ESI): 266.3 [M+1].

[0474] Step 3: Compound 54d (212 mg, 0.80 mmol) was dissolved in hydrochloric acid / ethyl acetate (3 mL), stirred at room temperature for 2 hours, and concentrated to dryness to obtain compound 54e. MS m / z (ESI): 166.2 [M+1].

[0475] Step 4: Compound Int-1 (250 mg, 0.61 mmol) and compound 54e (200 mg, 1.21 mmol) were dissolved in N,N-dimethylformamide (5 mL). N,N-diisopropylethylamine (0.40 mL, 2.43 mmol) was added at room temperature and reacted at 90°C under a nitrogen atmosphere for 1 hour. The reaction solution was purified by HPLC using a Gilson 306-1741 column, a Waters SunFire C18-10 μm-19*250 mm column, and a mobile phase of water (containing 0.1% formic acid) and acetonitrile, with a gradient of acetonitrile from 1% to 95%, at a flow rate of 20 mL / min, to afford compound 54. MS m / z (ESI): 541.4 [M+1]. 1 H NMR (400MHz, DMSO-d6): δ8.69(s,1H),8.07(s,1H),7.71(d,J=2.2Hz,1H),7.41(d,J=1.8Hz,1H),7 .20(d,J=8.6Hz,1H),6.71(dd,J=8.6,2.6Hz,1H),6.41(d,J=2.6Hz,2H),6.21(t,J=2.0Hz,1H),4. 06(s,1H),3.04(t,J=5.0Hz,4H),2.41(t,J=5.0Hz,4H),2.21(s,3H),1.97(dd,J=13.0,4.2Hz,3H) ,1.84(s,2H),1.62(d,J=10.2Hz,4H),1.24(s,1H),0.87–0.80(m,2H),0.60(dd,J=5.4,1.8Hz,2H).

[0476] Example 55. Preparation of Compound 55

[0477] Step 1: Dissolve compound 55a (500 mg, 2.48 mmol, Bid), triethylamine (0.69 mL, 4.97 mmol), and 4-dimethylaminopyridine (151.75 mg, 1.24 mmol) in dichloromethane (5 mL). Add p-toluenesulfonyl chloride (0.57 mL, 2.98 mmol) and stir at room temperature for 18 hours. The reaction solution was concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography (eluent system: petroleum ether:ethyl acetate = 20:1 to 5:1) to obtain compound 55b. MS m / z (ESI): 356.4 [M+1].

[0478] Step 2: Compound 55b (280 mg, 0.79 mmol) and compound 55c (53.63 mg, 0.79 mmol, Bid) were dissolved in N,N-dimethylformamide (5 mL). Tetrabutylammonium bromide (24.42 μL, 0.08 mmol) and cesium carbonate (513.32 mg, 1.58 mmol) were added, and the mixture was stirred at 80°C under a nitrogen atmosphere for 3.5 hours. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent system: petroleum ether:ethyl acetate = 10:1 to 3:1) to obtain compound 55d. MS m / z (ESI): 252.3 [M+1].

[0479] Step 3: Dissolve compound 55d (100 mg, 0.40 mmol) in hydrochloric acid / ethyl acetate (2 mL) and stir at room temperature for 2 hours. Concentrate the reaction mixture to dryness to obtain the title compound 55e. MS m / z (ESI): 152.2 [M+1].

[0480] Step 4: Compounds Int-1 (80 mg, 0.19 mmol) and 55e (58.74 mg, 0.39 mmol) were dissolved in N,N-dimethylformamide (5 mL). N,N-Diisopropylethylamine (0.12 mL, 0.73 mmol) was added at room temperature and stirred at 90°C under a nitrogen atmosphere for 1 hour. The reaction mixture was purified by HPLC using a Gilson 306-1741 column (Waters SunFire C18-10 μm-19 x 250 mm; mobile phase: water (containing 0.1% formic acid) and acetonitrile, gradient: acetonitrile 1% to 95%, flow rate: 20 mL / min) to afford compound 55. MS m / z (ESI): 527.2 [M+1]. 1H NMR (400MHz, Chloroform-d): δ8.27(d,J=7.4Hz,1H),8.11(s,1H),8.00(d,J=8.8Hz,1H),7.66(s,1H),7.56(d, J=1.8Hz,1H),7.42(d,J=2.3Hz,1H),6.80(dd,J=8.8,2.8Hz,1H),6.72(d,J=2.8Hz,1H),6.23(t,J=2.0Hz,1H), 4.86–4.77(m,2H),3.29(t,J=5.0Hz,4H),2.91(t,J=5.0Hz,4H),2.55(s,3H),2.48–2.39(m,1H),2.29(d,J=8.0 Hz,1H),2.21(d,J=14.6Hz,1H),2.07-2.00(m,3H),1.88(d,J=5.4Hz,1H),1.02-0.98(m,2H),0.70–0.60(m,2H).

[0481] Biological evaluation

[0482] Test Example 1: Compound Inhibition Experiment on ULK1 Protein Activity

[0483] 1. Test Purpose

[0484] In this experiment, the ADP-Glo ​​method was used to detect the inhibitory effect of the compound on the phosphorylation function of ULK1. 50 The inhibitory effects of the disclosed compounds on the ULK1 target were evaluated.

[0485] 2. Experimental Methods

[0486] Compound preparation: 3-fold serial dilutions were performed with DMSO using ECHO (Beckman, ECHO650) in a 384-well plate (PE, 6007290), with 10 concentration points. The highest concentration of the compound was 10 μM, and 50 nL was added to each well. 50 nL DMSO was added to the positive control wells and negative control wells, respectively.

[0487] Reaction procedure: Prepare a 32 nM ULK1 solution (Promega, V3521) and transfer 2.5 μL / well to the compound test wells and negative control wells (NC). Add 2.5 μL / well of 1× Assay buffer to the positive control wells (PC). Prepare a mixed solution of 100 μM ATP and 1.86 μM MBP and transfer 2.5 μL / well to the reaction plate. Initiate the reaction after centrifugation and incubate at room temperature for 60 minutes. After the reaction is complete, add 5 μL / well of ADP-Glo ​​Reagent (Promega, V9102) to the reaction plate, centrifuge, and incubate at room temperature for 40 minutes. Finally, add 10 μL / well of Kinase Detection Buffer; centrifuge and incubate at room temperature for 30 minutes. Chemiluminescence values ​​are read using Envision (PE, Envision2105).

[0488] Assay buffer: reaction buffer; Kinase Detection buffer: detection buffer, both are taken from the ADP-Glo ​​detection kit, purchased from Promega, model V9102.

[0489] The inhibition rate of the compound on ULK1 activity was calculated using the following formula:

[0490] Inhibition rate = (sample signal value - negative control signal value) / (positive control signal value - negative control signal value) x 100%. The log (inhibitor) vs. response-Variable slope analysis software GraphPad Prism 8 was used to fit the dose-effect curve to obtain the IC value of each compound on the enzyme activity. 50 value.

[0491] The experimental results of this test case are shown in Table 1 below:

[0492] Table 1: IC values ​​of the compounds of the present invention for inhibition of ULK1 50

[0493] The compounds of the present invention have been tested to have good inhibitory activity against ULK1. The activities of some compounds of the present invention measured by the above method are shown in Table 1, wherein A represents IC50 < 100nM; B represents 100nM < IC50 < 1μM; and C represents IC50 > 1μM.

[0494] Test Example 2: Inhibition of ATG13 phosphorylation levels in MIA PaCa-2 cells by compounds

[0495] 1. Test Purpose

[0496] The inhibitory effect of the compounds of the present disclosure on ULK1 was evaluated by testing the inhibitory effect of the compounds of the present disclosure on the phosphorylation level of ATG13 in MIA PaCa-2 cells.

[0497] 2. Experimental Methods

[0498] MIA PaCa-2 cells (ATCC, CRM-CRL-1420) were cultured in complete medium (DMEM (Gibco, 11965-092)) supplemented with 10% fetal bovine serum (Corning, 35-081-CV), 2.5% horse serum (Gibco, 16050-122), and 1% double-stranded antibody (Gibco, 15140-122). Experiments were performed according to the kit instructions (Cell Signaling Technology, 17208C).

[0499] Cell plating: MIA PaCa-2 cells with a confluence of 80% were digested, diluted with complete medium, and added to a 96-well cell culture plate (Costar, 3596), 20,000 cells per well, 90 μL.

[0500] Compound Incubation: Add 5 μL of Torin1 and 5 μL of serially diluted compound to each well to achieve a maximum compound concentration of 10 μM. Perform a five-fold serial dilution across eight concentrations, with a final Torin1 concentration of 100 nM. The DMSO content in the system is 0.1%. Incubate the reaction plate in an incubator at 37°C, 5% CO2 for 24 hours. Add 10 μL of Torin1 to the negative control well (NC) to achieve a final concentration of 100 nM. The DMSO content is 0.1%.

[0501] Reaction Assay: After incubation, wash the cell plate with pre-chilled DPBS (Corning, 21-031-CVC) to remove the compound and culture medium. Add 50 μL of pre-chilled cell lysis buffer to each well and incubate on ice for 10 minutes. Centrifuge the cell plate and transfer the supernatant to an ELISA plate. Simultaneously, add 50 μL of Phospho-Atg13 (ser355) rabbit detection antibody and incubate at room temperature with shaking for 60 minutes. After incubation, wash the plate four times with washing buffer and add 100 μL of TMB substrate for color development. Incubate in the dark with shaking for 15 minutes. Finally, add 100 μL of stop solution to each well and shake for 10 seconds to terminate the reaction. Over 10 minutes, absorbance measurements at 450 nm and 560 nm are collected using an Envision (Perkin Elmer, EnVision 2105).

[0502] 3. Data Analysis

[0503] The inhibition rate was calculated by subtracting the absorbance value at 560 nM from the absorbance value at 450 nm for each well. The inhibition rate formula is as follows: Inhibition rate = (sample signal value - negative control signal value) / (positive control signal value - negative control signal value) x 100%

[0504] The dose-effect curve was fitted using the log(inhibitor) vs. response-Variable slope of Graphpad Prism8 to obtain the IC of each compound for the inhibition of ATG13 phosphorylation level. 50 value.

[0505] The experimental results of this test case are shown in Table 2 below:

[0506] Table 2: IC values ​​of the compounds of the present invention for inhibiting ATG13 phosphorylation levels 50

[0507] The compounds of the present invention have good inhibitory activity against ULK1. The activities of some compounds of the present invention measured by the above method are shown in Table 1, where A represents IC50 < 100 nM; B represents 100 nM < IC50 < 1 μM; C represents IC50 > 1 μM

[0508] Test Example 3: Inhibition of autophagy levels in HEK293 GFP-LC3 stably transfected cells by compounds

[0509] 1. Test Purpose

[0510] The inhibitory effect of the disclosed compounds on intracellular autophagy was evaluated by testing the effect of the disclosed compounds on the fluorescence intensity of HEK293 GFP-LC3 stably transfected cells.

[0511] 2. Experimental Methods

[0512] HEK293 GFP-LC3 stably transfected cells (HEK293, ATCC, CRL-1573) were cultured in complete medium, DMEM (Gibco, 11965-092) containing 10% fetal bovine serum (Corning, 35-081-CV), 1% anti-antibody (Gibco, 15140-122), and 1 μg / mL Puromycin (Invitrogen-A1113803).

[0513] Cell plating: HEK293 GFP-LC3 stably transfected cells with a confluence of 80% were digested, diluted with culture medium without Puromycin, and added to 96-well cell culture plates (Geriner, 655090), with 12,000 cells per well in 90 μL.

[0514] Compound Incubation: Add 5 μL of Torin1 and 5 μL of serially diluted compound to each well, achieving a maximum compound concentration of 10 μM. Serially dilute the compound three-fold over eight concentrations, for a final Torin1 concentration of 100 nM. The DMSO content in the system is 0.1%. Positive control wells (PC) contain a final concentration of 0.1% DMSO, and negative control wells (NC) contain 100 nM Torin1 in 0.1% DMSO. Incubate the reaction plate in an incubator at 37°C, 5% CO2 for 24 hours.

[0515] Cell staining and fixation: Remove the cell plate and add 10 μL of Hochest 33342 nuclear staining reagent (Thermo, H1399) per well. Incubate at 37°C, 5% CO2 for 30 min. After incubation, discard the cell supernatant and add 100 μL of pre-chilled 4% paraformaldehyde per well to fix the cells for 15 min. The fixative solution is discarded, and 100 μL of PBS is added per well. The cells are then imaged and analyzed using a high-content cell imaging analyzer (PE, Operetta CLS). GFP fluorescence signals are collected for data processing.

[0516] 3. Data Analysis

[0517] The average GFP fluorescence signal intensity in the reaction wells was collected and the inhibition rate was calculated:

[0518] Inhibition rate = (sample signal value - negative control signal value) / (positive control signal value - negative control signal value) x 100%

[0519] The log(inhibitor) vs. response-Variable slope of Graphpad Prism8 was used to fit the dose-effect curve to obtain the IC of each compound on the inhibition of autophagy level in HEK293 GFP-LC3 stably transfected cells. 50 value.

[0520] The experimental results of this test case are shown in Table 3 below:

[0521] Table 3: IC values ​​of the compounds of the present invention for inhibiting autophagy levels in HEK293 GFP-LC3 stably transfected cells 50

[0522] The compounds of the present invention have good inhibitory activity against ULK1. The activities of some compounds of the present invention measured by the above method are shown in Table 1, where A represents IC50 < 100 nM; B represents 100 nM < IC50 < 1 μM; C represents IC50 > 1 μM

[0523] It should be noted that the present application is not limited to the above-mentioned embodiments. The above-mentioned embodiments are merely examples, and any embodiments having substantially the same structure and effect as the technical concept within the scope of the present application are all included in the technical scope of the present application. In addition, without departing from the scope of the present application, any other embodiments that can be conceived by those skilled in the art and that combine some of the constituent elements in the embodiments are also included in the scope of the present application.

Claims

1. A compound of Formula 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, or prodrug thereof: in, X1 is CH or N; X2 is N or CR4; X3 is N or CR5; R1 is selected from H, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 aryl and 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl are each optionally substituted with one or more R6; R2 is selected from H, halogen, cyano, nitro, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, R7O-, -SR7, -NR7R8, -NHCONR7R8, -NHCOR7, -CONR7R8 and -SO2R7, wherein the C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl are each optionally substituted with one or more R6; R3 is selected from H, cyano, halogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl and C3-C 10 Cycloalkyl; R4 is selected from H, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, R7O-, -NR7R8 and -NHCONR7R8, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl are each optionally substituted with one or more R6; Alternatively, R2, R4 and the groups connected to them together form a 3-12 membered monocyclic or spirocyclic heterocyclic ring, a C6-C 10 aromatic ring or 5-10 membered heteroaromatic ring, wherein the 3-12 membered monocyclic or spirocyclic heterocyclic ring, C6-C 10 The aromatic ring or 5-10 membered heteroaromatic ring is each substituted by one or more R6; R5 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl; Alternatively, R1, R5 and the groups connected thereto together form a 5-6 membered heterocyclic ring, a benzene ring or a 5-6 membered heteroaromatic ring; R6 is independently selected from halogen, cyano, nitro, amino, -NHCO(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl, wherein the C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl are each optionally substituted with one or more halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy; R7 and R8 are each independently selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group and C6-C 10 Aryl, wherein the C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-12 membered heterocyclic group or C6-C 10 The aryl groups are each optionally substituted with one or more R6; Or R7, R8 and the groups connected to them together form a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; R is selected from 3-12 membered heterocyclyl, 5-10 membered heteroaryl and -L-R9, wherein the 3-12 membered heterocyclyl or 5-10 membered heteroaryl are each optionally replaced by one or more R 10 replace; L is -(L1) m -(L2) n -(L3) p -; L1 is selected from -O-, -N(R 12 )-、-C(R 12 )(R 13 )-O-、-N(R 12 )CO- and -S-; L2 is selected from C1-C6 alkylene, C1-C6 heteroalkylene, C3-C 10 Cycloalkylene and 3-10 membered heterocyclylene; L3 is selected from -N(R 12 )-、-N(R 12 )C(O)- and -C(O)-; m, n and p are each independently selected from 0, 1 and 2, and m, n and p are not 0 at the same time; R9 is selected from C3-C 10 Cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclic group, the C3-C 10 Cycloalkyl, C6- C 10 Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group are each optionally substituted by one or more R 14 replace; R 10 Each is independently selected from C1-C6 alkyl, oxo, 5-10 membered heteroaryl, 3-12 membered heterocyclyl, R 11 C(O)-、R 11 C(O)N(R 12 )- and -NR 12 R 13 wherein the C1-C6 alkyl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group is each optionally substituted by one or more R 15 replace; R 11 Selected from C1-C6 alkyl and C3-C 10 Cycloalkyl; R 12 and R 13 Each independently selected from H, C1-C6 alkyl and C3-C 10 Cycloalkyl; R 14 Each is independently selected from H, halogen, cyano, oxo, C1-C6 alkyl, C1-C6 alkoxy, -CONR 12 R 13 and R 11 C(O)-; and R 15 Each is independently selected from H, halogen, cyano, oxo, C1-C6 alkyl, C3-C 10 Cycloalkyl and 3-12 membered heterocyclic groups, wherein the C1-C6 alkyl, C3-C 10 The cycloalkyl or 3-12 membered heterocyclyl is each optionally substituted with one or more substituents selected from C1-C6 alkyl and oxo; The conditions are: (1) When R9 is C3-C 10 Cycloalkyl, C6-C 10 When it is aryl or 5-10 membered heteroaryl, n is not 0; (2) When L is -(L1) m -(L2) n -(L3) p -, L1 is selected from -N(R 12 )-, m is 1, L2 is selected from C1-C6 alkylene, and when n is 1, L3 is not -N(R 12 )C(O)-; (3) When L is -(L1) m -(L2) n -(L3) p -, L1 is selected from -N(R 12 )-, m is 1, L2 is selected from C1-C6 alkylene, n is 1, p is 0, and R9 is a 3-12 membered heterocyclic group, the 3-12 membered heterocyclic group is substituted with oxo; and (4) When L is -(L1) m -(L2) n -(L3) p -, L1 is selected from -N(R 12 )-, m is 1, L2 is selected from C1-C6 alkylene, n is 1, p is 0, and R9 is a 5-10 membered heteroaryl, and R2 is not morpholinyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, or prodrug thereof, wherein: At most one of X1, X2, and X3 is N.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, or prodrug thereof, wherein: R1 is selected from H, C1-C6 alkoxy and C3-C6 cycloalkyl, preferably selected from H, cyclopropyl and methoxy.

4. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, or prodrug thereof, wherein: R5 is H.

5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, or prodrug thereof, wherein: R1, R5 and the groups connected to them together form a 5-6 membered heterocyclic ring, preferably a 5-6 membered oxygen-containing heterocyclic ring; Preferably, Part of The wavy line Indicates the point of attachment of a group to the rest of the molecule.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, or prodrug thereof, wherein: R3 is selected from H and C1-C6 haloalkyl, preferably, R3 is selected from C1-C6 haloalkyl, preferably, R3 is selected from H and trifluoromethyl, more preferably, R3 is selected from trifluoromethyl.

7. The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, or prodrug thereof, wherein: R2 is selected from H, C2-C6 alkynyl, 3-10-membered monocyclic, spirocyclic or cyclic heterocyclic group and R7O-, wherein the C2-C6 alkynyl or 3-10-membered monocyclic, spirocyclic or cyclic heterocyclic group is each optionally substituted by 1 or 2 R6; Preferably, R2 is selected from H, C2-C4 alkynyl, 3-6-membered monocyclic heterocyclyl, 7-10-membered spirocyclic or cyclic heterocyclyl, and R7O-, wherein the C2-C4 alkynyl, 3-6-membered monocyclic heterocyclyl, 7-10-membered spirocyclic or cyclic heterocyclyl are each optionally substituted by 1 or 2 R6; R6 are each independently selected from C1-C6 alkyl and 3-6-membered heterocyclyl, wherein the 3-6-membered heterocyclyl is optionally substituted by C1-C6 alkyl; R7 is selected from C1-C6 alkyl and 5-6 membered heterocyclyl, wherein the C1-C6 alkyl is optionally substituted by 3-6 membered heterocyclyl, and the 5-6 membered heterocyclyl and 3-6 membered heterocyclyl are each optionally substituted by C1-C6 alkyl; Preferably, R2 is selected from H, The wavy line Indicates the point of attachment of a group to the rest of the molecule.

8. The compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, or prodrug thereof, wherein: R4 is selected from H, C1-C6 alkyl, -NR7R8 and -NHCONR7R8, wherein the C1-C6 alkyl is optionally substituted with a 3-6 membered heterocyclyl; R7 is selected from H, R8 is selected from C6-C 10 Aryl, wherein the C6-C 10 The aryl group is optionally substituted with amino, -NHCO(C1-C6 alkyl); Or R7, R8 and the groups connected to them together form a 5-6 membered heterocyclic ring; Preferably, R4 is H, Preferably, R4 is H.

9. The compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, or prodrug thereof, wherein: R2, R4 and the group to which they are attached together form a 6-12-membered nitrogen-containing monocyclic heterocycle or a nitrogen-containing spirocyclic heterocycle, each of which is optionally substituted by one or more R6; Preferably, R2, R4 and the groups connected thereto together form a 6-12-membered nitrogen-containing monocyclic heterocycle or a nitrogen-containing spirocyclic heterocycle, wherein the 6-12-membered nitrogen-containing heterocycle is substituted by 1 or 2 C1-C6 alkyl groups; Preferably, R2, R4 and the groups connected thereto together form a 6-7-membered nitrogen-containing monocyclic heterocycle or a 7-12-membered nitrogen-containing spirocyclic heterocycle, and each of the 6-7-membered nitrogen-containing monocyclic heterocycle or the 7-12-membered nitrogen-containing spirocyclic heterocycle is substituted by 1 or 2 C1-C6 alkyl groups; Preferably, Part of Best More preferred Preferably, Part of Best The wavy line Indicates the point of attachment of a group to the rest of the molecule.

10. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, or prodrug thereof, wherein the compound is a compound of Formula 1A: in, Ring A is a 6-12 membered nitrogen-containing monocyclic heterocycle or a nitrogen-containing spirocyclic heterocycle; and R6 is a C1-C6 alkyl group, Preferably, Part of Preferably, More preferred The wavy line Indicates the point of attachment of a group to the rest of the molecule.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, or prodrug thereof, wherein the compound is a compound of Formula 1B': in, Ring B is selected from 3-12 membered heterocyclyl and 5-10 membered heteroaryl, preferably, ring B is selected from 3-12 membered heterocyclyl; and r is selected from 0, 1 and 2.

12. The compound of claim 11 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, or prodrug thereof, wherein: Ring B is a 5-12 membered spiro heterocyclic group or a 5-12 membered bridged heterocyclic group, preferably a 7-12 membered spiro heterocyclic group or a 7-12 membered bridged heterocyclic group, more preferably And R 10 Each independently selected from C1-C6 alkyl, oxo, 3-6 membered heterocyclic group and -NR 12 R 13 , preferably, R 10 Each is independently selected from methyl, oxo, amino and morpholinyl.

13. The compound of claim 11 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, or prodrug thereof, wherein: Ring B is a 3-10-membered monocyclic heterocyclic group or a 5-10-membered heteroaryl group, preferably a 4-7-membered monocyclic heterocyclic group or a 5-6-membered heteroaryl group, more preferably an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, 1,4-diazepanyl or pyrazolyl group; Preferably, ring B is a 3-10 membered monocyclic heterocyclic group, preferably a 4-7 membered monocyclic heterocyclic group, more preferably an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, 1,4-diazepanyl; R 10 Each is independently selected from C1-C6 alkyl, oxo, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, R 11 C(O)- and R 11 C(O)NH-, wherein the C1-C6 alkyl, 5-6 membered heteroaryl or 4-7 membered heterocyclyl is each optionally substituted by 1-4 R 15 replace; R 11 is a C4-C6 cycloalkyl group; and R 15 Each is independently selected from halogen, oxo, C1-C6 alkyl, C3-C6 cycloalkyl and 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl is each optionally substituted with one or more substituents selected from C1-C6 alkyl and oxo, Preferably, R 10 Each is independently selected from C1-C6 alkyl, oxo, pyrazolyl, piperidinyl, pyrrolidinyl, azetidinyl, C4-C6 cycloalkyl-C(O)- and C4-C6 cycloalkyl-C(O)-NH-, wherein the azetidinyl, pyrrolidinyl or piperidinyl is each optionally substituted with 1-4 C1-C6 alkyl or oxo, the C1-C6 alkyl is optionally substituted with 1-4 substituents selected from fluorine and C3-C6 cycloalkyl, and the pyrazolyl is optionally substituted with 1-4 C1-C6 alkyl; More preferably, R 10 Each is independently selected from methyl, oxo, pyrazolyl, piperidinyl, 3-methyl-1H-pyrazolyl, N-methylazetidinyl, N-methylpiperidinyl, cyclobutylcarbonyl, cyclobutylcarbonylamino, oxopyrrolidinyl, oxopiperidinyl, The wavy line Indicates the point of attachment of a group to the rest of the molecule.

14. The compound of any one of claims 11 to 13, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, or prodrug thereof, wherein the compound is a compound of Formula 1B-1, 1B-2, 1B-3, 1B-4, 1B-5, 1B-A, 1B-B, 1B-C, 1B-D, 1B-E, 1B-F or 1B-G: in, t is selected from 0, 1, 2 and 3; u, v, w, x, y and z are each independently selected from 1, 2 and 3; Y is selected from -CH- and -N-; and r is selected from 1 and 2.

15. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, or prodrug thereof, wherein the compound is a compound of Formula 1C: in, L is -(L1) m -(L2) n -(L3) p -; L1 is selected from -O- and -N(R 12 )-, preferably selected from -O- and -NH-; L2 is selected from C1-C6 alkylene and C3-C 10 Cycloalkylene, preferably selected from C1-C6 alkylene and C3-C6 cycloalkylene, more preferably selected from ethylene, propylene and cyclohexylene; L3 is selected from -N(R 12 )-、-N(R 12 )C(O)- and -C(O)-, preferably selected from -NH-, -NHC(O)- and -C(O)-, preferably, when L3 When it is -NHC(O)-, the amino part of the -NHC(O)- is connected to L2, and the carbonyl part is connected to ring C; m, n and p are each independently selected from 0 and 1, and m, n and p are not 0 at the same time; Preferably, L is selected from -O-, -O-cyclohexylene-, -NH-cyclohexylene-, -O-propylene-, -NH-propylene-, -ethylene-, -ethylene-NHC(O)-, and -O-propylene-C(O)-; Ring C is selected from C3-C 10 Cycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclic group, preferably selected from C3-C6 cycloalkyl, C6-C 10 Aryl, 5-6 membered heteroaryl and 5-7 membered heterocyclyl, preferably selected from cyclobutyl, phenyl, pyrazolyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, morpholinyl, 1,3-oxazinyl, azepanyl, 1,4-oxaazepanyl and 5-azaspiro[2.5]octanyl; R 14 Each is independently selected from H, halogen, cyano, oxo, C1-C6 alkyl, C1-C6 alkoxy, -CONR 12 R 13 and R 11 C(O)-, preferably, R 14 are each independently selected from H, fluoro, chloro, cyano, oxo, methyl, methoxy, -CONHCH3, and cyclobutyl-C(O)-; and s is selected from 0, 1 and 2.

16. The compound of claim 15 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, or prodrug thereof, wherein the compound is a compound of formula 1C-1, 1C-2, 1C-3, 1C-4 or IC-5: in, X is selected from a bond, -O-, -S-, -NH- and -CH2-O-; V is selected from -O-, -S-, -NR 12 -and-CHR 12 -; R 12 Selected from H and C1-C6 alkyl; h and l are each independently selected from 0, 1, 2 and 3; i is selected from 0, 1 and 2; and j and k are each independently selected from 1, 2 and 3.

17. The compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotope-labeled compound, metabolite, ester, or prodrug thereof, wherein the compound is a compound of formula (1D): in, R 10 As defined in claim 1; preferably, R 10 is selected from 3-12 membered heterocyclic groups, wherein the 3-12 membered heterocyclic groups are optionally substituted by one or more R 15 Substituted; preferably, R 10 is selected from 4-7 membered heterocyclic groups, wherein the 4-7 membered heterocyclic groups are optionally substituted by one or more R 15 More preferably, R 10 is selected from a 4-7 membered nitrogen-containing heterocyclic group (e.g., piperidinyl), wherein the 4-7 membered nitrogen-containing heterocyclic group is optionally substituted by one or more R 15 replace; R 15 As defined in claim 1; preferably, R 15 is selected from C1-C6 alkyl, more preferably, R 15 Selected from methyl.

18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, or prodrug thereof, wherein: L is -(L1) m -(L2) n -(L3) p -*, where the bond marked with "*" is connected to R9; L1 is selected from -O-, -N(R 12 )-、-C(R 12 )(R 13 )-O- and -N(R 12 )CO-; L2 is selected from C1-C6 alkylene, C1-C6 heteroalkylene, C3-C 10 Cycloalkylene and 3-10 membered heterocyclylene; L3 is selected from -N(R 12 )-、-N(R 12 )C(O)- and -C(O)-; m, n and p are each independently selected from 0, 1 and 2, and m, n and p are not 0 at the same time; Preferably, L1 is selected from -O-, -N(R 12 )-、#-C(R 12 )(R 13 )-O- and #-N(R 12 )CO-, where the bond marked with "#" connects to Preferably, L1 is selected from -O-, -N(R 12 )-; Preferably, L2 is selected from C1-C6 alkylene, C1-C6 heteroalkylene, C3-C6 cycloalkylene and 3-6 membered heterocyclylene; Preferably, L3 is selected from -N(R 12 )-、-N(R 12 )C(O)-$ and -C(O)-, wherein the bond indicated by "$" is connected to R9; Preferably, -(L1) m -(L2) n -(L3) p -* as a whole is selected from -L1-L2-*, -L1-, -L2-, -L1-L2-L3-*, -L1-L3-*, -L2-L3-*, wherein the bond marked with "*" is connected to R9; Preferably, -(L1) m -(L2) n -(L3) p -* as a whole is selected from -L1-, -L2-, -L1-L2-*, -L1-L2-L3-*, -L2-L3-*; Preferably, -(L1) m -(L2) n -(L3) p -* as a whole is selected from -L1-, -L1-L2-*, -L1-L2-L3-*; More preferably, -(L1) m -(L2) n -(L3) p -* as a whole is selected from -L1-L2-*, -L1-L2-L3-*; Preferably, -(L1) m -(L2) n -(L3) p -* as a whole is selected from -N(R 12 )-C3-C6 cycloalkylene-*, -N(R 12 )-、-N(R 12 )-3-6 membered heterocyclylene-C(O)-*, -N(R 12 )C(O)-*、-N(R 12 )-C1-C6 alkylene-*, -O-C3-C6 cycloalkylene-*, -O-, -O-3-6-membered heterocyclylene-C(O)-*, -O-C1-C6 alkylene-*, -O-C1-C6 alkylene-C(O)-*, -O-C1-C6 alkylene-N(R 12 )-*, -C1-C6 alkylene-, -C1-C6 alkylene-N(R 12 )-C(O)-*、-C(R 12 )(R 13 )-O-C1-C6 alkylene-*, wherein the bond marked with "*" is connected to R9; Preferably, -(L1) m -(L2) n -(L3) p -* as a whole is selected from -O-, -O-C1-C6 alkylene-*, -O-C1-C6 alkylene-C(O)-*, -N(R 12 )-C3-C6 cycloalkylene-*, -N(R 12 )-3-6 membered heterocyclylene-C(O)-*, -N(R 12 )-C1-C6 alkylene-*, -N(R 12 )C(O)-*、-N(R 12 )-、-C1-C6 alkylene-N(R 12 )-C(O)-*, -C1-C6 alkylene-, -O-3-6 membered heterocyclylene-C(O)-*; Preferably, -(L1) m -(L2) n -(L3) p -* as a whole is selected from -O-C1-C6 alkylene-*, -N(R 12 )-C1-C6 alkylene-*, -O-C1-C6 alkylene-C(O)-*, -N(R 12 )-C3-C6 cycloalkylene-*, -N(R 12 )-3-6 membered heterocyclylene-C(O)-*, -O-; More preferably, -(L1) m -(L2) n -(L3) p -* as a whole is selected from -O-C1-C6 alkylene-*, -N(R 12 )-C1-C6 alkylene-*,- N(R 12 )-C3-C6 cycloalkylene-*, -N(R 12 )-3-6 membered heterocyclylene-C(O)-*.

19. The compound of any one of claims 1 to 18 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, or prodrug thereof, provided that: (1) When R9 is optionally replaced by R 14 Substituted C3-C 10 Cycloalkyl, C6-C 10 When aryl or 5-10 membered heteroaryl, n is not 0; and / or (2) When L is -(L1) m -(L2) n -(L3) p -, L1 is selected from -N(R 12 )-, m is 1, L2 is selected from C1-C6 alkylene, and when n is 1, L3 is not -N(R 12 )C(O)-; and / or (3) When L is -(L1) m -(L2) n -(L3) p -, L1 is selected from -N(R 12 )-, m is 1, L2 is selected from C1-C6 alkylene, n is 1, p is 0, R9 is R 14 substituted 3-12 membered heterocyclic group, and at least one R 14 When it is an oxo substituent, the R2 is selected from C2-C6 alkynyl substituted by one or more R6 or R2, R4 and the group connected thereto together form a 7-12 membered spiro heterocycle optionally substituted by one or more R6; and / or (4) When L is -(L1) m -(L2) n -(L3) p -, L1 is selected from -N(R 12 )-, m is 1, L2 is selected from C1-C6 alkylene, n is 1, p is 0, and R9 is a 5-10 membered heteroaryl, R2 is not morpholinyl; and / or (5) When L is -(L1) m -(L2) n -(L3) p -, L1 is selected from -N(R 12 )-, m is 1, n is 0, p is 0, and R9 is a 3-12 membered heterocyclic group, the 3-12 membered heterocyclic group is a monocyclic ring and is substituted by at least one oxo group.

20. The compound of any one of claims 1-19 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, or prodrug thereof, wherein the compound is selected from:

21. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, or prodrug thereof, and one or more pharmaceutically acceptable carriers.

22. Use of a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, hydrate, N-oxide, isotopically labeled compound, metabolite, ester, or prodrug thereof, or a pharmaceutical composition according to claim 21 in the preparation of a medicament for treating a ULK1-mediated disease in a subject in need thereof; preferably, wherein the ULK1-mediated disease is characterized by abnormal autophagy; preferably, wherein the abnormal autophagy is induced by treatment; preferably, wherein the ULK1-mediated disease is cancer, preferably lung cancer, breast cancer or pancreatic cancer, such as non-small cell lung cancer, triple-negative breast cancer or pancreatic ductal adenocarcinoma, or the disease is tuberous sclerosis complex (TSC) or lymphangioleiomyomatosis (LAM).

23. The use according to claim 22, wherein the medicament is for co-administration with an additional therapeutic agent; preferably, wherein the additional therapeutic agent is a standard of care therapy, such as an mTOR inhibitor, carboplatin, a MEK inhibitor or a PARP inhibitor.

24. The use according to claim 22 or 23, wherein the medicament is used to degrade ATG13 in the subject.

25. A method for preparing the compound of claim 1, comprising the steps shown in the following synthetic route A or B: Synthetic Route A or Synthetic route B in: R1, R2, R3, R, X1, X2, X3 are as defined in claim 1.

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