TRICYCLIC COMPOUNDS ACT AS EGFR INHIBITORS

Abstract

The invention relates to a group of compounds, represented by the formula (I''), which are selective EGFR inhibitors, pharmaceuticals containing compounds, or useful intermediates for the preparation of compounds for the treatment of proliferative diseases, such as cancer.

Description

Tricyclic compounds as EGFR inhibitors

[0001] Cross-reference to related applications

[0002] This application claims priority and benefits from the following prior applications filed with the China National Intellectual Property Administration: Patent application No. 202010292186.8, filed April 14, 2020, entitled "Fused Tricyclic Compound as an EGFR Inhibitor"; Patent application No. 202010852717.4, filed August 22, 2020, entitled "Fused Tricyclic Compound as an EGFR Inhibitor"; Patent application No. 202110175424.1, filed February 9, 2021, entitled "Fused Tricyclic Compound as an EGFR Inhibitor"; and Patent application No. 202110312259.X, filed March 24, 2021, entitled "Fused Tricyclic Compound as an EGFR Inhibitor". The full text of all the above prior applications is incorporated herein by reference. Technical Field

[0003] This invention belongs to the field of medicinal chemistry, and specifically relates to novel compounds as selective EGFR inhibitors, pharmaceutical compositions containing said compounds, useful intermediates for preparing said compounds, and methods for treating cell proliferative diseases, such as cancer, using the compounds of this invention. Background Technology

[0004] Lung cancer is the leading cause of cancer incidence and mortality, seriously threatening human health and life. Lung cancer is mainly divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with approximately 80% being NSCLC.

[0005] EGFR, or epidermal growth factor receptor, is widely distributed on the surface of mammalian epithelial cells, fibroblasts, glial cells, and other cells. The EGFR signaling pathway plays a crucial role in physiological processes such as cell growth, proliferation, and differentiation. EGFR mutations are also one of the most common mutation types in NSCLC patients, especially in Asian populations, accounting for 40%–50%. Therefore, EGFR has always been one of the most popular targets in drug development.

[0006] Currently, marketed EGFR inhibitors are classified into first, second, and third generations. First-generation inhibitors are reversible targeted drugs, such as gefitinib, erlotinib, and icotinib. Second-generation inhibitors are irreversible targeted drugs, such as afatinib and dacomitinib. While first- and second-generation targeted drugs are highly effective, most patients develop resistance after 1-2 years of use. Among patients with EGFR inhibitor resistance, 50% of resistance is related to the T790M mutation. The third-generation EGFR targeted drug osimertinib can overcome tumor resistance caused by the T790M mutation, bringing better survival benefits to more lung cancer patients. However, third-generation targeted drugs inevitably develop resistance, primarily due to the C797S mutation. The C797S mutation manifests as a cysteine ​​residue mutation to a serine residue. This mutation disrupts the binding of the EGFR protein to third-generation targeted drugs, thus failing to prevent EGFR protein phosphorylation and activation of downstream signaling pathways. Currently, there are no mature treatments for the two main cis-triple mutations that occur after osimertinib resistance: Del19 / T790M / C797S and L858R / T790M / C797S. Clinical needs are urgent, and this invention is based on solving this problem.

[0007] Summary of the Invention

[0008] The present invention aims to provide a class of tricyclic compounds as selective EGFR inhibitors, pharmaceutical compositions containing said compounds, useful intermediates for preparing said compounds, and the use of said compounds in the preparation of cancer treatment drugs.

[0009] This invention provides compounds of formula (I”') or their stereoisomers, tautomers, or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotope-labeled derivatives.

[0010]

[0011] in,

[0012] R1 is selected from H, halogens, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, C 2-6 alkenyloxy group, C 2-6 alkynyloxy group, C 1-6 Alkylamino, C 1-6 Haloalkanes, C 3-6 Cycloalkylamino, 3-6 membered heterocyclic alkylamino, C 2-6 alkenylamino and C2-6 alkynylamino;

[0013] M is selected from N or CR a ;R a H, halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Heteroalkyl, or C 1-6 Halogenated alkyl groups;

[0014] Z is selected from N or CR6;

[0015] Z1 is selected from N or CR7;

[0016] Or, R a It can cyclize with R1 to form substituted or unsubstituted 5-8 membered heterocyclic groups or 5-8 membered carbocyclic groups;

[0017] Ring A is selected from substituted or unsubstituted 5-8 membered heterocyclic groups or 5-8 membered carbocyclic groups;

[0018] Ring B is absent or selected from aryl or 5-6-membered heteroaryl, 4-8-membered heterocyclic alkyl, or C-membered rings optionally substituted by one or more R2 groups. 4-8 cycloalkyl;

[0019] R2 is independently selected from H, halogens, -CN, and -C (=O)R. b -C(=O)NR b R c -S(=O)2R b -S(=O)(=NR) c )R b -NH2, -OH, -SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-6 Aryl, C 5-6 Arylalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, C 2-6 alkenyloxy group, C 1-6 Alkylamino, C 1-6 Haloalkanes, C 3-6 Cycloalkylamino, 3-6 membered heterocyclic alkylamino, C 2-6 alkenyl amino or -(CH2) r NR c R d r is arbitrarily selected from 0, 1, 2, or 3; wherein, C mentioned in R2 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C5-6 Aryl, C 5-6 Arylalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, C 2-6 alkenyloxy group, C 1-6 Alkylamino, C 1-6 Haloalkanes, C 3-6 Cycloalkylamino, 3-6 membered heterocyclic alkylamino or C 2-6 Alkenylamino groups are optionally surrounded by one or more C 1-3 Alkyl or C 1-3 Alkyl substitution;

[0020] R3 and R4 are each independently selected from H, halogens, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 1-6 Alkylamino, C 1-6 Haloalkanes, C 3-6 Cycloalkylamino, 3-6 membered heterocyclic alkylamino and C 2-6 alkenylamino;

[0021] Alternatively, R3 and R4 cyclize to form an aryl group, C 4-7 Cycloalkyl, 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl;

[0022] R5 is selected from substituted or unsubstituted -NH2, -C(=O)NR. b R c -S(=O)2R b -P(=O)R b R c -P(=O)R b NR c R d -P(=O)R b OR c -P(=O)OR b OR c -P(=S)R b R c -P(=S)R b NR c R d -P(=S)R b OR c -P(=S)OR b OR c -S(=O)2NR b R c R bS(=O)2NR c -、-N=S(=O)R b R c or R b N = S(=O)(R) c )-、-NR b C(O)R c or R c S(=NR b )(=O)NR d -;

[0023] R b R c R d Each is independently selected from H, -CN, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, C 4-6 Heterocyclic alkyl, C 5-10 Aryl or 5-10 heteroaryl groups;

[0024] Or, R b R c The atoms connected to it are cyclic to unsubstituted or optionally cyclic by one or more C atoms. 1-3 Alkyl or C 1-3 Alkoxy-substituted 5-6 membered heterocyclic alkyl groups;

[0025] R6, R7, and R8 are each independently selected from H, halogens, -CN, -OH, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 1-6 Alkylamino, C 1-6 Haloalkanes, C 3-6 Cycloalkylamino, 3-6 membered heterocyclic alkylamino and C 2-6 alkenylamino;

[0026] Alternatively, R5 and R6 can be cyclized to form a compound containing -P(=O)(R b )-、-P(=S)(R b )-、-N(R b )S(=O)2-、-S(=O)2N(R b )- or -S(=O)2 4-7 member ring;

[0027] Alternatively, R6 and R7 cyclize into C 4-6Cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl;

[0028] Alternatively, R7 and R8 can cyclize into C. 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl.

[0029] In some embodiments of the present invention, R1 is selected from H, halogen, -CN, C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy group. Preferably, R1 is selected from H, halogen, -CN, C. 1-6 Alkyl, C 1-6 Alkyl group.

[0030] In some embodiments of the present invention, M is selected from N or CR. a ;R a H, halogen, C 1-3 Alkyl, C 3-6 cycloalkyl or C 1-3 Halogenated alkyl group. Preferably, M is selected from N or CH.

[0031] In some embodiments of the invention, ring A is selected from substituted or unsubstituted 5-8 membered carbon cyclic groups or 5-8 membered heterocyclic groups containing one or two heteroatoms selected from O, S, and N; in some embodiments, ring A may contain a double bond; in some embodiments, one or two ring atoms on ring A may optionally be replaced by -C(=O), -N(=O), -S(=O), -S(=O)2, and ring A may also optionally be replaced by one or more R... x Group substitution, wherein R x Selected from H, -OH, -CN, -NH2, halogens, C 1-6 alkyl carbonyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 cycloalkyl-C 1-6 Alkyl-, 3-8 membered heterocyclic alkyl-C 1-6 Alkyl-, aryl-C 1-6 Alkyl-, C 5-13 Spirocyclic groups, 5-13 corpuscular spiroheterocyclic groups; wherein the C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 cycloalkyl-C 1-6 Alkyl-, 3-8 membered heterocyclic alkyl-C 1-6 Alkyl-, aryl-C 1-6 Alkyl-, C 5-13 Spirocyclic groups, 5-13 spirocyclic groups, or spiroheterocyclic groups are optionally denoted by one or more R groups.y Replaced; the R y Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, C 3-8 cycloalkyl-C 1-6 Alkyl-, 4-8 membered heterocyclic alkyl-C 1-6 Alkyl-, 5-10 aryl, 5-10 heteroaryl.

[0032] In some embodiments of the present invention, ring B is an aryl group or a 5-6 heteroaryl group optionally substituted by one or more R2 groups; the aryl group or the 5-6 heteroaryl group may be pyrroleyl, furanyl, thiophenyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, triazolyl, phenyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, or triazinyl.

[0033] In some embodiments of the present invention, R2 is independently selected from H, halogens, -CN, and -C(=O)R. b -S(=O)2R b -S(=O)(=NR) c )R b -NH2, -OH, -SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-6 Aryl, C 5-6 Arylalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, C 2-6 alkenyloxy group, C 1-6 Alkylamino, C 1-6 Haloalkanes, C 3-6 Cycloalkylamino, 3-6 membered heterocyclic alkylamino, C 2-6 alkenyl amino or -(CH2) r NR c R d r is arbitrarily selected from 0, 1, 2 or 3; wherein, the 3-6 membered heterocyclic alkyl group, C in R2 5-6 Arylalkyl groups are optionally surrounded by one or more C 1-3 Alkyl or C 1-3 Alkyl-substituted.

[0034] In some embodiments of the present invention, R3 and R4 are each independently selected from H, halogens, -CN, and C. 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl; or, R3 and R4 cyclize to form phenyl, C 4-7 Cycloalkyl, 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl containing one or two heteroatoms selected from O, S and N; preferably, the 5-6 membered heteroaryl can be pyrrolithyl, furanyl, thiophenyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazoleyl, triazolyl, phenyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl or triazinyl.

[0035] In some embodiments of the present invention, R5 is selected from substituted or unsubstituted -NH2, -C(=O)NR. b R c -S(=O)2R b -P(=O)R b R c -P(=O)R b NR c R d -P(=O)R b OR c -P(=O)OR b OR c -P(=S)R b R c -P(=S)R b NR c R d -P(=S)R b OR c -P(=S)OR b OR c -S(=O)2NR b R c R b S(=O)2NR c -、-N=S(=O)R b R c R b N = S(=O)(R) c )-、-NR b C(O)R c Alternatively, R5 and R6 cyclize to form a ring containing -P (=O)(R b )-、-P(=S)(R b )-、-N(R b )S(=O)2-、-S(=O)2N(R b )- or -S(=O)2 4-7 member ring.

[0036] In some embodiments of the present invention, Rb R c R d Each independently selected from H and C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl; or, R b R c The atoms connected to it are cyclic to unsubstituted or optionally cyclic by one or more C atoms. 1-3 Alkyl or C 1-3 Alkoxy-substituted 5-6 membered heterocyclic alkyl groups.

[0037] In some embodiments of the present invention, R6 and R7 are each independently selected from H, halogens, -CN, -OH, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 1-6 Alkylamino, C 1-6 Haloalkanes, C 3-6 Cycloalkylamino, 3-6 membered heterocyclic alkylamino and C 2-6 Alkenyl amino group; or, R6 and R7 cyclize to form C 4-6 Cycloalkyl, 4-6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl; preferably, the 5-6-membered heteroaryl can be pyrroleyl, furanyl, thiophenyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazoleyl, triazolyl, phenyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl or triazinyl.

[0038] In some embodiments of the present invention, R8 is H.

[0039] This invention provides compounds of formula (I”) or their stereoisomers, tautomers, or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically labeled derivatives thereof.

[0040]

[0041] in,

[0042] R1 is selected from H, halogens, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, C 2-6 alkenyloxy group, C 2-6 alkynyloxy group, C 1-6 Alkylamino, C 1-6 Haloalkanes, C 3-6 Cycloalkylamino, 3-6 membered heterocyclic alkylamino, C 2-6 alkenylamino and C 2-6 alkynylamino;

[0043] M is selected from N or CR a ;R a H, halogen, C 1-3 Alkyl, C 3-6 cycloalkyl or C 1-3 Halogenated alkyl groups;

[0044] Z is selected from N or CR6;

[0045] Z1 is selected from N or CR7;

[0046] Or, R a It can cyclize with R1 to form substituted or unsubstituted 5-8 membered heterocyclic groups;

[0047] Ring A is selected from substituted or unsubstituted 5-8 membered heterocyclic groups or 5-8 membered carbocyclic groups;

[0048] Ring B is an aryl group or a 5-6 heteroaryl group optionally substituted by one or more R2 groups; the aryl group or the 5-6 heteroaryl group may be pyrrole, furanyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, triazolyl, phenyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, or triazinyl.

[0049] R2 is independently selected from H, halogens, -CN, and -C (=O)R. b -S(=O)2R b -S(=O)(=NR) c )R b -NH2, -OH, -SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-6 Aryl, C 5-6 Arylalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, C 2-6 alkenyloxy group, C 1-6 Alkylamino, C 1-6 Haloalkanes, C 3-6Cycloalkylamino, 3-6 membered heterocyclic alkylamino, C 2-6 alkenyl amino or -(CH2) r NR c R d r can be arbitrarily selected from 0, 1, 2 or 3;

[0050] R3 and R4 are each independently selected from H, halogens, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 1-6 Alkylamino, C 1-6 Haloalkanes, C 3-6 Cycloalkylamino, 3-6 membered heterocyclic alkylamino and C 2-6 alkenylamino;

[0051] Alternatively, R3 and R4 cyclize to form an aryl group, C 4-7 Cycloalkyl, 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl;

[0052] R5 is selected from substituted or unsubstituted -NH2, -C(=O)NR. b R c -S(=O)2R b -P(=O)R b R c -P(=O)R b NR c R d -P(=O)R b OR c -P(=O)OR b OR c -P(=S)R b R c -P(=S)R b NR c R d -P(=S)R b OR c -P(=S)OR b OR c -S(=O)2NR b R c R b S(=O)2NR c -、-N=S(=O)R b R c or R b N = S(=O)(R) c )-、-NR b C(O)Rc ;

[0053] R b R c R d Each is independently selected from H, -CN, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, C 4-6 Heterocyclic alkyl, C 5-10 Aryl or 5-10 heteroaryl groups;

[0054] Or, R b R c The atoms connected to it are cyclized into 5-6 membered heterocyclic alkyl groups;

[0055] R6, R7, and R8 are each independently selected from H, halogens, -CN, -OH, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 1-6 Alkylamino, C 1-6 Haloalkanes, C 3-6 Cycloalkylamino, 3-6 membered heterocyclic alkylamino and C 2-6 alkenylamino;

[0056] Alternatively, R5 and R6 can be cyclized to form a compound containing -P(=O)(R b )-、-P(=S)(R b )-、-N(R b )S(=O)2-、-S(=O)2N(R b )- or -S(=O)2 4-7 member ring;

[0057] Alternatively, R6 and R7 cyclize into C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl;

[0058] Alternatively, R7 and R8 can cyclize into C. 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl.

[0059] This invention provides compounds of formula (I') or their stereoisomers, tautomers, or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically labeled derivatives thereof.

[0060]

[0061] in,

[0062] R1 is selected from H, halogens, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, C 2-6 alkenyloxy group, C 2-6 alkynyloxy group, C 1-6 Alkylamino, C 1-6 Haloalkanes, C 3-6 Cycloalkylamino, 3-6 membered heterocyclic alkylamino, C 2-6 alkenylamino and C 2-6 alkynylamino;

[0063] M is selected from N or CR a ;R a H, halogen, C 1-3 Alkyl, C 3-6 cycloalkyl or C 1-3 Halogenated alkyl groups;

[0064] Z is selected from N or CR6;

[0065] Or, R a It can cyclize with R1 to form substituted or unsubstituted 5-8 membered heterocyclic groups;

[0066] Ring A is selected from substituted or unsubstituted 5-8 membered heterocyclic groups or 5-8 membered carbocyclic groups;

[0067] Ring B is an aryl group or a 5-6 heteroaryl group optionally substituted by one or more R2 groups; the aryl group or the 5-6 heteroaryl group may be pyrrole, furanyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, triazolyl, phenyl, pyrimidinyl, pyridinyl, pyrazinyl or pyridazinyl.

[0068] R2 is independently selected from H, halogens, -CN, and -C (=O)R. b -S(=O)2R b -S(=O)(=NR) c )R b -NH2, -OH, -SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-6 Aryl, C5-6 Arylalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, C 2-6 alkenyloxy group, C 1-6 Alkylamino, C 1-6 Haloalkanes, C 3-6 Cycloalkylamino, 3-6 membered heterocyclic alkylamino and C 2-6 alkenylamino;

[0069] R3 and R4 are each independently selected from H, halogens, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 1-6 Alkylamino, C 1-6 Haloalkanes, C 3-6 Cycloalkylamino, 3-6 membered heterocyclic alkylamino and C 2-6 alkenylamino;

[0070] Alternatively, R3 and R4 cyclize to form an aryl group, C 4-7 Cycloalkyl, 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl;

[0071] R5 is selected from substituted or unsubstituted -NH2, -C(=O)NR. b R c -S(=O)2R b -P(=O)R b R c -P(=O)R b NR c R d -P(=O)R b OR c -P(=O)OR b OR c -P(=S)R b R c -P(=S)R b NR c R d -P(=S)R b OR c -P(=S)OR b OR c -S(=O)2NR b R c R b S(=O)2NR c -、-N=S(=O)R b R c or Rb N = S(=O)(R) c )-;

[0072] R b R c R d Each is independently selected from H, -CN, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, C 4-6 Heterocyclic alkyl, C 5-10 Aryl or 5-10 heteroaryl groups;

[0073] R6, R7, and R8 are each independently selected from H, halogens, -CN, -OH, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 1-6 Alkylamino, C 1-6 Haloalkanes, C 3-6 Cycloalkylamino, 3-6 membered heterocyclic alkylamino and C 2-6 alkenylamino;

[0074] Alternatively, R5 and R6 can be cyclized to form a ring containing -P (=O)R. b -4-7 elemental rings;

[0075] Alternatively, R6 and R7 cyclize into C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl;

[0076] Alternatively, R7 and R8 can cyclize into C. 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl.

[0077] This invention provides compounds of formula (I) or their stereoisomers, tautomers, or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically labeled derivatives thereof.

[0078]

[0079] in,

[0080] R1 is selected from H, halogens, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, C 2-6 alkenyloxy group, C 1-6 Alkylamino, C 1-6 Halogenated alkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclic alkylamino and C 2-6 alkenylamino;

[0081] M is selected from N or CR a ;

[0082] R a H, halogen, C 1-3 Alkyl, C 3-6 cycloalkyl or C 1-3 Halogenated alkyl groups;

[0083] Or, R a It can cyclize with R1 to form substituted or unsubstituted 5-8 membered heterocyclic groups;

[0084] Ring A is selected from substituted or unsubstituted 4-8 membered heterocyclic groups or 5-8 membered carbocyclic groups;

[0085] Ring B is an aryl group or a 5-6 heteroaryl group optionally substituted by one or more R2 groups; the aryl group or the 5-6 heteroaryl group may be pyrrole, furanyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, triazolyl, phenyl, pyrimidinyl, pyridinyl, pyrazinyl or pyridazinyl.

[0086] R2 is independently selected from H, halogens, -CN, and -C (=O)R. b -S(=O)2R b -S(=O)(=NR) c )R b -NH2, -OH, -SH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy and C 2-6 alkenyloxy group, C 1-6 Alkylamino, C 1-6 Halogenated alkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclic alkylamino and C 2-6 alkenylamino;

[0087] R3 and R4 are each independently selected from H, halogens, -CN, and C. 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 1-6 Alkylamino, C 1-6 Halogenated alkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclic alkylamino and C 2-6 alkenylamino;

[0088] Alternatively, R3 and R4 cyclize to form an aryl group, C 4-7 Cycloalkyl, 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl;

[0089] R5 is selected from substituted or unsubstituted -NH2, -C(=O)NR. b R c -S(=O)2R b -P(=O)R b R c -P(=O)R b NR c R d -S(=O)2NR b R c R b S(=O)2NR c -、-N=S(=O)R b R c or R b N = S(=O)(R) c )-;

[0090] R b R c R d Each is independently selected from H, -CN, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, C 4-6 Heterocyclic alkyl, C 5-10 Aryl or 5-10 heteroaryl groups;

[0091] R6, R7, and R8 are each independently selected from H, halogens, -CN, -OH, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 1-6 Alkylamino, C 1-6Halogenated alkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclic alkylamino and C 2-6 alkenylamino;

[0092] Alternatively, R5 and R6 can be cyclized to form a ring containing -P (=O)R. b -4-7 elemental rings;

[0093] Alternatively, R6 and R7 cyclize into C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl;

[0094] Alternatively, R7 and R8 can cyclize into C. 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl.

[0095] In the compounds of formula (I”'), formula (I”), formula (I’), and formula (I) of the present invention,

[0096] R1 is selected from H, halogens, -CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups;

[0097] M is selected from N or CH;

[0098] Ring A is selected from substituted or unsubstituted 5-8 membered heterocyclic groups or 5-8 membered carbocyclic groups;

[0099] Ring B is a 5-6 membered heteroaryl group optionally substituted by one or more R2 groups; the 5-6 membered heteroaryl group is pyrroleyl, furanyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, triazolyl, phenyl, pyrimidinyl, pyridinyl, pyrazinyl or pyridazinyl.

[0100] R2 is independently selected from H and C. 1-4 Alkyl, C 1-4 Haloalkyl, -(CH2) r NR c R d 3-6 membered heterocyclic alkyl groups, C 5-6 Arylalkyl, wherein r is arbitrarily selected from 0, 1, 2 or 3, wherein the 3-6 membered heterocyclic alkyl, C 5-6 Arylalkyl groups are optionally surrounded by one or more C 1-3 Alkyl or C 1-3 Alkyl substitution;

[0101] R3 and R4 are each independently selected from H, halogens, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6cycloalkyl;

[0102] Alternatively, R3 and R4 are cyclized to form a 5-6 membered heteroaryl group; the 5-6 membered heteroaryl group is pyrroleyl, furanyl, thiophenyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazoleyl, triazolyl, phenyl, pyrimidinyl, pyridinyl, pyrazinyl or pyridazinyl.

[0103] R5 is selected from -C(=O)NR b R c -P(=O)R b R c -P(=S)R b R c -S(=O)2NR b R c R b S(=O)2NR c -、-NR b C(O)R c ;

[0104] R b R c R d Each independently selected from H and C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl;

[0105] Or, R b R c The atoms connected to it are cyclic to unsubstituted or optionally cyclic by one or more C atoms. 1-3 Alkyl or C 1-3 Alkoxy-substituted 5-6 membered heterocyclic alkyl groups;

[0106] Alternatively, R5 and R6 can be cyclized to form a compound containing -P(=O)(R b )-、-P(=S)(R b )-、-N(R b )S(=O)2-、-S(=O)2N(R b )- or -S(=O)2 4-7 member ring;

[0107] R6, R7, and R8 are each independently selected from H, halogens, and C. 1-3 alkyl;

[0108] Alternatively, R8 is selected from H, and R6 and R7 are cyclized to form a 5-6 member heteroaryl group; the 5-6 member heteroaryl group is pyrroleyl, furanyl, thiophenyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazoleyl, triazolyl, phenyl, pyrimidinyl, pyridinyl, pyrazinyl or pyridazinyl.

[0109] In the compounds of formulas (I”'), (I”), (I’), and (I) of the present invention, R1 is selected from H, halogen, -CN, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy group; preferably, the R1 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, trifluoromethyl, trifluoromethoxy, trichloromethyl, trichloromethoxy, 2,2,2-trifluoroethoxy; more preferably, the R1 is selected from methoxy group.

[0110] In the compounds of formula (I”'), formula (I”), formula (I’), and formula (I) of the present invention, M is selected from N or CH, preferably, M is selected from CH.

[0111] In the compounds of formula (I”'), formula (I”), formula (I’), and formula (I) of the present invention, R2 is selected from H, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, -CH2CH2N(CH3)CH3,

[0112] In the compounds of formula (I”'), formula (I”), formula (I’), and formula (I) of the present invention, R2 is selected from H, methyl, ethyl, isopropyl, difluoromethyl, and trifluoromethyl; preferably, R2 is selected from methyl.

[0113] In the compounds of formula (I”'), formula (I”), formula (I’), and formula (I) of the present invention, R3 and R4 are each independently selected from H, F, Cl, Br, CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and cyclopropyl; preferably, R3 and R4 are each independently selected from H, F, Cl, Br, methyl, difluoromethyl, trifluoromethyl, and cyclopropyl; preferably, R3 is selected from H, and R4 is selected from Cl, Br, methyl, and trifluoromethyl.

[0114] In the compounds of formula (I”'), formula (I”), formula (I’), and formula (I) of the present invention, R3 is selected from H, and R4 is selected from H, F, Cl, Br, methyl, ethyl, difluoromethyl, trifluoromethyl, and cyclopropyl.

[0115] In the compounds of formula (I”'), formula (I”), formula (I’), and formula (I) of the present invention, R3 is selected from H, and R4 is selected from Cl, Br, and methyl.

[0116] In the compounds of formula (I”'), formula (I”), formula (I’), and formula (I) of the present invention, R3 is selected from H and R4 is selected from Br.

[0117] In the compounds of formulas (I”'), (I”), (I’), and (I) of the present invention, R3 and R4 are cyclized into thiophene and pyrrole rings, respectively, wherein the thiophene and pyrrole rings may optionally be converted by C 1-4 Alkyl groups are substituted.

[0118] In the compounds of formulas (I”'), (I”), (I’), and (I) of the present invention, R5 is selected from...

[0119] In the compounds of formulas (I”'), (I”), (I’), and (I) of the present invention, R5 is selected from...

[0120] In the compounds of formulas (I”'), (I”), (I’), and (I) of the present invention, R5 is selected from...

[0121] Preferably, R5 is selected from

[0122] Preferably, the R5 is selected from

[0123] In the compounds of formulas (I”'), (I”), (I’), and (I) of the present invention, R5 and R6 are cyclized into

[0124] In the compounds of formula (I”'), formula (I”), formula (I’), and formula (I) of the present invention, R6, R7, and R8 are each independently selected from H, methyl, or halogen; preferably, they are each independently selected from H or methyl.

[0125] In the compounds of formula (I”'), formula (I”), formula (I’), and formula (I) of the present invention, R6, R7, and R8 are selected from H.

[0126] In the compounds of formula (I”'), formula (I”), formula (I’), and formula (I) of the present invention, R6 and R8 are selected from H, and R7 is selected from F.

[0127] In the compounds of formula (I”'), formula (I”), formula (I’), and formula (I) of the present invention, R6 and R7 or R7 and R8 are independently cyclized into cyclobutane, cyclopentane, tetrahydropyrrole ring, tetrahydrofuran ring, tetrahydropyrrole ring, thiophene ring, imidazole ring, pyrazole ring, pyrrole ring, oxazole ring, thiazole ring, isoxazole ring, piperazine ring, isothiazine ring, benzene ring, pyridine ring, piperidine ring, pyrimidine ring, pyridazine ring, or pyrazine ring; preferably, R6 and R7 or R7 and R8 are independently cyclized into cyclobutane, pyridine ring, or pyrazine ring; more preferably, R6 and R7 are independently cyclized into pyrazine ring.

[0128] In the compounds of formulas (I”'), (I”), (I’), and (I) of the present invention, the structural unit Selected from R1, M, and R2 are as defined above; the above R x Selected from H, -OH, -CN, -NH2, halogens, C 1-6 alkyl carbonyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 cycloalkyl-C 1-6 Alkyl-, 3-8 membered heterocyclic alkyl-C 1-6 Alkyl-, aryl-C 1-6 Alkyl-, C 5-13 Spirocyclic groups, 5-13 corpuscular spiroheterocyclic groups; wherein the C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 cycloalkyl-C 1-6 Alkyl-, 3-8 membered heterocyclic alkyl-C 1-6 Alkyl-, aryl-C 1-6 Alkyl-, C 5-13 Spirocyclic groups, 5-13 spirocyclic groups, or spiroheterocyclic groups are optionally denoted by one or more R groups. y Replaced; the R y Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, C 3-8 cycloalkyl-C 1-6 Alkyl-, 4-8 membered heterocyclic alkyl-C 1-6 Alkyl-, 5-10 aryl, 5-10 heteroaryl.

[0129] When R x When directly bonded to a N atom, R x It is not -OH, -NH2, or halogen.

[0130] In the compounds of formulas (I”’), (I”), (I’), and (I) of the present invention, R x Selected from H, -OH, -CN, -NH2, halogens, C 1-6 alkyl carbonyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 cycloalkyl-C 1-6 Alkyl-, 3-8 membered heterocyclic alkyl-C 1-6 alkyl-; wherein the C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 cycloalkyl-C 1-6 Alkyl-, 3-8 membered heterocyclic alkyl-C 1-6 Alkyl-, aryl-C 1-6 Alkyl-optionally surrounded by one or more R y Replaced; the R y Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclic alkyl, C 3-8 cycloalkyl-C 1-6 Alkyl-, 4-8 membered heterocyclic alkyl-C 1-6 Alkyl-, 5-10 aryl, 5-10 heteroaryl.

[0131] In the compounds of formulas (I”’), (I”), (I’), and (I) of the present invention, R x Selected from H, -OH, -CN, -NH2, halogens, C 1-6 alkyl carbonyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-4 Alkyl-, 3-6 membered heterocyclic alkyl-C 1-4 Alkyl-, aryl-C 1-6 Alkyl-, 7-11 membered spiroheterocyclic group, wherein the C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-4 Alkyl-, 3-6 membered heterocyclic alkyl-C 1-4 Alkyl-, aryl-C 1-6 Alkyl- or spiroheterocyclic groups optionally surrounded by one or more R y Replaced; the R ySelected from H, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl-C 1-6 Alkyl-; preferably, R y Selected from H, F, methyl, ethyl, isopropyl, methoxy, FCH2CH2-.

[0132] In the compounds of formulas (I”’), (I”), (I’), and (I) of the present invention, R x Selected from H, -OH, -CN, -NH2, F, methyl, ethyl, isopropyl, trifluoroethyl, methyl carbonyl, Ring C is a 4-8 membered heterocyclic alkyl group, and ring D is an oxygen-containing 4-8 membered heterocyclic alkyl group; m and n are independently 0, 1, 2, or 3; R y As defined above.

[0133] In the compounds of formulas (I”’), (I”), (I’), and (I) of the present invention, R x Selected from H, -OH, -CN, -NH2, methyl, ethyl, isopropyl, methyl carbonyl, The ring C is a 4-8 membered heterocyclic alkyl group; m and n are independently 0, 1, 2 or 3.

[0134] In the compounds of formulas (I”’), (I”), (I’), and (I) of the present invention, R x Selected from H, -OH, -CN, -NH2, F, methyl, ethyl, isopropyl, trifluoroethyl, methyl carbonyl,

[0135] In the compounds of formulas (I”’), (I”), (I’), and (I) of the present invention, R x Selected from H, methyl, ethyl, isopropyl,

[0136] In the compounds of formulas (I”’), (I”), (I’), and (I) of the present invention, R x Selected from H, methyl, ethyl, isopropyl,

[0137] In the compounds of formulas (I”’), (I”), (I’), and (I) of the present invention, R xSelected from H, methyl, ethyl or isopropyl.

[0138] In the compounds of formulas (I”’), (I”), (I’), and (I) of the present invention, R x Selected from methyl or isopropyl.

[0139] In the compounds of formulas (I”'), (I”), (I’), and (I) of the present invention, the structural unit Selected from R1, M, R x R2 is as defined above.

[0140] In the compounds of formulas (I”'), (I”), (I’), and (I) of the present invention, the structural unit Selected from R1, M, R x As defined above.

[0141] In the compounds of formulas (I”'), (I”), (I’), and (I) of the present invention, the structural unit Selected from R1, M, R x R b R c R2 is as defined above.

[0142] Preferably, structural unit Selected from Among them, M, R1, R2, R x As defined above.

[0143] Preferably, the above-mentioned compound, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically labeled derivatives, are selected from...

[0144]

[0145] in,

[0146] X and Y are each independently selected from -C(=O)-, -C=C-, and -NR-. x -、-O-、-CR9R 10 -、-S(=O)-、-S(=O)2-;

[0147] X1 and X2 are each independently selected from N and NR2;

[0148] R9, R 10 Selected independently from H, halogens, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl;

[0149] R1, R2, R4, R5, R6, R7, R x M is as defined above.

[0150] Preferably, the above-mentioned compound, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically labeled derivatives, are selected from...

[0151]

[0152] in,

[0153] X and Y are each independently selected from -C(=O)- and -NR-, respectively. x -、-O-、-CR9R 10 -、-S(=O)-、-S(=O)2-;

[0154] X1 and X2 are each independently selected from N and NR2;

[0155] R9, R 10 Selected independently from H, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl;

[0156] R1, R2, R4, R5, R6, R7, R x As defined above.

[0157] Preferably, the above-mentioned compound, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically labeled derivatives, are selected from...

[0158]

[0159] Among them, R1, R2, R4, R5, R6, R7, R x M is as defined above.

[0160] Preferably, the above-mentioned compound, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically labeled derivatives, are selected from...

[0161]

[0162] Among them, R1, R2, R4, R5, R6, R7, R x As defined above.

[0163] More preferably, the above-mentioned compound, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically labeled derivatives, are selected from...

[0164]

[0165] Among them, R1, R2, R4, R5, R x M is as defined above.

[0166] More preferably, the above-mentioned compound, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically labeled derivatives, are selected from...

[0167]

[0168] Among them, R1, R2, R4, R5, R x As defined above.

[0169] More preferably, the above-mentioned compound, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically labeled derivatives, are selected from...

[0170]

[0171] Among them, R4, R5, R x M is as defined above.

[0172] More preferably, the above-mentioned compound, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically labeled derivatives, are selected from...

[0173]

[0174] Among them, R4, R5, R x As defined above.

[0175] More preferably, the above-mentioned compound, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically labeled derivatives, are selected from...

[0176]

[0177] Among them, R5, R x As defined above.

[0178] In some embodiments of the present invention, the compound of formula (I”’) above, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically labeled derivatives, are selected from (I”’-A).

[0179]

[0180] R1, M, R3, R4, R5, R8, ring A, Z, and Z1 are defined as above.

[0181] In some embodiments of the present invention, the compound of formula (I”’) above, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically labeled derivatives, are selected from (I”’-B).

[0182]

[0183] R1, M, R3, R4, R5, R8, ring A, ring B, Z, and Z1 are as defined above;

[0184] R w R z Each is independently selected from H, -OH, -CN, -NH2, halogens, and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclic alkyloxy, C 2-6 alkenyloxy group, C 2-6 alkynyloxy group, C 1-6 Alkylamino, C 1-6 Halogenated alkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocyclic alkylamino, C 2-6 alkenylamino and C 2-6 Entylamino.

[0185] Most preferably, the compound or its stereoisomers, tautomers, or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically labeled derivatives, including but not limited to:

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, and excipient. The pharmaceutical compositions provided by the present invention can be formulated for specific routes of administration, such as oral, parenteral, and rectal administration. Oral administration includes, for example, tablets, capsules (including sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersants), syrups, and emulsions; sublingual administration; sublingual administration; parenteral administration, for example, by subcutaneous, intravenous, intramuscular, or intrasternal injection, or by infusion techniques (e.g., as a sterile injectable aqueous or non-aqueous solution or suspension); nasal administration, including administration to the nasal mucosa, for example, by inhalation spray; topical administration, for example, in the form of creams or ointments; or rectal administration, for example, in the form of suppositories. They can be administered alone, but are usually administered with a pharmaceutical carrier selected according to the chosen route of administration and standard pharmaceutical practices.

[0197] "Pharmaceutically acceptable carriers" refers to media generally acceptable in the art for delivering bioactive pharmaceutical agents to animals, particularly mammals, including, depending on the route of administration and dosage form, adjuvants, excipients, or excipients such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispersants. Pharmaceutically acceptable carriers are formulated based on a multitude of factors, within the scope of those skilled in the art. These include, but are not limited to, the type and nature of the formulated active pharmaceutical agent, the target population to which the composition containing the pharmaceutical agent is to be administered, the intended route of administration of the composition, and the target therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media, as well as various solid and semi-solid dosage forms. In addition to the active pharmaceutical agent, such carriers include many different components and additives, and such additional components included in the formulation for various reasons (e.g., stabilizing active pharmaceutical agents, binders, etc.) are well known to those skilled in the art.

[0198] As a general guideline, when used to indicate specific effects, the daily oral dose of each active ingredient is in the range of about 0.001-5000 mg per day, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of the active ingredient; the most preferred intravenous dose during constant-rate infusion is in the range of about 0.01-10 mg / kg / min. The compounds of the present invention can be administered as a single daily dose, or the total daily dose can be administered in divided doses 2, 3, or 4 times daily.

[0199] The dosing regimen for the compounds used in this invention can, of course, be modified based on known factors, such as the pharmacodynamic characteristics of the specific agent and its mode and route of administration, the recipient's species, age, sex, health, medical condition and weight, the nature and severity of symptoms, the types of coexisting treatments, the frequency of treatment, the route of administration, the patient's renal and hepatic function, and the desired effect. The therapeutically effective dose of the compound, pharmaceutical composition, or combination thereof depends on the species, weight, age and individual circumstances of the recipient, the condition or disease being treated, or its severity. Physicians, clinicians, or veterinarians with ordinary skills can readily determine the effective amount of each active ingredient required to prevent, treat, or inhibit the progression of a condition or disease.

[0200] The present invention also provides the use of the above-described compounds or pharmaceutically acceptable salts thereof or the above-described pharmaceutical compositions in the preparation of medicaments for treating cancer.

[0201] Epidermal growth factor receptor (EGFR) is widely distributed on the surface of mammalian epithelial cells, fibroblasts, glial cells, and other cells. The EGFR signaling pathway plays a crucial role in physiological processes such as cell growth, proliferation, and differentiation. EGFR mutation is also one of the most common mutation types in NSCLC patients, especially in Asian populations, accounting for 40%–50%. Therefore, in some treatment regimens, the compounds of this invention can be used to treat cancers caused by high EGFR expression. These cancers include lymphoma, non-Hodgkin's lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, leukemia, gastric cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), cholangiocarcinoma, renal cancer, thyroid cancer, anaplastic large cell lymphoma, mesothelioma, multiple myeloma, and melanoma.

[0202] The present invention also provides a method for treating cancer, comprising administering to a patient a therapeutically effective amount of a compound of formula (I”'), formula (I”), formula (I’), or formula (I) above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. The cancers mentioned above include lymphoma, non-Hodgkin's lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, leukemia, gastric cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), cholangiocarcinoma, renal cancer, thyroid cancer, anaplastic large cell lymphoma, mesothelioma, multiple myeloma, and melanoma.

[0203] The compounds of formula (I”'), formula (I”), formula (I’) or formula (I) provided by the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, are used to treat cancers including lymphoma, non-Hodgkin's lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, leukemia, gastric cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), cholangiocarcinoma, renal cancer, thyroid cancer, anaplastic large cell lymphoma, mesothelioma, multiple myeloma, and melanoma.

[0204] In some embodiments of the present invention, the aforementioned cancer is lung cancer.

[0205] The present invention also provides an intermediate compound of formula (V), the intermediate compound or a pharmaceutically acceptable salt thereof, selected from:

[0206]

[0207] Among them, R 11 It can be -NH2 or -NO2;

[0208] Structural unit As defined above;

[0209] Further preferably, the intermediate compound represented by formula (V), or a pharmaceutically acceptable salt thereof, is selected from...

[0210]

[0211] Among them, R1, R2, R 11 R x As defined above.

[0212] Further preferred are intermediate compounds represented by formula (V), the intermediate compound or a pharmaceutically acceptable salt thereof, selected from...

[0213]

[0214] Among them, R 11 R x As defined above.

[0215] Technical effect

[0216] The compounds of this invention exhibit good inhibitory activity against EGFR (L858R / T790M / C797S) kinase, but weak inhibitory activity against wild-type EGFR kinase, indicating that the compounds of this invention have good kinase activity and selectivity.

[0217] The compounds of this invention exhibit strong inhibitory effects on the cell proliferation of the Ba / F3 Del19 / T790M / C797S EGFR triple mutant cell lines and the Ba / F3 L858R / T790M / C797S EGFR triple mutant cell line; however, they show weaker inhibitory effects on the EGFR wild-type cell line A431, indicating that the compounds of this invention possess excellent cell activity and selectivity. Attached Figure Description

[0218] Figure 1 shows the tumor growth curves of each group of animals in the in vivo drug efficacy study (mm). 3 ).

[0219] Figure 2 shows the weight curves (g) of animals in each group during the in vivo drug efficacy study.

[0220] Explanation and Definition

[0221] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense.

[0222] The term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0223] The term "pharmaceutically acceptable salt" refers to derivatives obtained by preparing compounds of the present invention with relatively non-toxic acids or bases. These salts can be prepared during the synthesis, isolation, and purification of the compounds, or by reacting the purified free form of the compounds with suitable acids or bases. When the compounds contain relatively acidic functional groups, they react with alkali metal, alkaline earth metal hydroxides, or organic amines to yield base addition salts, including alkali metal and alkaline earth metal-based cations such as sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations. When the compounds contain relatively basic functional groups, they react with organic or inorganic acids to yield acid addition salts.

[0224] The compounds provided by this invention also include prodrug forms, representing compounds that are rapidly converted in vivo to the parent compound of the above formula, and are converted to the compounds of this invention by chemical or biochemical methods in vivo or in vitro environments, such as by hydrolysis in the blood.

[0225] The compounds of this invention can exist in both unsolvated and solvated forms, with solvation including hydrate forms. Generally, the solvated form is equivalent to the unsolvated form and is also covered within the scope of this invention.

[0226] The compounds of the present invention exist as geometric isomers and stereoisomers, such as cis-trans isomers, enantiomers, diastereomers, racemic mixtures thereof, and other mixtures, all of which are within the scope of the present invention.

[0227] The term "enantiomer" refers to stereoisomers that are mirror images of each other.

[0228] The term "diastereomer" refers to a stereoisomer of a molecule that has two or more chiral centers and is not a mirror image of the molecule.

[0229] The term "cis-trans isomer" refers to the configuration in which the double bonds or single bonds of cyclic carbon atoms in a molecule cannot rotate freely.

[0230] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid.

[0231] This indicates that the carbon atom is a chiral carbon atom, and the structure represents optically pure compounds and mixtures thereof with a (R) or (S) configuration of the carbon atom.

[0232] The stereoisomers of the compounds of this invention can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. For example, an enantiomer of a compound of this invention can be prepared by asymmetric catalysis or chiral derivative derivatization. Alternatively, a single stereoisomer can be obtained from a mixture using chiral resolution techniques. Alternatively, it can be prepared directly from chiral starting materials. The separation of optically pure compounds in this invention is typically accomplished using preparative chromatography, employing chiral chromatographic columns to achieve the separation of chiral compounds.

[0233] The terms "optically pure" or "enantiomer enrichment" refer to the content of the isomer or enantiomer being greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0234] The absolute stereoconfiguration of a compound can be confirmed using conventional techniques in the art. For example, single-crystal X-ray diffraction can be used, or the chiral structure of the starting material and the reaction mechanism of asymmetric synthesis can be used to confirm the absolute configuration of the compound. Compounds marked "absolute configuration not determined" in this article are usually racemic compounds resolved into single isomers by chiral preparative HPLC or SFC, and then characterized and tested.

[0235] For example, the following formula represents compounds 117A and 117B as enantiomers derived from compound 84, but the absolute stereoconfigurations of 117A and 117B have not been determined.

[0236]

[0237] This invention also includes isotope-labeled compounds, including isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes are all within the scope of the present invention.

[0238] The term "pharmaceutically acceptable carrier" refers to a medium generally acceptable in the art for delivering a bioactive pharmaceutical agent to animals, particularly mammals. Depending on the route of administration and dosage form, this includes, for example, adjuvants, excipients, or excipients such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispersants. Pharmaceutically acceptable carriers are formulated based on a multitude of factors, within the scope of those skilled in the art. These include, but are not limited to, the type and nature of the formulated active pharmaceutical agent, the recipient to whom the composition containing the pharmaceutical agent is to be administered, the intended route of administration of the composition, and the target therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media, as well as various solid and semi-solid dosage forms. In addition to the active pharmaceutical agent, such carriers include many different components and additives, and the inclusion of such additional components in the formulation for various reasons (e.g., stabilizing active pharmaceutical agents, binders, etc.) is well known to those skilled in the art.

[0239] The term "excipient" generally refers to the carrier, diluent, and / or medium required to formulate an effective pharmaceutical composition.

[0240] The term "effective preventive or therapeutic dose" refers to a sufficient amount of the compound of the present invention or a pharmaceutically acceptable salt thereof for any medical treatment and / or prevention that has a reasonable effect / risk ratio for treating the disorder. However, it should be understood that the total daily dose of the compound of Formula I of the present invention or its pharmaceutically acceptable salt and composition must be determined by the attending physician within the bounds of reliable medical judgment. For any given patient, the specific effective therapeutic dose level must be determined based on a number of factors, including the disorder being treated and its severity; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health condition, sex, and diet; the timing, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors known in the medical field. For example, it is practiced in the art to start the dose of the compound below the level required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. Generally speaking, the dosage of the compound of Formula I of the present invention or its pharmaceutically acceptable salt for use in mammals, particularly humans, can be between about 0.001 and 1000 mg / kg body weight / day, for example between about 0.01 and 100 mg / kg body weight / day, for example between about 0.01 and 10 mg / kg body weight / day.

[0241] The term “optionally substituted” means that it may or may not be substituted, unless otherwise specified. The type and number of substituents may be arbitrary on the basis of chemical feasibility. For example, the term “optionally substituted by one or more R2s” means that it may or may not be substituted by one or more R2s.

[0242] When any variable (e.g., R2) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is substituted by 0-2 R2s, the group can optionally be substituted by at most two R2s, and R2 has independent options in each case.

[0243] When the number of a linking group is 0, for example, -O(CH2) n CH3, n=0 indicates that the linking group is a single bond, i.e., -OCH3.

[0244] When a substituent's bond can be cross-linked to two atoms on a ring, this substituent can bond to any atom on that ring. For example, structural units. This indicates that the substituent R1 can be substituted at any position on the benzene ring.

[0245] When the listed substituents do not specify which atom they are attached to in a compound included but not specifically mentioned in the general chemical formula, such substituents can be bonded to any of their atoms. For example, pyrazole as a substituent means that any carbon atom on the pyrazole ring is attached to the substituted group; when the structure contains... or When, it indicates that the atom is a bonding atom, for example and Both indicate that the N atom on the morpholine ring is a bonding atom.

[0246] Unless otherwise specified, "ring" refers to a saturated, partially saturated, or unsaturated monocyclic or polycyclic ring, including fused, spirocyclic, fused, or bridged rings. Representative "rings" include substituted or unsubstituted cycloalkyl, heterocyclic alkyl, cycloalkenyl, heterocyclic alkenyl, cycloalkynyl, heterocyclic alkynyl, aryl, or heteroaryl groups. The term "hetero" refers to the substituted or unsubstituted heteroatom and its oxidation form, which is generally selected from N, O, and S, and the oxidation form generally includes NO, SO, and S(O)2. The nitrogen atom may be substituted, i.e., NR (R is H or another substituent defined herein). The number of atoms on the ring is usually defined as the ring number; for example, "3-6 membered heterocyclic alkyl" refers to a ring consisting of 3-6 atoms arranged in a ring, each ring optionally containing 1-3 heteroatoms, i.e., N, O, S, NO, SO, S(O)2, or NR, each ring optionally substituted by an R group, R being a group defined herein.

[0247] Unless otherwise specified, the terms "carbocyclic" or "carbocyclic group" refer to stable cyclic structures composed of carbon atoms, which can be monocyclic, bicyclic, or tricyclic, and can be saturated, partially unsaturated, or unsaturated (aromatic). Any of these carbon rings can fused to one or more aromatic rings or heterocyclic rings to form bicyclic, tricyclic, or other polycyclic structures. For example, structural units... In this context, ring A can be a 5-8 membered carbon cyclic group, examples of which include, but are not limited to, 5-8 membered carbon cyclic groups. R1, R2, R x M is a group defined in the text.

[0248] Unless otherwise specified, the term "heterocycle" or "heterocyclic group" means a stable monocyclic, bicyclic, or tricyclic ring containing a heteroatom or heteroatomic group. These rings can be saturated, partially unsaturated, or unsaturated (aromatic), and contain a carbon atom and one, two, or three cyclic heteroatoms independently selected from N, O, S, NO, SO, S(O)₂, or NR. Any of these heterocycles can fused to one or more aromatic rings or aromatic heterocycles to form bicyclic, tricyclic, or other polycyclic rings. For example, structural units... In this context, ring A can be a 5-8 membered heterocyclic group, examples of which include, but are not limited to, […]. R1, R2, R x M is a group defined in the text.

[0249] Unless otherwise specified, the term "aryl" refers to an unsaturated, usually aromatic, hydrocarbon group, which can be a monocyclic or fused rings. C is preferred. 5-10 Aryl, more preferably C 5-8 Aryl, with the most preferred monocyclic C 5-6 Aryl; examples of aryl include, but are not limited to, phenyl and naphthyl.

[0250] Unless otherwise specified, the term "heteroaryl" refers to a stable monocyclic or polycyclic aromatic hydrocarbon containing at least one heteroatom (N, O, S, NO, SO, S(O)₂, or NR). Five- or six-membered monocyclic heteroaryls are preferred. Examples of heteroaryls include, but are not limited to, pyrrole, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thiophene, pyridinyl, and pyrimidinyl.

[0251] Unless otherwise specified, the term "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group. C is preferred. 1-6 Alkyl groups, more preferably C 1-3 Alkyl groups, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, n-hexyl, etc.

[0252] Unless otherwise specified, the term "heteroalkyl" means an alkyl group in which one or more carbon atoms are replaced by heteroatoms selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatoms are optionally quaternized, including but not limited to "alkoxy", "alkamino", and "alkthio"; examples of "heteroalkyl" include, but are not limited to, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -N(CH3)2, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -S(O)2-CH3, -CH2-CH2-S(O)2-CH3, etc.

[0253] Unless otherwise specified, "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds. Preferably C 2-8 Alkenyl groups, examples of which include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, etc.

[0254] Unless otherwise specified, "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds. C is preferred. 2-8 Alkynyl groups, examples of which include, but are not limited to, ethynyl, propynyl, butynyl, and penynyl.

[0255] Unless otherwise specified, the term "halogen" refers to a fluorine, chlorine, bromine, or iodine atom.

[0256] Unless otherwise specified, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms. C is preferred. 1-6 Halogenated alkyl, more preferably C 1-3Haloalkyl groups, examples of which include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, etc.

[0257] Unless otherwise specified, the term "alkoxy" refers to an alkyl group connected by an oxygen bridge, i.e., a group obtained by substituting a hydrogen atom in a hydroxyl group with an alkyl group. Preferably C 1-6 Alkoxy, more preferably C 1-3 Alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, neopentoxy, and n-hexyloxy.

[0258] Unless otherwise specified, the term "cycloalkyloxy" refers to a cycloalkyl group connected by an oxygen bridge, that is, a group obtained by substituting a hydrogen atom in a cycloalkyl group with a hydrogen atom. Cycloalkyloxy groups are preferably 3-7, 4-7, or 5-7 cycloalkoxy groups. Examples of cycloalkyloxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

[0259] Unless otherwise specified, the term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by halogen atoms. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, and 2,2,2-trichloroethoxy.

[0260] Unless otherwise specified, "cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon group. Cycloalkyl is preferably a 3-8 member monocyclic alkyl group, more preferably a 3-6 member monocyclic alkyl group, and examples of such monocyclic alkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0261] Unless otherwise specified, "heterocyclic alkyl" refers to mono- and poly-heterocyclic alkyl groups containing a certain number of heteroatoms in the ring, wherein the heteroatoms are generally selected from N, O, S, NO, SO, S(O)2, and NR. Heterocyclic alkyl groups are preferably 3- to 8-membered mono-heterocyclic alkyl groups, more preferably 3- to 6-membered mono-heterocyclic alkyl groups, and examples of such mono-heterocyclic alkyl groups include, but are not limited to, ethylene oxide, tetrahydropyrrolyl, piperidinyl, piperazine, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, 1,3-dioxolane, 1,4-dioxane, etc.

[0262] Unless otherwise specified, "spirocyclic group" refers to a bicyclic or polycyclic hydrocarbon group in which two monocyclic rings share a carbon atom. Spirocyclic groups are preferably 5-13 membered spirocyclic groups, 6-12 membered spirocyclic groups, or 7-11 membered spirocyclic groups. The 6-12 membered spirocyclic group refers to a hydrocarbon group whose spirocyclic skeleton structure consists of 6-12 atoms. Examples of spirocyclic groups include, but are not limited to, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, spiro[2.6]nonyl, spiro[3.3]heptyl, spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[4.6]undecyl, spiro[5.5]undecyl, spiro[5.6]dodecyl, spiro[6.6]tridecyl, and spiro[6.7]tetradecyl.

[0263] Unless otherwise specified, "spiroheterocyclic group" refers to a spirocyclic group in which one or more carbon atoms in the spirocyclic skeleton are replaced by heteroatoms selected from N, O, and S. Spiroheterocyclic groups are preferably 5-13 membered spiroheterocyclic groups, 6-12 membered spiroheterocyclic groups, or 7-11 membered spiroheterocyclic groups. Examples of spirocyclic groups include, but are not limited to, 2-oxa-7-azaspiro[5.3]nonane-7-yl, 2-oxa-7-azaspiro[4.4]nonane-7-yl, 2-oxa-6-azaspiro[3.3]heptane-6-yl, 2-oxa-8-azaspiro[4.5]decane-8-yl, 1,4,9-triazaspiro[5.5]undecane-9-yl, 3-oxa-9-azaspiro[5.5]undecane-9-yl, 2,6-diazaspiro[3.3]heptane-2-yl, 2,7-diazaspiro[5.3]nonane-7-yl, 2,7-dioxaspiro[5.3]nonyl, and 3,9-diazaspiro[5.5]. Undecane-3-yl, 1-oxa-4,9-diazaspiro[5.5] Undecane-9-yl, 1-oxa-4,8-diazaspiro[5.4] Decane-8-yl, 3-azaspiro[5.5] Undecane-3-yl, 7-azaspiro[3.5] Decane-7-yl, 1-oxa-4,9-diazaspiro[5.5] Undecane-4-yl, 6-oxa-2,9-diazaspiro[4.5] Decane-9-yl, 9-oxa-2,6-diazaspiro[4.5] Decane-6-yl, 3-azaspiro[5.5] Undecane-3-yl, 4-oxa-1,9-diazaspiro[5.5] Undecane-9-yl.

[0264] The term "containing P(=O)R" b "4-7 member ring" refers to a ring with The structural group, n is 0, 1, 2 or 3; R b The group defined in the text contains -P (=S)(R) b )-、-N(R b )S(=O)2-、-S(=O)2N(Rb The 4-7 membered rings of -S(=O)2 represent respectively The structure is given by R, where n is 0, 1, 2, or 3. b This refers to the functional group defined in the text.

[0265] In particular, all combinations of substituents and / or their variants are permitted only if such combinations produce stable compounds.

[0266] In this embodiment of the invention, the title compound was named using Chemdraw to convert the compound structure. If there is a discrepancy between the compound name and the compound structure, the name can be determined by combining relevant information and reaction routes; if it cannot be confirmed by other means, the given compound structure shall prevail.

[0267] The preparation methods for some compounds in this invention reference the preparation methods for the aforementioned similar compounds. Those skilled in the art should understand that when using or referring to the referenced preparation methods, the reactant ratios, reaction solvents, reaction temperatures, etc., can be appropriately adjusted according to the different reactants.

[0268] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0269] The abbreviations and their corresponding chemical names used in the embodiments of this invention are as follows:

[0270]

[0271] Detailed Implementation

[0272] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE III HD 400 or Bruker AVANCE III HD 300 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0273] The determinations were performed using LC-MS with an electrospray ionization (ESI) source. The determinations were performed using a SHIMADZU LC-20AP. XR And SPD-M20A high-performance liquid chromatography.

[0274] Thin-layer chromatography uses Yantai Xinnuo Chemical GF254 silica gel plates. The TLC size is 0.15mm to 0.20mm. Column chromatography generally uses 200-300 mesh silica gel from Chenghua Chemical as the carrier.

[0275] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0276] Example 1:

[0277] Preparation of intermediate 1A

[0278]

[0279] Compound 1A-1:

[0280] 3-Fluoro-4-bromoanisole (20 g, 98 mmol) was dissolved in concentrated sulfuric acid (80 mL) at 0 °C. Potassium nitrate (9.86 g, 98 mmol) was then added in portions to the reaction mixture, and stirring continued at this temperature for 30 minutes. After TLC monitoring showed the starting material had disappeared, the reaction mixture was slowly poured into ice water (500 g) to quench the reaction. The mixture was extracted with ethyl acetate (200 mL × 3 times), and the organic phases were combined. The organic phases were washed with saturated brine (200 mL × 3 times), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give 11.2 g of compound 1A-1.

[0281] 1 H NMR (300MHz, CDCl3) δ8.19 (d, J = 7.2 Hz, 1H), 6.91 (d, J = 9.9 Hz, 1H), 3.99 (s, 3H).

[0282] Intermediate 1A:

[0283] Compound 1A-1 (3 g, 12 mmol) was dissolved in 1,4-dioxane (20 mL) at room temperature and under a nitrogen atmosphere. Then, bis(diphenylphosphino)-boronate (3.3 g, 13 mmol), potassium acetate (2.4 g, 24 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.88 g, 1.2 mmol) were added sequentially to the reaction mixture. The reaction mixture was heated to 80 °C and stirred for 16 hours. After the starting material disappeared under TLC monitoring, the reaction mixture was cooled to room temperature and quenched with water (100 mL). The mixture was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (100 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give 1.5 g of compound 1A.

[0284] 1 H NMR (300MHz, CDCl3) δ8.36 (d, J = 6.0 Hz, 1H), 6.76 (d, J = 10.5 Hz, 1H), 4.00 (s, 3H), 1.37 (s, 12H).

[0285] Preparation of intermediate 1B

[0286]

[0287] Compound 1B-1:

[0288] 6-Aminoquinoxaline (59 g, 406.4 mmol) was dissolved in N,N-dimethylformamide (600 mL), and N-iodosuccinimide (100.6 g, 447.1 mmol) was added in portions at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the starting material disappeared as monitored by LCMS, water (3000 mL) was added to quench the reaction mixture. The mixture was extracted with ethyl acetate (1000 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (500 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2) to give 50 g of compound 1B-1.

[0289] MS(ESI)M / Z:272.0[M+H] + .

[0290] Compound 1B-2:

[0291] Compound 1B-1 (40 g, 147.6 mmol) was dissolved in N,N-dimethylformamide (400 mL) at room temperature and under nitrogen atmosphere. Then, dimethylphosphine oxide (17.3 g, 221.4 mmol), palladium acetate (3.3 g, 14.7 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (12.8 g, 22.1 mmol), and N,N-diisopropylethylamine (38.1 g, 295.1 mmol) were added sequentially to the reaction mixture. The reaction mixture was heated to 120 °C and stirred for 16 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethanol (100 mL × 3 times). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 30 g of compound 1B-2.

[0292] MS(ESI)M / Z:222.0[M+H] + .

[0293] Intermediate 1B:

[0294] Compound 1B-2 (5 g, 22.6 mmol) was dissolved in N,N-dimethylformamide (100 mL) at room temperature and under nitrogen protection. Sodium hydride (60%, 1.99 g, 49.8 mmol) was then added in portions to the reaction mixture at 0 °C, and stirring was continued at this temperature for 30 minutes. Then, 2,4-dichloro-5-bromopyrimidine (6.18 g, 27.1 mmol) was added to the reaction mixture at 0 °C, and the mixture was brought to room temperature and stirred for 2 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with a saturated ammonium chloride aqueous solution (600 mL). The mixture was extracted with ethyl acetate (200 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (500 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give 3 g of compound 1B.

[0295] Preparation of intermediate 1C

[0296]

[0297] Compound 1C-1:

[0298] Triethyl phosphoroacetate (61.1 g, 273 mmol) was dissolved in tetrahydrofuran (120 mL). Then, under a nitrogen atmosphere and at 0 °C, sodium hydride (60%, 10.9 g, 273 mmol) was added to the reaction solution, and stirring was continued at this temperature for 30 minutes. A tetrahydrofuran solution of 1-methyl-1H-pyrazole-5-carboxaldehyde (20 g, 182 mmol) was added to the reaction solution. The reaction system was brought to room temperature and stirred for 1.5 hours. After LCMS monitoring showed the disappearance of the starting material, a saturated ammonium chloride aqueous solution (100 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (300 mL × 3 times), the organic phases were combined, washed with saturated brine (100 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 33 g of compound 1C-1.

[0299] MS(ESI)M / Z:181.2[M+H] + .

[0300] Compound 1C-2:

[0301] Compound 1C-1 (33 g, 183.1 mmol) was dissolved in ethanol (500 mL). Wet palladium on carbon (10%, 6.6 g) was added to the reaction mixture. After purging the reaction system three times with hydrogen, the mixture was stirred at room temperature for 1 hour. After LCMS monitoring showed the starting material had disappeared, the reaction mixture was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate (30 mL × 3 times), and the resulting filtrate was concentrated under reduced pressure to give 33 g of compound 1C-2.

[0302] MS(ESI)M / Z:183.1[M+H] + .

[0303] Compound 1C-3:

[0304] Compound 1C-2 (32 g, 175.6 mmol) was dissolved in ethanol (320 mL). Then, sodium hydroxide (1 N, 352 mL) was added to the reaction mixture. The reaction system was heated to 70 °C and stirred for 1 hour. After LCMS monitoring showed the starting material had disappeared, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the ethanol. The pH of the aqueous phase was adjusted to 3 with dilute hydrochloric acid (1 N) and washed with ethyl acetate (100 mL × 3 times). The organic phases were combined, washed with saturated brine (100 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 25 g of compound 1C-3.

[0305] MS(ESI)M / Z:155.1[M+H] + .

[0306] Compound 1C-4:

[0307] Under a nitrogen atmosphere, compound 1C-3 (5 g, 32.4 mmol) and diphenyl azide phosphate (DPPA, 9.8 g, 35.7 mmol) were dissolved in tert-butanol (80 mL). Triethylamine (13.1 g, 129.7 mmol) and di-tert-butyl dicarbonate (21.2 g, 97.3 mmol) were then added to the reaction mixture, and stirring was continued at room temperature for 1 hour. The reaction mixture was heated to 80 °C and stirred for 16 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate (100 mL). The mixture was extracted with ethyl acetate (200 mL × 3 times), and the organic phases were combined, washed with saturated brine (100 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 5.8 g of compound 1C-4.

[0308] MS(ESI)M / Z:226.1[M+H] + .

[0309] Compound 1C-5:

[0310] Compound 1C-4 (500 mg, 2.22 mmol) was dissolved in N,N-dimethylformamide (4 mL) at 0 °C under nitrogen atmosphere. Sodium hydride (60%, 69 mg, 1.7 mmol) was then added to the reaction mixture. The reaction mixture was stirred at 0 °C for 30 minutes. Iodomethane (329 mg, 2.3 mmol) was then added to the reaction mixture. The reaction mixture was brought to room temperature and stirred for 2 hours. After LCMS monitoring showed the starting material had disappeared, a saturated ammonium chloride aqueous solution (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (50 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1) to give 450 mg of compound 1C-5.

[0311] MS(ESI, m / z): 240.1 [M+H] + .

[0312] Compound 1C-6:

[0313] Compound 1C-5 (400 mg, 1.7 mmol) was dissolved in acetonitrile (2 mL). Then, N-iodosuccinimide (451 mg, 2.0 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was brought to room temperature and stirred for 2 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 600 mg of compound 1C-6.

[0314] MS(ESI,m / z):366.0[M+H] + .

[0315] Compound 1C-7:

[0316] Under a nitrogen atmosphere, compounds 1C-6 (664 mg, 1.8 mmol) and 1A (450 mg, 1.5 mmol) were dissolved in a mixed solvent of dioxane (6 mL) and water (1.2 mL). Subsequently, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (124 mg, 0.15 mmol) and sodium carbonate (321 mg, 3.0 mmol) were added to the reaction mixture. The reaction system was heated to 80 °C and stirred for 2 hours. After the starting material disappeared under LCMS monitoring, the reaction mixture was cooled to room temperature and quenched with water (20 mL). The mixture was extracted with ethyl acetate (30 mL × 3 times), the organic phases were combined, washed with saturated brine (30 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2) to give 440 mg of compound 1C-7.

[0317] MS(ESI)M / Z:409.2[M+H] + .

[0318] Compound 1C-8:

[0319] Compound 1C-7 (430 mg, 1.1 mmol) was dissolved in a dioxane solution (4 M, 4 mL) in hydrochloric acid and stirred at room temperature for 1 hour. After LCMS monitoring showed that the starting material had disappeared, the reaction solution was concentrated under reduced pressure to give 400 mg of compound 1C-8.

[0320] MS(ESI)M / Z:309.2[M+H] + .

[0321] Compound 1C-9:

[0322] Compound 1C-8 (100 mg, 0.3 mmol) and potassium carbonate (120 mg, 0.9 mmol) were dissolved in N,N-dimethylformamide (2 mL). The reaction mixture was heated to 100 °C and stirred for 1 hour. After the starting material disappeared as monitored by LCMS, the reaction solution was cooled to room temperature and purified directly using a reversed-phase C18 column. The purification conditions were as follows: 40 g C18 reversed-phase column; mobile phase: water (containing 10 mM ammonium bicarbonate) and acetonitrile; flow rate: 35 mL / min; gradient: acetonitrile from 40% to 80% over 30 minutes; detection wavelength: 254 nm. The product was collected, lyophilized under reduced pressure to obtain 50 mg of compound 1C-9.

[0323] MS(ESI)M / Z:289.2[M+H] + .

[0324] Intermediate 1C:

[0325] Compound 1C-9 (50 mg, 0.17 mmol) was dissolved in a mixed solvent of ethanol (1 mL) and water (0.2 mL). Then, iron powder (48 mg, 0.9 mmol) and ammonium chloride (14 mg, 0.26 mmol) were added to the reaction solution, and the reaction mixture was heated to 80 °C and stirred for 2 hours. After LCMS monitoring showed the starting material had disappeared, the reaction solution was cooled to room temperature and filtered. The filter cake was washed with ethanol (10 mL × 5 times), and the filtrate was concentrated under reduced pressure to obtain 50 mg of intermediate compound 1C.

[0326] MS(ESI)M / Z:259.2[M+H] + .

[0327] Preparation of Compound 1

[0328]

[0329] Compounds 1C (40 mg, 0.16 mmol) and 1B (64 mg, 0.16 mmol) were dissolved in N-methylpyrrolidone (2 mL). Then, methanesulfonic acid (45 mg, 0.47 mmol) was added to the reaction mixture. The reaction system was heated to 100 °C and stirred for 3 hours. After LCMS monitoring showed the starting material had disappeared, the reaction mixture was cooled to room temperature and purified by reversed-phase C18 column chromatography. Purification conditions: 40 g C18 reversed-phase column; mobile phase: water (containing 0.1% formic acid) and acetonitrile; flow rate: 35 mL / min; gradient: acetonitrile from 10% to 50% over 20 minutes; detection wavelength: 254 nm. The product was collected, lyophilized under reduced pressure to give 20 mg of compound 1.

[0330] MS(ESI, m / z): 634.2, 636.2 [M+H] + .

[0331] 1 H NMR(300MHz,CD3OD)δ8.82(d,J=2.1Hz,1H),8.76-8.67(m,2H),8.25(s,1H),8.09(s,1 H),7.52(d,J=9.6Hz,1H),6.89(s,1H),6.66(s,1H),3.92(s,3H),3.69(s,3H),3.30(br s, 2H), 3.06 (br s, 5H), 2.17 (d, J = 14.4Hz, 6H).

[0332] Example 2:

[0333]

[0334] Compound 2A:

[0335] 5-Bromo-2,4-dichloropyrimidine (2 g, 8.8 mmol) was dissolved in N,N-dimethylformamide (30 mL), followed by the addition of anhydrous potassium carbonate (3.64 g, 26.3 mmol) and 2-(dimethylphospho)aniline (1.48 g, 8.8 mmol). The reaction mixture was heated to 60 °C and stirred for 12 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and quenched with water (150 mL). The mixture was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (80 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 2.96 g of compound 2A.

[0336] MS(ESI)M / Z:360.0,362.0[M+H] + .

[0337] Compound 2:

[0338] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 2A (100 mg, 0.28 mmol) to prepare 13 mg of compound 2.

[0339] MS(ESI, m / z): 582.3, 584.3 [M+H] + .

[0340] 1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.38(s,1H),8.26(s,1H),8.16(s,1H),7.71(s,1H),7.57(s,1H),7.50-7.45(m,1H), 7.08-6.99(m,2H),6.58(s,1H),3.77(s,3H),3.75(s,3H),3.19(t,J=5.2Hz,2H),3.03-3.00(m,5H),1.75(d,J=13.6Hz,6H).

[0341] Example 3:

[0342] Preparation of intermediate 3A

[0343]

[0344] Compound 3A-1:

[0345] A solution of methylamine in tetrahydrofuran (2M, 106.7 mL, 213.4 mmol) and triethylamine (10.8 g, 106.7 mmol) were dissolved in dichloromethane (80 mL). Cyclopropylsulfonyl chloride (10 g, 71.1 mmol) was then added dropwise to the reaction mixture at 0 °C. The reaction mixture was brought to room temperature and stirred for 24 hours. After the starting material was observed to have disappeared under TLC monitoring, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (100 mL). Cesium carbonate (31.1 g, 95.4 mmol) and o-nitrobenzene (15.5 g, 95.4 mmol) were then added to the reaction mixture, and stirring was continued at room temperature for 16 hours. After the starting material was observed to have disappeared under LCMS monitoring, water (100 mL) was added to quench the reaction mixture. The mixture was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (100 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 14 g of compound 3A-1.

[0346] MS(ESI)M / Z:257.0[M+H] + .

[0347] Compound 3A-2:

[0348] Compound 3A-1 (14 g, 55 mmol) was dissolved in a mixed solvent of ethanol (50 mL) and ethyl acetate (50 mL). Then, wet palladium on carbon (10%, 600 mg) was added to the reaction mixture. After purging the reaction system three times with hydrogen (1 atm), the reaction mixture was stirred at room temperature for 16 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate (30 mL × 3 times), and the resulting filtrate was concentrated under reduced pressure to give 12 g of compound 3A-2.

[0349] MS(ESI)M / Z:227.1[M+H] + .

[0350] Intermediate 3A:

[0351] According to the preparation method of 2A in Example 2, the raw material was replaced with 3A-2 (12g, 53mmol) to prepare 9g of compound 3A.

[0352] MS(ESI, m / z): 416.9, 418.9 [M+H] + .

[0353] Preparation of compound 3

[0354]

[0355] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 3A (80 mg, 0.3 mmol) to prepare 96 mg of compound 3.

[0356] MS(ESI, m / z): 638.9, 640.9 [M+H] + .

[0357] 1 H NMR(300MHz,DMSO-d6)δ8.30-8.13(m,4H),7.72(s,1H),7.60-7.55(m,2H),7.06-7.01(m,2H),6.60(s,1H),3.7 7(s,3H),3.75(s,3H),3.22-3.19(m,5H),3.04-3.01(m,5H),2.89-2.81(m,1H),1.07-1.05(m,2H),0.88(s,2H).

[0358] Example 4:

[0359] Preparation of intermediate 4A

[0360]

[0361] Compound 4A-1:

[0362] Methanesulfonyl methylamine (34.8 g, 319 mmol) and o-fluoronitrobenzene (30 g, 212.6 mmol) were dissolved in acetonitrile (400 mL). Cesium carbonate (138.6 g, 425 mmol) was then added to the reaction mixture, and stirring was continued at room temperature for 16 hours. After LCMS monitoring showed the disappearance of the starting material, water (300 mL) was added to quench the reaction mixture. The mixture was extracted with ethyl acetate (300 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (150 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give 30 g of compound 4A-1.

[0363] 1 H NMR (400MHz, DMSO-d6) δ7.97-7.95(m,1H),7.87-7.75(m,2H),7.67-7.58(m,1H),3.29(s,3H),3.06(s,3H).

[0364] Compound 4A-2:

[0365] According to the method for preparing 3A-2 from 3A-1 in Example 3, the raw material was replaced with 4A-1 (15g, 65mmol) to prepare 12g of compound 4A-2.

[0366] MS(ESI,m / z):201.0[M+H] + .

[0367] Intermediate 4A:

[0368] According to the preparation method of 2A in Example 2, the raw material was replaced with 4A-2 (5g, 25mmol) to prepare 3g of intermediate compound 4A.

[0369] MS(ESI, m / z): 390.9, 392.9 [M+H] + .

[0370] Preparation of compound 4

[0371]

[0372] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 4A (152 mg, 0.4 mmol) to prepare 25 mg of compound 4.

[0373] MS(ESI, m / z): 613.1, 615.1 [M+H] + .

[0374] 1 H NMR(300MHz,DMSO-d6)δ8.29-8.25(m,3H),8.19(s,1H),7.72(s,1H),7.55-7.53(m,2H),7.07-6.93 (m,2H),6.60(s,1H),3.77(s,3H),3.76(s,3H),3.22-3.19(m,5H),3.11(s,3H),3.04-3.01(m,5H).

[0375] Example 5:

[0376]

[0377] Intermediate 5A:

[0378] According to the method for preparing 1B in Example 1B-2, the raw material was replaced with 2,4-dichloro-5-methylpyrimidine (5.53 g, 34 mmol) to prepare 4.2 g of compound 5A.

[0379] MS(ESI, m / z): 348.3, 350.3 [M+H] + .

[0380] Compound 5:

[0381] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 5A (80 mg, 0.23 mmol) to prepare 53 mg of compound 5.

[0382] MS(ESI, m / z): 570.3 [M+H] + .

[0383] 1 H NMR (400MHz, CDCl3) δ12.56(s,1H),9.15(dd,J=9.6,4.4Hz,1H),8.67-8.66(m,2H),8.31-8.23(m,2H),7.87(s,1H),7.59(d,J=9.2Hz,1H ),7.23(s,1H),6.57(s,1H),3.90(s,3H),3.75(s,3H),3.33(t,J=5.6Hz,2H),3.08-3.05(m,5H),2.28(s,3H),2.13(s,3H),2.09(s,3H).

[0384] Example 6:

[0385] Preparation of intermediate 6A

[0386]

[0387] Compound 6A-1:

[0388] According to the method for preparing 1C-6 from 1C-5 in Example 1, the raw material was replaced with 1C-4 (3.5g, 15.5mmol) to prepare 3.57g of compound 6A-1.

[0389] MS(ESI,m / z):352.0[M+H] + .

[0390] Compound 6A-2:

[0391] Following the method for preparing 1C-7 from 1C-6 in Example 1, the raw material was replaced with 6A-1 (3.4 g, 9.7 mmol) to prepare 2.8 g of compound 6A-2.

[0392] MS(ESI, m / z): 395.3 [M+H] + .

[0393] Compound 6A-3:

[0394] Following the method for preparing 1C-9 from 1C-8 in Example 1, the raw material was replaced with 6A-2 (2.7 g, 6.8 mmol) to prepare 1.2 g of compound 6A-3.

[0395] MS(ESI, m / z): 375.2 [M+H] + .

[0396] Compound 6A-4:

[0397] Following the method for preparing 1C-8 from 1C-7 in Example 1, the raw material was replaced with 6A-3 (1.2 g, 3.3 mmol) to prepare 0.84 g of compound 6A-4.

[0398] MS(ESI,m / z):275.0[M+H] + .

[0399] Compound 6A-5:

[0400] Compound 6A-4 (300 mg, 1.1 mmol) and cesium carbonate (1.07 g, 3.3 mmol) were dissolved in N,N-dimethylformamide (6 mL). Iodopropane (1.86 g, 10.9 mmol) was then added to the reaction mixture. The reaction system was heated to 80 °C and stirred for 16 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was cooled to room temperature and quenched with water (30 mL). The mixture was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (50 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 75 mg of compound 6A-5.

[0401] MS(ESI, m / z): 317.2 [M+H] + .

[0402] Intermediate 6A:

[0403] According to the method for preparing 1C from 1C-9 in Example 1, the raw materials were replaced with 6A-5 (75 mg, 0.24 mmol) to prepare 48 mg of intermediate compound 6A.

[0404] MS(ESI, m / z): 287.2 [M+H] + .

[0405] Preparation of compound 6

[0406]

[0407] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 6A (48 mg, 0.17 mmol) to prepare 19 mg of compound 6.

[0408] MS(ESI, m / z): 662.3, 664.3 [M+H] + .

[0409] 1H NMR (400MHz, CDCl3) δ12.47 (s, 1H), 8.88 (dd, J=9.2, 4.0Hz, 1H), 8.69 (d, J= 2.0Hz,1H),8.67(d,J=2.0Hz,1H),8.37(s,1H),8.27(s,1H),7.63(s,1H),7 .35(s,1H),7.00(s,1H),6.56(s,1H),3.88(s,4H),3.70(s,3H),3.35-3.27 (m,2H),3.00-2.91(m,2H),2.15(s,3H),2.12(s,3H),1.31(d,J=6.4Hz,6H).

[0410] Example 7:

[0411]

[0412] Intermediate 7A:

[0413] According to the method for preparing 1B in Example 1B-2, the raw materials were replaced with 2,4-dichloro-5-methylpyrimidine (578 mg, 3.55 mmol) and 2-(dimethylphosphono)aniline (300 mg, 2.96 mmol) to prepare 300 mg of compound 7A.

[0414] MS(ESI, m / z): 296.1, 298.1 [M+H] + .

[0415] Compound 7:

[0416] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 7A (80 mg, 0.27 mmol) to prepare 111 mg of formate of compound 7.

[0417] MS(ESI, m / z): 518.2 [M+H] + .

[0418] 1H NMR (400MHz, CD3OD) δ8.48(dd,J=8.4,4.4Hz,1H),8.32(s,1H),7.91(s,1H),7.73(s,1H),7.55-7.49(m,1H),7.38(s,1H),7.20-7.16(m,1H) ,7.10-7.06(m,1H),6.66(s,1H),3.87(s,3H),3.80(s,3H),3.27(t,J= 5.6Hz,2H),3.06-3.03(m,5H),2.17(s,3H),1.89(s,3H),1.85(s,3H).

[0419] Example 8:

[0420] Preparation of intermediate 8A

[0421]

[0422] Compound 8A-1:

[0423] According to the preparation method of 1C-1 in Example 1, the raw material was replaced with 1-methyl-1H-pyrazole-3-carboxaldehyde (10g, 90.8mmol) to prepare 16g of compound 8A-1.

[0424] MS(ESI, m / z): 181.2 [M+H] + .

[0425] Compound 8A-2:

[0426] According to the method for preparing 1C-2 from 1C-1 in Example 1, the raw material was replaced with 8A-1 (16.8g, 93.2mmol) to prepare 16g of compound 8A-2.

[0427] MS(ESI, m / z): 183.1 [M+H] + .

[0428] Compound 8A-3:

[0429] Compound 8A-2 (3 g, 16.5 mmol) was dissolved in hexafluoroisopropanol (20 mL). N-iodosuccinimide (7.4 g, 32.9 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After the starting material disappeared as monitored by LCMS, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in water (100 mL), and the mixture was extracted with dichloromethane (3 × 100 mL). The combined organic phases were washed with saturated brine (150 mL x 3 times), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 40 / 1) to give 4.5 g of compound 8A-3.

[0430] MS(ESI, m / z): 309.1 [M+H] + .

[0431] Compound 8A-4:

[0432] According to the method for preparing 1C-7 from 1C-6 in Example 1, the raw material was replaced with 8A-3 (750 mg, 2.4 mmol) to prepare 470 mg of compound 8A-4.

[0433] MS(ESI, m / z): 352.2 [M+H] + .

[0434] Compound 8A-5:

[0435] Compound 8A-4 (380 mg, 1.1 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and water (2 mL). Lithium hydroxide (130 mg, 5.4 mmol) was then added to the reaction mixture, and stirring was continued at room temperature for 2 hours. After LCMS monitoring showed the starting material had disappeared, the reaction mixture was diluted with water (20 mL) and the pH was adjusted to 2 with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate (50 mL x 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (50 mL x 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 330 mg of compound 8A-5.

[0436] MS(ESI, m / z): 324.1 [M+H] + .

[0437] Compound 8A-6:

[0438] Following the method for preparing 1C-4 from 1C-3 in Example 1, the raw material was replaced with 8A-5 (350 mg, 1.1 mmol) to prepare 260 mg of compound 8A-6.

[0439] MS(ESI, m / z): 395.1 [M+H] + .

[0440] Compound 8A-7:

[0441] Compound 8A-6 (260 mg, 0.66 mmol) was dissolved in N,N-dimethylformamide (10 mL). Subsequently, sodium hydride (60%, 40 mg, 1 mmol) was added to the reaction mixture at 0 °C. The reaction system was brought to room temperature and stirred for 2 hours. After LCMS monitoring showed the starting material had disappeared, water (30 mL) was added to quench the reaction mixture. The mixture was extracted with ethyl acetate (50 mL x 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (50 mL x 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 230 mg of compound 8A-7.

[0442] MS(ESI, m / z): 375.2 [M+H] + .

[0443] Compound 8A-8:

[0444] According to the method for preparing 1C-8 from 1C-7 in Example 1, the raw material was replaced with 8A-7 (240 mg, 0.64 mmol) to prepare 160 mg of compound 8A-8.

[0445] MS(ESI, m / z): 275.1 [M+H] + .

[0446] Compound 8A-9:

[0447] Compound 8A-8 (240 mg, 0.88 mmol) was dissolved in N,N-dimethylformamide (10 mL). Subsequently, sodium hydride (60%, 350 mg, 8.75 mmol) was added to the reaction solution at 0 °C, and stirring was continued at this temperature for 30 minutes. Iodomethane (1.2 g, 8.5 mmol) was then added to the reaction solution. The reaction system was brought to room temperature and stirred for 1 hour. After LCMS monitoring showed the disappearance of the starting material, water (30 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (50 mL x 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to give 140 mg of compound 8A-9.

[0448] MS(ESI, m / z): 289.1 [M+H]+ .

[0449] Intermediate 8A:

[0450] Compound 8A-9 (70 mg, 0.24 mmol) was dissolved in ethanol (5 mL). Then, platinum dioxide (20 mg) was added to the reaction mixture. After purging the reaction system with hydrogen three times, the mixture was stirred at room temperature for 16 hours. After LCMS monitoring showed the starting material had disappeared, the reaction mixture was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate (10 mL x 3 times), and the resulting filtrate was concentrated under reduced pressure to give 60 mg of compound 8A.

[0451] MS(ESI)M / Z:259.1[M+H] + .

[0452] Preparation of compound 8

[0453]

[0454] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw material was replaced with 8A (70 mg, 0.17 mmol) to prepare 37 mg of compound 8.

[0455] MS(ESI, m / z): 634.2, 636.2 [M+H] + .

[0456] 1 H NMR(300MHz,DMSO-d6)δ12.67(s,1H),8.83-8.79(m,3H),8.36(s,1H),8.25(s,1H),7.77(s,1H),7.65(s,1H),7.56(s,1 H),6.59(s,1H),3.79(s,3H),3.57(s,3H),3.22-3.18(m,2H),3.01(s,3H),2.98-2.94(m,2H),2.04(s,3H),1.99(s,3H).

[0457] Example 9:

[0458] Preparation of intermediate 9A

[0459]

[0460] Compound 9A-1:

[0461] According to the method for preparing 1A from 1A-1 in Example 1, the raw material was replaced with methyl 2-bromo-5-methoxybenzoate (10g, 40.8mmol) to prepare 10g of compound 9A-1.

[0462] MS(ESI,m / z):293.1[M+H] + .

[0463] Compound 9A-2:

[0464] According to the method for preparing 1C-7 from 1C-6 in Example 1, the raw materials were replaced with 9A-1 (10g, 34.2mmol) and 4-bromo-1-methyl-pyrazole-5-carboxaldehyde (6.47g, 34.2mmol) to prepare 4.7g of compound 9A-2.

[0465] MS(ESI, m / z): 275.1 [M+H] + .

[0466] Compound 9A-3:

[0467] Compound 9A-2 (2.4 g, 8.75 mmol) was dissolved in concentrated sulfuric acid (25 mL) at 0 °C. Potassium nitrate (973 mg, 9.63 mmol) was then added in portions to the reaction mixture, and stirring continued at this temperature for 10 minutes. After TLC monitoring showed the starting material had disappeared, the reaction mixture was slowly poured into ice water (100 g) to quench the reaction. The mixture was extracted with ethyl acetate (100 mL x 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (100 mL x 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2) to give 650 mg of compound 9A-3.

[0468] MS(ESI, m / z): 320.1 [M+H] + .

[0469] Compound 9A-4:

[0470] Compound 9A-3 (1.4 g, 4.4 mmol) and a tetrahydrofuran solution of methylamine (2 M, 8.77 mL, 17.54 mmol) were dissolved in methanol (10 mL). Glacial acetic acid (276 mg, 4.6 mmol) was then added to the reaction mixture, and stirring was continued at room temperature for 16 hours. Sodium borohydride (332 mg, 8.77 mmol) was added to the reaction mixture, and stirring was continued at room temperature for 2 hours. After LCMS monitoring showed the starting material had disappeared, water (50 mL) was added to quench the reaction mixture. The mixture was extracted with ethyl acetate (50 mL x 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (50 mL x 3 times), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 540 mg of compound 9A-4.

[0471] MS(ESI, m / z): 303.1 [M+H] + .

[0472] Intermediate 9A:

[0473] Following the method from 1C-9 to 1C in Example 1, the raw material was replaced with 9A-4 (100 mg, 0.33 mmol) to prepare 80 mg of compound 9A.

[0474] MS(ESI,m / z):273.1[M+H] + .

[0475] Preparation of compound 9

[0476]

[0477] Compound 9:

[0478] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 9A (60 mg, 0.22 mmol) to prepare 25 mg of compound 9.

[0479] MS(ESI, m / z): 648.1, 650.1 [M+H] + .

[0480] 1 H NMR (400MHz, CDCl3) δ12.65(s,1H),8.88(dd,J=9.2,3.6Hz,1H),8.74(s,2H),8.43(s,1H),8.34(s,1H),7.85(s ,1H),7.57(s,2H),6.98(s,1H),4.34(s,2H),3.99(s,3H),3.93(s,3H),3.26(s,3H),2.17(s,3H),2.13(s,3H).

[0481] Example 10:

[0482] Preparation of intermediate 10A

[0483]

[0484] Compound 10A-1:

[0485] According to the method for preparing 1C-8 from 1C-7 in Example 1, the raw material was replaced with 6A-2 (300 mg, 0.76 mmol) to prepare 260 mg of compound 10A-1.

[0486] MS(ESI, m / z): 295.2 [M+H]+ .

[0487] Compound 10A-2:

[0488] Compound 10A-1 (370 mg, 1.12 mmol) and 1-methyl-3-azacyclobutanone (95 mg, 1.12 mmol) were dissolved in dichloromethane (7 mL). Triethylamine (453 mg, 4.48 mmol) and tetraisopropyl titanate (636 mg, 2.24 mmol) were then added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Sodium borohydride (85 mg, 2.24 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for another 1 hour. After LCMS monitoring showed the starting material had disappeared, the reaction mixture was purified using a reversed-phase C18 column under the following conditions: 40 g C18 reversed-phase column; mobile phase: water (containing 10 mM ammonium bicarbonate) and acetonitrile; flow rate: 35 mL / min; gradient: acetonitrile increased from 5% to 40% over 20 minutes; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure to give 70 mg of compound 10A-2.

[0489] MS(ESI)M / Z:364.2[M+H] + .

[0490] Compound 10A-3:

[0491] According to the method for preparing 1C-9 from 1C-8 in Example 1, the raw material was replaced with 10A-2 (70 mg, 0.19 mmol) to prepare 50 mg of compound 10A-3.

[0492] MS(ESI, m / z): 344.1 [M+H] + .

[0493] Intermediate 10A:

[0494] According to the method for preparing 1C from 1C-9 in Example 1, the raw material was replaced with 10A-3 (50 mg, 0.15 mmol) to prepare 50 mg of compound 10A.

[0495] MS(ESI, m / z): 314.2 [M+H] + .

[0496] Preparation of compound 10

[0497]

[0498] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 10A (50 mg, 0.12 mmol) to prepare 8 mg of compound 10.

[0499] MS(ESI, m / z): 689.3, 691.3 [M+H] + .

[0500] 1 H NMR (400MHz, CD3OD) δ8.82(d,J=2.0Hz,1H),8.73(d,J=2.0Hz,1H),8.66-8.63(m,1H),8.52(brs,1H),8.25(s,1H),8.18(s,1H),7.47(d,J=9.6Hz,1H), 6.84(s,1H),6.24(s,1H),4.57-4.54(m,1H),4.32-4.28(m,2H),3.89(s,3H),3.85-3.82(m,2 H),3.68(s,3H),3.31-3.30(m,2H),3.13-3.10(m,2H),2.80(s,3H),2.17(s,3H),2.13(s,3H).

[0501] Example 11:

[0502] Preparation of intermediate 11A

[0503]

[0504] Compound 11A-1:

[0505] Under a nitrogen atmosphere, compound 9A-4 (100 mg, 0.33 mmol) was dissolved in tetrahydrofuran (2 mL). Then, a borane-dimethyl sulfide solution (251 mg, 3.31 mmol) was added to the reaction mixture, and stirring was continued at room temperature for 16 hours. After the starting material disappeared as monitored by LCMS, methanol (5 mL) was added to quench the reaction. The mixture was heated to 60 °C and stirred for 1 hour, then cooled to 0 °C. A white solid precipitated, which was filtered and dried to give 60 mg of compound 11A-1.

[0506] MS(ESI, m / z): 289.1 [M+H] + .

[0507] Intermediate 11A:

[0508] According to the method for preparing 1C from 1C-9 in Example 1, the raw material was replaced with 11A-1 (125 mg, 0.43 mmol) to prepare 100 mg of compound 11A.

[0509] MS(ESI, m / z): 259.1 [M+H] + .

[0510] Preparation of compound 11

[0511]

[0512] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 11A (90 mg, 0.35 mmol) to prepare 20 mg of compound 11.

[0513] MS(ESI, m / z): 634.2, 636.2 [M+H] + .

[0514] 1 H NMR (300MHz, CDCl3) δ12.55(s,1H),8.88(dd,J=9.6,4.2Hz,1H),8.74-8.72(m,2H),8.52(s,1H),8.34(s,1H),7.64(d,J=9.3Hz,1H) ,7.56(s,1H),7.00(s,1H),6.74(s,1H),4.16(s,2H),3.94(s,3H),3.93(s,2H),3.75(s,3H),2.55(s,3H),2.19(s,3H),2.14(s,3H).

[0515] Example 12:

[0516] Preparation of intermediate 12A

[0517]

[0518] Compound 12A-1:

[0519] According to the method for preparing 8A-9 from 8A-8 in Example 8, the raw materials were replaced with 6A-4 (150 mg, 0.55 mmol) and bromomethylcyclopropane (736 mg, 5.45 mmol) to prepare 160 mg of compound 12A-1.

[0520] MS(ESI, m / z): 329.2 [M+H] + .

[0521] Intermediate 12A:

[0522] According to the method for preparing 1C from intermediate 1C-9 in Example 1, the raw material was replaced with 12A-1 (80 mg, 0.24 mmol) to prepare 70 mg of compound 12A.

[0523] MS(ESI, m / z): 299.1 [M+H] +

[0524] Preparation of compound 12

[0525]

[0526] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 12A (70 mg, 0.24 mmol) to prepare 30 mg of compound 12.

[0527] MS(ESI, m / z): 674.3, 676.3 [M+H] + .

[0528] 1 H NMR(300MHz, CDCl3)δ12.51(s,1H),8.89(dd,J=9.6,3.9Hz,1H),8.71-8.68(m,2H),8.37(s,1H),8.27(s,1H),7.66- 7.63(m,1H),7.36(s,1H),7.04(s,1H),6.56(s,1H),3.90(s,3H),3.74(s,3H),3.48-3.45(m,2H),3.17(d,J=6.3Hz, 2H),3.07-3.04(m,2H),2.17(s,3H),2.12(s,3H),1.13-1.07(m,1H),0.67-0.61(m,2H),0.30-0.27(m,2H).

[0529] Example 13:

[0530] Preparation of intermediate 13A

[0531]

[0532] According to the method for preparing 1B in Example 1B-2, the raw material was replaced with 2,4,5-trichloropyrimidine (5.37 g, 29.3 mmol) to prepare 4.5 g of compound 13A.

[0533] MS(ESI, m / z): 367.9, 369.9 [M+H] + .

[0534] Preparation of compound 13

[0535]

[0536] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 13A (100 mg, 0.27 mmol) to prepare 73 mg of compound 13.

[0537] MS(ESI, m / z): 590.3, 592.3 [M+H] + .

[0538] 1 H NMR (300MHz, DMSO-d6) δ12.84(s,1H),8.96(s,1H),8.82(dd,J=11.4,1.8Hz,2H),8.42(s,1H),8.19(s,1H) ,7.72(s,1H),7.59(s,1H),7.52(s,1H),6.65(s,1H),3.80(s,3H),3.73(s,3H),3.24-3.20(m,2H),3.04(br s,5H),2.04(s,3H),1.99(s,3H).

[0539] Example 14:

[0540] Preparation of compound 14

[0541]

[0542] Compound 14A:

[0543] According to the method for preparing 2A in Example 2, the raw materials were replaced with 2,4,5-trichloropyrimidine (13g, 71mmol) and 2-(dimethylphosphono)aniline (10g, 59mmol) to prepare 14.4g of compound 14A.

[0544] MS(ESI, m / z): 316.0, 318.0 [M+H] + .

[0545] Compound 14:

[0546] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 14A (80 mg, 0.25 mmol) to prepare 80 mg of compound 14.

[0547] MS(ESI, m / z): 538.3, 540.3 [M+H] + .

[0548] 1H NMR (300MHz, CDCl3) δ10.88(s,1H),8.62(dd,J=8.4,4.5Hz,1H),8.43(s,1H),8.13(s,1H),7.38(s,1H), 7.32-7.17(m,3H),7.02-6.97(m,1H),6.57(s,1H),3.92(s,3H),3.84(s,3H),3.32-3.28(m,2H),3.06(br s,5H),1.88(s,3H),1.84(s,

[0549] 3H).

[0550] Example 15:

[0551] Preparation of intermediate 15A

[0552]

[0553] Compound 15A-1:

[0554] Compound 6A-4 (100 mg, 0.37 mmol) was dissolved in acetic anhydride (1.5 mL). The reaction mixture was heated to 140 °C and stirred for 1 hour. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 90 mg of compound 15A-1.

[0555] MS(ESI, m / z): 317.2 [M+H] + .

[0556] Intermediate 15A:

[0557] According to the method for preparing 1C from intermediate 1C-9 in Example 1, the raw material was replaced with 15A-1 (80 mg, 0.25 mmol) to prepare 66 mg of compound 15A.

[0558] MS(ESI, m / z): 287.1 [M+H] + .

[0559] Preparation of compound 15

[0560]

[0561] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 15A (50 mg, 0.17 mmol) to prepare 17 mg of compound 15.

[0562] MS(ESI, m / z): 662.2, 664.2 [M+H]+ .

[0563] 1 H NMR (300MHz, CDCl3) δ12.62 (s, 1H), 8.86 (dd, J = 9.6, 4.2Hz, 1H), 8.75-8.73 (m,2H),8.61(s,1H),8.36(s,1H),7.70-7.63(m,2H),6.99(s,1H),6.73(s, 1H),4.85(dd,J=13.2,5.7Hz,1H),3.94(s,3H),3.71(s,3H),3.53-3.41(m, 1H),3.13-3.03(m,1H),2.94-2.89(m,1H),2.21-2.14(m,6H),1.99(s,3H).

[0564] Example 16:

[0565] Preparation of intermediate 16A

[0566]

[0567] According to the method for preparing 1C from intermediate 1C-9 in Example 1, the starting material was replaced with 6A-4 (100 mg, 0.25 mmol) to prepare 70 mg of compound 16A.

[0568] MS(ESI, m / z): 245.2 [M+H] + .

[0569] Preparation of compound 16

[0570]

[0571] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 16A (60 mg, 0.25 mmol) to prepare 13 mg of compound 16.

[0572] MS(ESI, m / z): 620.2, 622.2 [M+H] + .

[0573] 1H NMR(300MHz,DMSO-d6)δ12.65(s,1H),8.84-8.79(m,3H),8.34(s,1H),8.24(s,1H),7.63(s,2H),7.53(s,1H),6.5 8(s,1H),5.93(s,1H),3.71(s,3H),3.70(s,3H),3.28-3.23(m,2H),2.98-2.95(m,2H),2.03(s,3H),1.99(s,3H).

[0574] Example 17:

[0575] Preparation of compound 17

[0576]

[0577] Compound 17A:

[0578] According to the method for preparing 2A in Example 2, the raw materials were replaced with 2,4-dichloro-5-fluoropyrimidine (2g, 11.98mmol) and 2-(dimethylphosphono)aniline (2.03g, 11.98mmol) to prepare 1.9g of compound 17A.

[0579] MS(ESI, m / z): 300.0, 302.0 [M+H] + .

[0580] Compound 17:

[0581] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 17A (60 mg, 0.2 mmol) to prepare 21 mg of compound 17.

[0582] MS(ESI, m / z): 522.3 [M+H] + .

[0583] 1 H NMR (300MHz, CDCl3) δ11.41(s,1H),8.82-8.76(m,1H),8.44(s,1H),8.00(s,1H),7.56(s,1H),7. 34-7.20(s,3H),7.00(s,1H),6.59(s,1H),3.92(s,3H),3.84(s,3H),3.32-3.27(m,2H),3.07(br s,5H),1.86(m,6H).

[0584] 19 F NMR (282MHz, CDCl3) δ-164.46.

[0585] Example 18:

[0586] Preparation of intermediate 18A

[0587]

[0588] Compound 18A-1

[0589] Compound 1C-9 (100 mg, 0.35 mmol) was dissolved in dichloromethane (2 mL) under a nitrogen atmosphere and at 0 °C. Boron tribromide (174 mg, 0.69 mmol) was then added to the reaction mixture. The reaction system was brought to room temperature and stirred for 16 hours. After the starting material disappeared as monitored by LCMS, water (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL x 3 times), and the combined organic phases were washed with saturated brine (30 mL x 3 times), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to give 50 mg of compound 18A-1.

[0590] MS(ESI, m / z): 275.1 [M+H] + .

[0591] Compound 18A-2:

[0592] Compound 18A-1 (75 mg, 0.27 mmol) and potassium carbonate (113 mg, 0.82 mmol) were dissolved in N,N-dimethylformamide (20 mL). Iodopropane (139 mg, 0.82 mmol) was added to the reaction solution at 0 °C. The reaction system was heated to 60 °C and stirred for 16 hours. After the starting material disappeared as monitored by LCMS, the reaction solution was cooled to room temperature and quenched with water (10 mL). The mixture was extracted with ethyl acetate (20 mL x 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (30 mL x 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to give 70 mg of compound 18A-2.

[0593] MS(ESI, m / z): 317.1 [M+H] + .

[0594] Intermediate 18A:

[0595] According to the method for preparing 1C from intermediate 1C-9 in Example 1, the raw material was replaced with 18A-2 (70 mg, 0.22 mmol) to prepare 55 mg of compound 18A.

[0596] MS(ESI, m / z): 287.1 [M+H] +

[0597] Preparation of compound 18

[0598]

[0599] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 18A (50 mg, 0.18 mmol) and 7A (52 mg, 0.18 mmol) to prepare 20 mg of compound 18.

[0600] MS(ESI, m / z): 546.0 [M+H] + .

[0601] 1 H NMR (300MHz, CDCl3) δ10.49 (s, 1H), 8.74 (dd, J = 8.7, 4.5Hz, 1H), 8.48 (s, 1H), 7.92 (s,1H),7.52(s,1H),7.37(s,1H),7.26-7.19(m,1H),7.16-7.10(m,1H),6.96-6.9 0(m,1H),6.59(s,1H),4.62-4.54(m,1H),3.83(s,3H),3.29(t,J=5.4Hz,2H),3.04 (t,J=5.7Hz,5H),2.22(s,3H),1.87(s,3H),1.83(s,3H),1.41(s,3H),1.39(s,3H).

[0602] Example 19:

[0603] Preparation of intermediate 19A

[0604]

[0605] Compound 19A-1:

[0606] According to the method for preparing 8A-9 from 8A-8 in Example 8, the raw materials were replaced with 6A-4 (200 mg, 0.73 mmol) and iodoethane (341 mg, 2.19 mmol) to prepare 150 mg of compound 19A-1.

[0607] MS(ESI, m / z): 303.2 [M+H] + .

[0608] Intermediate 19A:

[0609] According to the method for preparing 1C from intermediate 1C-9 in Example 1, the raw material was replaced with 19A-1 (150 mg, 0.5 mmol) to prepare 100 mg of compound 19A.

[0610] MS(ESI,m / z):273.1[M+H] + .

[0611] Preparation of compound 19

[0612]

[0613] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 19A (60 mg, 0.22 mmol) and 7A (65 mg, 0.22 mmol) to prepare 33 mg of compound 19.

[0614] MS(ESI, m / z): 532.2 [M+H] + .

[0615] 1 H NMR (300MHz, CDCl3) δ10.49(s,1H),8.74(dd,J=8.7,4.5Hz,1H),8.45(s,1H),7.92(s,1H),7.50(s,1H),7.44(s,1H),7.25-7.14(m,1H),6.97-6.92 (m,2H),6.57(s,1H),3.89(s,3H),3.83(s,3H),3.39-3.29(m,4H),3.01-2 .98(m,2H),2.22(s,3H),1.87(s,3H),1.82(s,3H),1.31(t,J=6.9Hz,3H).

[0616] Example 20:

[0617] Preparation of compound 20

[0618]

[0619] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 19A (60 mg, 0.22 mmol) and 2A (79 mg, 0.22 mmol) to prepare 33 mg of compound 20.

[0620] MS(ESI, m / z): 596.2, 598.2 [M+H] + .

[0621] 1H NMR (300MHz, CDCl3) δ10.61(s,1H),8.50(dd,J=8.6,4.5Hz,1H),8.41(s,1H),8.23(s,1H),7.33-7.20(m,4H),7.03-6.97(m,1H) ,6.57(s,1H),3.89(s,3H),3.83(s,3H),3.39-3.32(m,4H),3.01-2.97(m,2H),1.88(s,3H),1.84(s,3H),1.31(t,J=7.2Hz,3H).

[0622] Example 21:

[0623] Preparation of intermediate 21A

[0624]

[0625] Compound 21A-1:

[0626] 4-Bromo-3-nitro-1,2-phenylenediamine (10 g, 43 mmol) and glyoxal aqueous solution (40%, 15.01 g, 103 mmol) were dissolved in water (400 mL). The reaction system was heated to 100 °C and stirred for 4 hours. After the starting material disappeared as monitored by TLC, the reaction solution was cooled to room temperature. The precipitated solid was filtered, washed with water (20 mL x 3 times), and dried to give 13.4 g of crude compound 21A-1.

[0627] 1 H NMR (300MHz, DMSO-d6) δ8.16 (d, J = 1.8 Hz, 1H), 9.11 (d, J = 2.1 Hz, 1H), 8.30 (d, J = 5.4 Hz, 2H).

[0628] Compound 21A-2:

[0629] According to the method for preparing 1C from intermediate 1C-9 in Example 1, the raw material was replaced with 21A-1 (11g, 43.3mmol) to prepare 5.3g of compound 21A-2.

[0630] MS(ESI, m / z): 223.8, 225.8 [M+H] + .

[0631] Compound 21A-3:

[0632] Compound 21A-2 (3.7 g, 17 mmol) was dissolved in N,N-dimethylformamide (50 mL) under nitrogen atmosphere. Then, sodium hydride (60%, 2.6 g, 66 mmol) was added to the reaction mixture at 0 °C, and stirring was continued for 30 minutes. Cyclopropanesulfonyl chloride (7 g, 50 mmol) was then added dropwise. The reaction mixture was brought to room temperature and stirred for 2 hours. After LCMS monitoring showed the starting material had disappeared, saturated ammonium chloride aqueous solution (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (80 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 1.5 g of compound 21A-3.

[0633] MS(ESI, m / z): 431.8, 433.8 [M+H] + .

[0634] Compound 21A-4:

[0635] Compound 21A-3 (2.2 g, 5.1 mmol) was dissolved in methanol (25 mL), followed by the addition of sodium hydroxide (8.1 g, 102 mmol). The reaction mixture was heated to 90 °C and stirred for 2 hours. After the starting material disappeared under LCMS monitoring, the reaction mixture was concentrated under reduced pressure and diluted with water (50 mL). The pH was adjusted to 6 with concentrated hydrochloric acid. The mixture was extracted with chloroform / isopropanol (3 / 1, 80 mL × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (80 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 0.94 g of compound 21A-4.

[0636] MS(ESI, m / z): 327.9, 329.9 [M+H] + .

[0637] Compound 21A-5:

[0638] Compound 21A-4 (930 mg, 2.8 mmol) and anhydrous potassium carbonate (789 mg, 5.7 mmol) were dissolved in N,N-dimethylformamide (10 mL). Iodomethane (603 mg, 4.3 mmol) was then added to the reaction mixture at 0 °C. The reaction mixture was brought to room temperature and stirred for 2 hours. After the starting material disappeared as monitored by LCMS, water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (80 mL × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (80 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 930 mg of compound 21A-5.

[0639] MS(ESI, m / z): 341.9, 343.9 [M+H] + .

[0640] Compound 21A-6:

[0641] Under nitrogen atmosphere, compound 21A-5 (950 mg, 2.8 mmol), tert-butyl carbamate (488 mg, 4.2 mmol), cesium carbonate (1.8 g, 5.6 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (235 mg, 0.28 mmol), and 2-dicyclohexylphospho-2,4,6-triisopropylbiphenyl (132 mg, 0.28 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction mixture was heated to 90 °C and stirred for 4 hours. After the starting materials disappeared as monitored by LCMS, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 810 mg of compound 21A-6.

[0642] MS(ESI,m / z):379.0[M+H] + .

[0643] Compound 21A-7:

[0644] Compound 21A-6 (810 mg, 2.1 mmol) was dissolved in ethyl acetate solution of hydrogen chloride (4 M, 10 mL) and stirred at room temperature for 2 hours. After the starting material disappeared as monitored by LCMS, the reaction solution was concentrated under reduced pressure and diluted with water (10 mL). The pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (80 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 660 mg of crude compound 21A-7.

[0645] MS(ESI, m / z): 279.2 [M+H] + .

[0646] Intermediate 21A:

[0647] According to the method for preparing 1B in Example 1B-2, the raw materials were replaced with compound 21A-7 (620 mg, 2.2 mmol) to prepare 700 mg of compound 21A.

[0648] MS(ESI, m / z): 468.9, 470.9 [M+H] + .

[0649] Preparation of compound 21

[0650]

[0651] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 21A (110 mg, 0.23 mmol) to prepare 29 mg of compound 21.

[0652] MS(ESI, m / z): 691.3, 693.3 [M+H] + .

[0653] 1H NMR(400MHz, CDCl3) δ9.35(s,1H),8.85(d,J=1.6Hz,1H),8.79(d,J=1.6Hz,1H),8.4 3(d,J=9.2Hz,1H),8.23-7.93(m,2H),7.58(d,J=9.2Hz,1H),7.02(s,1H),3.93(s,3H ),3.74(s,3H),3.61-3.46(m,4H),3.19-2.98(m,4H),2.93-2.89(m,2H),2.79-2.71 (m,1H),1.37-1.29(m,1H),1.17-1.08(m,1H),0.83-0.75(m,1H),0.68-0.58(m,1H).

[0654] Example 22:

[0655] Preparation of compound 22

[0656]

[0657] Compound 2 (70 mg, 0.12 mmol) was dissolved in methanol (6 mL). Palladium on carbon (10%, 25 mg) was added to the reaction solution. The reaction system was purged with hydrogen three times and then stirred at room temperature for 3 hours. After the starting material disappeared as monitored by LCMS, the palladium on carbon was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 27 mg of compound 22.

[0658] MS(ESI, m / z): 504.3 [M+H] + .

[0659] 1 H NMR(300MHz, CDCl3)δ10.91(s,1H),8.65-8.44(m,2H),8.30(s,1H),7.96(d ,J=6.3Hz,1H),7.54(s,1H),7.25-7.17(m,1H),7.13-7.08(m,1H),6.98-6. 92(m,1H),6.58(s,1H),6.16(d,J=6.0Hz,1H),3.91(s,3H),3.84(s,3H),3. 33-3.29(m,2H),3.07(s,3H),3.06-3.04(m,2H),1.86(s,3H),1.82(s,3H).

[0660] Example 23:

[0661] Preparation of intermediate 23A

[0662]

[0663] Compound 23A-1:

[0664] Compound 6A-4 (100 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (3 mL) under nitrogen atmosphere. Then, sodium hydride (60%, 22 mg, 0.5 mmol) was added to the reaction mixture at 0 °C, and stirring was continued for 30 minutes. Cyanogen bromide (386 mg, 3.6 mmol) was then added. The reaction mixture was brought to room temperature and stirred for 3 hours. After LCMS monitoring showed the starting material had disappeared, the reaction mixture was purified by reversed-phase C18 column chromatography. Purification conditions: column: 40 g C18 reversed-phase column; mobile phase: water (containing 10 mM ammonium bicarbonate) and acetonitrile; flow rate: 35 mL / min; gradient: acetonitrile increased from 10% to 80% over 20 minutes; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure to give 65 mg of compound 23A-1.

[0665] MS(ESI, m / z): 300.2 [M+H] + .

[0666] Intermediate 23A:

[0667] According to the method for preparing 1C from intermediate 1C-9 in Example 1, the raw material was replaced with 23A-1 (55 mg, 0.18 mmol) to prepare 50 mg of compound 23A.

[0668] MS(ESI, m / z): 270.2 [M+H] + .

[0669] Preparation of compound 23:

[0670]

[0671] Under nitrogen atmosphere, compound 23A (50 mg, 0.18 mmol), 7A (38 mg, 0.13 mmol), cesium carbonate (121 mg, 0.37 mmol), tris(dibenzylindeneacetone)dipalladium(0) (17 mg, 0.019 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (11 mg, 0.019 mmol) were dissolved in 1,4-dioxane (1 mL). The reaction mixture was heated to 90 °C and stirred for 4 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 17 mg of compound 23.

[0672] MS(ESI, m / z): 529.3 [M+H] + .

[0673] 1 H NMR (300MHz, CDCl3) δ10.51(s,1H),8.78(s,1H),8.69-8.65(m,1H),7.99(s,1H),7.42(s,2H),7.33-7.26(m,2H),7.05-7.00(m ,1H),6.91(s,1H),3.95(s,3H),3.86(s,3H),3.85-3.81(m,2H),3.23(t,J=5.7Hz,2H),2.24(s,3H),1.89(s,3H),1.84(s,3H).

[0674] Example 24:

[0675] Preparation of intermediate 24A

[0676]

[0677] According to the method for preparing 1A from intermediate 1A-1 in Example 1, the raw material was replaced with 4-bromo-2-nitrobenzene ether (20g, 86.16mmol) to prepare 19.7g of compound 24A.

[0678] 1 H NMR (300MHz, CDCl3) δ8.27 (d, J = 1.5 Hz, 1H), 7.96 (dd, J = 8.4, 1.8 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 4.00 (s, 3H), 1.36 (s, 12H).

[0679] Preparation of intermediate 24B

[0680]

[0681] Compound 24B-1:

[0682] Compound 1C-2 (6 g, 32.9 mmol) was dissolved in dichloromethane (100 mL). Then, N-bromosuccinimide (8.8 g, 49.4 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was heated to room temperature and stirred for 1 hour. After the starting material disappeared as monitored by LCMS, the reaction mixture was quenched in water (100 mL). The mixture was extracted with dichloromethane (100 mL × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (80 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 8.5 g of compound 24B-1.

[0683] MS(ESI)M / Z:261.1,263.1[M+H] + .

[0684] Compound 24B-2:

[0685] According to the method for preparing 1C-7 from 1C-6 in Example 1, the raw materials were replaced with 24B-1 (2g, 7.6mmol) and 24A (2.57g, 9.2mmol) to prepare 2g of compound 24B-2.

[0686] MS(ESI, m / z): 334.1 [M+H] + .

[0687] Compound 24B-3:

[0688] Compound 24B-2 (2 g, 6.0 mmol) was dissolved in ethanol (20 mL). Then, an aqueous solution of sodium hydroxide (2 N, 9 mL) was added to the reaction mixture. The reaction system was stirred at room temperature for 1 hour. After LCMS monitoring showed the starting material had disappeared, the reaction mixture was concentrated under reduced pressure and the pH was adjusted to 2 with 1 N hydrochloric acid. The precipitated solid was filtered and dried to give 1.5 g of compound 24B-3.

[0689] MS(ESI, m / z): 306.2 [M+H] + .

[0690] Compound 24B-4:

[0691] Compound 24B-3 (1.1 g, 3.6 mmol) was dissolved in a mixed solvent of ethanol (25 mL) and tetrahydrofuran (25 mL). Platinum dioxide (221 mg, 0.97 mmol) was then added to the reaction mixture. After purging the reaction system three times with hydrogen, the mixture was stirred at room temperature for 2 hours. After LCMS monitoring showed the starting material had disappeared, the reaction mixture was filtered through diatomaceous earth. The filter cake was washed with dichloromethane (30 mL × 3 times), and the resulting filtrate was concentrated under reduced pressure to give 0.95 g of compound 24B-4.

[0692] MS(ESI, m / z): 276.2 [M+H] + .

[0693] Intermediate 24B:

[0694] Compound 24B-4 (1 g, 3.6 mmol) was dissolved in polyphosphoric acid (15 mL). The reaction mixture was heated to 100 °C and stirred for 48 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was poured into ice water (80 g). The mixture was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (80 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 0.65 g of compound 24B.

[0695] MS(ESI)M / Z:258.2[M+H] + .

[0696] Preparation of compound 24

[0697]

[0698] Compound 24C:

[0699] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 24B (250 mg, 0.97 mmol) to prepare 200 mg of compound 24C.

[0700] MS(ESI, m / z): 633.3, 635.2 [M+H] + .

[0701] Compound 24:

[0702] Compound 24C (100 mg, 0.16 mmol) was dissolved in methanol (2 mL). Sodium borohydride (12 mg, 0.3 mmol) was added to the reaction solution at 0 °C. The reaction system was brought to room temperature and stirred for 2 hours. After the starting material disappeared as monitored by LCMS, saturated ammonium chloride aqueous solution (10 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 60 mg of compound 24.

[0703] MS(ESI) M / Z: 634.9, 636.9 [M+H] + .

[0704] 1 H NMR (300MHz, CDCl3) δ12.68(s,1H),8.87(dd,J=9.6,4.2Hz,1H),8.74-8.72(m,2H),8.43(s,1H),8.30(s,1H),7.60(s,2H),7.05(s, 1H),7.01(s,1H),4.90(d,J=8.1Hz,1H),3.95(s,3H),3.73(s,3H),3.09-2.98(m,2H),2.47-2.28(m,2H),2.18(s,3H),2.14(s,3H).

[0705] Example 25:

[0706] Preparation of compound 25

[0707]

[0708] Compound 25A:

[0709] Under nitrogen atmosphere, compound 2 (120 mg, 0.21 mmol), pinacol vinylborate (63 mg, 0.41 mmol), palladium acetate (5 mg, 0.02 mmol), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (13 mg, 0.03 mmol), and potassium phosphate (131 mg, 0.62 mmol) were dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (0.6 mL). The reaction mixture was heated to 85 °C and stirred for 4 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 70 mg of compound 25A.

[0710] MS(ESI, m / z): 530.3 [M+H] + .

[0711] Compound 25:

[0712] Compound 25A (70 mg, 0.13 mmol) was dissolved in ethanol (5 mL). Wet palladium on carbon (10%, 50 mg) was added to the reaction mixture. After purging the reaction system three times with hydrogen, the mixture was stirred at room temperature for 2 hours. After LCMS monitoring showed the starting material had disappeared, the reaction mixture was filtered through diatomaceous earth. The filter cake was washed with ethanol (5 mL × 3 times), and the resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 53 mg of compound 25A.

[0713] MS(ESI, m / z): 532.3 [M+H] + .

[0714] 1 H NMR (300MHz, CDCl3) δ10.82 (s, 1H), 8.94 (s, 1H), 8.64 (dd, J = 8.1, 4.5Hz, 1H), 8. 17(s,1H),7.80(s,1H),7.42(s,1H),7.25-7.18(m,1H),7.08-6.96(m,1H),6.96- 6.90(m,1H),6.58(s,1H),3.89(s,3H),3.83(s,3H),3.32-3.29(m,2H),3.07-3.0 4(m,5H),2.63(q,J=7.5Hz,2H),1.86(s,3H),1.82(s,3H),1.30(t,J=7.5Hz,3H).

[0715] Example 26:

[0716] Preparation of compound 26

[0717]

[0718] Compound 26A:

[0719] 2,4-Dichloro-5-trifluoromethylpyrimidine (2 g, 9.2 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by the addition of anhydrous potassium carbonate (1.5 g, 11.1 mmol) and 2-(dimethylphospho)aniline (1.6 g, 9.2 mmol). The reaction mixture was heated to 80 °C and stirred for 12 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and quenched with water (150 mL). The mixture was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (80 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 0.35 g of compound 26A.

[0720] MS(ESI)M / Z:350.1,352.1[M+H] + .

[0721] Compound 26:

[0722] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 26A (108 mg, 0.31 mmol) to prepare 41 mg of compound 26.

[0723] MS(ESI, m / z): 572.3 [M+H] + .

[0724] 1 H NMR (300MHz, CDCl3) δ10.35(s,1H),8.40-8.32(m,3H),7.49(s,1H),7.37-7.29(m,1H),7.17-6.98(m,2H) ,6.56(s,1H),3.97(s,3H),3.83(s,3H),3.31-3.27(m,2H),3.05-3.02(m,5H),1.88(s,3H),1.83(s,3H).

[0725] 19 F NMR (282MHz, CDCl3) δ-60.82.

[0726] Example 27:

[0727] Preparation of compound 27

[0728]

[0729] Compounds 6A (80 mg, 0.28 mmol) and 2A (101 mg, 0.28 mmol) were dissolved in N-methylpyrrolidone (2 mL). Then, methanesulfonic acid (81 mg, 0.84 mmol) was added to the reaction mixture. The reaction system was heated to 95 °C and stirred for 16 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was cooled to room temperature and purified by reversed-phase C18 column chromatography. Purification conditions: 80 g C18 reversed-phase column; mobile phase: water (containing 0.1% formic acid) and acetonitrile; flow rate: 50 mL / min; gradient: acetonitrile from 15% to 55% over 25 minutes; detection wavelength: 254 nm. The product was collected and concentrated under reduced pressure to give 60 mg of compound 27.

[0730] MS(ESI, m / z): 610.2, 612.2 [M+H] + .

[0731] 1 H NMR(300MHz,DMSO-d6)δ10.93(s,1H),8.39(s,1H),8.22(s,1H),8.16(s,1H),7.72(s,1H), 7.56(s,1H),7.52-7.44(m,1H),7.07-6.99(m,2H),6.57(s,1H),3.98-3.89(m,1H),3.75(br s,6H),3.22-3.18(m,2H),2.96-2.92(m,2H),1.78(s,3H), 1.73(s,3H),1.29(s,3H),1.27(s,3H).

[0732] Example 28:

[0733] Preparation of compound 28

[0734]

[0735] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 2A (162 mg, 0.45 mmol) and 16A (110 mg, 0.45 mmol) to prepare 15 mg of compound 28.

[0736] MS(ESI, m / z): 568.2, 570.2 [M+H] + .

[0737] 1H NMR(300MHz,DMSO-d6)δ10.95(s,1H),8.40(s,1H),8.18(s,1H),8.14(s,1H),7.63(s,1H),7.61(s,1H),7.51-7.44(m,1H),7.07- 6.99(m,2H),6.53(s,1H),5.87(s,1H),3.73(s,3H),3.68(s,3H),3.26-3.24(m,2H),2.98-2.94(m,2H),1.77(s,3H),1.73(s,3H).

[0738] Example 29:

[0739] Preparation of intermediate 29A

[0740]

[0741] Compound 29A-1:

[0742] Compound 1A-1 (1 g, 4 mmol), potassium carbonate (1.11 g, 8 mmol), and N-methylethanolamine (0.45 g, 6 mmol) were dissolved in N,N-dimethylformamide (20 mL). The reaction mixture was heated to 80 °C and stirred for 2 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and quenched in water (100 mL). The mixture was extracted with ethyl acetate (80 mL × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (80 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to give 1 g of compound 29A-1.

[0743] MS(ESI) M / Z: 305.0, 307.0 [M+H] + .

[0744] Compound 29A-2:

[0745] According to the method for preparing 1C-7 from 1C-6 in Example 1, the raw materials were replaced with 29A-1 (1g, 3.3mmol) and 1-(2-tetrahydropyranyl)-1H-pyrazole-5-boronate pinacol ester (1.37g, 4.92mmol) to prepare 0.15g of compound 29A-2.

[0746] MS(ESI, m / z): 377.3 [M+H] + .

[0747] Compound 29A-3:

[0748] Compound 29A-2 (300 mg, 0.8 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1 mL) and triethylsilane (185 mg, 1.6 mmol) were then added to the reaction mixture, and the mixture was stirred at room temperature for 5 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to give 90 mg of compound 29A-3.

[0749] MS(ESI)M / Z:292.9[M+H] + .

[0750] Compound 29A-4:

[0751] Triphenylphosphine (129 mg, 0.5 mmol) was dissolved in tetrahydrofuran (2 mL) under nitrogen atmosphere. Diethyl azodicarbonate (97 mg, 0.56 mmol) was added to the reaction mixture at 0 °C, and stirring was continued at 0 °C for 1 hour (until a milky white turbid liquid formed). Compound 29A-3 (90 mg, 0.31 mmol) was added to the reaction mixture, and stirring was continued at room temperature for 4 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to give 35 mg of compound 29A-4.

[0752] MS(ESI)M / Z:275.1[M+H] + .

[0753] Intermediate 29A:

[0754] According to the method for preparing 1C from intermediate 1C-9 in Example 1, the raw material was replaced with 29A-4 (35 mg, 0.13 mmol) to prepare 20 mg of compound 29A.

[0755] MS(ESI, m / z): 245.2 [M+H] + .

[0756] Preparation of compound 29

[0757]

[0758] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 2A (51.66 mg, 0.14 mmol) and 29A (35 mg, 0.14 mmol) to prepare 7.6 mg of compound 29.

[0759] MS(ESI, m / z): 568.2, 570.2 [M+H] + .

[0760] 1 H NMR (300MHz, CDCl3) δ10.58(s,1H),8.39(s,1H),8.34(s,1H),8.23(s,1H),7.39(s,1H),7.30(s,1H),7.23(s,1H),7.01(s ,2H),6.56(s,1H),6.04(s,1H),4.46-4.42(m,2H),3.95(s,3H),3.63-3.59(m,2H),2.98(s,3H),1.87(s,3H),1.83(s,3H).

[0761] Example 30:

[0762] Preparation of compound 30

[0763]

[0764] Under nitrogen atmosphere, compound 2 (300 mg, 0.52 mmol), cyclopropylboronic acid (133 mg, 1.55 mmol), potassium phosphate (328 mg, 1.55 mmol), palladium acetate (12 mg, 0.05 mmol), and tricyclohexylphosphine (14 mg, 0.05 mmol) were dissolved in a mixed solvent of toluene (2 mL) and water (0.4 mL). The reaction mixture was heated to 100 °C and stirred for 24 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was added to water (10 mL). The mixture was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 91 mg of compound 30.

[0765] MS(ESI)M / Z:544.3[M+H] + .

[0766] 1H NMR (300MHz, CDCl3) δ10.43(s,1H),8.72-8.67(m,1H),8.52(s,1H),7.95(s,1 H),7.38(s,1H),7.33-7.30(m,1H),7.27-7.15(m,2H),7.00-6.93(m,1H),6.56 (s,1H),3.91(s,3H),3.83(s,3H),3.31-3.27(m,2H),3.06-3.02(m,5H),1.87 (s,3H),1.83(s,3H),1.77-1.70(m,1H),1.10-0.99(m,2H),0.67-0.55(m,2H).

[0767] Example 31:

[0768] Preparation of intermediate 31A

[0769]

[0770] Compound 31A-1:

[0771] Compound 9A-3 (600 mg, 1.88 mmol) and sodium methoxide (5 mg, 0.09 mmol) were dissolved in methanol (12 mL). Sodium borohydride (284 mg, 7.52 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. After LCMS monitoring showed the starting material had disappeared, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 550 mg of compound 31A-1.

[0772] MS(ESI)M / Z:294.1[M+H] + .

[0773] Compound 31A-2:

[0774] Compound 31A-1 (850 mg, 2.9 mmol) and carbon tetrabromide (3.84 g, 11.59 mmol) were dissolved in tetrahydrofuran (10 mL) under nitrogen atmosphere. Triphenylphosphine (3.04 g, 11.59 mmol) was then added to the reaction mixture, and stirring was continued at room temperature for 5 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give 130 mg of compound 31A-2.

[0775] MS(ESI)M / Z:418.0,420.0,422.0[M+H] + .

[0776] Compound 31A-3:

[0777] Compound 31A-2 (880 mg, 2.1 mmol), tetrabutylammonium bromide (162 mg, 0.5 mmol), and p-methanesulfonylmethylisocyanate (451 mg, 2.3 mmol) were dissolved in dichloromethane (24 mL). Then, a solution of sodium hydroxide (428 mg, 10.71 mmol) in water (6 mL) was added to the reaction mixture at 0 °C. The reaction mixture was brought to room temperature and stirred for 16 hours. After the starting material disappeared as monitored by LCMS, the two phases were separated, and the aqueous phase was extracted with dichloromethane (20 mL). The organic phases were combined and an aqueous solution of hydrochloric acid (7 mL, 37%) was added, and the mixture was stirred at room temperature for 3 hours. The two phases were then separated, and the organic phase was washed successively with water (40 mL), saturated sodium bicarbonate (40 mL), and brine (40 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give 360 ​​mg of compound 31A-3.

[0778] MS(ESI)M / Z:288.1[M+H] + .

[0779] Compound 31A-4:

[0780] Compound 31A-3 (100 mg, 0.35 mmol) was dissolved in methanol (4 mL). Sodium borohydride (20 mg, 0.5 mmol) was then added to the reaction mixture at 0 °C. The reaction mixture was brought to room temperature and stirred for 1 hour. After the starting material disappeared as monitored by LCMS, water (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 85 mg of compound 31A-4.

[0781] MS(ESI)M / Z:290.1[M+H] + .

[0782] Intermediate 31A:

[0783] According to the method for preparing 1C from intermediate 1C-9 in Example 1, the raw material was replaced with 31A-4 (85 mg, 0.29 mmol) to prepare 65 mg of compound 31A.

[0784] MS(ESI, m / z): 260.1 [M+H] + .

[0785] Preparation of compound 31

[0786]

[0787] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 31A (65mg, 0.25mmol) to prepare 30mg of compound 31.

[0788] MS(ESI, m / z): 635.1, 637.1 [M+H] + .

[0789] 1 H NMR (300MHz, CDCl3) δ12.97(s,1H),8.87-8.70(m,3H),8.43(s,1H),8.21(s,1H),8.14(s,1H),7.59(d,J=9.6Hz,1H), 7.10(s,1H),6.80(s,1H),4.49-4.47(m,1H),3.92(s,3H),3.77(s,3H),3.24-2.95(m,5H),2.17(s,3H),2.13(s,3H).

[0790] Example 32:

[0791] Preparation of intermediate 32A

[0792]

[0793] According to the method for preparing 1B in Example 1-2, the raw material was replaced with 2-nitroaniline (5.0 g, 36.2 mmol) to prepare 3.2 g of compound 32A.

[0794] MS(ESI, m / z): 328.8, 330.8 [M+H] + .

[0795] Preparation of compound 32

[0796]

[0797] Compound 32B:

[0798] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 32A (200 mg, 0.61 mmol) to prepare 270 mg of compound 32B.

[0799] MS(ESI, m / z): 551.0, 553.0 [M+H] + .

[0800] Compound 32C:

[0801] According to the method for preparing 1C from intermediate 1C-9 in Example 1, the raw material was replaced with 32B (130 mg, 0.24 mmol) to prepare 80 mg of compound 32C.

[0802] MS(ESI, m / z): 521.2, 523.2 [M+H] + .

[0803] Compound 32:

[0804] Compound 32C (40 mg, 0.08 mmol) was dissolved in pyridine (1.5 mL) at 0 °C. Methanesulfonyl chloride (27 mg, 0.24 mmol) was then added to the reaction mixture. The reaction mixture was brought to room temperature and stirred for 3 hours. After LCMS monitoring showed the starting material had disappeared, the reaction mixture was purified using a C18 reversed-phase column. Purification conditions: 80 g C18 reversed-phase column; mobile phase: water (containing 0.1% formic acid) and acetonitrile; flow rate: 50 mL / min; gradient: acetonitrile increased from 5% to 40% over 30 minutes; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure to give 21 mg of compound 32C.

[0805] MS(ESI, m / z): 599.0, 601.0 [M+H] + .

[0806] 1 H NMR(300MHz, CDCl3)δ8.17(s,1H),8.13(s,1H),7.68-7.59(m,1H),7.49(s,1H) ),7.39(d,J=7.5Hz,1H),7.17-7.12(m,3H),6.52(s,1H),3.89(s,3H),3.85(s, 3H),3.27(s,2H),3.04(br s,5H),2.91(s,3H).

[0807] Example 33:

[0808] Preparation of intermediate 33A

[0809]

[0810] Compound 33A-1:

[0811] According to the method for preparing 24B-1 from intermediate 1C-2 in Example 24, the raw material was replaced with 1-methyl-1H-pyrazole-5-carboxaldehyde (59.7 g, 542 mmol) to prepare 80 g of compound 33A-1.

[0812] 1H NMR (300MHz, CDCl3) δ9.91 (s, 1H), 7.54 (s, 1H), 4.18 (s, 3H).

[0813] Compound 33A-2:

[0814] Compound 33A-1 (60 g, 317.4 mmol) was dissolved in ethanol (500 mL) at 0 °C. Sodium borohydride (6 g, 158.7 mmol) was then added to the reaction mixture in portions. The reaction mixture was brought to room temperature and stirred for 1 hour. After the starting material disappeared as monitored by LCMS, the reaction mixture was concentrated under reduced pressure. Water (300 mL) was added to the mixture to dilute it, and the pH was adjusted to 6 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate (300 mL × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (200 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 60 g of compound 33A-2.

[0815] MS(ESI)M / Z:191.2,193.2[M+H] + .

[0816] Compound 33A-3:

[0817] Compound 33A-2 (60 g, 314 mmol) was dissolved in dichloromethane (500 mL) at 0 °C. Then, thionyl chloride (18.68 g, 157 mmol) was added dropwise to the reaction mixture. The reaction system was brought to room temperature and stirred for 16 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was concentrated under reduced pressure. The mixture was diluted with dichloromethane (300 mL) and slowly added dropwise to a saturated sodium bicarbonate aqueous solution (300 mL). The mixture was extracted with dichloromethane (300 mL × 2 times), and the organic phases were combined. The organic phase was washed with saturated brine (300 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 62 g of compound 33A-3.

[0818] MS(ESI)M / Z:209.0,211.0[M+H] + .

[0819] Compound 33A-4:

[0820] Compound 33A-3 (62 g, 296 mmol) and sodium cyanide (17.41 g, 355 mmol) were dissolved in dimethyl sulfoxide (300 mL). The reaction mixture was heated to 50 °C and stirred for 16 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was poured into saturated sodium bicarbonate (500 mL). The mixture was extracted with ethyl acetate (300 mL × 2 times), and the organic phases were combined. The organic phase was washed with saturated brine (300 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 15 g of compound 33A-4.

[0821] MS(ESI)M / Z:200.0,202.0[M+H] + .

[0822] Compound 33A-5:

[0823] Compound 33A-4 (5 g, 25 mmol) and sodium hydroxide (10 g, 250 mmol) were dissolved in water (100 mL). The reaction mixture was heated to 100 °C and stirred for 16 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and the pH was adjusted to 1 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate (200 mL × 2 times), and the organic phases were combined. The organic phase was first washed with saturated brine (150 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5 g of compound 33A-5.

[0824] MS(ESI) M / Z: 218.7, 220.7 [M+H] + .

[0825] Compound 33A-6:

[0826] Compound 33A-5 (1 g, 4.6 mmol) was dissolved in tetrahydrofuran (10 mL) under nitrogen atmosphere. Borane-tetrahydrofuran solution (1 M, 10 mL) was then added to the reaction mixture. The reaction mixture was heated to 40 °C and stirred for 16 hours. After LCMS monitoring showed the starting material had disappeared, the reaction mixture was cooled to room temperature and slowly added to methanol (40 mL). The reaction mixture was then heated to 60 °C and stirred for 30 minutes. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 0.8 g of compound 33A-6.

[0827] MS(ESI)M / Z:205.0,207.0[M+H] + .

[0828] Compound 33A-7:

[0829] Compound 33A-6 (300 mg, 1.46 mmol) and imidazole (120 mg, 1.76 mmol) were dissolved in N,N-dimethylformamide (3 mL). Then, tert-butyldimethylchlorosilane (265 mg, 1.76 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was brought to room temperature and stirred for 2 hours. After the starting material disappeared under LC-MS monitoring, water (10 mL) was added to quench the reaction mixture. The mixture was extracted with ethyl acetate (20 mL × 2 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / methyl tert-butyl ether = 2 / 1) to give 140 mg of compound 33A-7.

[0830] MS(ESI)M / Z:319.1,321.1[M+H] + .

[0831] Compound 33A-8:

[0832] Compound 33A-7 (330 mg, 1.03 mmol) was dissolved in tetrahydrofuran (5 mL) under nitrogen atmosphere. Then, n-butyllithium (2.5 M, 0.6 mL, 1.5 mmol) was added to the reaction mixture at -78 °C, and stirring was continued at this temperature for 1 hour. Isopropanol pinacol borate (230 mg, 1.2 mmol) was added to the reaction mixture, and stirring was continued at this temperature for 1 hour. After LCMS monitoring showed the starting material had disappeared, the reaction mixture was quenched with saturated ammonium chloride aqueous solution (10 mL). The mixture was extracted with ethyl acetate (20 mL × 2 times), and the organic phases were combined. The organic phase was first washed with saturated brine (10 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / methyl tert-butyl ether = 1 / 1) to give 300 mg of compound 33A-8.

[0833] MS(ESI)M / Z:367.2[M+H] + .

[0834] Compound 33A-9:

[0835] According to the method for preparing 1C-7 from 1C-6 in Example 1, the raw materials were replaced with 33A-8 (100 mg, 0.273 mmol) and 1A-1 (55 mg, 0.22 mmol) to prepare 100 mg of compound 33A-9.

[0836] MS(ESI, m / z): 410.2 [M+H] + .

[0837] Compound 33A-10:

[0838] Compound 33A-9 (100 mg, 0.24 mmol) was dissolved in tetrahydrofuran (2 mL). A tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 1 mL) was then added to the reaction mixture, and the mixture was stirred at room temperature for 5 hours. After LCMS monitoring showed the starting material had disappeared, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 40 mg of compound 33A-10.

[0839] MS(ESI)M / Z:276.1[M+H] + .

[0840] Intermediate 33A:

[0841] According to the method for preparing 1C from intermediate 1C-9 in Example 1, the raw material was replaced with 33A-10 (40 mg, 0.15 mmol) to prepare 30 mg of compound 33A.

[0842] MS(ESI, m / z): 246.1 [M+H] + .

[0843] Preparation of compound 33

[0844]

[0845] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw material was replaced with 33A (25 mg, 0.1 mmol) to prepare 20 mg of compound 33.

[0846] MS(ESI, m / z): 621.1, 623.1 [M+H] + .

[0847] 1 H NMR (300MHz, CDCl3) δ12.66(s,1H),8.91-8.86(m,1H),8.73-8.70(m,2H),8.34(s,1H),8.29(s,1H),7.72(d,J=9.3Hz,1H),7.5 8(s,1H),6.99(s,1H),6.63(s,1H),4.40-4.36(m,2H),3.88(s,3H),3.73(s,3H),3.19-3.15(m,2H),2.18(s,3H),2.13(s,3H).

[0848] Example 34:

[0849] Preparation of intermediate 34A

[0850]

[0851]

[0852] Compound 34A-1:

[0853] 1H-pyrazole-5-carboxaldehyde (3.7 g, 38 mmol) and potassium phosphate (16 g, 77 mmol) were dissolved in N,N-dimethylformamide (50 mL). Then, p-methoxybenzyl chloride (PMB-Cl, 6 g, 38 mmol) was added to the reaction mixture. The reaction system was heated to 80 °C and stirred for 3 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was poured into water (150 mL). The mixture was extracted with ethyl acetate (100 mL × 2 times), and the organic phases were combined. The organic phase was first washed with saturated brine (100 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 4 g of compound 34A-1.

[0854] MS(ESI)M / Z:217.2[M+H] + .

[0855] Compound 34A-2:

[0856] According to the method for preparing compound 1C-1 in Example 1, the raw material was replaced with 34A-1 (2g, 9mmol) to prepare 2.6g of compound 34A-2.

[0857] MS(ESI, m / z): 287.1 [M+H] + .

[0858] Compound 34A-3:

[0859] According to the method for preparing compound 1C-2 using 1C-1 in Example 1, the raw material was replaced with 34A-2 (2.6 g, 9 mmol) to prepare 2.4 g of compound 34A-3.

[0860] MS(ESI, m / z): 289.1 [M+H] + .

[0861] Compound 34A-4:

[0862] According to the method for preparing compound 1C-3 from 1C-2 in Example 1, the raw material was replaced with 34A-3 (2.6 g, 9 mmol) to prepare 2 g of compound 34A-4.

[0863] MS(ESI, m / z): 259.1 [MH]- .

[0864] Compound 34A-5:

[0865] According to the method for preparing compound 1C-4 from 1C-3 in Example 1, the raw material was replaced with 34A-4 (2g, 7.7mmol) to prepare 1.8g of compound 34A-5.

[0866] MS(ESI, m / z): 332.2 [M+H] + .

[0867] Compound 34A-6:

[0868] According to the method for preparing compound 1C-5 from 1C-4 in Example 1, the raw material was replaced with 34A-5 (1.8g, 5.4mmol) to prepare 1.6g of compound 34A-6.

[0869] MS(ESI, m / z): 346.3 [M+H] + .

[0870] Compound 34A-7:

[0871] According to the method for preparing compound 1C-6 from 1C-5 in Example 1, the raw material was replaced with 34A-6 (2g, 5.8mmol) to prepare 2.1g of compound 34A-7.

[0872] MS(ESI,m / z):472.0[M+H] + .

[0873] Compound 34A-8:

[0874] According to the method for preparing compound 1C-7 from 1C-6 in Example 1, the raw material was replaced with 34A-7 (1.3g, 4.2mmol) to prepare 1.9g of compound 34A-8.

[0875] MS(ESI, m / z): 515.3 [M+H] + .

[0876] Compound 34A-9:

[0877] According to the method for preparing compound 1C-8 from 1C-7 in Example 1, the raw material was replaced with 34A-8 (1.9g, 3.7mmol) to prepare 1g of compound 34A-9.

[0878] MS(ESI, m / z): 415.2 [M+H] + .

[0879] Compound 34A-10:

[0880] According to the method for preparing compound 1C-9 from 1C-8 in Example 1, the raw material was replaced with 34A-9 (1g, 2.4mmol) to prepare 0.8g of compound 34A-10.

[0881] MS(ESI, m / z): 395.3 [M+H] + .

[0882] Compound 34A:

[0883] According to the method for preparing compound 1C from 1C-9 in Example 1, the raw materials were replaced with 34A-10 (300 mg, 0.76 mmol) to prepare 200 mg of compound 34A.

[0884] MS(ESI, m / z): 365.2 [M+H] + .

[0885] Preparation of compound 34

[0886]

[0887] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 34A (202 mg, 0.56 mmol) and 2A (200 mg, 0.56 mmol) to prepare 200 mg of compound 34.

[0888] MS(ESI, m / z): 688.3, ​​690.3 [M+H] + .

[0889] 1 H NMR (300MHz, CDCl3) δ10.84(s,1H),8.69-8.65(m,1H),8.31(s,1H),8.27(s,1H),7.32-7.27(m,2H),7.20-7.17(m,3H),7.05-7.00(m,1H),6.91 -6.88(m,2H),6.61(s,1H),5.16(s,2H),3.97(s,3H),3.87(s,3H),3.39 -3.37(m,2H),3.26-3.23(m,2H),3.11(s,3H),1.93(s,3H),1.89(s,3H).

[0890] Example 35:

[0891] Preparation of intermediate 35A

[0892]

[0893] Compound 35A-1:

[0894] 6-Aminoquinoxaline (10 g, 68.89 mmol) was dissolved in concentrated sulfuric acid (20 mL). Potassium nitrate (9.054 g, 89.55 mmol) was added in portions to the reaction mixture at 0 °C, and stirring was continued for 30 minutes at this temperature. After the starting material disappeared as monitored by LCMS, the reaction mixture was poured into ice water (100 g). The pH was adjusted to 8 with 1 M sodium hydroxide aqueous solution. The mixture was extracted with ethyl acetate (200 mL × 2 times), and the organic phases were combined. The organic phase was first washed with saturated brine (100 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 2 g of compound 35A-1.

[0895] MS(ESI)M / Z:191.2[M+H] + .

[0896] Intermediate 35A:

[0897] According to the method for preparing 1B in Example 1B-2, the raw material was replaced with 35A-1 (50 mg, 0.26 mmol) to prepare 40 mg of compound 35A.

[0898] MS(ESI, m / z): 381.0, 383.0 [M+H] + .

[0899] Preparation of compound 35

[0900]

[0901] Compound 35B:

[0902] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 35A (200 mg, 0.52 mmol) to prepare 130 mg of compound 35B.

[0903] MS(ESI, m / z): 603.0, 605.0 [M+H] + .

[0904] Compound 35C:

[0905] According to the method for preparing 1C from intermediate 1C-9 in Example 1, the raw material was replaced with 35B (130 mg, 0.22 mmol) to prepare 76 mg of compound 35C.

[0906] MS(ESI, m / z): 573.1, 575.1 [M+H] + .

[0907] Compound 35:

[0908] According to the method for preparing intermediate 32C in Example 32, the raw material was replaced with 35C (65mg, 0.11mmol) to prepare 33mg of compound 35.

[0909] MS(ESI, m / z): 650.9, 652.9 [M+H] + .

[0910] 1 H NMR (300MHz, CDCl3) δ9.13 (s, 1H), 8.91-8.69 (m, 2H), 8.59 (d, J = 9.3Hz, 1H), 8.27 (s, 2H), 7.59 (s,2H),7.39(s,1H),6.75(s,1H),6.53(s,1H),3.91(s,3H),3.69(s,3H),3.31(s,2H),3.03(br s,5H),2.96(s,3H).

[0911] Example 36:

[0912] Preparation of intermediate 36A

[0913]

[0914] Compound 36A-1:

[0915] Under nitrogen atmosphere, 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 13.3 mmol) was dissolved in N,N-dimethylformamide (25 mL). Then, sodium hydride (60%, 0.69 g, 17.3 mmol) was added in portions to the reaction mixture at 0 °C, and stirring was continued at this temperature for 30 minutes. 2-(trimethylsilyl)ethoxymethyl chloride (2.88 g, 17.3 mmol) was added to the reaction mixture. The reaction system was brought to room temperature and stirred for 1 hour. After LCMS monitoring showed the disappearance of the starting material, water (100 mL) was added to quench the reaction mixture. The mixture was extracted with ethyl acetate (100 mL × 2 times), and the organic phases were combined. The organic phase was first washed with saturated brine (100 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give 3.9 g of compound 36A-1.

[0916] MS(ESI)M / Z:318.1,320.1[M+H] + .

[0917] Intermediate 36A:

[0918] According to the method for preparing 1B in Example 1B-2, the raw materials were replaced with 36A-1 (1.1 mg, 3.55 mmol) and 2-(dimethylphosphono)aniline (0.5 g, 2.96 mmol) to prepare 1.1 g of compound 36A.

[0919] MS(ESI, m / z): 451.2, 452.2 [M+H] + .

[0920] Preparation of compound 36

[0921]

[0922] Compound 36B:

[0923] Under nitrogen atmosphere, compound 36A (200 mg, 0.44 mmol), 1C (126 mg, 0.49 mmol), tris(dibenzylacetone)palladium (41 mg, 0.044 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (32 mg, 0.07 mmol), and potassium carbonate (123 mg, 0.89 mmol) were dissolved in tert-butanol (8 mL). The reaction mixture was heated to 110 °C and stirred for 2 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 260 mg of compound 36B.

[0924] MS(ESI)M / Z: 673.4 [M+H] + .

[0925] Compound 36:

[0926] Compound 36B (260 mg, 0.39 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (1.5 mL) was then added to the reaction mixture, and the mixture was stirred at room temperature for 1.5 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was concentrated under reduced pressure. Methanol (5 mL) and potassium carbonate (300 mg) were added to the residue, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 45 mg of compound 36B.

[0927] MS(ESI)M / Z:543.3[M+H] + .

[0928] 1H NMR (400MHz, CDCl3) δ11.26 (s, 1H), 9.69 (s, 1H), 8.89 (dd, J = 8.4, 4.4Hz, 1H), 8.50(s,1H),7.62(s,1H),7.41(s,1H),7.30-7.14(m,2H),7.00-6.85(m,1H), 6.79(d,J=3.6Hz,1H),6.56(d,J=4.0Hz,2H),3.90(s,3H),3.82(s,3H),3.29( t,J=5.6Hz,2H),3.04(d,J=5.6Hz,2H),3.00(s,3H),1.86(s,3H),1.82(s,3H).

[0929] Example 37:

[0930] Preparation of compound 37

[0931]

[0932] Compound 34 (40 mg, 0.06 mmol) was dissolved in trifluoroacetic acid (1 mL). The reaction mixture was heated to 100 °C and stirred for 6 hours. After the starting material disappeared as monitored by LCMS, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was then prepared under high pressure (preparation conditions: reversed-phase column XBridge Shield RP18 OBD Column 30 x 150 mm, 5 μm; mobile phase A: water (0.1% formic acid); mobile phase B: acetonitrile; flow rate 25 mL / min; gradient from 10% B to 90% B over 28 minutes; detection wavelength 254 nm). 10 mg of compound 37 was obtained.

[0933] MS(ESI) M / Z: 568.0, 570.0 [M+H] + .

[0934] 1 H NMR(300MHz, CDCl3)δ10.71(s,1H),8.45-8.43(m,2H),8.22(s,1H),7.55(s,1H),7.35-7.30(m,3H),7.18 -7.11(m,1H),7.02-6.98(m,1H),6.61(s,1H),3.92(s,3H),3.31-3.06(m,7H),1.89(s,3H),1.85(s,3H).

[0935] Example 38:

[0936] Preparation of intermediate 38A

[0937]

[0938] Compound 24B (100 mg, 0.39 mmol) and triethylsilane (226 mg, 1.9 mmol) were dissolved in trifluoroacetic acid (4 mL). The reaction mixture was heated to 60 °C and stirred for 5 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column. Purification conditions: 40 g C18 reversed-phase column; mobile phase: water (containing 0.1% formic acid) and acetonitrile; flow rate: 35 mL / min; gradient: acetonitrile from 5% to 95% over 20 minutes; detection wavelength: 254 nm. The product was collected, lyophilized under reduced pressure, to give 90 mg of compound 38A.

[0939] MS(ESI,m / z):244.2[M+H] + .

[0940] Preparation of compound 38

[0941]

[0942] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 38A (90 mg, 0.37 mmol) and 2A (133 mg, 0.37 mmol) to prepare 10 mg of compound 38.

[0943] MS(ESI, m / z): 567.2, 569.2 [M+H] + .

[0944] 1 H NMR(400MHz, CDCl3)δ10.80(s,1H),8.45-8.42(m,1H),8.31(s,1H),8.18(s,1H),7.52(s,1H)7.32-7.28(m,1H),7.18-7.12(m,2H),7.03 -6.99(m,1H),6.66(s,1H),3.88(s,3H),3.78(s,3H),2.93-2.89(m,2H),2.81-2.79(m,2H),2.14-2.07(m,2H),1.86(s,3H),1.83(s,3H).

[0945] Example 39:

[0946] Preparation of compound 39

[0947]

[0948] Compound 37 (100 mg, 0.18 mmol) and potassium carbonate (49 mg, 0.35 mmol) were dissolved in N,N-dimethylformamide (2 mL). Iodoethane (41 mg, 0.26 mmol) was added to the reaction mixture. The reaction system was heated to 50 °C and stirred for 2 hours. After the starting material disappeared under LCMS monitoring, the reaction mixture was cooled to room temperature and water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL × 2 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 10 mg of compound 39.

[0949] MS(ESI)M / Z:595.9,597.9[M+H] + .

[0950] 1 H NMR (300MHz, CDCl3) δ10.78 (s, 1H), 8.63 (dd, J = 8.4, 4.5Hz, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 7.26-7. 18(m,2H),7.10(s,1H),6.98-6.93(m,1H),6.54(s,1H),3.99(q,J=7.2Hz,2H),3.89(s,3H),3.30(br s,2H),3.15(br s,2H),3.03(s,3H),1.87(s,3H),1.82(s,3H),1.37(t,J=7.2Hz,3H).

[0951] Example 40:

[0952] Preparation of intermediate 40A

[0953]

[0954] Compound 40A-1:

[0955] According to the method for preparing compound 24 using 24C in Example 24, the raw material was replaced with 24B (700 mg, 2.72 mmol) to prepare 400 mg of compound 40A-1.

[0956] MS(ESI, m / z): 260.1 [M+H] + .

[0957] Compound 40A-2:

[0958] Compound 40A-1 (400 mg, 1.54 mmol) was dissolved in 1,2-dichloroethane (8 mL). Then, m-chloroperoxybenzoic acid (799 mg, 4.63 mmol) was added to the reaction mixture. The reaction system was heated to 80 °C and stirred for 1 hour. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and water (20 mL) was added. The mixture was extracted with dichloromethane (20 mL × 2 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 160 mg of compound 40A-2.

[0959] MS(ESI, m / z): 290.1 ​​[M+H] + .

[0960] Compound 40A-3:

[0961] Compound 40A-2 (75 mg, 0.26 mmol) was added to N,N-dimethylformamide (2 mL) under nitrogen atmosphere. Then, sodium hydride (60%, 31 mg, 0.78 mmol) was added in portions to the reaction mixture at 0 °C, and stirring was continued at this temperature for 30 minutes. Iodomethane (110 mg, 0.78 mmol) was added to the reaction mixture. The reaction system was brought to room temperature and stirred for 2 hours. After the starting material disappeared as monitored by LCMS, water (20 mL) was added to quench the reaction mixture. The mixture was extracted with ethyl acetate (20 mL × 2 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 75 mg of compound 40A-3.

[0962] MS(ESI)M / Z:304.1[M+H] + .

[0963] Intermediate 40A:

[0964] According to the method for preparing compound 8A in Example 8-9, the raw materials were replaced with 40A-3 (75 mg, 0.25 mmol) to prepare 65 mg of compound 40A.

[0965] MS(ESI,m / z):274.1[M+H] + .

[0966] Preparation of compound 40

[0967]

[0968] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 40A (65 mg, 0.24 mmol) and 2A (86 mg, 0.24 mmol) to prepare 10 mg of compound 40.

[0969] MS(ESI, m / z): 564.9, 566.9 [M+H] + .

[0970] 1 H NMR (400MHz, CDCl3) δ10.70(s,1H),8.53-8.34(m,2H),8.23(s,1H),7.76(s,1H),7.34-7.28(m,1H),7.16-7.12(m,2H),7.03-6.99(m,1 H),6.74(s,1H),6.51(d,J=11.2Hz,1H),5.82-5.76(m,1H),3.92(s,3H),3.86(s,3H),3.33(d,J=6.0Hz,2H),1.87(s,3H),1.84(s,3H).

[0971] Example 41:

[0972] Preparation of intermediate 41A

[0973]

[0974] Compound 41A-1:

[0975] Compound 6A-4 (500 mg, 1.8 mmol) and triethylamine (553 mg, 5.5 mmol) were dissolved in dichloromethane (10 mL). Then, bromoacetyl bromide (736 mg, 3.65 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was brought to room temperature and stirred for 16 hours. After the starting material disappeared as monitored by LCMS, water (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL × 2 times), and the organic phases were combined. The organic phase was washed with saturated brine (30 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 720 mg of compound 41A-1.

[0976] MS(ESI)M / Z:395.0,397.0[M+H] + .

[0977] Compound 41A-2:

[0978] Compound 41A-1 (670 mg, 1.7 mmol) and diisopropylethylamine (657 mg, 5.09 mmol) were dissolved in N,N-dimethylformamide (15 mL). Subsequently, 4-fluoropiperidine hydrochloride (355 mg, 2.54 mmol) was added to the reaction mixture, and stirring was continued at room temperature for 16 hours. After LCMS monitoring showed the disappearance of the starting material, water (50 mL) was added to quench the reaction mixture. The mixture was extracted with ethyl acetate (50 mL × 2 times), and the organic phases were combined. The organic phase was first washed with saturated brine (50 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 690 mg of compound 41A-2.

[0979] MS(ESI)M / Z:417.9[M+H] + .

[0980] Compound 41A-3:

[0981] According to the method for preparing 11A-1 from 9A-4 in Example 11, the raw material was replaced with 41A-2 (450 mg, 1.08 mmol) to prepare 298 mg of compound 41A-3.

[0982] MS(ESI, m / z): 404.1 [M+H] + .

[0983] Intermediate 41A:

[0984] According to the method for preparing compound 1C using 1C-9 in Example 1, the raw material was replaced with 41A-3 (100 mg, 0.25 mmol) to prepare 90 mg of compound 41A.

[0985] MS(ESI, m / z): 374.1 [M+H] + .

[0986] Preparation of compound 41

[0987]

[0988] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 41A (90 mg, 0.24 mmol) and 2A (87 mg, 0.24 mmol) to prepare 64 mg of compound 41.

[0989] MS(ESI, m / z): 697.1, 699.1 [M+H] + .

[0990] 1H NMR (300MHz, CDCl3) δ10.57(s,1H),8.53-8.39(m,2H),8.24(s,1H),7.39-7.29(m,2H),7.28-7.16(m,2H),7.05-6.94(m,1H),6.59(s,1H),4.88 -4.72(m,1H),3.91(s,3H),3.84(s,3H),3.75-3.70(m,2H),3.39-3.35( m,2H),3.10-2.65(m,8H),2.23-1.91(m,4H),1.89(s,3H),1.85(s,3H).

[0991] Example 42:

[0992] Preparation of intermediate 42A

[0993]

[0994] Compound 42A-1:

[0995] Ethyl 5-bromothiazol-4-carboxylate (10 g, 42.36 mmol) was dissolved in dichloromethane (80 mL) under nitrogen atmosphere. Then, a toluene solution of diisobutylaluminum hydride (1.5 M, 56.5 mL, 84.74 mmol) was added to the reaction mixture at -78 °C, and stirring was continued at this temperature for 3 hours. After LC-MS monitoring showed the starting material had disappeared, a saturated aqueous solution of sodium potassium tartrate (200 mL) and dichloromethane (100 mL) were added to the reaction mixture, and stirring was continued at room temperature for 1 hour. The mixture was extracted with dichloromethane (100 mL × 2 times), and the organic phases were combined. The organic phase was first washed with saturated brine (100 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 6 g of compound 42A-1.

[0996] MS(ESI, m / z): 191.9, 193.9 [M+H] + .

[0997] Compound 42A-2:

[0998] According to the method for preparing compound 1C-1 in Example 1, the raw material was replaced with 42A-1 (6g, 31.25mmol) to prepare 7.4g of compound 42A-2.

[0999] MS(ESI, m / z): 261.7, 263.7 [M+H] + .

[1000] Compound 42A-3:

[1001] Compound 42A-2 (7.4 g, 28.23 mmol), sodium acetate (4.63 g, 56.46 mmol), and p-toluenesulfonyl hydrazine (21.03 g, 112.9 mmol) were dissolved in ethanol (80 mL). The reaction mixture was heated to 90 °C and stirred for 3 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water (100 mL) was added to the residue. The mixture was extracted with ethyl acetate (100 mL × 2 times), and the organic phases were combined. The organic phase was washed with saturated brine (100 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give 6.4 g of compound 42A-3.

[1002] MS(ESI) M / Z: 263.9, 265.9 [M+H] + .

[1003] Compound 42A-4:

[1004] Compound 42A-3 (3.3 g, 12.49 mmol) was dissolved in a mixed solvent of tetrahydrofuran (30 mL) and methanol (10 mL). Lithium hydroxide (1.2 g, 49.97 mmol) and water (10 mL) were added to the reaction mixture. The reaction system was heated to 50 °C and stirred for 5 hours. After LCMS monitoring showed the starting material had disappeared, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water (20 mL) was added to dilute the reaction mixture, and the pH was adjusted to 4 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (100 mL × 2 times), and the organic phases were combined. The organic phase was washed with saturated brine (50 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2.5 g of compound 42A-4.

[1005] MS(ESI)M / Z: 234.0, 236.0 [MH] - .

[1006] Compound 42A-5:

[1007] According to the method for preparing compound 1C-4 from 1C-3 in Example 1, the raw material was replaced with 42A-4 (3g, 12.7mmol) to prepare 2.5g of compound 42A-5.

[1008] MS(ESI, m / z): 306.8, 308.8 [M+H] + .

[1009] Compound 42A-6:

[1010] According to the method for preparing compound 1C-7 from 1C-6 in Example 1, the raw material was replaced with 42A-5 (2.5g, 8.14mmol) to prepare 2.8g of compound 42A-6.

[1011] MS(ESI, m / z): 398.1 [M+H] + .

[1012] Compound 42A-7:

[1013] Compound 42A-6 (1 g, 2.52 mmol) was dissolved in dichloromethane (10 mL). A solution of ethyl acetate containing hydrogen chloride (4 M, 5 mL) was then added to the reaction mixture, and stirring was continued at room temperature for 1 hour. After the starting material was observed to have disappeared under LCMS monitoring, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (10 mL), and potassium carbonate (1.74 g, 12.6 mmol) was added. The reaction mixture was heated to 90 °C and stirred for 1 hour. After the starting material was observed to have disappeared under LCMS monitoring, the reaction mixture was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (50 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 0.4 g of compound 42A-7.

[1014] MS(ESI)M / Z:277.9[M+H] + .

[1015] Compound 42A-8:

[1016] According to the method for preparing compound 8A-9 from 8A-8 in Example 8, the raw material was replaced with 42A-7 (150 mg, 0.54 mmol) to prepare 117 mg of compound 42A-8.

[1017] MS(ESI,m / z):292.2[M+H] + .

[1018] Intermediate 42A:

[1019] According to the method for preparing compound 1C from 1C-9 in Example 1, the raw materials were replaced with 42A-8 (117 mg, 0.4 mmol) to prepare 92 mg of compound 42A.

[1020] MS(ESI, m / z): 262.3 [M+H] + .

[1021] Preparation of compound 42

[1022]

[1023] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 42A (70 mg, 0.27 mmol) and 2A (96 mg, 0.27 mmol) to prepare 35 mg of compound 42.

[1024] MS(ESI, m / z): 585.1, 587.1 [M+H] + .

[1025] 1 H NMR (300MHz, CDCl3) δ10.75(s,1H),8.47(s,1H),8.45-8.40(m,1H),8.37(s,1H),8.22(s,1H),7.55 (s,1H),7.26-7.21(m,1H),7.15-7.09(m,1H),6.97-6.92(m,1H),6.54(s,1H),3.93(s,3H),3.36(br s,4H),3.08(s,3H),1.89(s,3H),1.85(s,3H).

[1026] Example 43:

[1027] Preparation of intermediate 43A

[1028]

[1029] Compound 43A-1

[1030] Under nitrogen atmosphere, 2-iodo-4-fluoroaniline (3 g, 12.66 mmol), dimethylphosphine oxide (1.18 g, 15.2 mmol), palladium acetate (142 mg, 0.63 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (549 mg, 0.95 mmol), and diisopropylethylamine (3.27 g, 25.32 mmol) were dissolved in N,N-dimethylformamide (30 mL). The reaction mixture was heated to 120 °C and stirred for 16 hours. After the starting material disappeared as monitored by LCMS, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 0.65 g of compound 43A-1.

[1031] MS(ESI)M / Z:187.9[M+H] + .

[1032] Intermediate 43A:

[1033] According to the method for preparing 2A in Example 2, the raw material was replaced with 43A-1 (450 mg, 2.4 mmol) to prepare 200 mg of compound 43A.

[1034] MS(ESI, m / z): 377.6, 379.6 [M+H] + .

[1035] Preparation of compound 43

[1036]

[1037] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw material was replaced with 43A (33 mg, 0.087 mmol) to prepare 10 mg of compound 43.

[1038] MS(ESI, m / z): 600.2, 602.2 [M+H] + .

[1039] 1 H NMR(300MHz, CDCl3)δ10.39(s,1H),8.36-8.30(m,2H),8.20(s,1H),7.46(s,1H),7.18(s, 1H),7.01-6.93(m,1H),6.77-6.71(m,1H),6.57(s,1H),3.92(s,3H),3.84(s,3H),3.32(br s,2H),3.06(br s,5H),1.89(s,3H),1.85(s,3H).

[1040] Example 44:

[1041] Preparation of intermediate 44A

[1042]

[1043] Compound 44A-1:

[1044] According to the method for preparing 43A in Example 43, the raw material was replaced with 2-iodo-3-aminopyridine (500 mg, 2.27 mmol) to prepare 300 mg of compound 44A-1.

[1045] MS(ESI, m / z): 171.1 [M+H] + .

[1046] Intermediate 44A:

[1047] According to the method for preparing 2A in Example 2, the raw material was replaced with 44A-1 (800 mg, 4.7 mmol) to prepare 730 mg of compound 44A.

[1048] MS(ESI, m / z): 360.9, 362.9 [M+H] + .

[1049] Preparation of compound 44

[1050]

[1051] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw material was replaced with 44A (80 mg, 0.22 mmol) to prepare 33 mg of compound 44.

[1052] MS(ESI, m / z): 583.1, 585.1 [M+H] + .

[1053] 1 H NMR (300MHz, CDCl3) δ11.04(s,1H),9.01-8.96(m,1H),8.29(s,1H),8.24(s,1H),8.19-8.17( m,1H),7.48(s,1H),7.19(s,1H),6.96(s,1H),6.58(s,1H),3.91(s,3H),3.85(s,3H),3.32(br s,2H),3.07(br s,5H),1.91(s,3H),1.86(s,3H).

[1054] Example 45:

[1055] Preparation of compound 45

[1056]

[1057] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 14A (60 mg, 0.19 mmol) and 6A (49 mg, 0.19 mmol) to prepare 49 mg of compound 45.

[1058] MS(ESI, m / z): 566.1, 568.1 [M+H] + .

[1059] 1H NMR(300MHz, CDCl3)δ10.79(s,1H),8.64-8.59(m,1H),8.42(s,1H),8.13(s,1H),7. 38(s,1H),7.31-7.23(m,1H),7.19(s,2H),7.01-6.95(m,1H),6.58(s,1H),3.88(br s,4H),3.82(s,3H),3.30(br s,2H),2.95(br s,2H),1.87(s,3H),1.83(s,3H),1.33(s,3H),1.27(s,3H).

[1060] Example 46:

[1061] Preparation of intermediate 46A

[1062]

[1063] Compound 46A-1:

[1064] Compound 31A-1 (180 mg, 0.61 mmol) was dissolved in 50% sulfuric acid aqueous solution (5 mL). The reaction system was heated to 85 °C and stirred for 4 hours. After the starting material disappeared under LCMS monitoring, the reaction solution was cooled to room temperature and the pH was adjusted to 8 with 1 M sodium hydroxide. The mixture was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (30 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give 35 mg of compound 46A-1.

[1065] MS(ESI)M / Z:276.0[M+H] + .

[1066] Intermediate 46A:

[1067] According to the method for preparing compound 1C from 1C-9 in Example 1, the raw material was replaced with 46A-1 (45 mg, 0.16 mmol) to prepare 35 mg of compound 46A.

[1068] MS(ESI, m / z): 246.1 [M+H] + .

[1069] Preparation of compound 46

[1070]

[1071] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 46A (35 mg, 0.14 mmol) and 2A (51 mg, 0.14 mmol) to prepare 19 mg of compound 46.

[1072] MS(ESI, m / z): 569.2, 571.2 [M+H] + .

[1073] 1 H NMR (400MHz, CDCl3) δ10.55(s,1H),8.56(s,1H),8.42(dd,J=8.4,4.4Hz,1H),8.26(s,1H),7.57(s,1H),7.37-7.30(m,1H),7.25-7.2 1(m,1H),7.10(s,1H),7.08-6.99(m,1H),6.71(s,1H),5.04(s,2H),4.64(s,2H),3.90(s,3H),3.74(s,3H),1.88(s,3H),1.85(s,3H).

[1074] Example 47:

[1075] Preparation of intermediate 47A

[1076]

[1077] Compound 47A-1:

[1078] Compound 10A-1 (200 mg, 0.61 mmol), N-methyl-4-piperidinone (342 mg, 3.03 mmol), and sodium acetate (99 mg, 1.21 mmol) were dissolved in methanol (3 mL) and stirred at room temperature for 30 minutes. Acetic acid (73 mg, 1.21 mmol) and sodium cyanoborohydride (76 mg, 1.21 mmol) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 16 hours. After the starting material was observed to have disappeared under LCMS monitoring, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (3 mL) and potassium carbonate (200 mg) was added. The reaction mixture was heated to 110 °C and stirred for 3 hours. After the starting material was observed to have disappeared under LCMS monitoring, the reaction mixture was cooled to room temperature and poured into water (30 mL). The mixture was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (50 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 160 mg of compound 47A-1.

[1079] MS(ESI)M / Z:372.2[M+H] + .

[1080] Intermediate 47A:

[1081] According to the method for preparing compound 1C from 1C-9 in Example 1, the raw material was replaced with 47A-1 (160 mg, 0.43 mmol) to prepare 130 mg of compound 47A.

[1082] MS(ESI, m / z): 342.2 [M+H] + .

[1083] Preparation of compound 47

[1084]

[1085] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 47A (130 mg, 0.38 mmol) and 2A (137 mg, 0.38 mmol) to prepare 44 mg of compound 47.

[1086] MS(ESI, m / z): 665.0, 667.0 [M+H] + .

[1087] 1 H NMR(300MHz, CDCl3)δ10.57(s,1H),8.49-8.45(m,2H),8.24(s,1H),7.35-7 .17(m,4H),7.03-6.98(m,1H),6.52(s,1H),3.86(s,3H),3.80(s,3H),3.52- 3.45(m,1H),3.43-3.36(m,4H),2.94(t,J=5.7Hz,2H),2.59(s,3H),2.57-2 .50(m,2H),2.31-2.15(m,2H),2.02-1.92(m,2H),1.86(s,3H),1.82(s,3H).

[1088] Example 48:

[1089] Preparation of intermediate 48A

[1090]

[1091] Compound 48A-1:

[1092] Under nitrogen atmosphere, compound 1A-1 (2 g, 8.0 mmol), trimethylsilylacetylene (2.36 g, 24 mmol), tetrakis(triphenylphosphine)palladium (1.85 g, 1.6 mmol), and cuprous iodide (0.15 g, 0.8 mmol) were dissolved in triethylamine (20 mL). The reaction mixture was heated to 80 °C and stirred for 16 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 15 / 1) to give 1.73 g of compound 48A-1.

[1093] 1 H NMR (400MHz, CDCl3) δ8.07 (d, J = 7.2 Hz, 1H), 6.79 (d, J = 10.4 Hz, 1H), 3.97 (s, 3H), 0.26 (s, 9H).

[1094] Compound 48A-2:

[1095] Compound 48A-1 (2.6 g, 9.7 mmol) and ethyl azide (1.26 g, 9.7 mmol) were dissolved in toluene (30 mL). The reaction mixture was heated to 100 °C and stirred for 2 days. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give 2.8 g of compound 48A-2.

[1096] MS(ESI, m / z): 397.2 [M+H] + .

[1097] 1 H NMR(300MHz, CDCl3)δ7.95(d,J=7.5Hz,1H),6.96(d,J=10.5Hz,1H), 5.03 (s, 2H), 4.20 (q, J = 7.2Hz, 2H), 4.07 (s, 3H), 1.25 (t, J = 7.2Hz, 3H), 0.23 (s, 9H).

[1098] Compound 48A-3:

[1099] Compound 48A-2 (2.8 g, 7.1 mmol) was dissolved in tetrahydrofuran (20 mL) at 0 °C. Tetrabutylammonium fluoride (1.85 g, 7.1 mmol) was then added to the reaction mixture. The reaction mixture was brought to room temperature and stirred for 2 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 1 g of compound 48A-3.

[1100] MS(ESI, m / z): 325.1 [M+H] + .

[1101] Compound 48A-4:

[1102] According to the method for preparing compound 42A-4 from 42A-3 in Example 42, the raw material was replaced with 48A-3 (300 mg, 0.9 mmol) to prepare 200 mg of compound 48A-4.

[1103] MS(ESI,m / z):297.1[M+H] + .

[1104] Compound 48A-5:

[1105] Compound 48A-4 (300 mg, 1.0 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (501 mg, 1.3 mmol) were dissolved in N,N-dimethylformamide (5 mL) and stirred at room temperature for 30 min. Then, methylamine hydrochloride (137 mg, 2.0 mmol) and diisopropylethylamine (524 mg, 4.1 mmol) were added to the reaction mixture, and stirring was continued at room temperature for 16 h. After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was purified by a C18 reversed-phase column. Purification conditions: 40 g C18 reversed-phase column; mobile phase: water (containing 10 mM ammonium bicarbonate) and acetonitrile; flow rate: 35 mL / min; gradient: acetonitrile from 20% to 70% over 20 min; detection wavelength: 254 nm. The product was collected, lyophilized under reduced pressure to give 100 mg of compound 48A-5.

[1106] MS(ESI, m / z): 310.1 [M+H] + .

[1107] Compound 48A-6:

[1108] Compound 48A-5 (100 mg, 0.3 mmol) and potassium carbonate (89 mg, 0.6 mmol) were dissolved in N,N-dimethylformamide (1 mL). The reaction mixture was heated to 80 °C and stirred for 1 hour. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature. The reaction mixture was purified by C18 reversed-phase column. Purification conditions: 40 g C18 reversed-phase column; mobile phase: water (containing 10 mM ammonium bicarbonate) and acetonitrile; flow rate: 35 mL / min; gradient: acetonitrile from 20% to 60% over 20 minutes; detection wavelength: 254 nm. The product was collected, lyophilized under reduced pressure, to give 45 mg of compound 48A-6.

[1109] MS(ESI, m / z): 290.1 ​​[M+H] + .

[1110] Intermediate 48:

[1111] Compound 48A-6 (45 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL). Borane dimethyl sulfide (59 mg, 0.78 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. After LCMS monitoring showed the starting material had disappeared, methanol (1 mL) was slowly added to quench the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was dissolved in ethanol (2 mL) and water (0.4 mL). Iron powder (43 mg, 0.78 mmol) and ammonium chloride (13 mg, 0.23 mmol) were then added. The reaction mixture was heated to 80 °C and stirred for 2 hours. After LCMS monitoring showed the starting material had disappeared, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to obtain 40 mg of crude compound 48A.

[1112] MS(ESI, m / z): 246.2 [M+H] + .

[1113] Preparation of compound 48

[1114]

[1115] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 48A (40 mg, 0.16 mmol) and 2A (41 mg, 0.1 mmol) to prepare 25 mg of compound 48.

[1116] MS(ESI, m / z): 568.9, 570.9 [M+H] + .

[1117] 1 H NMR (300MHz, CDCl3) δ10.67(s,1H),8.49(s,1H),8.32(s,1H),8.23(s,1H),7.40-7.33(m,1H),7.55(m,1H),7.15-7 .03(m,3H),6.53(s,1H),4.77-4.67(m,2H),3.97(s,3H),3.60-3.57(m,2H),3.09(s,3H),1.91(s,3H),1.87(s,3H).

[1118] Example 49:

[1119] Preparation of intermediate 49A

[1120]

[1121] Compound 49A-1:

[1122] According to the method for preparing compound 9A-4 from 9A-3 in Example 9, the raw material was replaced with 2,4-dimethoxybenzylamine (786 mg, 4.7 mmol) to prepare 410 mg of compound 49A-1.

[1123] MS(ESI, m / z): 439.1 [M+H] + .

[1124] Compound 49A-2:

[1125] According to the method for preparing compound 1C from 1C-9 in Example 1, the raw material was replaced with 49A-1 (380 mg, 0.87 mmol) to prepare 308 mg of compound 49A-2.

[1126] MS(ESI, m / z): 409.2 [M+H] + .

[1127] Intermediate 49A:

[1128] According to the method for preparing compound 11A-1 from 9A-4 in Example 11, the raw material was replaced with 49A-1 (250 mg, 0.61 mmol) to prepare 212 mg of compound 49A.

[1129] MS(ESI, m / z): 395.2 [M+H] + .

[1130] Preparation of compound 49

[1131]

[1132] Compound 49B:

[1133] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 49A (100 mg, 0.25 mmol) and 2A (91 mg, 0.25 mmol) to prepare 117 mg of compound 49B.

[1134] MS(ESI, m / z): 718.1, 720.1 [M+H] + .

[1135] Compound 49:

[1136] According to the method for preparing compound 37 in Example 37, 34, the raw material was replaced with 49B (100 mg, 0.14 mmol) to prepare 26 mg of compound 49.

[1137] MS(ESI,m / z):568.1.1,570.1[M+H] + .

[1138] 1 H NMR (300MHz, CDCl3) δ10.60(s,1H),8.56(s,1H),8.47(dd,J=8.7,4.5Hz,1H),8.27(s,1H),7.50(s,1H),7.38-7.31(m,1H),7.25(d,J=8 .1Hz,1H),7.19(s,1H),7.09-7.04(m,1H),6.70(s,1H),4.27(s,2H),3.97(s,2H),3.92(s,3H),3.79(s,3H),1.90(s,3H),1.85(s,3H).

[1139] Example 50:

[1140] Preparation of intermediate 50A

[1141]

[1142] Compound 50A-1:

[1143] Compound 40A-2 (150 mg, 0.52 mmol) and triphenylphosphine (204 mg, 0.78 mmol) were dissolved in tetrahydrofuran (5 mL) under nitrogen atmosphere. Diethyl azodicarbonate (135 mg, 0.78 mmol) was then added to the reaction mixture at 0 °C. The reaction mixture was brought to room temperature and stirred for 16 hours. After the starting material disappeared as monitored by LC-MS, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give 70 mg of compound 50A-1.

[1144] MS(ESI,m / z):419.0[M+1] + .

[1145] Intermediate 50A:

[1146] According to the method for preparing compound 1C from 1C-9 in Example 1, the raw material was replaced with 50A-1 (65 mg, 0.16 mmol) to prepare 56 mg of compound 50A.

[1147] MS(ESI, m / z): 389.2 [M+H] + .

[1148] Preparation of Compound 50

[1149]

[1150] Compound 50B:

[1151] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 50A (56 mg, 0.14 mmol) and 2A (52 mg, 0.14 mmol) to prepare 38 mg of compound 50B.

[1152] MS(ESI, m / z): 712.1, 714.1 [M+H] + .

[1153] Compound 50:

[1154] Compound 50B (38 mg, 0.05 mmol) was dissolved in methanol (2 mL). Hydrazine hydrate (27 mg, 0.54 mmol) was then added to the reaction mixture, and stirring was continued at room temperature for 2 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified using a C18 reversed-phase column. Purification conditions: 40 g C18 reversed-phase column; mobile phase: water (containing 0.1% formic acid) and acetonitrile; flow rate: 35 mL / min; gradient: acetonitrile from 15% to 55% over 25 minutes; detection wavelength: 254 nm. The product was collected, lyophilized under reduced pressure, to give 8 mg of compound 50.

[1155] MS(ESI, m / z): 582.1, 584.1 [M+H] + .

[1156] 1 H NMR(300MHz, CDCl3)δ10.53(s,1H),8.55(s,1H),8.40(s,1H),8.23(s,1H),8.22(s,1H)7.50(s,1H) ,7.19(s,1H)7.21(s,2H),7.03(s,1H),6.85(s,1H),4.35(s,1H),3.89(s,3H),3.75(s,3H),2.91(br s,2H),2.22(br s,2H),2.24(br s,2H),1.88(s,3H).

[1157] Example 51:

[1158] Preparation of intermediate 51A

[1159]

[1160] Compound 33-5 (4.9 g, 22.37 mmol) was dissolved in methanol (50 mL). Then, thionyl chloride (3.99 g, 33.56 mmol) was added dropwise to the reaction solution at 0 °C. The reaction solution was brought to room temperature and stirred for 16 hours. After the starting material disappeared as monitored by LCMS, the reaction solution was concentrated under reduced pressure and water (50 mL) was added. The pH was adjusted to 7 with sodium hydroxide (1 N) at 0 °C. The mixture was extracted with dichloromethane (50 mL × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (50 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4.4 g of compound 51A.

[1161] MS(ESI)M / Z:233.1,235.1[M+H] + .

[1162] Preparation of intermediate 51B

[1163]

[1164] Compound 51B-1:

[1165] Compounds 2-methoxy-3-nitro-6-chloropyridine (5 g, 26.5 mmol) and 2,4-dimethoxybenzamine (4.43 g, 26.5 mmol) were dissolved in acetonitrile (50 mL) and N,N-dimethylformamide (25 mL). Triethylamine (2.68 g, 26.5 mmol) was then added to the reaction mixture, and stirring was continued at room temperature for 5 hours. After the starting material disappeared under LC-MS monitoring, water (200 mL) was added to quench the reaction mixture. The mixture was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (80 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 6 g of compound 51B-1.

[1166] MS(ESI)M / Z:320.1[M+H] + .

[1167] Compound 51B-2:

[1168] Compound 51B-1 (6 g, 18.79 mmol) was dissolved in N,N-dimethylformamide (50 mL). N-bromosuccinimide (6.69 g, 37.58 mmol) was then added to the reaction mixture, and stirring was continued at room temperature for 16 hours. After LCMS monitoring showed the disappearance of the starting material, water (300 mL) was added to quench the reaction mixture. The mixture was extracted with ethyl acetate (300 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (200 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 7 g of compound 51B-2.

[1169] MS(ESI)M / Z:475.9,477.9,479.9[M+H] + .

[1170] Compound 51B-3:

[1171] According to the method for preparing compound 37 in Example 37, 34, the raw material was replaced with 51B-2 (6.5g, 13.63mmol) to prepare 3g of compound 51B-3.

[1172] MS(ESI, m / z): 248.1, 250.1 [M+H] + .

[1173] Compound 51B-4:

[1174] According to the method for preparing compound 1A in Example 1A-1, the raw material was replaced with 51B-3 (3g, 12.1mmol) to prepare 1.5g of compound 51B-4.

[1175] MS(ESI, m / z): 296.1 [M+H] + .

[1176] Compound 51B-5:

[1177] Under nitrogen atmosphere, compound 51B-4 (1 g, 3.39 mmol), 51A (658 mg, 2.82 mmol), methanesulfonic acid (tri-tert-butylphosphino) (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (162 mg, 0.28 mmol), tri-tert-butylphosphine tetrafluoroborate (82 mg, 0.28 mmol), and potassium phosphate (1199 mg, 5.65 mmol) were dissolved in a mixed solvent of dioxane (20 mL) and water (0.2 mL). The reaction mixture was heated to 60 °C and stirred for 16 hours. After the starting material disappeared as monitored by LCMS, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 3) to give 760 mg of compound 51B-5.

[1178] MS(ESI)M / Z:322.2[M+H] + .

[1179] Compound 51B-6:

[1180] Compound 51B-5 (260 mg, 0.81 mmol) was dissolved in a mixed solvent of tetrahydrofuran (4 mL), methanol (2 mL), and water (2 mL). Lithium hydroxide (39 mg, 1.62 mmol) was added to the reaction mixture, and stirring was continued at room temperature for 2 hours. After LCMS monitoring showed the starting material had disappeared, the reaction mixture was concentrated under reduced pressure and the pH was adjusted to 3 with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 170 mg of crude compound 51B-6.

[1181] MS(ESI)M / Z:308.1[M+H] + .

[1182] Compound 51B-7:

[1183] Compound 51B-6 (400 mg, 1.3 mmol) was dissolved in N,N-dimethylformamide (5 mL). 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (594 mg, 1.56 mmol) and N,N-diisopropylethylamine (505 mg, 3.91 mmol) were added to the reaction mixture, and stirring was continued at room temperature for 16 hours. After LCMS monitoring showed the disappearance of the starting material, water (20 mL) was added to quench the reaction mixture. The mixture was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 300 mg of crude compound 51B-7.

[1184] MS(ESI)M / Z:290.1[M+H] + .

[1185] Compound 51B-8:

[1186] According to the method for preparing compound 11A-1 from 9A-4 in Example 11, the raw material was replaced with 51B-7 (170 mg, 0.59 mmol) to prepare 140 mg of compound 51B-8.

[1187] MS(ESI, m / z): 276.1 [M+H] + .

[1188] Compound 51B:

[1189] According to the method for preparing compound 1C using 1C-9 in Example 1, the raw material was replaced with 51B-8 (140 mg, 0.51 mmol) to prepare 53 mg of compound 51B.

[1190] MS(ESI, m / z): 246.1 [M+H] + .

[1191] Preparation of compound 51

[1192]

[1193] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 51B (57 mg, 0.23 mmol) and 2A (84 mg, 0.23 mmol) to prepare 14 mg of compound 51.

[1194] MS(ESI, m / z): 569.1, 571.1 [M+H] + .

[1195] 1 H NMR(300MHz, CDCl3)δ10.59(s,1H),8.60(s,1H),8.44(dd,J=8.4,4.5Hz,1H),8.23(s,1H),7.39-7.19(m,4H),7.0 6-7.01(m,1H),3.94(s,3H),3.82(s,3H),3.48(t,J=5.1Hz,2H),3.02(t,J=5.1Hz,2H),1.89(s,3H),1.85(s,3H).

[1196] Example 52:

[1197] Preparation of compound 52

[1198]

[1199] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 51B (80 mg, 0.33 mmol) to prepare 25 mg of compound 52.

[1200] MS(ESI, m / z): 621.1, 623.1 [M+H] + .

[1201] 1 H NMR(300MHz, CDCl3)δ12.52(s,1H),8.88(dd,J=9.6,4.2Hz,1H),8.72–8.69( m,2H),8.53(s,1H),8.30(s,1H),7.76(s,1H),7.07(s,2H),3.95(s,3H),3.74 (s, 3H), 3.51 (t, J = 5.1Hz, 2H), 3.03 (t, J = 5.1Hz, 2H), 2.18 (s, 3H), 2.13 (s, 3H).

[1202] Example 53:

[1203] Preparation of compound 53

[1204]

[1205] Compound 53A:

[1206] Compounds 6A (2.7 g, 9.43 mmol) and 35A (3.6 g, 9.43 mmol) were dissolved in N-methylpyrrolidone (30 mL). Then, methanesulfonic acid (2.72 g, 28.28 mmol) was added to the reaction mixture. The reaction system was heated to 95 °C and stirred for 3 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and purified by reversed-phase C18 column. Purification conditions: 330 g C18 reversed-phase column; mobile phase: water (containing 0.1% formic acid) and acetonitrile; flow rate: 70 mL / min; gradient: acetonitrile from 10% to 50% over 20 minutes; detection wavelength: 254 nm. The product was collected and concentrated under reduced pressure to give 3.4 g of compound 53A.

[1207] MS(ESI, m / z): 631.2, 633.2 [M+H] + .

[1208] Compound 53B:

[1209] Compound 53A (3.4 g, 5.38 mmol) was dissolved in a mixed solvent of ethanol (40 mL) and water (8 mL). Then, iron powder (1.50 g, 26.92 mmol) and ammonium chloride (0.86 g, 16.15 mmol) were added to the reaction solution, and the reaction mixture was heated to 80 °C and stirred for 2 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 2.8 g of compound 53B.

[1210] MS(ESI, m / z): 601.2, 603.2 [M+H] + .

[1211] Compound 53:

[1212] Compound 53B (2.8 g, 4.66 mmol) was dissolved in pyridine (20 mL) at 0 °C. Methanesulfonyl chloride (1.07 g, 9.31 mmol) was then added to the reaction mixture. The reaction mixture was heated to 50 °C and stirred for 1 hour. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and quenched with water (3 mL). The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1). The crude product was purified by C18 reversed-phase column chromatography. Purification conditions: 330 g C18 reversed-phase column; mobile phase: water (containing 0.1% formic acid) and acetonitrile; flow rate: 70 mL / min; gradient: acetonitrile increased from 5% to 60% over 30 minutes; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure to give 2.2 g of compound 53B.

[1213] MS(ESI, m / z): 679.2, 681.2 [M+H] + .

[1214] 1 H NMR (300MHz, CDCl3) δ9.11 (s, 1H), 8.84-8.79 (m, 2H), 8.60 (d, J = 9.3Hz, 1H), 8.33 (s, 1H) ,8.28(s,1H),7.58(s,2H),6.74(s,1H),6.54(s,1H),3.89(s,4H),3.67(s,3H),3.30(br s, 2H), 2.95 (br s, 5H), 1.31 (d, J = 6.3Hz, 6H).

[1215] 1H NMR (300MHz, DMSO-d6) δ9.89(br s,1H),8.94(d,J=1.8Hz,1H),8.85(d,J=2.1Hz,1H),8.81(s,1H),8.68(br s,1H),8.35(s,1H),8.27(s,1H),7.74(s,1H),7.49(s,1H),7.40(s,1H),6.58(s,1H),3.99-3.91(m,1H),3 .76(s,3H),3.71(s,3H),3.22(t,J=5.4Hz,2H),3.01(s,3H),2.94(t,J=5.4Hz,2H),1.29(d,J=6.3Hz,6H).

[1216] Example 54:

[1217] Preparation of compound 54

[1218]

[1219] Compound 54A:

[1220] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 6A (130 mg, 0.46 mmol) and 32A (150 mg, 0.46 mmol) to prepare 110 mg of compound 54A.

[1221] MS(ESI, m / z): 579.3, 581.3 [M+H] + .

[1222] Compound 54B:

[1223] According to the method for preparing 1C from intermediate 1C-9 in Example 1, the raw material was replaced with 54A (100 mg, 0.17 mmol) to prepare 89 mg of compound 54B.

[1224] MS(ESI, m / z): 549.3, 551.3 [M+H] + .

[1225] Compound 54:

[1226] According to the method for preparing intermediate 32C in Example 32, the raw material was replaced with 54B (80 mg, 0.15 mmol) to prepare 47 mg of compound 54.

[1227] MS(ESI, m / z): 627.2, 629.2 [M+H] + .

[1228] 1H NMR (300MHz, CDCl3) δ8.19(s,1H),8.16(s,1H),7.64(dd,J=7.5,1.5Hz,1H),7.45(s,1H),7.38(d,J=7.5Hz,1H),7.32-7.3 0(m,1H),7.21-7.12(m,4H),6.53(s,1H),3.92-3.67(m,7H),3.29-3.26(m,2H),2.94-2.90(m,5H),1.31(d,J=6.6Hz,6H).

[1229] Example 55:

[1230] Preparation of intermediate 55A

[1231]

[1232] Compound 55A-1:

[1233] 2-Methylimidazole (3 g, 36.5 mmol) and anhydrous potassium carbonate (10.1 g, 73.1 mmol) were dissolved in acetonitrile (25 mL). N-tert-butyloxycarbonyl-bromoethylamine (8.2 g, 36.5 mmol) was then added to the reaction mixture. The reaction system was heated to 70 °C and stirred for 16 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by reversed-phase C18 column under the following conditions: 120 g C18 reversed-phase column; mobile phase: water (containing 10 mM ammonium bicarbonate) and acetonitrile; flow rate: 60 mL / min; gradient: acetonitrile from 30% to 80% over 30 minutes; detection wavelength: 220 nm. The product was collected and lyophilized under reduced pressure to give 1.7 g of compound 55A-1.

[1234] MS(ESI)M / Z:226.3[M+H] + .

[1235] Compound 55A-2:

[1236] Compound 55A-1 (2.5 g, 11.1 mmol) was dissolved in acetonitrile (50 mL). N-iodosuccinimide (3.8 g, 16.7 mmol) was then added to the reaction mixture. The reaction mixture was heated to 120 °C using a microwave reactor and stirred for 4 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified using a reversed-phase C18 column under the following conditions: 120 g C18 reversed-phase column; mobile phase: water (containing 10 mM ammonium bicarbonate) and acetonitrile; flow rate: 60 mL / min; gradient: acetonitrile from 30% to 80% over 30 minutes; detection wavelength: 220 nm. The product was collected and lyophilized under reduced pressure to give 1.1 g of compound 55A-2.

[1237] MS(ESI)M / Z:352.1[M+H] + .

[1238] Compound 55A-3:

[1239] Compound 55A-2 (900 mg, 2.56 mmol), 1A (990 mg, 3.33 mmol), and anhydrous potassium carbonate (708 mg, 5.13 mmol) were dissolved in 1,4-dioxane (8 mL) and water (2 mL). Then, 1,1'-bis(di-tert-butylphosphine)ferrocene dipalladium chloride (167 mg, 0.26 mmol) was added to the reaction mixture. The reaction system was heated to 80 °C and stirred for 2 hours. After the starting material disappeared under LCMS monitoring, the reaction mixture was cooled to room temperature and quenched with water (10 mL). The mixture was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (30 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 300 mg of compound 55A-3.

[1240] MS(ESI)M / Z:395.2[M+H] + .

[1241] Compound 55A-4:

[1242] According to the method for preparing compound 42A-7 from 42A-6 in Example 42, the raw material was replaced with 55A-3 (270 mg, 0.68 mmol) to prepare 130 mg of compound 55A-4.

[1243] MS(ESI, m / z): 274.8 [M+H] + .

[1244] Compound 55A-5:

[1245] According to the method for preparing compound 8A-9 from 8A-8 in Example 8, the raw material was replaced with 55A-4 (130 mg, 0.47 mmol) to prepare 90 mg of compound 55A-5.

[1246] MS(ESI, m / z): 289.1 [M+H] + .

[1247] Intermediate 55A:

[1248] According to the method for preparing compound 1C from 1C-9 in Example 1, the raw material was replaced with 55A-5 (90 mg, 0.31 mmol) to prepare 70 mg of compound 55A.

[1249] MS(ESI, m / z): 259.2 [M+H] + .

[1250] Preparation of compound 55

[1251]

[1252] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 55A (72 mg, 0.28 mmol) and 2A (101 mg, 0.28 mmol) to prepare 37 mg of compound 55.

[1253] MS(ESI, m / z): 582.0, 584.0 [M+H] + .

[1254] 1 H NMR(300MHz,DMSO-d6)δ10.91(s,1H),8.34-8.30(m,1H),8.22(s,1H),8.17(s,1H),7.57(s,1H),7.53-7.45(m,1H),7.03-6.97(m,2H), 6.77(s,1H),6.66(s,1H),4.03(t,J=5.4Hz,2H),3.82(s,3H),3.41(t,J=5.4Hz,2H),2.90(s,3H),2.37(s,3H),1.75(d,J=13.5Hz,6H).

[1255] Example 56:

[1256] Preparation of intermediate 56A

[1257]

[1258] Compound 56A-1:

[1259] According to the method for preparing compound 1C-6 from 1C-5 in Example 1, the raw material was replaced with 34A-5 (10g, 30.2mmol) to prepare 12.5g of compound 56A-1.

[1260] MS(ESI, m / z): 458.1 [M+H] + .

[1261] Compound 56A-2:

[1262] According to the method for preparing compound 1C-7 from 1C-6 in Example 1, the raw material was replaced with 56A-1 (12.1g, 26.5mmol) to prepare 10g of compound 56A-2.

[1263] MS(ESI, m / z): 501.2 [M+H] + .

[1264] Compound 56A-3:

[1265] According to the method for preparing compound 1C-9 from 1C-8 in Example 1, the raw material was replaced with 56A-2 (3g, 6.0mmol) to prepare 2.4g of compound 56A-3.

[1266] MS(ESI,m / z):401.0[M+H] + .

[1267] Compound 56A-4:

[1268] Compound 56A-3 (2.4 g, 6.0 mmol) and acetone (0.7 g, 12.0 mmol) were dissolved in methanol (20 mL). Anhydrous sodium acetate (1.5 g, 18.0 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. Glacial acetic acid (0.72 g, 12.0 mmol) and sodium cyanoborohydride (0.75 g, 12.0 mmol) were then added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. After the starting material was observed to have disappeared under LCMS monitoring, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (30 mL), and then anhydrous potassium carbonate (4.2 g, 30.5 mmol) was added to the reaction mixture. The reaction mixture was heated to 110 °C and stirred for 4 hours. After the starting material was observed to have disappeared under LCMS monitoring, the reaction mixture was cooled to room temperature and quenched with water (150 mL). The mixture was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (80 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 2.12 g of compound 56A-4.

[1269] MS(ESI)M / Z:423.2[M+H] + .

[1270] Intermediate 56A:

[1271] According to the method for preparing compound 1C from 1C-9 in Example 1, the raw material was replaced with 56A-4 (2.12 g, 5.02 mmol) to prepare 1.67 g of compound 56A.

[1272] MS(ESI, m / z): 393.3 [M+H] + .

[1273] Preparation of compound 56

[1274]

[1275] Compound 56B:

[1276] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 55A (2.4 g, 6.12 mmol) and 2A (1.98 g, 5.5 mmol) to prepare 2.88 g of compound 56B.

[1277] MS(ESI, m / z): 716.3, 718.3 [M+H] + .

[1278] Compound 56C:

[1279] According to the method for preparing compound 37 in Example 37, the raw material was replaced with 56B (2.88 g, 4.02 mmol) to prepare 1.2 g of compound 56C.

[1280] MS(ESI, m / z): 596.2, 598.2 [M+H] + .

[1281] Compound 56:

[1282] Compound 56C (100 mg, 0.17 mmol) and anhydrous potassium carbonate (232 mg, 1.68 mmol) were dissolved in N,N-dimethylformamide (2 mL), followed by the addition of 2-bromo-N,N-dimethylethylamine hydrobromide (195 mg, 0.84 mmol). The reaction mixture was heated to 120 °C and stirred for 2 days. After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was cooled to room temperature and prepared under high pressure. The preparation conditions were as follows: XSelect CSH Prep C18 OBD column, 19 x 250 mm, 5 μm; mobile phase A: water (0.1% formic acid); mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 25% B to 70% B in 25 min; detection wavelength: 254 / 220 nm. The product was collected and lyophilized under reduced pressure to obtain 3 mg of compound 56.

[1283] MS(ESI, m / z): 667.2, 669.2 [M+H] + .

[1284] 1 H NMR (300MHz, CDCl3) δ10.58(s,1H),8.51(s,1H),8.42(s,1H),8.23(s,1H),7.45(s,1H),7.29-7.19(m,3H),6.98-6.95(m,1H),6.57(s,1H), 4.28-4.26(m,2H),3.93-3.89(m,4H),3.33-3.30(m,2H),3.02-2.96( m, 4H), 2.41 (s, 6H), 1.86 (d, J = 13.2Hz, 6H), 1.33 (s, 3H), 1.31 (s, 3H).

[1285] Example 57:

[1286] Preparation of compound 57

[1287]

[1288] Compound 57:

[1289] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw material was replaced with 49A (100 mg, 0.25 mmol) to prepare 133 mg of compound 57.

[1290] MS(ESI, m / z): 770.3, 772.3 [M+H] + .

[1291] 1H NMR (300MHz, CDCl3) δ12.56 (s, 1H), 8.95 (dd, J = 9.6Hz, 4.2Hz, 1H), 8.73-8.70 (m, 2 H),8.53(s,1H),8.35(s,1H),7.74(d,J=9.6Hz,1H),7.49(s,1H),7.25-7.18(m,1H ),7.03(s,1H),6.58(s,1H),6.51-6.45(m,2H),4.17(s,2H),4.06(s,2H),3.90(s, 3H),3.84(s,3H),3.78(s,3H),3.71(s,2H),3.64(s,3H),2.19(s,3H),2.15(s,3H).

[1292] Example 58:

[1293] Preparation of compound 58

[1294]

[1295] Compound 58A:

[1296] Compound 2-(dimethylphosphono)aniline (1.37 g, 8.1 mmol) and 2,4-dichlorothiophene[3,2-d]pyrimidine (1.99 g, 9.72 mmol) were dissolved in N,N-dimethylformamide (20 mL), followed by the addition of diisopropylethylamine (2.09 g, 16.2 mmol). The reaction mixture was heated to 110 °C and stirred for 2 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and quenched with water (100 mL). The mixture was extracted with ethyl acetate (80 mL × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (80 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give 1.82 g of compound 58A.

[1297] MS(ESI) M / Z: 338.1, 340.1 [M+H] + .

[1298] Compound 58:

[1299] Under a nitrogen atmosphere, compound 58A (100 mg, 0.3 mmol), 1C (76 mg, 0.3 mmol), and anhydrous potassium carbonate (82 mg, 0.59 mmol) were dissolved in tert-butanol (3 mL). Tris(dibenzylacetone)dipalladium (27 mg, 0.03 mmol) and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (21 mg, 0.04 mmol) were then added to the reaction mixture. The reaction system was heated to 110 °C and stirred for 2 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 103 mg of compound 58.

[1300] MS(ESI)M / Z:560.2[M+H] + .

[1301] 1 H NMR (300MHz, CDCl3) δ11.38(s,1H),8.96-8.87(m,1H),8.69(s,1H),7.71(m,J=5.4Hz,1H),7.66(s,1H),7.61(s,1H),7.28(s,1H),7.26(s,1H),7 .25-7.19(m,1H),7.03-6.97(m,1H),6.59(s,1H),3.93(s,3H),3.85(s, 3H), 3.32 (t, J = 5.4Hz, 2H), 3.10-3.03 (m, 5H), 1.90 (s, 3H), 1.86 (s, 3H).

[1302] Example 59:

[1303] Preparation of compound 59

[1304]

[1305] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 10A (71 mg, 0.23 mmol) and 2A (65 mg, 0.18 mmol) to prepare 12 mg of compound 59.

[1306] MS(ESI, m / z): 637.2, 639.2 [M+H] + .

[1307] 1H NMR (300MHz, CDCl3) δ10.59(s,1H),8.57(s,1H),8.50-8.41(m,2H),8.26(s,1H),7.39 (s,1H),7.37-7.31(m,1H),7.27-7.20(m,1H),7.08-6.99(m,1H),6.23(s,1H),4.54(t ,J=7.2Hz,1H),4.33(t,J=8.1Hz,2H),3.89(s,3H),3.84(s,3H),3.45(t,J=8.1Hz,2H) ,3.28(t,J=6.0Hz,2H),3.02(t,J=6.0Hz,2H),2.65(s,3H),1.89(s,3H),1.85(s,3H).

[1308] Example 60:

[1309] Preparation of intermediate 60A

[1310]

[1311] Compound 60A-1:

[1312] Under a nitrogen atmosphere and at 0°C, sodium hydride (60%, 0.69 g, 17.25 mmol) was dissolved in N,N-dimethylformamide (25 mL). Then, 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 13.3 mmol) was added in portions to the reaction mixture, and stirring was continued at this temperature for 10 minutes. Subsequently, 2-(trimethylsilyl)ethoxymethyl chloride (2.88 g, 17.29 mmol) was added to the reaction mixture, and stirring was continued at this temperature for 10 minutes. The reaction system was then raised to room temperature and stirred for 1 hour. After LCMS monitoring showed the disappearance of the starting material, water (100 mL) was added to quench the reaction mixture. The mixture was extracted with ethyl acetate (80 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (80 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to give 3.9 g of compound 60A-1.

[1313] MS(ESI)M / Z:318.1,320.1[M+H] + .

[1314] Intermediate 60A:

[1315] According to the method for preparing compound 1B in Example 1B-2, the raw material was replaced with 60A-1 (5.76g, 18.08mmol) to prepare 3g of compound 60A.

[1316] MS(ESI, m / z): 503.3, 505.3 [M+H] + .

[1317] Preparation of compound 60

[1318]

[1319] Compound 60B:

[1320] According to the method for preparing compound 58 using 58A and 1C in Example 58, the raw materials were replaced with 60A (80 mg, 0.16 mmol) to prepare 70 mg of compound 60B.

[1321] MS(ESI, m / z): 725.4 [M+H] + .

[1322] Compound 60:

[1323] According to the method for preparing compound 36 using 36B in Example 36, the raw materials were replaced with 60B (148 mg, 0.2 mmol) to prepare 21 mg of compound 60.

[1324] MS(ESI, m / z): 595.2 [M+H] + .

[1325] 1 H NMR (300MHz, CDCl3) δ13.04(s,1H),9.77(dd,J=9.6,4.2Hz,1H),8.68(m,4H),7.87(d,J=9.6Hz,1H),7.64(s,1H),7.16(s,1H),6.87(dd,J=3.6,2. 1Hz,1H),6.74(dd,J=3.6,2.1Hz,1H),6.61(s,1H),3.96(s,3H),3.83(s, 3H), 3.34 (t, J = 5.4Hz, 2H), 3.11-3.06 (m, 5H), 2.18 (s, 3H), 2.13 (s, 3H).

[1326] Example 61:

[1327] Preparation of compound 61

[1328]

[1329] Compound 61A:

[1330] According to the method for preparing compound 1B in Example 1B-2, the raw material was replaced with 2,4-dichlorothiophene[3,2-d]pyrimidine (1.85g, 9.04mmol) to prepare 1g of compound 61A.

[1331] MS(ESI, m / z): 390.0, 392.0 [M+H] + .

[1332] Compound 61:

[1333] According to the method for preparing compound 58 using 58A and 1C in Example 58, the raw materials were replaced with 61A (100 mg, 0.26 mmol) to prepare 46 mg of compound 61.

[1334] MS(ESI, m / z): 612.2 [M+H] + .

[1335] 1 H NMR (300MHz, CDCl3) δ13.22 (s, 1H), 9.54 (dd, J = 9.6Hz, 4.2Hz, 1H), 8.72-8.70 (m, 2H), 8.65 (s, 1H), 7.83-7.76 (m, 2H), 7.57-7.51 (m,2H),7.30(s,1H),6.62(s,1H),3.95(s,3H),3.82(s,3H),3.36(t,J=5.4Hz,2H),3.13-3.07(m,5H),2.19(s,3H),2.14(s,3H).

[1336] Example 62:

[1337] Preparation of compound 62

[1338]

[1339] Compound 62:

[1340] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 47A (100 mg, 0.29 mmol) and 1B (100 mg, 0.24 mmol) to prepare 42 mg of compound 62.

[1341] MS(ESI, m / z): 717.3, 719.3 [M+H] + .

[1342] 1H NMR (300MHz, CDCl3) δ12.63(s,1H),8.86-8.78(m,3H),8.26(s,1H),8.20(s,1H),7.74(s,1H),7.55(s,1H),7.45(s,1H),6.58(s,1H),3.7 6(s,3H),3.70(s,3H),3.28-3.26(m,2H),2.96-2.86(m,4H),2.23(s, 3H),2.18-2.06(m,3H),2.04(s,3H),1.99(s,3H),1.90-1.80(m,4H).

[1343] Example 63:

[1344] Preparation of intermediate 63A

[1345]

[1346] Compound 63A-1:

[1347] According to the method for preparing compound 47A-1 from 10A-1 in Example 47, the raw material was replaced with tert-butyl 3-oxozyracyclobut-1-carboxylic acid (2.2 g, 12.9 mmol) to prepare 0.9 g of compound 63A-1.

[1348] MS(ESI, m / z): 430.2 [M+H] + .

[1349] Compound 63A-2:

[1350] Compound 63A-1 (300 mg, 0.7 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of trifluoroacetic acid (1 mL) and stirring at room temperature for 2 hours. After LCMS monitoring showed the starting material had disappeared, the mixture was concentrated under reduced pressure. The resulting residue was dissolved in methanol (5 mL). Acetone (203 mg, 3.49 mmol) was added to the reaction mixture, and stirring was continued at room temperature for 30 minutes. Sodium cyanoborohydride (88 mg, 1.4 mmol) was added to the reaction mixture, and stirring was continued at room temperature for 2 hours. After LCMS monitoring showed the starting material had disappeared, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 150 mg of compound 63A-2.

[1351] MS(ESI)M / Z:372.2[M+H] + .

[1352] Intermediate 63:

[1353] According to the method for preparing compound 1C using 1C-9 in Example 1, the raw material was replaced with 63A-2 (150 mg, 0.4 mmol) to prepare 87 g of compound 63A.

[1354] MS(ESI, m / z): 342.2 [M+H] + .

[1355] Preparation of compound 63

[1356]

[1357] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw material was replaced with 63A (87 mg, 0.26 mmol) to prepare 64 mg of compound 63.

[1358] MS(ESI, m / z): 717.2, 719.2 [M+H] + .

[1359] 1 H NMR (400MHz, CDCl3) δ12.50 (s, 1H), 8.87 (dd, J = 9.2Hz, 4.4Hz, 1H), 8.71 (d, J = 1.6Hz, 1H), 8. 68(d,J=1.6Hz,1H),8.53(s,1H),8.3(s,1H),7.63(s,1H),7.32(s,1H),6.99(s,1H),6.27(s, 1H),4.53-4.44(m,1H),4.16(t,J=8.0Hz,2H),3.88(s,3H),3.72(s,3H),3.30-3.20(m,4H),3 .00(t,J=6.0Hz,2H),2.79-2.71(m,1H),2.16(s,3H),2.12(s,3H),1.11(s,3H),1.09(s,3H).

[1360] Example 64:

[1361] Preparation of compound 64

[1362]

[1363] Compound 28 (100 mg, 0.18 mmol) and 3-oxetane (63 mg, 0.88 mmol) were dissolved in methanol (3 mL) and stirred at room temperature for 30 minutes. Acetic acid (21 mg, 0.35 mmol) and sodium cyanoborohydride (22 mg, 0.35 mmol) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. After the starting material disappeared as monitored by LCMS, water (10 mL) was added to quench the reaction mixture. The mixture was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (30 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 64 mg of compound 64A.

[1364] MS(ESI, m / z): 624.2, 626.2 [M+H] + .

[1365] 1 H NMR (300MHz, CDCl3) δ10.67(s,1H),8.50-8.40(m,2H),8.23(s,1H),7.39(s,1 H),7.36-7.30(m,1H),7.27-7.15(m,2H),7.06-6.98(m,1H),6.01(s,1H),4.96 (t,J=6.3Hz,2H),4.86-4.76(m,1H),4.71(t,J=6.0Hz,2H),3.86(s,3H),3.84( s, 3H), 3.37 (t, J = 6.0Hz, 2H), 3.07 (t, J = 6.0Hz, 2H), 1.89 (s, 3H), 1.85 (s, 3H).

[1366] Example 65:

[1367] Preparation of intermediate 65A

[1368]

[1369] Compound 65A-1:

[1370] According to the method for preparing compound 47A-1 from 10A-1 in Example 47, the raw material was replaced with tert-butyl 3-fluoro-4-oxopiperidin-1-carboxylate (828 mg, 3.81 mmol) to prepare 50 mg of compound 65A-1.

[1371] MS(ESI, m / z): 476.2 [M+H] + .

[1372] Compound 65A-2:

[1373] According to the method for preparing compound 63A-2 in Example 63 (63A-1), the raw material was replaced with an aqueous formaldehyde solution (40%, 200 mg, 2.67 mmol) to prepare 200 mg of compound 65A-2.

[1374] MS(ESI, m / z): 390.2 [M+H] + .

[1375] Intermediate 65A:

[1376] According to the method for preparing compound 1C using 1C-9 in Example 1, the raw material was replaced with 65A-2 (110 mg, 0.28 mmol) to prepare 64 mg of compound 65A.

[1377] MS(ESI, m / z): 360.2 [M+H] + .

[1378] Preparation of compound 65

[1379]

[1380] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 65A (30 mg, 0.08 mmol) and 2A (30 mg, 0.08 mmol) to prepare 11 mg of compound 65.

[1381] MS(ESI, m / z): 683.2, 685.2 [M+H] + .

[1382] 1 H NMR(300MHz, CDCl3)δ10.53(s,1H),8.48-8.42(m,1H),8.24(s,1H),8.21(s,1H),7. 45(s,1H),7.36-7.29(m,1H),7.26-7.14(m,2H),7.04-7.97(m,1H),6.59(s,1H),4.8 7(d,J=48.0Hz,1H),3.88(s,3H),3.83(s,3H),3.73-3.71(m,1H),3.55-3.05(m,5H) ,2.96-2.92(m,1H),2.53-2.29(m,6H),1.90(s,3H),1.85(s,3H),1.83-1.76(m,1H).

[1383] 19 F NMR (282MHz, CDCl3) δ-196.73.

[1384] Example 66:

[1385] Preparation of compounds 66A and 66B

[1386]

[1387] Compound 65 (168 mg, 0.25 mmol) was prepared and separated using a chiral column under the following conditions: chiral column: Lux 5 μm Cellulose-4, 2.12 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mM ammonia-methanol solution); mobile phase B: ethanol; flow rate: 20 mL / min; elution with 50% B isocratic elution over 51 minutes; detection wavelength: 205 / 260 nm; RT1: 22 minutes; RT2: 34.5 minutes. The products were collected and lyophilized under reduced pressure to obtain 15 mg of compound 66A (100% ee) with a retention time of RT1: 22 minutes, and 12 mg of compound 66B (99.7% ee) with a retention time of RT2: 34.5 minutes.

[1388] Compounds 66A and 66B are enantiomers, and their absolute configurations are undetermined.

[1389] 66A:MS(ESI,m / z):683.3,685.3[M+H] + .

[1390] 66B:MS(ESI,m / z):683.2,685.2[M+H] + .

[1391] 66A: 1 H NMR (300MHz, CDCl3) δ10.83(s,1H),8.56-8.47(m,2H),8.30(s,1H),7.75(s,1H),7.43-7.36(m,1H),7.27(t,J=8.1Hz,1H),7.14-7.06(m,1H),6. 69(s,1H),5.01(d,J=48.0Hz,1H),3.96(s,3H),3.89(s,3H),3.84-3.31 (m,6H),3.23-3.93(m,3H),2.88-2.64(m,5H),1.96(s,3H),1.91(s,3H).

[1392] 19 F NMR (282MHz, CDCl3) δ-196.86.

[1393] 66B: 1H NMR (300MHz, CDCl3) δ10.72(s,1H),8.58-8.51(m,2H),8.31(s,1H),7.45(s,1H),7.42-7.36(m,1H),7.28(t,J=8.1Hz,1H),7.12-7.05(m,1H),6. 68(s,1H),5.01(d,J=48.0Hz,1H),3.95(s,3H),3.89(s,3H),3.84-3.31 (m,6H),3.23-3.93(m,3H),2.88-2.64(m,5H),1.96(s,3H),1.91(s,3H).

[1394] 19 F NMR (282MHz, CDCl3) δ-196.86.

[1395] Example 67:

[1396] Preparation of compound 67

[1397]

[1398] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw material was replaced with 65A (30 mg, 0.08 mmol) to prepare 19 mg of compound 67.

[1399] MS(ESI, m / z): 735.2, 737.2 [M+H] + .

[1400] 1 H NMR (300MHz, CDCl3) δ12.48 (s, 1H), 8.88 (dd, J = 8.4Hz, 1.8Hz, 1H), 8.73-8.69 (m, 2H), 8.30 (s,1H),8.18(s,1H),7.66-7.61(m,1H),7.44(s,1H),7.01(s,1H),6.66(s,1H),4.89(d,J=4 8.3Hz,1H),3.89(s,3H),3.77-3.75(m,1H),3.72(s,3H),3.55-3.04(m,5H),3.00-2.96(m,1 H), 2.54-2.28 (m, 6H), 2.18 (d, J = 4.8Hz, 3H), 2.14 (d, J = 4.8Hz, 3H), 1.81 (d, J = 12.9Hz, 1H).

[1401] 19 F NMR (282MHz, CDCl3) δ-196.72.

[1402] Example 68:

[1403] Preparation of compound 68

[1404]

[1405] Compound 67 (50 mg, 0.07 mmol) was prepared by chiral column under the following conditions: chiral column CHIRALPAK IC, 2 x 25 cm, 5 μm; mobile phase A: n-hexane: methyl tert-butyl ether = 1:1 (0.5% 2M ammonia-methanol solution); mobile phase B: ethanol; flow rate: 20 mL / min; isocratic elution with 30% B for 25 minutes; detection wavelength: 260 / 210 nm; RT: 23.47 min. The product was collected and lyophilized under reduced pressure to obtain 11 mg of compound 68 with a retention time of RT: 23.47 min (one of four possible corresponding isomers was isolated; 100% ee).

[1406] MS(ESI, m / z): 735.2, 737.2 [M+H] + .

[1407] 1 H NMR (300MHz, CDCl3) δ12.51 (s, 1H), 8.89 (dd, J = 9.3Hz, 5.1Hz, 1H), 8.73-8.69 (m, 2H), 8.43 (s, 1H), 8.31(s,1H),7.69-7.61(m,1H),7.35(s,1H),7.03(s,1H),6.60(s,1H),4.89(d,J=49.5Hz,1H),3.89 (s,3H),3.85-3.75(m,1H),3.73(s,3H),3.55-3.35(m,1H),3.34-3.22(m,2H),3.20-3.05(m,2H),2. 99-2.90(m,1H),2.55-2.26(m,6H),2.18(d,J=4.8Hz,3H),2.14(d,J=4.8Hz,3H),1.86-1.85(m,1H).

[1408] Example 69:

[1409] Preparation of intermediate 69A

[1410]

[1411] Compound 69A-1:

[1412] Compound 63A-1 (250 mg, 0.58 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (0.5 mL) was then added to the reaction mixture, and stirring continued at room temperature for 2 hours. After the starting material was observed to have disappeared under LCMS monitoring, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of anhydrous potassium carbonate (482 mg, 3.5 mmol) and 1-bromo-2-fluoroethane (370 mg, 2.9 mmol). The reaction mixture was heated to 80 °C and stirred for 2 hours. After the starting material was observed to have disappeared under LCMS monitoring, the reaction mixture was cooled to room temperature and quenched with water (20 mL). The mixture was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (30 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 100 mg of compound 69A-1.

[1413] MS(ESI, m / z): 376.2 [M+H] + .

[1414] Intermediate 69A:

[1415] According to the method for preparing compound 1C from 1C-9 in Example 1, the raw material was replaced with 69A-1 (100 mg, 0.27 mmol) to prepare 60 mg of compound 69A.

[1416] MS(ESI, m / z): 346.2 [M+H] + .

[1417] Preparation of compound 69

[1418]

[1419] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 69A (60 mg, 0.17 mmol) and 2A (52 mg, 0.15 mmol) to prepare 20 mg of compound 69.

[1420] MS(ESI, m / z): 669.2, 671.2 [M+H] + .

[1421] 1H NMR(300MHz, CDCl3)δ10.54(s,1H),8.51-8.39(m,2H),8.24(s,1H), 7.46(s,1H),8.38-7.17(m,3H),7.06-6.97(m,1H),6.25(s,1H),4.70-4.62(m,1H),4.55-4.44(m,2H),4.19-4.07(m ,2H),3.88(s,3H),3.84(s,3H),3.43-3.41(m,2H),3.31-3.21(m,2H),3.11-2.92(m,4H),1.90(s,3H),1.86(s,3H).

[1422] Example 70:

[1423] Preparation of intermediate 70A

[1424]

[1425] Compound 70A-1:

[1426] According to the method for preparing compound 63A-2 from 63A-1 in Example 63, the raw material was replaced with cyclopropaneformaldehyde (230 mg, 3.3 mmol) to prepare 430 mg of compound 70A-1.

[1427] MS(ESI, m / z): 384.2 [M+H] + .

[1428] Intermediate 70A:

[1429] According to the method for preparing compound 1C from 1C-9 in Example 1, the raw material was replaced with 70A-1 (150 mg, 0.39 mmol) to prepare 120 mg of compound 70A.

[1430] MS(ESI, m / z): 354.2 [M+H] + .

[1431] Preparation of compound 70

[1432]

[1433] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw material was replaced with 70A (120 mg, 0.34 mmol) to prepare 55 mg of compound 69.

[1434] MS(ESI, m / z): 729.2, 731.2 [M+H] + .

[1435] 1 H NMR (300MHz, CDCl3) δ12.52(s,1H),8.88(dd,J=9.6Hz,4.2Hz,1H),8.73-8.69(m,2H),8.52(s,1H),8.32(s,1H),7.65(d,J=9.6Hz,1H),7.37(s,1H), 7.00(s,1H),6.27(s,1H),4.65-4.53(m,1H),4.37-4.29(m,2H),3.91(s,3H),3.74(s,3H),3.41(t,J=8.1Hz,2H),3.29(t,J=5.7Hz,2H), 3.02(t,J=5.7Hz,2H),2.70(d,J=7.2Hz,2H),2.18(s,3H),2.14(s,3H),0.982-0.840(m,1H),0.625-0.542(m,2H),0.267-0.194(m,2H).

[1436] Example 71:

[1437] Preparation of compound 71

[1438]

[1439] Compound 71:

[1440] According to the method for preparing compound 37 in Example 37, 34, the raw material was replaced with 57 (133 mg, 0.17 mmol) to prepare 12 mg of compound 71.

[1441] MS(ESI,m / z):620.1.1,622.1[M+H] + .

[1442] 1 H NMR (300MHz, CDCl3) δ12.53(s,1H),8.88-8.83(m,1H),8.74-8.70(m,2H),8.52(s,1H),8.33(s,1H),7.68-7.65(m,1H) ,7.54(s,1H),6.99(s,1H),6.77(s,1H),4.36(s,2H),4.04(s,2H),3.93(s,3H),3.75(s,3H),2.18(s,3H),2.13(s,3H).

[1443] Example 72:

[1444] Preparation of compound 72

[1445]

[1446] Compound 71 (146 mg, 0.24 mmol), glacial acetic acid (71 mg, 1.18 mmol), and acetone (137 mg, 2.35 mmol) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 30 minutes. Sodium cyanoborohydride (249 mg, 1.18 mmol) was then added to the reaction mixture, and stirring continued at room temperature for 2 hours. After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added to quench the reaction mixture. The mixture was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (30 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 98 mg of compound 72.

[1447] MS(ESI, m / z): 662.2, 664.2 [M+H] + .

[1448] 1 H NMR (300MHz, CDCl3) δ12.56(s,1H),8.95(dd,J=9.6Hz,4.2Hz,1H),8.73-8.70(m,2H),8.49(s,1H),8.34(s,1H),7.68(d,J=9.9Hz,1H),7.51(s,1H ),6.99(s,1H),6.73(s,1H),4.23(s,2H),3.95-3.92(m,5H),3.76(s,3H) ,3.23-3.12(m,1H),2.19(s,3H),2.14(s,3H),1.28(s,3H),1.26(s,3H).

[1449] Example 73:

[1450] Preparation of intermediate 73A

[1451]

[1452] Compound 73A-1:

[1453] Compound 6A-4 (200 mg, 0.73 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of trifluoroacetic anhydride (766 mg, 3.65 mmol) and stirring at room temperature for 1 hour. After the starting material disappeared as monitored by LCMS, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 250 mg of compound 73A-1.

[1454] MS(ESI, m / z): 371.2 [M+H] + .

[1455] Compound 73A-2:

[1456] According to the method for preparing compound 11A-1 from 9A-4 in Example 11, the raw material was replaced with 73A-1 (168 mg, 0.45 mmol) to prepare 93 mg of compound 73A-2.

[1457] MS(ESI, m / z): 357.1 [M+H] + .

[1458] Intermediate 73A:

[1459] According to the method for preparing compound 1C using 1C-9 in Example 1, the raw material was replaced with 73A-2 (93 mg, 0.26 mmol) to prepare 70 mg of compound 73A.

[1460] MS(ESI, m / z): 327.2 [M+H] + .

[1461] Preparation of compound 73

[1462]

[1463] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 73A (70 mg, 0.21 mmol) and 2A (77 mg, 0.21 mmol) to prepare 43 mg of compound 73.

[1464] MS(ESI, m / z): 650.2, 652.2 [M+H] + .

[1465] 1 H NMR (300MHz, CDCl3) δ10.61(s,1H),8.52-8.44(m,2H),8.25(s,1H),7.38-7.19(m,3H),7.06-6.98(m,1H),6.67(s,1H) ,3.90(s,3H),3.84(s,3H),3.83-3.75(m,2H),3.49(t,J=5.7Hz,2H),3.05(t,J=5.7Hz,2H),1.89(s,3H),1.85(s,3H).

[1466] 19 F NMR (282MHz, CDCl3) δ-70.35.

[1467] Example 74:

[1468] Preparation of intermediate 74A

[1469]

[1470] Compound 74A-1:

[1471] Compound 33A-5 (500 mg, 2.28 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1042 mg, 2.74 mmol), and stirring was continued at room temperature for 30 minutes. Cyclopropylamine (196 mg, 3.42 mmol) and diisopropylethylamine (738 mg, 5.71 mmol) were then added to the reaction mixture, and stirring was continued at room temperature for 3 hours. After the starting material disappeared as monitored by LCMS, water (30 mL) was added to quench the reaction mixture. The mixture was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (30 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1) to give 500 mg of compound 74A-1.

[1472] MS(ESI, m / z): 258.0, 260.0 [M+H] + .

[1473] Compound 74A-2:

[1474] Under a nitrogen atmosphere, compounds 74A-1 (700 mg, 2.71 mmol), 1A (967 mg, 3.25 mmol), and anhydrous potassium phosphate (1.1 g, 5.42 mmol) were dissolved in dioxane (10 mL) and water (1 mL). Then, tri-tert-butylphosphine methanesulfonic acid (2-amino-1,1-biphenyl-2-yl)palladium(II) (155 mg, 0.27 mmol) and tri-tert-butylphosphine tetrafluoroborate (79 mg, 0.27 mmol) were added to the reaction mixture. The reaction system was heated to 50 °C and stirred for 4 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1) to give 700 mg of compound 74A-2.

[1475] MS(ESI, m / z): 349.2 [M+H] + .

[1476] Compound 74A-3:

[1477] Compound 74A-2 (680 mg, 1.95 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of anhydrous potassium carbonate (1079 mg, 7.81 mmol). The reaction mixture was heated to 100 °C and stirred for 3 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and quenched with water (50 mL). The mixture was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (30 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1) to give 230 mg of compound 74A-3.

[1478] MS(ESI, m / z): 329.2 [M+H] + .

[1479] Compound 74A-4:

[1480] According to the method for preparing compound 11A-1 from 9A-4 in Example 11, the raw material was replaced with 74A-3 (240 mg, 0.73 mmol) to prepare 110 mg of compound 74A-4.

[1481] MS(ESI, m / z): 315.2 [M+H] + .

[1482] Compound 74A:

[1483] According to the method for preparing compound 1C from 1C-9 in Example 1, the raw material was replaced with 74A-4 (110 mg, 0.35 mmol) to prepare 80 mg of compound 74A.

[1484] MS(ESI, m / z): 285.3 [M+H] + .

[1485] Preparation of compound 74

[1486]

[1487] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw material was replaced with 74A (70 mg, 0.25 mmol) to prepare 15 mg of compound 74.

[1488] MS(ESI, m / z): 660.2, 662.2 [M+H] + .

[1489] 1H NMR (300MHz, CDCl3) δ12.58 (s, 1H), 8.95 (dd, J = 9.6Hz, 4.2Hz, 1H), 8.72-8.68 (m, 2H),8.33(s,1H),8.27(s,1H),7.70-7.58(m,1H),7.45(s,1H),7.00(s,1H),6.90 (s,1H),3.93(s,3H),3.71(s,3H),3.53(t,J=5.7Hz,2H),3.00(t,J=5.7Hz,2H),2 .80-2.72(m,1H),2.17(s,3H),2.13(s,3H),0.84-0.77(m,2H),0.61-0.55(m,2H).

[1490] Example 75:

[1491] Preparation of compound 75

[1492]

[1493] Compound 75A:

[1494] According to the method for preparing compound 56 in Example 56C, the raw material was replaced with tert-butyl 4-methanesulfonyloxypiperidine-1-carboxylate (281 mg, 1.01 mmol) to prepare 250 mg of compound 75A.

[1495] MS(ESI, m / z): 779.4, 781.4 [M+H] + .

[1496] Compound 75:

[1497] According to the method for preparing compound 63A-2 in Example 63 (63A-1), the raw material was replaced with an aqueous formaldehyde solution (37%, 177 mg, 2.18 mmol) to prepare 7 mg of compound 75.

[1498] MS(ESI, m / z): 693.4, 695.4 [M+H] + .

[1499] 1H NMR (300MHz, CDCl3) δ10.59(s,1H),8.54(s,1H),8.28(s,1H),7.46(s,1H),7.38-7 .28(m,2H),7.28-7.15(m,2H),7.04-6.95(m,1H),6.63(s,1H),4.13(s,1H),4.04-3 .91(m,4H),3.37(t,J=5.7Hz,2H),3.32-3.15(m,3H),3.03(t,J=5.7Hz,2H),2.60-2 .31(m,6H),2.22-2.02(m,2H),1.95(s,3H),1.90(s,3H),1.40(s,3H),1.38(s,3H).

[1500] Example 76:

[1501] Preparation of intermediate 76A

[1502]

[1503] Compound 76A-1:

[1504] Compound 1B-2 (5 g, 22.81 mmol) was dissolved in toluene (125 mL) under a nitrogen atmosphere, followed by the addition of Lawesson reagent (18.45 g, 45.62 mmol). The reaction mixture was heated to 95 °C and stirred for 16 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give 3 g of compound 76A-1.

[1505] MS(ESI, m / z): 238.2 [M+H] + .

[1506] Compound 76A:

[1507] According to the method for preparing compound 1B in Example 1B-2, the raw material was replaced with 76A-1 (3g, 12.64mmol) to prepare 2g of compound 76A.

[1508] MS(ESI, m / z): 428.0, 430.0 [M+H] + .

[1509] Preparation of compound 76

[1510]

[1511] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 76A (109 mg, 0.25 mmol) and 47A (87 mg, 0.25 mmol) to prepare 2 mg of compound 76.

[1512] MS(ESI, m / z): 733.2, 735.2 [M+H] + .

[1513] 1 H NMR (300MHz, CDCl3) δ11.72(s,1H),8.78(d,J=1.8Hz,1H),8.71(d,J=1.8Hz,1H),8.42(s,1H), 8.35(s,1H),8.23(dd,J=9.6Hz,4.2Hz,1H),7.65(d,J=9.3Hz,1H),7.48(s,1H),6.59-6.49(m,1 H),6.46(s,1H),3.88(s,3H),3.61(s,3H),3.55-3.44(m,3H),3.39(t,J=5.7Hz,2H),2.89(t,J= 5.7Hz,2H),2.73-2.60(m,5H),2.51(s,3H),2.46(s,3H),2.37-2.21(m,2H),2.03-1.93(m,2H).

[1514] Example 77:

[1515] Preparation of compounds 77A and 77B

[1516]

[1517] According to the method for preparing compound 56 in Example 56C, the raw materials were replaced with 3-bromoepoxide (103 mg, 0.75 mmol) to prepare 6 mg of compound 77A and 4 mg of compound 77B.

[1518] 77A:MS(ESI,m / z):652.2,654.2[M+H] + .

[1519] 77B:MS(ESI,m / z):652.2,654.2[M+H] + .

[1520] 77A: 1H NMR(400MHz, CDCl3)δ10.56(s,1H),8.50-8.42(m,2H),8.21(s,1H),7.47(s, 1H),7.31-7.25(m,1H),7.21(s,1H),7.15(s,1H),6.93(t,J=7.6Hz,1H),6.54 (s,1H),5.43-5.34(m,1H),5.23(t,J=6.4Hz,2H),5.00(t,J=6.4Hz,2H),3.93 -3.84(m,4H),3.26(t,J=5.6Hz,2H),2.86(t,J=5.6Hz,2H),1.87(s,3H),1.84 (s,3H),1.30(s,3H),1.28(s,3H).

[1521] 77B: 1 H NMR (400MHz, CDCl3) δ10.77 (s, 1H), 8.66 (dd, J = 8.4Hz, 4.4Hz, 1H), 8.34 (s, 1H), 8. 22(s,1H),7.43(s,1H),7.26-7.18(m,2H),7.06(s,1H),6.90(t,J=8.0Hz,1H),6.5 6(s,1H),5.27-5.17(m,1H),4.96-4.86(m,4H),3.94-3.86(m,4H),3.31(t,J=5.2H z, 2H), 3.10 (t, J = 5.2Hz, 2H), 1.87 (s, 3H), 1.84 (s, 3H), 1.30 (s, 3H), 1.29 (s, 3H).

[1522] Example 78:

[1523] Preparation of compound 78

[1524]

[1525] According to the method for preparing compound 72 in Example 72, 71, the raw materials were replaced with compound 50 (40 mg, 0.07 mmol) and paraformaldehyde (31 mg, 0.35 mmol) to prepare 17 mg of compound 78.

[1526] MS(ESI, m / z): 610.2, 612.2 [M+H] + .

[1527] 1H NMR (400MHz, CDCl3) δ10.57 (s, 1H), 8.39 (dd, J = 8.8Hz, 4.4Hz, 1H), 8.26 (s, 1H), 8.23 ​​( s,1H),7.55(s,1H),7.36-7.29(m,1H),7.22(t,J=7.6Hz,1H),7.14(s,1H),7.04(t,J= 7.6Hz,1H),6.78(s,1H),3.97-3.90(m,4H),3.79(s,3H),3.18-3.05(m,1H),3.04-3.9 4(m,1H),2.69-2.58(m,1H),2.52(s,6H),2.42-2.31(m,1H),1.88(s,3H),1.85(s,3H).

[1528] Example 79:

[1529] Preparation of compound 79

[1530]

[1531] According to the method for preparing compound 72 in Example 72, 71, the raw materials were replaced with compound 51 (50 mg, 0.09 mmol) and formaldehyde aqueous solution (40%, 13 mg, 0.18 mmol) to prepare 35 mg of compound 79.

[1532] MS(ESI, m / z): 583.2, 585.2 [M+H] + .

[1533] 1 H NMR (300MHz, CDCl3) δ10.69(s,1H),8.58(s,1H),8.45(dd,J=8.7Hz,4.5Hz,1H),8.21(s,1H),7.35-7.29(m,1H),7.27-7.14(m,3H) ,7.06-6.98(m,1H),3.99(s,3H),3.83(s,3H),3.38(t,J=5.4Hz,2H),3.16(s,3H),3.03(t,J=5.4Hz,2H),1.88(s,3H),1.84(s,3H).

[1534] Example 80:

[1535] Preparation of compound 80

[1536]

[1537] According to the method for preparing compound 72 in Example 72, 71, the raw materials were replaced with compound 52 (100 mg, 0.16 mmol) and formaldehyde aqueous solution (40%, 24 mg, 0.32 mmol) to prepare 33 mg of compound 80.

[1538] MS(ESI, m / z): 635.2, 637.2 [M+H] + .

[1539] 1 H NMR(300MHz,DMSO-d6)δ8.84-8.77(m,2H),8.72(s,1H),8.53(s,1H),8.25(s,1H),8.00(s,1H),7.57(s,1H),3 .85(s,3H),3.71(s,3H),3.33(t,J=4.2Hz,2H),3.15(s,3H),3.03(t,J=4.2Hz,2H),2.03(s,3H),1.98(s,3H).

[1540] Example 81:

[1541] Preparation of intermediate 81A

[1542]

[1543] Compound 81A-1:

[1544] According to the method for preparing compound 1C from 1C-9 in Example 1, the raw material was replaced with 35A (2.4g, 6.3mmol) to prepare 2g of compound 81A-1.

[1545] MS(ESI, m / z): 351.1, 353.1 [M+H] + .

[1546] Compound 81A:

[1547] According to the method for preparing compound 32 using 32C in Example 32, the raw material was replaced with 81A-1 (590 mg, 1.68 mmol) to prepare 300 mg of compound 81A.

[1548] MS(ESI, m / z): 429.0, 431.0 [M+H] + .

[1549] Preparation of compound 81

[1550]

[1551] Compounds 81A (88 mg, 0.2 mmol), 51B (50 mg, 0.2 mmol), and ammonium chloride (109 mg, 2 mmol) were dissolved in ethanol (2 mL). The reaction mixture was heated to 85 °C and stirred for 16 hours. After the starting material was observed to disappear by LCMS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 40 mg of compound 81.

[1552] MS(ESI, m / z): 638.1, 640.1 [M+H] + .

[1553] 1 H NMR (300MHz, CDCl3) δ9.14(s,1H),8.86-8.79(m,2H),8.56(d,J=9.6Hz,1H),8.43(s,1H),8.28(s,1H),7.68(s,1H ),7.58(s,1H),7.06(s,1H),3.94(s,3H),3.70(s,3H),3.48(t,J=4.8Hz,2H),2.99(t,J=4.8Hz,2H),2.95(s,3H).

[1554] Example 82:

[1555] Preparation of compound 82

[1556]

[1557] According to the method for preparing compound 72 in Example 72, 71, the raw materials were replaced with compound 52 (85 mg, 0.14 mmol) to prepare 20 mg of compound 82.

[1558] MS(ESI, m / z): 663.2, 665.2 [M+H] + .

[1559] 1 H NMR(400MHz,DMSO-d6)δ12.63(s,1H),8.84-8.77(m,2H),8.74(s, 1H),8.51(s,1H),8.25(s,1H),8.02(s,1H),7.58(s,1H),7.53(s,1H),4.59-4.43(m,1H),3.83(s,3H),3.7 2(s,3H),3.27(t,J=5.2Hz,2H),2.95(t,J=5.2Hz,2H),2.02(s,3H),1.99(s,3H),1.31(s,3H),1.29(s,3H).

[1560] Example 83:

[1561] Preparation of compound 83

[1562]

[1563] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 44A (126 mg, 0.35 mmol) and 6A (100 mg, 0.35 mmol) to prepare 33 mg of compound 83.

[1564] MS(ESI, m / z): 611.2, 613.2 [M+H] + .

[1565] 1 H NMR(300MHz, CDCl3)δ11.03(s,1H),9.04-8.96(m,1H),8.30(s,1H),8.24(s, 1H),8.18(d,J=4.5Hz,1H),7.50(s,1H),7.12(s,1H),6.99-6.91(m,1H),6.5 8(s,1H),3.98-3.90(m,1H),3.88(s,3H),3.84(s,3H),3.32(t,J=4.8Hz,2H) ,2.97(t,J=4.8Hz,2H),1.90(s,3H),1.86(s,3H),1.35(s,3H),1.32(s,3H).

[1566] Example 84:

[1567] Preparation of intermediate 84A

[1568]

[1569] Compound 84A-1:

[1570] According to the method for preparing compound 47A-1 from 10A-1 in Example 47, the raw material was replaced with tert-butyl 3-oxopiperidin-1-carboxylate (1693 mg, 8.5 mmol) to prepare 500 mg of compound 84A-1.

[1571] MS(ESI, m / z): 458.1 [M+H] + .

[1572] Compound 84A-2:

[1573] According to the method for preparing compound 63A-2 in Example 63 (63A-1), the raw material was replaced with an aqueous formaldehyde solution (40%, 82 mg, 1.1 mmol) to prepare 80 mg of compound 84A-2.

[1574] MS(ESI, m / z): 372.2 [M+H] + .

[1575] Intermediate 84A:

[1576] According to the method for preparing compound 1C using 1C-9 in Example 1, the raw material was replaced with 84A-2 (80 mg, 0.22 mmol) to prepare 45 mg of compound 84A.

[1577] MS(ESI, m / z): 342.2 [M+H] + .

[1578] Preparation of compound 84

[1579]

[1580] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw material was replaced with 84A (70 mg, 0.21 mmol) to prepare 8 mg of compound 84.

[1581] MS(ESI, m / z): 717.2, 719.2 [M+H] + .

[1582] 1 H NMR(300MHz,DMSO-d6)δ12.62(s,1H),8.86-8.71(m,3H),8.37(s,1H),8.26(s,1H),7 .76(s,1H),7.55(s,1H),7.44(s,1H),6.60(s,1H),3.77(s,3H),3.70(s,3H),3.65-3 .59(m,2H),3.09-3.00(m,2H),2.97-2.88(m,2H),2.84-2.77(m,1H),2.28(s,3H),2. 20(t,J=10.5Hz,1H),2.04(s,3H),1.99(s,3H),1.96-1.87(m,2H),1.74-1.53(m,3H).

[1583] Example 85:

[1584] Preparation of compound 85

[1585]

[1586] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 6A (100 mg, 0.35 mmol) and 5A (109 mg, 0.31 mmol) to prepare 46 mg of compound 85.

[1587] MS(ESI, m / z): 598.3 [M+H] + .

[1588] 1 H NMR (400MHz, CDCl3) δ12.36 (s, 1H), 9.20 (dd, J = 9.6Hz, 4.4Hz, 1H), 8.66-8.64 (m,2H),8.38(s,1H),7.95(s,1H),7.76-7.56(m,2H),7.21(s,1H),6.58(s,1H) ,3.96-3.89(m,1H),3.38(s,3H),3.73(s,3H),3.32(t,J=5.6Hz,2H),2.97(t,J =5.6Hz,2H),2.28(s,3H),2.13(s,3H),2.10(s,3H),1.33(s,3H),1.31(s,3H).

[1589] Example 86:

[1590] Preparation of intermediate 86A

[1591]

[1592] Compound 86A-1: 91

[1593] According to the method for preparing compound 51B-1 from 2-methoxy-3-nitro-6-chloropyridine in Example 51, the raw material was replaced with isopropylamine (1.57 g, 26.5 mmol) to prepare 3 g of compound 86A-1.

[1594] MS(ESI,m / z):212.1[M+H] + .

[1595] Compound 86A-2:

[1596] According to the method for preparing compound 24B-1 using 1C-2 in Example 24, the raw material was replaced with 86A-1 (3g, 14.2mmol) to prepare 3.81g of compound 86A-2.

[1597] MS(ESI,m / z):290.0,292.0[M+H] + .

[1598] Compound 86A-3:

[1599] According to the method for preparing compound 1A in Example 1A-1, the raw material was replaced with 86A-2 (5.3g, 18.3mmol) to prepare 3.54g of compound 86A-3.

[1600] MS(ESI, m / z): 338.3 [M+H] + .

[1601] Compound 86A-4:

[1602] According to the method for preparing compound 51B-5 from 51B-4 in Example 51, the raw material was replaced with 86A-3 (3.54 g, 10.5 mmol) to prepare 1.7 g of compound 86A-4.

[1603] MS(ESI, m / z): 364.1 [M+H] + .

[1604] Compound 86A-5:

[1605] According to the method for preparing compound 51B-6 from 51B-5 in Example 51, the raw material was replaced with 86A-4 (1.7g, 4.68mmol) to prepare 1.6g of compound 86A-5.

[1606] MS(ESI, m / z): 350.3 [M+H] + .

[1607] Compound 86A-6:

[1608] According to the method for preparing compound 51B-7 from 51B-6 in Example 51, the raw material was replaced with 86A-5 (1.72g, 4.92mmol) to prepare 1.4g of compound 86A-6.

[1609] MS(ESI, m / z): 332.3 [M+H] + .

[1610] Compound 86A-7:

[1611] According to the method for preparing compound 11A-1 from 9A-4 in Example 11, the raw material was replaced with 86A-6 (1.4g, 4.23mmol) to prepare 1.3g of compound 86A-7.

[1612] MS(ESI, m / z): 318.1 [M+H] + .

[1613] Compound 86A:

[1614] According to the method for preparing compound 1C from 1C-9 in Example 1, the raw materials were replaced with 86A-7 (1.35g, 4.25mmol) to prepare 0.9g of compound 86A.

[1615] MS(ESI, m / z): 288.2 [M+H] + .

[1616] Preparation of compound 86

[1617]

[1618] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 86A (75 mg, 0.26 mmol) and 81A (112 mg, 0.26 mmol) to prepare 56 mg of compound 86.

[1619] MS(ESI, m / z): 680.2, 682.2 [M+H] + .

[1620] 1 H NMR (300MHz, DMSO-d6) δ10.00 (s, 1H), 9.02 (d, J = 5.1Hz, 1H), 8.93 (d, J = 5. 1Hz,1H),8.86(s,1H),8.70(s,1H),8.58(s,1H),8.34(s,1H),8.08(s,1H), 7.66-7.40(m,2H),4.67-4.52(m,1H),3.88(s,3H),3.80(s,3H),3.35(t,J =5.4Hz,2H),3.08(s,3H),3.03(t,J=5.4Hz,2H),1.38(s,3H),1.36(s,3H).

[1621] Example 87:

[1622] Preparation of intermediate 87A

[1623]

[1624] Compound 87A-1:

[1625] According to the method for preparing compound 47A-1 from 10A-1 in Example 47, the raw material was replaced with tetrahydropyranone (204 mg, 2.04 mmol) to prepare 163 mg of compound 87A-1.

[1626] MS(ESI, m / z): 359.2 [M+H] + .

[1627] Intermediate 87A:

[1628] According to the method for preparing compound 1C using 1C-9 in Example 1, the raw material was replaced with 87A-1 (163 mg, 0.46 mmol) to prepare 130 mg of compound 87A.

[1629] MS(ESI, m / z): 329.3 [M+H] + .

[1630] Preparation of compound 87

[1631]

[1632] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 87A (50 mg, 0.15 mmol) and 2A (55 mg, 0.15 mmol) to prepare 26 mg of compound 87.

[1633] MS(ESI, m / z): 652.2, 654.2 [M+H] + .

[1634] 1 H NMR (300MHz, CDCl3) δ10.67(s,1H),8.48(dd,J=8.1Hz,4.2Hz,1H),8.42(s,1H),8.22(s,1H),7.43(s,1H),7.35-7.25(m,2H),7.23-7.15(m,1H),7 .04-6.96(m,1H),6.57(s,1H),4.13-4.04(m,2H),3.88(s,3H),3.83(s,3 H),3.66-3.36(m,5H),3.00-2.93(m,2H),1.97-1.86(m,7H),1.84(s,3H).

[1635] Example 88:

[1636] Preparation of compound 88

[1637]

[1638] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw material was replaced with 87A (50 mg, 0.15 mmol) to prepare 45 mg of compound 88.

[1639] MS(ESI, m / z): 704.2, 706.2 [M+H] + .

[1640] 1H NMR (300MHz, CDCl3) δ12.54 (s, 1H), 8.89 (dd, J = 9.6Hz, 4.2Hz, 1H), 8.73-8.68 (m, 2H), 8.40 (s, 1H), 8.30 (s, 1H), 7.70 -7.60(m,1H),7.41(s,1H),7.03(s,1H),6.58(s,1H),4.14-4.03(m,2H),3.89(s,3H),3.72(m,3H),3.67-3.56(m,1H), 3.55-3.40(m,4H),3.03-2.93(m,2H),2.18(s,3H),2.13(s,3H),2.00-1.83(m,4H).

[1641] Example 89:

[1642] Preparation of compound 89

[1643]

[1644] Compound 89A:

[1645] According to the method for preparing compound 72 in Example 72, 71, the raw materials were replaced with compound 52 (150 mg, 0.24 mmol) and tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid (102 mg, 0.48 mmol) to prepare 88 mg of compound 89A.

[1646] MS(ESI, m / z): 815.2, 817.2 [M+H] + .

[1647] Compound 89:

[1648] According to the method for preparing compound 63A-2 from 63A-1 in Example 63, the raw material was replaced with 89A (50 mg, 0.06 mmol) to prepare 16 mg of compound 89.

[1649] MS(ESI, m / z): 729.2, 731.2 [M+H] + .

[1650] 1H NMR (400MHz, CDCl3) δ12.50 (s, 1H), 8.87 (dd, J = 9.6Hz, 4.0Hz, 1H), 8.72-8.65 (m, 2H) ,8.48(s,1H),8.28(s,1H),7.59(s,1H),7.25(s,1H),6.98(s,1H),6.20(s,1H),4.04 -3.94(m,3H),3.86(s,3H),3.84-3.79(m,2H),3.72(s,3H),3.20(t,J=6.0Hz,2H),2. 99(t,J=6.0Hz,2H),2.72-2.64(m,5H),2.30-2.23(m,2H),2.15(s,3H),2.11(s,3H).

[1651] Example 90:

[1652] Preparation of compound 90

[1653]

[1654] According to the method for preparing compound 63A-2 from 63A-1 in Example 63, the raw materials were replaced with 89A (50 mg, 0.06 mmol) and acetone (11 mg, 0.14 mmol) to prepare 4 mg of compound 90.

[1655] MS(ESI, m / z): 757.2, 759.2 [M+H] + .

[1656] 1 H NMR (300MHz, CDCl3) δ12.49 (s, 1H), 8.88 (dd, J = 9.6Hz, 4.2Hz, 1H), 8.75-8.64 (m, 2H), 8.53 (s,1H),8.38(s,1H),8.30(s,1H),7.67-7.53(m,1H),6.98(s,1H),6.22(s,1H),4.09-3.92 (m,3H),3.87(s,3H),3.83-3.77(m,2H),3.73(s,3H),3.26-3.14(m,2H),3.07-3.92(m,3H) ,2.75-2.67(m,2H),2.30-2.55(m,2H),2.18(s,3H),2.13(s,3H),1.26(s,3H),1.24(s,3H).

[1657] Example 91: Preparation of Intermediate 91A

[1658]

[1659] Compound 90A-1:

[1660] Under a nitrogen atmosphere, ethyl dichlorophosphate (5 g, 30.69 mmol) was dissolved in dichloromethane. The reaction solution was cooled to -78 °C, and a tetrahydrofuran solution of vinyl magnesium bromide (1 M, 68 mL, 68 mmol) was added. The mixture was stirred at this temperature for 1 hour. After the starting material disappeared as monitored by LCMS, 1 N hydrochloric acid (100 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (150 mL × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (150 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 1.1 g of compound 90A-1.

[1661] MS(ESI)M / Z:147.3[M+H] + .

[1662] Compound 91A-2:

[1663] Compound 91A-1 (1.4 g, 9.58 mmol) was dissolved in ethanol (10 mL), followed by the addition of 2,4-dimethoxybenzamine (1.92 g, 11.45 mmol). The reaction mixture was heated to 90 °C and stirred for 4 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 2 g of compound 91A-2.

[1664] MS(ESI)M / Z:314.1[M+H] + .

[1665] Compound 91A-3:

[1666] Under a nitrogen atmosphere, compound 91A-2 (1.1 g, 3.51 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL). Subsequently, a tetrahydrofuran solution of lithium aluminum hydride (1 M, 2.81 mL, 2.81 mmol) was added to the reaction mixture at 0 °C, and stirring was continued at this temperature for 1 hour. After LCMS monitoring showed the disappearance of the starting material, water (0.1 mL), 15% sodium hydroxide aqueous solution (0.1 mL), and water (0.3 mL) were added to quench the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 0.27 g of compound 91A-3.

[1667] MS(ESI)M / Z:270.1[M+H]+ .

[1668] Compound 91A-4:

[1669] According to the method for preparing compound 1B-2 in Example 1B-1, the raw material was replaced with 91A-3 (220 mg, 0.82 mmol) to prepare 200 mg of compound 91A-4.

[1670] MS(ESI,m / z):413.1[M+H] + .

[1671] Intermediate 91A:

[1672] According to the method for preparing compound 1B in Example 1B-2, the raw materials were replaced with 91A-4 (150 mg, 0.36 mmol) to prepare 78 mg of compound 91A.

[1673] MS(ESI, m / z): 603.1, 605.1 [M+H] + .

[1674] Preparation of compound 91

[1675]

[1676] Compound 91B:

[1677] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 91A (78 mg, 0.13 mmol) and 6A (37 mg, 0.13 mmol) to prepare 50 mg of compound 91B.

[1678] MS(ESI, m / z): 853.4, 855.4 [M+H] + .

[1679] Compound 91C:

[1680] According to the method for preparing compound 37 in Example 37, 34, the raw material was replaced with 91B (50 mg, 0.06 mmol) to prepare 35 mg of compound 91C.

[1681] MS(ESI, m / z): 703.3, 705.3 [M+H] + .

[1682] Compound 91:

[1683] According to the method for preparing compound 72 in Example 72, 71, the raw materials were replaced with compound 91C (35 mg, 0.05 mmol) and formaldehyde aqueous solution (40%, 19 mg, 0.25 mmol) to prepare 10 mg of compound 91.

[1684] MS(ESI, m / z): 717.2, 719.2 [M+H] + .

[1685] 1 H NMR (300MHz, CDCl3) δ11.72 (s, 1H), 9.12 (d, J = 1.8Hz, 1H), 8.83-8.78 (m, 1H) ,8.77(d,J=1.8Hz,1H),8.34(s,1H),8.31(s,1H),7.76-7.64(m,1H),7.33(s ,1H),6.91(s,1H),6.60(s,1H),3.93-3.80(m,9H),3.72-3.65(m,4H),3.38- 3.28(m,2H),3.01-2.92(m,5H),2.47-2.30(m,2H),1.34(s,3H),1.32(s,3H).

[1686] Example 92:

[1687] Preparation of intermediate 92

[1688]

[1689] Compound 92A-1:

[1690] 5-Iodo-1-methyl-1H-pyrazole (9.5 g, 45.67 mmol) and ethyl bromodifluoroacetate (13.91 g, 68.51 mmol) were dissolved in dimethyl sulfoxide (100 mL), followed by the addition of copper powder (5.80 g, 91.35 mmol). The reaction mixture was heated to 80 °C and stirred for 16 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and quenched with water (500 mL). The mixture was extracted with ethyl acetate (200 mL × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (200 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / methyl tert-butyl ether = 1 / 1) to give 6.22 g of compound 92A-1.

[1691] MS(ESI)M / Z:205.3[M+H] + .

[1692] Compound 92A-2:

[1693] Compound 92A-1 (2.95 g, 14.45 mmol) was dissolved in acetonitrile (50 mL), followed by the addition of N-bromosuccinimide (5.66 g, 31.79 mmol). The reaction mixture was heated to 50 °C and stirred for 16 hours. After the starting material disappeared as monitored by LCMS, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / methyl tert-butyl ether = 1 / 1) to give 3.26 g of compound 92A-2.

[1694] MS(ESI)M / Z:283.0,285.0[M+H] + .

[1695] Compound 92A-3:

[1696] According to the method for preparing compound 91A-3 from 91A-2 in Example 91, the raw material was replaced with 92A-2 (3.76g, 13.28mmol) to prepare 1.6g of compound 92A-3.

[1697] MS(ESI,m / z):241.0,243.0[M+H] + .

[1698] Compound 92A-4:

[1699] Compound 92A-3 (1.8 g, 7.47 mmol) and pyridine (1.3 g, 16.430 mmol) were dissolved in acetonitrile (15 mL), and then trifluoromethanesulfonic anhydride (4.21 g, 14.97 mmol) was added dropwise to the reaction solution at 0 °C. The reaction solution was brought to room temperature and stirred for 1 hour, then ammonia (12 mL) was added. The reaction system was heated to 50 °C and stirred for 16 hours. LC-MS monitoring showed good disappearance of the starting material. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (30 mL), followed by the addition of triethylamine (1.52 g, 15 mmol) and di-tert-butyl dicarbonate (8.18 g, 37.49 mmol), and stirring was continued at room temperature for 2 hours. The reaction solution was quenched with water (80 mL). The mixture was extracted with ethyl acetate (100 mL × 2 times), and the organic phases were combined. The organic phase was first washed with saturated brine (100 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / methyl tert-butyl ether = 1 / 1) to give 1.6 g of compound 92A-4.

[1700] MS(ESI)M / Z:340.0,342.0[M+H] + .

[1701] Compound 92A-5:

[1702] According to the method for preparing compound 51B-5 from 51B-4 in Example 51, the raw materials were replaced with 92A-4 (650 mg, 1.91 mmol) and 1A (681 mg, 2.29 mmol) to prepare 700 mg of compound 92A-5.

[1703] MS(ESI, m / z): 431.2 [M+H] + .

[1704] Compound 92A-6:

[1705] According to the method for preparing compound 42A-7 from 42A-6 in Example 42, the raw material was replaced with 92A-5 (700 mg, 1.63 mmol) to prepare 387 mg of compound 92A-6.

[1706] MS(ESI,m / z):311.0[M+H] + .

[1707] Intermediate 92A:

[1708] According to the method for preparing compound 1C from 1C-9 in Example 1, the raw materials were replaced with 92A-6 (120 mg, 0.39 mmol) to prepare 100 mg of compound 92A.

[1709] MS(ESI,m / z):281.1[M+H] + .

[1710] Preparation of compound 92

[1711]

[1712] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 92A (100 mg, 0.36 mmol) and 2A (129 mg, 0.36 mmol) to prepare 38 mg of compound 92.

[1713] MS(ESI, m / z): 604.1, 606.1 [M+H] + .

[1714] 1H NMR (300MHz, CDCl3) δ10.60 (s, 1H), 8.53 (s, 1H), 8.43 (dd, J = 9.6Hz, 4.2Hz, 1H), 8.25 (s, 1H), 7.36-7.30 (m, 2H), 7.26-7 .15(m,2H),7.04-6.96(m,1H),6.43(s,1H),4.10(s,3H),3.89(s,3H),3.59(t,J=12.0Hz,2H),1.89(s,3H),1.85(s,3H).

[1715] 19 F NMR (282MHz, CDCl3) δ-92.73.

[1716] Example 93:

[1717] Preparation of compound 93

[1718]

[1719] Compound 93A:

[1720] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 16A (48 mg, 0.19 mmol) and 76A (100 mg, 0.23 mmol) to prepare 50 mg of compound 93A.

[1721] MS(ESI, m / z): 636.2, 638.2 [M+H] + .

[1722] Compound 93B:

[1723] According to the method for preparing compound 72 in Example 72, 71, the raw materials were replaced with compound 93A (50 mg, 0.08 mmol) and tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid (33 mg, 0.16 mmol) to prepare 62 mg of compound 93B.

[1724] MS(ESI, m / z): 831.2, 833.2 [M+H] + .

[1725] Compound 93:

[1726] According to the method for preparing compound 63A-2 from 63A-1 in Example 63, the raw material was replaced with 93B (62mg, 0.08mmol) to prepare 7mg of compound 93.

[1727] MS(ESI, m / z): 745.2, 747.2 [M+H]+ .

[1728] 1 H NMR (400MHz, CDCl3) δ11.74(s,1H),8.77(d,J=1.6Hz,1H),8.69(d,J=1.6Hz,1H),8.32-8.29(m,2H),8 .21(dd,J=9.6Hz,4.8Hz,1H),7.65-7.58(m,1H),7.39(s,1H),6.52(s,1H),6.14(s,1H),4.49-4.22(m, 2H),4.01-3.95(m,1H),3.85(s,3H),3.63(s,3H),3.27-3.05(m,2H),2.99-2.89(m,2H),2.79(s,3H), 2.49(s,3H),2.45(s,3H),2.17-2.08(m,1H),2.01-1.95(m,1H),1.29-1.19(m,3H),0.91-0.80(m,1H).

[1729] Example 94:

[1730] Preparation of compound 94

[1731]

[1732] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 6A (70 mg, 0.24 mmol) and 7A (72 mg, 0.24 mmol) to prepare 20 mg of compound 94.

[1733] MS(ESI, m / z): 546.3 [M+H] + .

[1734] 1 H NMR (300MHz, CDCl3) δ10.94(s,1H),8.66(dd,J=9.6Hz,4.8Hz,1H),8.23(s,1H),7.76(s,1H),7.42(s,1H),7.27-7.18(m,1H),7.11-7.02(m,1H), 7.00-6.93(m,1H),6.59(s,1H),3.99-3.90(m,1H),3.88(s,3H),3.83(s,3H),3.32(t,J=5.4Hz ,2H),2.96(t,J=5.4Hz,2H),2.23(s,3H),1.87(s,3H),1.82(s,3H),1.35(s,3H),1.33(s,3H).

[1735] Example 95:

[1736] Preparation of compound 95

[1737]

[1738] Compound 95A:

[1739] According to the method for preparing 1B in Example 1B-2, the raw materials were replaced with 4-amino-3-iodopyridine (500 mg, 2.27 mmol) and 2,4,5-trichloropyrimidine (414 mg, 2.27 mmol) to prepare 290 mg of compound 95A.

[1740] MS(ESI, m / z): 366.9, 368.9 [M+H] + .

[1741] Compound 95B:

[1742] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 6A (100 mg, 0.35 mmol) and 95A (128 mg, 0.35 mmol) to prepare 65 mg of compound 95B.

[1743] MS(ESI, m / z): 617.1, 619.1 [M+H] + .

[1744] Compound 95:

[1745] According to the method for preparing compound 1B-2 in Example 1, 1B-1 was used, but the raw material was replaced with 95B (60 mg, 0.1 mmol) to prepare 20 mg of compound 95.

[1746] MS(ESI, m / z): 567.2, 569.2 [M+H] + .

[1747] 1H NMR (300MHz, CDCl3) δ11.43 (s, 1H), 8.77 (t, J = 5.4Hz, 1H), 8.35 (d, J = 9.0Hz ,1H),8.28(s,1H),8.20(s,1H),8.06(s,1H),7.55(s,1H),7.21(s,1H),6.60 (s,1H),4.00-3.91(m,1H),8.89(s,3H),8.84(s,3H),3.33(t,J=5.4Hz,2H) ,2.98(t,J=5.4Hz,2H),1.83(s,3H),1.89(s,3H),1.35(s,3H),1.33(s,3H).

[1748] Example 96:

[1749] Preparation of intermediate 96A

[1750]

[1751] Compound 96A-1:

[1752] According to the method for preparing compound 47A-1 from 10A-1 in Example 47, the raw material was replaced with N-tert-butoxycarbonyl-4-piperidinone (1.35 g, 6.8 mmol) to prepare 0.9 g of compound 96A-1.

[1753] MS(ESI, m / z): 458.3 [M+H] + .

[1754] Compound 96A:

[1755] According to the method for preparing compound 1C from 1C-9 in Example 1, the raw material was replaced with 96A-1 (900 mg, 1.97 mmol) to prepare 750 mg of compound 96A.

[1756] MS(ESI, m / z): 427.1 [M+H] + .

[1757] Preparation of compound 96

[1758]

[1759] Compound 96B:

[1760] According to the method for preparing compound 81 using 81A and 51B in Example 81, the raw materials were replaced with 96A (100 mg, 0.23 mmol) and 1B (106 mg, 0.26 mmol) to prepare 65 mg of compound 96B.

[1761] MS(ESI, m / z): 803.4, 805.4 [M+H] + .

[1762] Compound 96:

[1763] According to the method for preparing compound 63A-2 from 63A-1 in Example 63, the raw materials were replaced with 96B (65 mg, 0.08 mmol) and 3,3-difluorocyclobutanone (46 mg, 0.43 mmol) to prepare 3 mg of compound 96.

[1764] MS(ESI, m / z): 793.2, 795.2 [M+H] + .

[1765] 1 H NMR (300MHz, CDCl3) δ12.48 (s, 1H), 8.89 (dd, J = 9.6Hz, 4.8Hz, 1H), 8.73-8.68 (m, 2H), 8.40 (s, 1H),8.30(s,1H),7.70-7.60(m,1H),7.37(s,1H),7.00(s,1H),6.54(s,1H),3.88(s,3H),7.72( s,3H),3.49-3.39(m,3H),3.12-3.01(m,2H),2.97(t,J=5.4Hz,2H),2.81-2.66(m,3H),2.62-2 .44(m,2H),2.18(s,3H),2.13(s,3H),2.04-1.92(m,3H),1.34-1.24(m,2H),0.95-0.83(m,1H).

[1766] Compound 97:

[1767] Preparation of compound 97

[1768]

[1769] Compound 97A:

[1770] According to the method for preparing 1B in Example 1B-2, the raw material was replaced with 4-amino-3-iodopyridine (500 mg, 2.27 mmol) to prepare 130 mg of compound 97A.

[1771] MS(ESI, m / z): 410.8, 412.8 [M+H] + .

[1772] Compound 97B:

[1773] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 6A (91 mg, 0.32 mmol) and 97A (130 mg, 0.32 mmol) to prepare 71 mg of compound 97B.

[1774] MS(ESI, m / z): 661.0, 663.0 [M+H] + .

[1775] Compound 97:

[1776] According to the method for preparing compound 1B-2 in Example 1, the raw material was replaced with 97B (70 mg, 0.11 mmol) to prepare 23 mg of compound 97.

[1777] MS(ESI, m / z): 611.2, 613.2 [M+H] + .

[1778] 1 H NMR (300MHz, CDCl3) δ11.23(s,1H),8.73-8.66(m,1H),8.35(d,J=8.4Hz,1H),8.32-8.25(m,2H),8.07(s,1H),7.51(s,1H),7.17(s,1H),6.60(s,1 H),4.00-3.91(m,1H),3.89(s,3H),3.83(s,3H),3.33(t,J=5.4Hz,2H),2 .98(t,J=5.4Hz,2H),1.93(s,3H),1.89(s,3H),1.35(s,3H),1.32(s,3H).

[1779] Example 98:

[1780] Preparation of compound 98

[1781]

[1782] Compound 98A:

[1783] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw material was replaced with 56A (300 mg, 0.76 mmol) to prepare 336 mg of compound 98A.

[1784] MS(ESI, m / z): 768.2, 770.2 [M+H] + .

[1785] Compound 98B:

[1786] According to the method for preparing compound 37 in Example 37, the raw material was replaced with 98A (326 mg, 0.42 mmol) to prepare 265 mg of compound 98B.

[1787] MS(ESI, m / z): 648.0, 650.0 [M+H] + .

[1788] Compound 98:

[1789] According to the method for preparing compound 56 using 56C in Example 56, the raw materials were replaced with compound 98B (260 mg, 0.4 mmol) and 3-bromoepoxide (165 mg, 1.2 mmol) to prepare 50 mg of compound 98.

[1790] MS(ESI, m / z): 704.2, 706.2 [M+H] + .

[1791] 1 H NMR (300MHz, CDCl3) δ12.57 (s, 1H), 9.02 (dd, J = 9.3Hz, 5.2Hz, 1H), 8.71 (d, J = 2.1Hz, 1H), 8.67 (d,J=2.1Hz,1H),8.46(s,1H),8.29(s,1H),7.69-7.59(m,1H),7.36(s,1H),7.18(s,1H),6.58 (s,1H),5.41-5.29(m,1H),5.14(t,J=6.6Hz,2H),4.98(t,J=6.6Hz,2H),3.98-3.86(m,4H),3. 31(t,J=5.4Hz,2H),2.88(t,J=5.4Hz,2H),2.19(s,3H),2.14(s,3H),1.33(s,3H),1.31(s,3H).

[1792] Compound 99:

[1793] Preparation of intermediate 99A

[1794]

[1795] Compound 99A-1:

[1796] Under a nitrogen atmosphere, 2-methyl-3-bromopyridine (5 g, 28.9 mmol) was dissolved in tetrahydrofuran (80 mL). Then, at -78 °C, a tetrahydrofuran solution of lithium diisopropylaminoacetate (2 M, 14.5 mmol, 29 mmol) was slowly added dropwise to the reaction solution while stirring at this temperature for 1 hour. N,N-dimethylformamide (2.11 g, 28.9 mmol) was added dropwise to the reaction solution while stirring at this temperature for 30 minutes. After the starting material disappeared as monitored by LCMS, the reaction solution was quenched with methanol (30 mL). Subsequently, glacial acetic acid (1.74 g, 28.9 mmol) and sodium borohydride (1.31 g, 34.68 mmol) were added to the reaction solution. The reaction solution was brought to room temperature and stirred for 10 minutes. Finally, a saturated sodium bicarbonate aqueous solution (100 mL) was added to quench the reaction solution. The mixture was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated brine (100 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 4.5 g of compound 99A-1.

[1797] MS(ESI, m / z): 201.8, 203.8 [M+H] + .

[1798] Compound 99A-2:

[1799] According to the method for preparing compound 51A-1 from 40A-2 in Implementation 51, the raw material was replaced with 99A-1 (2g, 9.89mmol) to prepare 2.5g of compound 99A-2.

[1800] MS(ESI, m / z): 330.9, 332.9 [M+H] + .

[1801] Compound 99A-3:

[1802] Compound 99A-2 (2.5 g, 7.55 mmol) was dissolved in ethanol (30 mL), followed by the addition of hydrazine hydrate (1.51 g, 30.19 mmol). The reaction mixture was heated to 80 °C and stirred for 16 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was cooled to room temperature, and the precipitated solid was filtered and dried. The filter cake was dissolved in dichloromethane (30 mL), and triethylamine (1.81 g, 17.88 mmol) and di-tert-butyl carbonate (2.93 g, 13.43 mmol) were added to the reaction mixture, which was then stirred for another 16 hours at room temperature. The reaction mixture was quenched with water (80 mL). The mixture was extracted with ethyl acetate (80 mL × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (80 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 2.5 g of compound 99A-3.

[1803] MS(ESI, m / z): 300.9, 302.9 [M+H] + .

[1804] Compound 99A-4:

[1805] According to the method for preparing 1C-7 from 1C-6 in Example 1, the raw material was replaced with 99A-3 (800 mg, 2.65 mmol) to prepare 470 mg of compound 99A-4.

[1806] MS(ESI, m / z): 392.1 [M+H] + .

[1807] Compound 99A-5:

[1808] According to the method for preparing 42A-7 from 42A-6 in Example 42, the raw material was replaced with 99A-4 (700 mg, 1.78 mmol) to prepare 400 mg of compound 99A-5.

[1809] MS(ESI,m / z):272.2[M+H] + .

[1810] Compound 99A-6:

[1811] According to the method for preparing compound 8A-9 from 8A-8 in Example 8, the raw material was replaced with 99A-5 (400 mg, 1.66 mmol) to prepare 230 mg of compound 99A-6.

[1812] MS(ESI, m / z): 286.3 [M+H] + .

[1813] Intermediate 99A:

[1814] According to the method for preparing compound 1C from 1C-9 in Example 1, the raw material was replaced with 99A-6 (230 mg, 0.81 mmol) to prepare 160 mg of compound 99A.

[1815] MS(ESI, m / z): 256.3 [M+H] + .

[1816] Preparation of Compound 99

[1817]

[1818] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 99A (35 mg, 0.14 mmol) and 2A (50 mg, 0.14 mmol) to prepare 20 mg of compound 99.

[1819] MS(ESI, m / z): 579.1, 581.1 [M+H] + .

[1820] 1 H NMR(400MHz, CDCl3)δ10.55(s,1H),8.46-8.34(m,1H),8.33-8.26(m,1H), 8.22(s,1H),8.20(s,1H),7.49-7.35(m,2H),7.24-7.15(m,1H),7.11(dd, J=6.4,6.8Hz,1H),6.87-6.76(m,2H),6.57(s,1H),3.96(s,3H),3.59(t,J =6.4Hz,2H),3.03(t,J=6.4Hz,2H),2.79(s,3H),1.83(s,3H),1.80(s,3H).

[1821] Example 100:

[1822] Preparation of Compound 100

[1823]

[1824] Compound 100A:

[1825] According to the method for preparing 2A in Example 2, the raw materials were replaced with 44A-1 (1g, 5.88mmol) and 2,4,5-trichloropyrimidine (2.16g, 11.75mmol) to prepare 75mg of compound 100A.

[1826] MS(ESI, m / z): 317.2, 319.2 [M+H] + .

[1827] Compound 100:

[1828] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 100A (70 mg, 0.22 mmol) and 6A (63 mg, 0.22 mmol) to prepare 20 mg of compound 100.

[1829] MS(ESI, m / z): 567.2, 569.2 [M+H] + .

[1830] 1 H NMR(400MHz, CDCl3)δ11.20(s,1H),9.09-9.04(m,1H),8.28(s,1H),8.16( d,J=4.4Hz,1H),8.12(s,1H),7.52(s,1H),7.15(s,1H),6.93(s,1H),6.57( s,1H),3.96-3.88(m,1H),3.87(s,3H),3.83(s,3H),3.30(t,J=5.6Hz,2H), 2.96(t,J=5.6Hz,2H),1.88(s,3H),1.85(s,3H),1.32(s,3H),1.31(s,3H).

[1831] Example 101:

[1832] Preparation of intermediate 101A

[1833]

[1834] Compound 101A-1:

[1835] According to the method for preparing compound 76A-1 in Example 76 1B-2, the raw material was replaced with 2-(dimethyloxyphospho)aniline (5g, 29.6mmol) to prepare 770mg of compound 101A-1.

[1836] MS(ESI, m / z): 186.2 [M+H] + .

[1837] Intermediate 101A:

[1838] According to the method for preparing compound 2A from 2-(dimethylphosphoxy)aniline in Example 2, the raw material was replaced with 101A-1 (770 mg, 4.16 mmol) to prepare 330 g of compound 101A.

[1839] MS(ESI, m / z): 376.0, 378.0 [M+H] + .

[1840] Preparation of compound 101

[1841]

[1842] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 101A (80 mg, 0.22 mmol) and 47A (76 mg, 0.22 mmol) to prepare 88 mg of compound 101.

[1843] MS(ESI, m / z): 681.2, 683.2 [M+H] + .

[1844] 1 H NMR(300MHz,CD3OD)δ8.25(s,1H),7.80-7.60(m,3H),7.44-7.13(m, 3H),6.65(s,1H),3.89(s,3H),3.87-3.78(m,4H),3.63(d,J=12.6Hz,2H),3.38(t,J=5.1Hz,2H),3 .28-3.16(m,2H),3.03(t,J=5.1Hz,2H),2.92(s,3H),2.24-2.13(m,4H),2.11(s,3H),2.06(s,3H).

[1845] Example 102:

[1846] Preparation of compound 102

[1847]

[1848] According to the method for preparing compound 22 in Example 22, the raw material was replaced with 27 (120 mg, 0.2 mmol) to prepare 30 mg of compound 102.

[1849] MS(ESI, m / z): 532.3 [M+H] + .

[1850] 1H NMR (400MHz, CDCl3) δ11.02(s,1H),9.09(s,1H),8.54(dd,J=8.4Hz,4.4Hz,1H),8.15(s,1H ),7.88(d,J=6.0Hz,1H),7.51(s,1H),7.22-7.14(m,1H),7.06-6.98(m,1H),6.96-6.90(m,1 H),6.58(s,1H),6.12(d,J=6.4Hz,1H),3.98-3.88(m,1H),3.85(s,3H),3.81(s,3H),3.30( t,J=5.6Hz,2H),2.95(t,J=5.6Hz,2H),1.83(s,3H),1.80(s,3H),1.33(s,3H),1.31(s,3H).

[1851] Example 103:

[1852] Preparation of intermediate 103A

[1853]

[1854] According to the method for preparing 1B in Example 1B-2, the raw materials were replaced with 35A-1 (700 mg, 3.68 mmol) and 2,4,5-trichloropyrimidine (1350 mg, 7.36 mmol) to prepare 720 mg of compound 103A.

[1855] MS(ESI, m / z): 337.0, 339.0 [M+H] + .

[1856] Preparation of compound 103

[1857]

[1858] Compound 103B:

[1859] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 103A (150 mg, 0.46 mmol) and 6A (127 mg, 0.46 mmol) to prepare 100 mg of compound 103B.

[1860] MS(ESI, m / z): 587.0, 589.0 [M+H] + .

[1861] Compound 103C:

[1862] According to the method for preparing 1C from intermediate 1C-9 in Example 1, the raw material was replaced with 103B (100 mg, 0.17 mmol) to prepare 80 mg of compound 103C.

[1863] MS(ESI, m / z): 557.3, 559.3 [M+H] + .

[1864] Compound 103:

[1865] According to the method for preparing intermediate 32C in Example 32, the raw material was replaced with 103C (50mg, 0.09mmol) to prepare 20mg of compound 103.

[1866] MS(ESI, m / z): 635.3, 637.3 [M+H] + .

[1867] 1 H NMR (400MHz, CDCl3) δ9.16(s,1H),8.81(d,J=2.0Hz,1H),8.78(d,J=2.0Hz,1H),8.63(d,J=9.2Hz,1H),8.32(s,1H),8.17(s,1H),7.63-7.51(m ,2H),7.30(s,1H),6.77(s,1H),6.53(s,1H),3.93-3.80(m,4H),3.66( s,3H),3.33-3.24(m,2H),2.96-2.86(m,5H),1.30(s,3H),1.28(s,3H).

[1868] Example 104:

[1869] Preparation of intermediate 104A

[1870]

[1871] According to the method for preparing 1B in Example 1B-2, the raw materials were replaced with 35A-1 (500 mg, 2.63 mmol) and 2,4-dichloro-5-methylpyrimidine (857 mg, 5.26 mmol) to prepare 510 mg of compound 104A.

[1872] MS(ESI, m / z): 317.2, 319.2 [M+H] + .

[1873] Preparation of compound 104

[1874]

[1875] Compound 104B:

[1876] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 104A (100 mg, 0.32 mmol) and 6A (90 mg, 0.32 mmol) to prepare 80 mg of compound 104B.

[1877] MS(ESI, m / z): 567.3 [M+H] + .

[1878] Compound 104C:

[1879] According to the method for preparing 1C from intermediate 1C-9 in Example 1, the raw material was replaced with 104B (75 mg, 0.13 mmol) to prepare 65 mg of compound 104C.

[1880] MS(ESI, m / z): 536.8 [M+H] + .

[1881] Compound 104:

[1882] According to the method for preparing intermediate 32C in Example 32, the raw material was replaced with 104C (50 mg, 0.09 mmol) to prepare 20 mg of compound 104.

[1883] MS(ESI, m / z): 615.4 [M+H] + .

[1884] 1 H NMR (400MHz, CDCl3) δ8.81-8.77(m,2H),8.75(d,J=1.6Hz,1H),8.69(d,J=9.6Hz,1H),8.29(s,1H),7.95(s,1H),7.86(s,1H),7.51(d,J=9.2Hz, 1H),6.84(s,1H),6.53(s,1H),3.92-3.84(m,4H),3.66(s,3H),3.29(t, J=5.6Hz,2H),2.95-2.87(m,5H),2.25(s,3H),1.30(s,3H),1.28(s,3H).

[1885] Example 105:

[1886] Preparation of compound 105

[1887]

[1888] Compound 105A:

[1889] According to the method for preparing compound 81 using 81A and 51B in Example 81, the raw materials were replaced with 96A (227 mg, 0.53 mmol) and 101A (200 mg, 0.53 mmol) to prepare 146 mg of compound 105A.

[1890] MS(ESI, m / z): 767.2, 769.2 [M+H] + .

[1891] Compound 105:

[1892] According to the method for preparing compound 63A-2 from 63A-1 in Example 63, the raw material was replaced with 105A (70 mg, 0.09 mmol) to prepare 8 mg of compound 105.

[1893] MS(ESI, m / z): 709.3, 711.3 [M+H] + .

[1894] 1 H NMR (400MHz, CDCl3) δ9.32 (s, 1H), 8.38 (s, 1H), 8.25 (s, 1H), 7.95 (dd, J = 8.4Hz, 3.2Hz, 1H), 7.53-7.46(m,1H),7.32(s,1H),7.26-7.21(m,1H),7.13-7.05(m,1H),6.90(s,1H),6.48(s,1 H),3.85(s,3H),3.78(s,3H),3.51-3.23(m,6H),2.94(t,J=5.6Hz,2H),2.61(t,J=12.8Hz,2H ),2.40-2.32(m,2H),2.10(s,3H),2.06(s,3H),2.03-1.95(m,2H),1.28(s,3H),1.26(s,3H).

[1895] Example 106:

[1896] Preparation of compound 106

[1897]

[1898] According to the method for preparing intermediate 32C in Example 32, the raw materials were replaced with 53B (100 mg, 0.17 mmol) and acetic anhydride (34 mg, 0.33 mmol) to prepare 63 mg of compound 106.

[1899] MS(ESI, m / z): 643.2, 645.2 [M+H] + .

[1900] 1 H NMR (300MHz, CDCl3) δ9.36 (s, 1H), 9.19 (s, 1H), 8.80 (d, J = 2.1Hz, 1H), 8.76 (d ,J=2.1Hz,1H),8.31(s,1H),8.22(s,1H),8.19(d,J=6.3Hz,1H),7.50(d,J=9.6 Hz,1H),7.38(s,1H),6.62-6.31(m,2H),3.94-3.78(m,4H),3.62(s,3H),3.26( t,J=5.4Hz,2H),2.87(t,J=5.4Hz,2H),2.48(s,3H),1.30(s,3H),1.27(s,3H).

[1901] Example 107:

[1902] Preparation of compound 107

[1903]

[1904] According to the method for preparing compound 72 in Example 72, 71, the raw materials were replaced with compound 81 (40 mg, 0.06 mmol) and formaldehyde aqueous solution (40%, 10 mg, 0.13 mmol) to prepare 10 mg of compound 107.

[1905] MS(ESI, m / z): 652.1, 654.1 [M+H] + .

[1906] 1 H NMR (300MHz, CDCl3) δ9.16 (s, 1H), 8.82 (m, 2H), 8.52 (d, J = 9.4Hz, 1H), 8.38 (s, 1H), 8.26 (s, 1H), 7.61 (s, 2H), 7.24 (s,1H),6.74(s,1H),3.99(s,3H),3.71(s,3H),3.44-3.34(m,2H),3.16(s,3H),3.00(t,J=5.1Hz,2H),2.95(s,3H).

[1907] Example 108:

[1908] Preparation of compound 108

[1909]

[1910] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 99A (80 mg, 0.31 mmol) to prepare 40 mg of compound 108.

[1911] MS(ESI, m / z): 631.1, 633.1 [M+H] + .

[1912] 1 H NMR (300MHz, CDCl3) δ12.48(s,1H),8.83(dd,J=8.4,5.2Hz,1H),8.76(d,J=2.1Hz,1H),8.71(d,J=1.8Hz,1H),8.31-8.27(m,3H),7.70(d,J=9.3Hz,1H) ,7.43(s,1H),7.32(s,1H),6.75(s,1H),6.67(s,1H),3.99(s,3H),3.60(t, J=6.6Hz,2H),3.02(t,J=6.6Hz,2H),2.81(s,3H),2.16(s,3H),2.11(s,3H).

[1913] Example 109:

[1914] Preparation of intermediate 109A

[1915]

[1916] Compound 109A-1:

[1917] Compound 1B-1 (6.9 g, 25.46 mmol) and triethylamine (12.88 g, 127.28 mmol) were dissolved in methanol (100 mL), followed by the addition of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.86 g, 2.55 mmol). The reaction mixture was purged with carbon monoxide (50 atm) and heated to 70 °C with stirring for 16 hours. After the starting material was observed to have disappeared under LCMS monitoring, the reaction mixture was cooled to room temperature and vented under reduced pressure, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 10) to give 1.5 g of compound 109A-1.

[1918] MS(ESI)M / Z:204.3[M+H] + .

[1919] Intermediate 109A:

[1920] According to the method for preparing 1B using 1B-2 in Example 1, the raw material was replaced with 109A-1 (1.5g, 7.38mmol) to prepare 0.5g of compound 109A.

[1921] MS(ESI, m / z): 394.0, 396.0 [M+H] + .

[1922] Preparation of compound 109

[1923]

[1924] Compound 109B:

[1925] According to the method for preparing compound 81 using 81A and 51B in Example 81, the raw materials were replaced with 109A (350 mg, 0.89 mmol) and 6A (254 mg, 0.89 mmol) to prepare 400 mg of compound 109B.

[1926] MS(ESI, m / z): 644.2, 646.2 [M+H] + .

[1927] Compound 109C:

[1928] According to the method for preparing compound 1C-3 from 1C-2 in Example 1, the raw material was replaced with 109B (400 mg, 0.62 mmol) to prepare 150 mg of compound 109C.

[1929] MS(ESI, m / z): 630.1, 632.1 [M+H] + .

[1930] Compound 109:

[1931] According to the method for preparing compound 48A-5 from 48A-4 in Example 48, the raw material was replaced with 109C (50 mg, 0.08 mmol) to prepare 7 mg of compound 109.

[1932] MS(ESI, m / z): 657.2, 659.2 [M+H] + .

[1933] 1H NMR (300MHz, CDCl3) δ8.84(d,J=1.8Hz,1H),8.74(d,J=1.8Hz,1H),8.65(d,J=9.3Hz ,1H),8.50(s,1H),8.42(s,1H),8.25(s,1H),7.65(s,1H),7.35(s,1H),6.90(s,1H) ,6.58(s,1H),3.99-3.91(m,4H),3.68(s,3H),3.53-3.48(m,1H),3.35(s,3H),3.18 -3.11(m,1H),3.04-2.99(m,1H),2.93(s,3H),2.89-2.83(m,1H),1.36-1.29(m,6H).

[1934] Example 110:

[1935]

[1936] Compound 110A-1:

[1937] 2-Amino-3-nitro-4-chloropyridine (3 g, 17.29 mmol) and an aqueous solution of chloroacetaldehyde (40%, 5.09 g, 25.928 mmol) were dissolved in 1,4-dioxane (10 mL) and stirred at room temperature for 2 hours. After the starting material disappeared as monitored by LCMS, the precipitated solid was filtered, and the filter cake was washed with diethyl ether (5 mL × 3). The filter cake was dried to give 2.8 g of compound 110A-1.

[1938] MS(ESI, m / z): 198.3, 200.3 [M+H] + .

[1939] Compound 110A-2:

[1940] Compound 110A-1 (800 mg, 4.05 mmol) was dissolved in ammonia-methanol (7 M, 20 mL) and stirred at room temperature for 2 hours. After the starting material disappeared as monitored by LCMS, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 100 mg of compound 110A-2.

[1941] MS(ESI, m / z): 179.2 [M+H] + .

[1942] Intermediate 110A:

[1943] According to the method for preparing compound 1B in Example 1B-2, the raw materials were replaced with 110A-2 (500 mg, 2.81 mmol) to prepare 480 mg of compound 110A.

[1944] MS(ESI, m / z): 368.9, 370.9 [M+H] + .

[1945] Preparation of compound 110

[1946]

[1947] Compound 110B:

[1948] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 110A (290 mg, 0.79 mmol) and 6A (150 mg, 0.52 mmol) to prepare 160 mg of compound 110B.

[1949] MS(ESI, m / z): 619.1, 621.1 [M+H] + .

[1950] Compound 110C:

[1951] According to the method for preparing 1C from intermediate 1C-9 in Example 1, the raw material was replaced with 110B (150 mg, 0.24 mmol) to prepare 130 mg of compound 110C.

[1952] MS(ESI, m / z): 589.3, 591.3 [M+H] + .

[1953] Compound 110:

[1954] According to the method for preparing intermediate 32C in Example 32, the raw material was replaced with 110C (150mg, 0.25mmol) to prepare 16mg of compound 110.

[1955] MS(ESI, m / z): 667.2, 669.2 [M+H] + .

[1956] 1H NMR (300MHz, CDCl3) δ8.90(s,1H),8.31(s,1H),8.23(s,1H),8.03(d,J=5.4Hz,1H),7.52(s,2H),7.30(s,2H),7.23(s,1 H),6.55(s,1H),3.86(s,4H),3.78(s,3H),3.32-3.23(m,2H),3.17(s,3H),2.97-2.90(m,2H),1.31(s,3H),1.30(s,3H).

[1957] Example 111:

[1958] Preparation of intermediate 111A

[1959]

[1960] Compound 111A-1:

[1961] 2-Methyl-4-aminopyridine (6 g, 55.48 mmol) and sodium carbonate (4.12 g, 38.84 mmol) were dissolved in water (30 mL). Potassium iodide (11.97 g, 72.13 mmol) and iodine (11.27 g, 44.39 mmol) were then added to the reaction solution in portions. The reaction mixture was heated to 100 °C and stirred for 5 hours. After the starting material disappeared as monitored by LC-MS, the reaction solution was cooled to room temperature. The mixture was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined. The organic phase was first washed with saturated sodium thiosulfate aqueous solution (50 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 0.83 g of compound 111A-1.

[1962] MS(ESI,m / z):235.0[M+H]+.

[1963] Compound 111A-2:

[1964] According to the method for preparing compound 1B-2 in Example 1B-1, the raw material was replaced with 111A-1 (400 mg, 1.71 mmol) to prepare 238 mg of compound 111A-2.

[1965] MS(ESI, m / z): 185.3 [M+H] + .

[1966] Intermediate 111A:

[1967] According to the method for preparing compound 1B using 1B-2 in Example 1, the raw materials were replaced with 111A-2 (238 mg, 1.29 mmol) to prepare 27 mg of compound 111A.

[1968] MS(ESI, m / z): 375.0, 377.0 [M+H] + .

[1969] Preparation of compound 111

[1970]

[1971] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 111A (22 mg, 0.06 mmol) and 6A (17 mg, 0.06 mmol) to prepare 6 mg of compound 111.

[1972] MS(ESI, m / z): 625.2, 627.2 [M+H] + .

[1973] 1 H NMR (400MHz, CDCl3) δ12.33(s,1H),8.51(dd,J=6.0,3.2Hz,1H),8.27(s,2H),7.94(s,1H),7.44(s,1H),7.11(s,1H),6.56(s,1H),3.93-3.8 6(m,1H),3.86(s,3H),3.81(s,3H),3.29(t,J=5.2Hz,2H),2.95(t,J=5.6Hz,2H),2.59(s,3H),2.01(d,J=13.2Hz,6H),1.31(d,J=6.4Hz,6H).

[1974] Example 112:

[1975] Preparation of intermediate 112A

[1976]

[1977] Compound 112A-1:

[1978] According to the method for preparing compound 1C-3 from compound 1C-2 in Example 1, the raw material was replaced with 8A-3 (2.05 g, 6.65 mmol) to prepare 1.19 g of compound 112A-1.

[1979] MS(ESI, m / z): 280.9 [M+H] + .

[1980] Compound 112A-2:

[1981] According to the method for preparing compound 1C-4 from compound 1C-3 in Example 1, the raw material was replaced with 112A-1 (1.2g, 4.29mmol) to prepare 952mg of compound 112A-2.

[1982] MS(ESI, m / z): 352.1 [M+H] + .

[1983] Compound 112A-3:

[1984] According to the method for preparing compound 1C-7 from compound 1C-6 in Example 1, the raw material was replaced with 112A-2 (930 mg, 2.65 mmol) to prepare 885 mg of compound 112A-3.

[1985] MS(ESI, m / z): 395.2 [M+H] + .

[1986] Compound 112A-4:

[1987] According to the method for preparing compound 1C-8 from compound 1C-7 in Example 1, the raw material was replaced with 112A-3 (885 mg, 2.24 mmol) to prepare 645 mg of compound 112A-4.

[1988] MS(ESI, m / z): 295.1 [M+H] + .

[1989] Compound 112A-5:

[1990] According to the method for preparing compound 56A-4 from compound 56A-3 in Example 56, the raw material was replaced with 112A-4 (330 mg, 1.12 mmol) to prepare 260 mg of compound 112A-5.

[1991] MS(ESI, m / z): 317.3 [M+H] + .

[1992] Intermediate 112A:

[1993] According to the method for preparing 1C from intermediate 1C-9 in Example 1, the raw material was replaced with 112A-5 (260 mg, 0.82 mmol) to prepare 160 mg of compound 112A.

[1994] MS(ESI, m / z): 287.3 [M+H] + .

[1995] Preparation of compound 112

[1996]

[1997] According to the method for preparing compound 1 using 1B and 1C in Example 1, the raw materials were replaced with 112A (57 mg, 0.2 mmol) and 81A (86 mg, 0.2 mmol) to prepare 36 mg of compound 112.

[1998] MS(ESI, m / z): 679.2, 681.2 [M+H] + .

[1999] 1 H NMR (400MHz, CDCl3) δ9.08(s,1H),8.83(d,J=2.0Hz,1H),8.79(d,J=2.0Hz,1H),8.73(d,J=9.6Hz,1H),8.26(s,1H),8.12(s,1H),7.72(s,1H),7.52(s, 1H),7.23(s,1H),7.04(s,1H),6.53(s,1H),3.86(s,4H),3.49(s,3H),3 .33-3.27(m,2H),3.10-3.02(s,2H),2.93(s,3H),1.30(d,J=6.8Hz,6H).

[2000] Example 113:

[2001] Preparation of compound 113

[2002] ...

Claims

1. A compound represented by formula (I''), or a stereoisomer, tautomer or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, or isotope-labeled derivative thereof, in, R 1 Selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocycloalkyloxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino, C 2-6 Alkenylamino and C 2-6 Alkynylamino; M is selected from N or CR a ; Z is selected from N or CR 6 ; Z 1 Select from N or CR 7 ; R a H, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl or C 1-6 Haloalkyl; Or, R a With R 1 Cyclization to a substituted or unsubstituted 5-8 membered heterocyclic group or a 5-8 membered carbocyclic group; Ring A is selected from substituted or unsubstituted 5-8 membered heterocyclic group or 5-8 membered carbocyclic group; Ring B is absent or is selected from optionally replaced by one or more R 2 substituted aryl or 5-6 membered heteroaryl, 4-8 membered heterocycloalkyl or C 4-8 Cycloalkyl; R 2 Each independently selected from H, halogen, -CN, -C(=O)R b 、-C(=O)NR b R c 、-S(=O) 2 R b 、-S(=O)(=NR c )R b 、-NH 2 、-OH、-SH、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-6 Aryl, C 5-6 Arylalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocycloalkyloxy, C 2-6 Alkenyloxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino, C 2-6 Alkenylamino or -(CH 2 ) r NR c R d , r is arbitrarily selected from 0, 1, 2 or 3; wherein R 2 C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-6 Aryl, C 5-6 Arylalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocycloalkyloxy, C 2-6 Alkenyloxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino or C 2-6 The alkenylamino group is optionally substituted with one or more C 1-3 Alkyl or C 1-3 Alkoxy substitution; R 3 , R 4 Each independently selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino and C 2-6 Alkenylamino; Or, R 3 With R 4 Cyclization to aromatic groups, C 4-7 Cycloalkyl, 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl; R 5 selected from substituted or unsubstituted -NH 2 、-C(=O)NR b R c 、-S(=O) 2 R b 、-P(=O)R b R c 、-P(=O)R b NR c R d 、-P(=O)R b OR c 、-P(=O)OR b OR c 、-P(=S)R b R c 、-P(=S)R b NR c R d 、-P(=S)R b OR c 、-P(=S)OR b OR c 、-S(=O) 2 NR b R c 、R b S(=O) 2 NR c -、-N=S(=O)R b R c 或R b N=S(=O)R c -、-NR b C(O)R c 或R c S(=NR b )(=O)NR d -; R b , R c , R d Each independently selected from H, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, C 4-6 Heterocycloalkyl, C 5-10 Aryl or 5-10 membered heteroaryl; Or, R b , R c The atoms to which they are commonly attached are cyclized to be unsubstituted or optionally substituted with one or more C 1-3 Alkyl or C 1-3 Alkoxy-substituted 5-6-membered heterocycloalkyl; R 6 , R 7 , R 8 Each independently selected from H, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 1-6 Haloalkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino and C 2-6 Alkenylamino; Or, R 5 With R 6 Cyclization to form -P(=O)(R b )-、-P(=S)(R b )-、-N(R b )S(=O) 2 -、-S(=O) 2 N(R b )-or-S(=O) 2 4-7 membered ring; Or, R 6 With R 7 Cyclization to C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl; Or, R 7 With R 8 Cyclization to C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl.

2. A compound as shown in formula (I'') according to claim 1, in, R 1 Selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Preferably, R 1 Selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy.

3. A compound as shown in formula (I'') according to claim 1, in, M is selected from N or CR a , where R a H, halogen, C 1-3 Alkyl, C 3-6 Cycloalkyl or C 1-3 Preferably, M is selected from N or CH.

4. A compound as claimed in claim 1, in, Ring A is selected from a substituted or unsubstituted 5-8 membered carbocyclic group or a 5-8 membered heterocyclic group containing 1 or 2 heteroatoms selected from O, S and N; Preferably, ring A may contain a double bond; or Preferably, 1 or 2 ring atoms on ring A may be optionally substituted with -C(=O), -N(=O), -S(=O), -S(=O) 2 Ring A may also be optionally replaced by one or more R x Group substituted, wherein R x Selected from H, -OH, -CN, -NH 2 , halogen, C 1-6 Alkylcarbonyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 Cycloalkyl-C 1-6 Alkyl-, 3-8 membered heterocycloalkyl-C 1-6 Alkyl-, aryl-C 1-6 Alkyl-, C 5-13 Spirocyclyl, 5-13 membered spiroheterocyclyl; wherein the C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 Cycloalkyl-C 1-6 Alkyl-, 3-8 membered heterocycloalkyl-C 1-6 Alkyl-, aryl-C 1-6 Alkyl-, C 5-13 Spirocyclyl, 5-13 membered spirocyclyl, spiro heterocyclyl, optionally substituted by one or more R y wherein said R y Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, C 3-8 Cycloalkyl-C 1-6 Alkyl-, 4-8 membered heterocycloalkyl-C 1-6 Alkyl-, 5-10 membered aryl, 5-10 membered heteroaryl.

5. A compound as shown in formula (I'') according to claim 1, in, Ring B is optionally substituted with one or more R 2 The substituted aryl or 5-6 membered heteroaryl; the aryl, 5-6 membered heteroaryl can be pyrrolyl, furyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, triazolyl, phenyl, pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl or triazinyl.

6. A compound as shown in formula (I'') according to claim 1, in, R 2 Each independently selected from H, halogen, -CN, -C(=O)R b 、-S(=O) 2 R b 、-S(=O)(=NR c )R b 、-NH 2 、-OH、-SH、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-6 Aryl, C 5-6 Arylalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocycloalkyloxy, C 2-6 Alkenyloxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino, C 2-6 Alkenylamino or -(CH 2 ) r NR c R d , r is arbitrarily selected from 0, 1, 2 or 3; wherein R 2 The 3-6 membered heterocycloalkyl, C 5-6 Arylalkyl is optionally substituted with one or more C 1-3 Alkyl or C 1-3 Alkoxy substitution.

7. A compound as shown in formula (I'') as claimed in claim 1, in, R 3 , R 4 Each independently selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl; Or, R 3 With R 4 Cyclization to phenyl, C 4-7 Cycloalkyl, 5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from O, S and N, or 5-6 membered heteroaryl; preferably, the 5-6 membered heteroaryl can be pyrrolyl, furyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, triazolyl, phenyl, pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl or triazinyl.

8. A compound as shown in formula (I'') according to claim 1, in, R 5 selected from substituted or unsubstituted -NH 2 、-C(=O)NR b R c 、-S(=O) 2 R b 、-P(=O)R b R c 、-P(=O)R b NR c R d 、-P(=O)R b OR c 、-P(=O)OR b OR c 、-P(=S)R b R c 、-P(=S)R b NR c R d 、-P(=S)R b OR c 、-P(=S)OR b OR c 、-S(=O) 2 NR b R c 、R b S(=O) 2 NR c -、-N=S(=O)R b R c 、R b N=S(=O)(R c )-、-NR b C(O)R c ; Or, R 5 With R 6 Cyclization to form -P(=O)(R b )-、-P(=S)(R b )-、-N(R b )S(=O) 2 -、-S(=O) 2 N(R b )-or-S(=O) 2 4-7 membered ring.

9. A compound as shown in formula (I'') as claimed in claim 1, in, R b , R c , R d Each independently selected from H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl; Or, R b , R c The atoms to which they are commonly attached are cyclized to be unsubstituted or optionally substituted with one or more C 1-3 Alkyl or C 1-3 Alkoxy-substituted 5-6-membered heterocycloalkyl.

10. A compound according to formula (I'') as claimed in claim 1, in, R 6 and R 7 Each independently selected from H, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino and C 2-6 Alkenylamino; Or, R 6 With R 7 Cyclization to C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl; preferably, the 5-6 membered heteroaryl can be pyrrolyl, furyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, triazolyl, phenyl, pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl or triazinyl.

11. A compound according to formula (I'') as claimed in claim 1, in, R 8 For H.

12. A compound represented by formula (I"), or a stereoisomer, tautomer or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, or isotope-labeled derivative thereof, in, R 1 Selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocycloalkyloxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino, C 2-6 Alkenylamino and C 2-6 Alkynylamino; M is selected from N or CR a ; R a H, halogen, C 1-3 Alkyl, C 3-6 Cycloalkyl or C 1-3 Haloalkyl; Z is selected from N or CR 6 ; Z 1 Select from N or CR 7 ; Or, R a With R 1 Cyclization to a substituted or unsubstituted 5-8 membered heterocyclic group; Ring A is selected from substituted or unsubstituted 5-8 membered heterocyclic group or 5-8 membered carbocyclic group; Ring B is optionally substituted with one or more R 2 The substituted aryl or 5-6 membered heteroaryl; the aryl or 5-6 membered heteroaryl may be pyrrolyl, furyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, triazolyl, phenyl, pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl or triazinyl; R 2 Each independently selected from H, halogen, -CN, -C(=O)R b 、-S(=O) 2 R b 、-S(=O)(=NR c )R b 、-NH 2 、-OH、-SH、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-6 Aryl, C 5-6 Arylalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocycloalkyloxy, C 2-6 Alkenyloxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino, C 2-6 Alkenylamino or -(CH 2 ) r NR c R d , r is arbitrarily selected from 0, 1, 2 or 3; R 3 , R 4 Each independently selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino and C 2-6 Alkenylamino; Or, R 3 With R 4 Cyclization to aromatic groups, C 4-7 Cycloalkyl, 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl; R 5 selected from substituted or unsubstituted -NH 2 、-C(=O)NR b R c 、-S(=O) 2 R b 、-P(=O)R b R c 、-P(=O)R b NR c R d 、-P(=O)R b OR c 、-P(=O)OR b OR c 、-P(=S)R b R c 、-P(=S)R b NR c R d 、-P(=S)R b OR c 、-P(=S)OR b OR c 、-S(=O) 2 NR b R c 、R b S(=O) 2 NR c -、-N=S(=O)R b R c or R b N=S(=O)(R c )-、-NR b C(O)R c ; R b , R c , R d Each independently selected from H, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, C 4-6 Heterocycloalkyl, C 5-10 Aryl or 5-10 membered heteroaryl; Or, R b , R c The atoms commonly connected thereto are cyclized to form a 5-6 membered heterocycloalkyl group; R 6 , R 7 , R 8 Each independently selected from H, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino and C 2-6 Alkenylamino; Or, R 5 With R 6 Cyclization to form -P(=O)(R b )-、-P(=S)(R b )-、-N(R b )S(=O) 2 -、-S(=O) 2 N(R b )-or-S(=O) 2 4-7 membered ring; Or, R 6 With R 7 Cyclization to C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl; Or, R 7 With R 8 Cyclization to C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl.

13. A compound represented by formula (I'), or a stereoisomer, tautomer or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, or isotope-labeled derivative thereof, in, R 1 Selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocycloalkyloxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino, C 2-6 Alkenylamino and C 2-6 Alkynylamino; M is selected from N or CR a ; Z is selected from N or CR 6 ; R a H, halogen, C 1-3 Alkyl, C 3-6 Cycloalkyl or C 1-3 Haloalkyl; Or, R a With R 1 Cyclization to a substituted or unsubstituted 5-8 membered heterocyclic group; Ring A is selected from substituted or unsubstituted 5-8 membered heterocyclic group or 5-8 membered carbocyclic group; Ring B is optionally substituted with one or more R 2 The substituted aryl or 5-6 membered heteroaryl; the aryl or 5-6 membered heteroaryl may be pyrrolyl, furyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, triazolyl, phenyl, pyrimidinyl, pyridyl, pyrazinyl or pyridazinyl; R 2 Each independently selected from H, halogen, -CN, -C(=O)R b 、-S(=O) 2 R b 、-S(=O)(=NR c )R b 、-NH 2 、-OH、-SH、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-6 Aryl, C 5-6 Arylalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocycloalkyloxy, C 2-6 Alkenyloxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino and C 2-6 Alkenylamino; R 3 , R 4 Each independently selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino and C 2-6 Alkenylamino; Or, R 3 With R 4 Cyclization to aromatic groups, C 4-7 Cycloalkyl, 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl; R 5 selected from substituted or unsubstituted -NH 2 、-C(=O)NR b R c 、-S(=O) 2 R b 、-P(=O)R b R c 、-P(=O)R b NR c R d 、-P(=O)R b OR c 、-P(=O)OR b OR c 、-P(=S)R b R c 、-P(=S)R b NR c R d 、-P(=S)R b OR c 、-P(=S)OR b OR c 、-S(=O) 2 NR b R c 、R b S(=O) 2 NR c -、-N=S(=O)R b R c or R b N=S(=O)R c -; R b , R c , R d Each independently selected from H, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, C 4-6 Heterocycloalkyl, C 5-10 Aryl or 5-10 membered heteroaryl; R 6 , R 7 , R 8 Each independently selected from H, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 1-6 Haloalkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino and C 2-6 Alkenylamino; Or, R 5 With R 6 Cyclization to form a P(=O)R b 4-7 membered ring; Or, R 6 With R 7 Cyclization to C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl; Or, R 7 With R 8 Cyclization to C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl.

14. A compound represented by formula (I), or a stereoisomer, tautomer or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, or isotope-labeled derivative thereof, in, R 1 Selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocycloalkyloxy, C 2-6 Alkenyloxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino and C 2-6 Alkenylamino; M is selected from N or CR a ; R a H, halogen, C 1-3 Alkyl, C 3-6 Cycloalkyl or C 1-3 Haloalkyl; Or, R a With R 1 Cyclization to a substituted or unsubstituted 5-8 membered heterocyclic group; Ring A is selected from substituted or unsubstituted 4-8 membered heterocyclic group or 5-8 membered carbocyclic group; Ring B is optionally substituted with one or more R 2 The substituted aryl or 5-6 membered heteroaryl; the aryl or 5-6 membered heteroaryl may be pyrrolyl, furyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, triazolyl, phenyl, pyrimidinyl, pyridyl, pyrazinyl or pyridazinyl; R 2 Each independently selected from H, halogen, -CN, -C(=O)R b 、-S(=O) 2 R b 、-S(=O)(=NR c )R b 、 -NH 2 、-OH、-SH、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocycloalkyloxy and C 2-6 Alkenyloxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino and C 2-6 Alkenylamino; R 3 , R 4 Each independently selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino and C 2-6 Alkenylamino; Or, R 3 With R 4 Cyclization to aromatic groups, C 4-7 Cycloalkyl, 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl; R 5 Selected from substituted or unsubstituted -NH 2 、-C(=O)NR b R c 、-S(=O) 2 R b 、-P(=O)R b R c 、-P(=O)R b NR c R d 、-S(=O) 2 NR b R c , R b S(=O) 2 NR c -、-N=S(=O)R b R c or R b N=S(=O)R c -; R b , R c , R d Each independently selected from H, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, C 4-6 Heterocycloalkyl, C 5-10 Aryl or 5-10 membered heteroaryl; R 6 , R 7 , R 8 Each independently selected from H, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino and C 2-6 Alkenylamino; Or, R 5 With R 6 Cyclization to form a P(=O)R b 4-7 membered ring; Or, R 6 With R 7 Cyclization to C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl; Or, R 7 With R 8 Cyclization to C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl.

15. The compound according to any one of claims 1 to 14, in, R 1 Selected from H, halogen, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy; M is selected from N or CH; Ring A is selected from substituted or unsubstituted 5-8 membered heterocyclic group or 5-8 membered carbocyclic group; Ring B is optionally substituted with one or more R 2 substituted 5-6 membered heteroaryl; the 5-6 membered heteroaryl is pyrrolyl, furanyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, triazolyl, phenyl, pyrimidinyl, pyridyl, pyrazinyl or pyridazinyl; R 2 Each independently selected from H, C 1-4 Alkyl, C 1-4 Haloalkyl, -(CH 2 ) r NR c R d , 3-6 membered heterocycloalkyl, C 5-6 Arylalkyl, wherein said r is arbitrarily selected from 0, 1, 2 or 3, said 3-6 membered heterocycloalkyl, C 5-6 Arylalkyl is optionally substituted with one or more C 1-3 Alkyl or C 1-3 Alkoxy substitution; R 3 , R 4 Each independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl; Or, R 3 With R 4 Cyclization to form a 5-6 membered heteroaryl; the 5-6 membered heteroaryl is pyrrolyl, furanyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, triazolyl, phenyl, pyrimidinyl, pyridyl, pyrazinyl or pyridazinyl; R 5 selected from -C(=O)NR b R c 、-P(=O)R b R c 、-P(=S)R b R c 、-S(=O) 2 NR b R c 、R b S(=O) 2 NR c -、-NR b C(O)R c ; R b , R c , R d Each independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl; Or, R b , R c The atoms to which they are commonly attached are cyclized to be unsubstituted or optionally substituted with one or more C 1-3 Alkyl or C 1-3 Alkoxy-substituted 5-6-membered heterocycloalkyl; Or, R 5 With R 6 Cyclization to form -P(=O)(R b )-、-P(=S)(R b )-、-N(R b )S(=O) 2 -、-S(=O) 2 N(R b )-or-S(=O) 2 4-7 membered ring; R 6 , R 7 , R 8 Each independently selected from H, halogen, C 1-3 alkyl; Or, R 8 Selected from H, R 6 With R 7 Cyclization to form a 5-6 membered heteroaryl; the 5-6 membered heteroaryl is pyrrolyl, furanyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, triazolyl, phenyl, pyrimidinyl, pyridyl, pyrazinyl or pyridazinyl.

16. The compound of any one of claims 1-15, wherein said M is selected from N or CH; preferably, M is CH.

17. The compound according to any one of claims 1 to 16, wherein R 1 Selected from H, halogen, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy; Preferably, wherein said R 1 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, trifluoromethyl, trifluoromethoxy, trichloromethyl, trichloromethoxy, 2,2,2-trifluoroethoxy; More preferably, wherein said R 1 Selected from methoxy.

18. The compound according to any one of claims 1 to 17, wherein R 2 is selected from H, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, -CH 2 CH 2 N(CH 3 )CH 3 , Preferably, wherein said R 2 is selected from H, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl; More preferably, wherein said R 2 Selected from methyl.

19. The compound according to any one of claims 1 to 18, wherein R 3 , R 4 Each is independently selected from H, F, Cl, Br, CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, cyclopropyl; Preferably, wherein said R 3 Selected from H, R 4 Each is independently selected from H, F, Cl, Br, methyl, difluoromethyl, trifluoromethyl, and cyclopropyl; More preferably, wherein said R 3 Selected from H, R 4 Independently selected from F, Cl, Br, methyl, ethyl, difluoromethyl, trifluoromethyl; More preferably, wherein said R 3 Selected from H, R 4 Selected from Cl, Br, methyl; Still more preferably, wherein said R 3 Selected from H, R 4 Selected from Br. Or, wherein the R 3 , R 4 Cyclization to a thiophene ring and a pyrrole ring, wherein the thiophene ring and the pyrrole ring may be optionally C 1-4 Alkyl substituted.

20. The compound according to any one of claims 1 to 19, wherein R 5 Selected from Preferably, wherein said R 5 Selected from Preferably, wherein said R 5 Selected from Preferably, wherein said R 5 Selected from or Preferably, wherein said R 5 Selected from or R 5 With R 6 Cyclization 21. The compound of any one of claims 1 to 20, wherein R 6 , R 7 , R 8 are each independently selected from H, methyl or halogen; or, R 6 , R 8 Selected from H, R 7 Selected from F; or, R 6 , R 7 , R 8 Each is independently selected from H or methyl, preferably H; Or, wherein the R 6 With R 7 or R 7 With R 8 Independently cyclize to cyclobutane, cyclopentane, tetrahydropyrrole ring, tetrahydrofuran ring, tetrahydropyran ring, thiophene ring, imidazole ring, pyrazole ring, pyrrole ring, oxazole ring, thiazole ring, isoxazole ring, piperazine ring, isothiazole ring, benzene ring, pyridine ring, piperidine ring, pyrimidine ring, pyridazine ring, pyrazine ring; Preferably, R 6 With R 7 or R 7 With R 8 Independently cyclizes to cyclobutane, pyridine or pyrazine rings; More preferably, R 6 With R 7 Independently cyclizes to the pyrazine ring.

22. The compound of any one of claims 1 to 21, wherein the structural unit in, R 1 As defined in any one of claims 1 to 21; M is as defined in any one of claims 1 to 21; R 2 As defined in any one of claims 1 to 21; R x Selected from H, -OH, -CN, -NH 2 , halogen, C 1-6 Alkylcarbonyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 Cycloalkyl-C 1-6 Alkyl-, 3-8 membered heterocycloalkyl-C 1-6 Alkyl-, aryl-C 1-6 Alkyl-, C 5-13 Spirocyclyl, 5-13 membered spiroheterocyclyl; wherein the C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 Cycloalkyl-C 1-6 Alkyl-, 3-8 membered heterocycloalkyl-C 1-6 Alkyl-, aryl-C 1-6 Alkyl-, C 5-13 Spirocyclyl, 5-13 membered spiro heterocyclyl, optionally substituted by one or more R y wherein said R y Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, C 3-8 Cycloalkyl-C 1-6 Alkyl-, 4-8 membered heterocycloalkyl-C 1-6 Alkyl-, 5-10 membered aryl, 5-10 membered heteroaryl.

23. The compound according to claim 22, in, R x Selected from H, -OH, -CN, -NH 2 , halogen, C 1-6 Alkylcarbonyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 Cycloalkyl-C 1-6 Alkyl-, 3-8 membered heterocycloalkyl-C 1-6 Alkyl-; wherein the C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 Cycloalkyl-C 1-6 Alkyl-, 3-8 membered heterocycloalkyl-C 1-6 Alkyl-, aryl-C 1-6 Alkyl-optionally substituted with one or more R y replaced by; Or, R x Selected from H, -OH, -CN, -NH 2 , halogen, C 1-6 Alkylcarbonyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-4 Alkyl-, 3-6 membered heterocycloalkyl-C 1-4 Alkyl-, aryl-C 1-6 Alkyl-, 7-11 membered spiro heterocyclic group, wherein the C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-4 Alkyl-, 3-6 membered heterocycloalkyl-C 1-4 Alkyl-, aryl-C 1-6 Alkyl-, spiro heterocyclic group is optionally substituted by one or more R y replaced by; Among them, the R y Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocycloalkyl, C 3-8 Cycloalkyl-C 1-6 Alkyl-, 4-8 membered heterocycloalkyl-C 1-6 alkyl-, 5-10 membered aryl, 5-10 membered heteroaryl; preferably, the R y Selected from H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl-C 1-6 Alkyl-; preferably, R y is selected from H, F, methyl, ethyl, isopropyl, methoxy, FCH 2 CH 2 -; Among them, when R x When directly connected to a N atom, R x Not -OH, -NH 2 and halogen.

24. The compound according to claim 22 or 23, in, R x Selected from H, -OH, -CN, -NH 2 , F, methyl, ethyl, isopropyl, trifluoroethyl, methylcarbonyl, wherein ring C is a 4-8 membered heterocycloalkyl, ring D is an oxygen-containing 4-8 membered heterocycloalkyl; m and n are independently 0, 1, 2 or 3; R y As defined in claim 22 or 23; Preferably, R x Selected from H, -OH, -CN, -NH 2 , methyl, ethyl, isopropyl, methylcarbonyl, wherein ring C is a 4-8 membered heterocycloalkyl group; m and n are independently 0, 1, 2 or 3; R y as defined in claim 22 or 23; Preferably, R x Selected from H, -OH, -CN, -NH 2 , F, methyl, ethyl, isopropyl, trifluoroethyl, methylcarbonyl, Preferably, R x Selected from H, methyl, ethyl, isopropyl, Preferably, R x Selected from H, methyl, ethyl, isopropyl, Preferably, R x is selected from H, methyl, ethyl or isopropyl; Preferably, R x Selected from methyl or isopropyl.

25. The compound of claim 22 or 23, wherein the structural unit R 1 , M, R x as defined in claim 22 or 23; or The structural unit Selected from Where R 1 , M, R x , R b , R c , R 2 as defined in claim 22 or 23; or The structural unit Selected from in, M.R 1 , R 2 , R x As defined in claim 22 or 23.

26. A compound as described in any one of claims 1 to 25, selected from or in, X and Y are each independently selected from -C(=O)-, -C=C-, -NR x -、-O-、-CR 9 R 10 -、-S(=O)-、-S(=O) 2 -; X 1 , X 2 Each independently selected from N, NR 2 ; R 9 , R 10 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl; R 1 As defined in any one of claims 1 to 25; R 2 As defined in any one of claims 1 to 25; R 4 As defined in any one of claims 1 to 25; R 5 As defined in any one of claims 1 to 25; R 6 , R 7 As defined in any one of claims 1 to 25; R x As defined in any one of claims 22 to 25; M, if present, is as defined in any one of claims 1-25.

27. The compound of claim 26, selected from or in, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R x As defined in claim 26; M, if present, is as defined in claim 26.

28. The compound of claim 27, selected from or in, R 1 , R 2 , R 4 , R 5 , R x As defined in claim 27; M, if present, is as defined in claim 27.

29. The compound of claim 28, selected from or in, R 4 , R 5 , R x As defined in claim 28; M, if present, is as defined in claim 28.

30. The compound of claim 29, selected from in, R 5 , R x As defined in claim 29.

31. A compound as described in any one of claims 1 to 30, or a stereoisomer, tautomer, or pharmaceutically acceptable salt, prodrug, hydrate, solvate, or isotope-labeled derivative thereof, selected from:

32. A pharmaceutical composition comprising the compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

33. Use of the compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 32 in the preparation of a drug for treating cancer.

34. The use of claim 33, wherein the cancer comprises lymphoma, non-Hodgkin's lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, leukemia, gastric cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), bile duct cancer, renal cancer, thyroid cancer, anaplastic large cell lymphoma, mesothelioma, multiple myeloma, melanoma.

35. The use according to claim 34, wherein the cancer is lung cancer.

36. A compound represented by formula (V) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in, R 11 For -NH 2 or-NO 2 ; R 1 As defined in any one of claims 1 to 31; Ring A and Ring B are as defined in any one of claims 1 to 31; M is as defined in any one of claims 1 to 31; Structural unit As defined in any one of claims 22 to 31.

37. The compound of claim 36 or its stereoisomer, or a pharmaceutically acceptable salt thereof, selected from: in, R 1 As defined in any one of claims 1 to 31; R 11 As defined in claim 36; R 2 As defined in any one of claims 1 to 31; R x As defined in any one of claims 22 to 31.

38. The compound of claim 37 or its stereoisomer, or a pharmaceutically acceptable salt thereof, selected from: in, R 11 , R x As defined in claim 37.

39. Use of the compound or stereoisomer thereof, or pharmaceutically acceptable salt thereof, of any one of claims 36 to 38 in the preparation of the compound or stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate or isotope-labeled derivative thereof of any one of claims 1 to 31.

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