Tricyclic compounds as EGFR inhibitors

Abstract

The present invention provides a class of compounds represented by formula (I'") as selective EGFR inhibitors, pharmaceutical compositions containing the compounds, useful intermediates for preparing the compounds, and methods of using the compounds of the present invention to treat cell proliferative diseases, such as cancer.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of the following prior applications filed with the State Intellectual Property Office of China: Application No. 202010292186.8, filed on April 14, 2020, entitled “Fused Tricyclic Compounds as EGFR Inhibitors”; Application No. 202010852717.4, filed on August 22, 2020, entitled “Fused Tricyclic Compounds as EGFR Inhibitors”; Application No. 202110175424.1, filed on February 9, 2021, entitled “Fused Tricyclic Compounds as EGFR Inhibitors”; and Application No. 202110312259.X, filed on March 24, 2021, entitled “Fused Tricyclic Compounds as EGFR Inhibitors”. The entire text of the above prior applications is incorporated herein by reference. Technical Field

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

[0004] Lung cancer is the leading cancer in terms of morbidity and mortality, and poses a serious threat to human health and life. Lung cancer is mainly divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), of which approximately 80% is 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 the most common type of mutation in NSCLC patients, particularly in Asian populations, where they can account for 40% to 50%. Therefore, EGFR has long been one of the most sought-after targets in drug development.

[0006] Currently, marketed EGFR inhibitors are categorized into first, second, and third generations. The first generation comprises reversible targeted drugs, such as gefitinib, erlotinib, and icotinib. The second generation comprises irreversible targeted drugs, such as afatinib and dacomitinib. While first and second generation targeted drugs offer significant efficacy, most patients develop resistance after one to two years of treatment. Among patients with EGFR inhibitor resistance, 50% of this resistance is associated with the T790M mutation. The third-generation EGFR targeted drug, osimertinib, overcomes tumor resistance caused by the T790M mutation, providing improved survival benefits for more lung cancer patients. However, resistance to third-generation targeted drugs is also inevitable, primarily due to the C797S mutation. The C797S mutation, a cysteine-to-serine mutation, disrupts EGFR protein binding to third-generation targeted drugs, preventing EGFR phosphorylation and activation of downstream signaling pathways. Currently, there is no mature treatment for the two main cis triple mutations that appear after osimertinib resistance: Del19 / T790M / C797S and L858R / T790M / C797S. The clinical demand is imminent, and the present invention is based on solving this problem. Summary of the Invention

[0007] The present invention aims to provide a class of tricyclic compounds as selective EGFR inhibitors, pharmaceutical compositions containing the compounds, useful intermediates for preparing the compounds, and the use of the compounds in preparing drugs for treating cancer.

[0008] The present invention provides a compound represented by formula (I'') or a stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, or isotope-labeled derivative thereof.

[0009]

[0010] in,

[0011] R1 is selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, 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 2-6Alkynylamino;

[0012] 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 alkyl halide;

[0013] Z is selected from N or CR6;

[0014] Z1 is selected from N or CR7;

[0015] Or, R a Cyclize with R1 to form a substituted or unsubstituted 5-8 membered heterocyclic group or 5-8 membered carbocyclic group;

[0016] Ring A is selected from substituted or unsubstituted 5-8 membered heterocyclic group or 5-8 membered carbocyclic group;

[0017] Ring B is absent or selected from aryl or 5-6 membered heteroaryl, 4-8 membered heterocycloalkyl or C optionally substituted with one or more R2 4-8 Cycloalkyl;

[0018] R2 is independently selected from H, halogen, -CN, -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 Halogenated alkyl, 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 -(CH2) r NR c R d , r is arbitrarily selected from 0, 1, 2 or 3; wherein, C in R2 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 5-6 Aryl, C5-6 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 Alkenylamino is optionally substituted by one or more C 1-3 Alkyl or C 1-3 Alkoxy substitution;

[0019] R3 and R4 are each independently selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, 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;

[0020] Alternatively, R3 and R4 are cyclized to form an aryl group, C 4-7 Cycloalkyl, 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl;

[0021] 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)R c or R c S(=NR b )(=O)NR d -;

[0022] R b 、R c 、R d Each independently selected from H, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, C 4-6 Heterocycloalkyl, C 5-10 Aryl or 5-10 membered heteroaryl;

[0023] 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;

[0024] R6, R7, R8 are each independently selected from H, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, 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;

[0025] Alternatively, R5 and R6 are cyclized to form a -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 membered ring;

[0026] Alternatively, R6 and R7 are cyclized to form C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl;

[0027] Alternatively, R7 and R8 are cyclized to form C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl.

[0028] 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 Halogenated alkyl, C 1-6 Preferably, R1 is selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy.

[0029] 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 Preferably, M is selected from N or CH.

[0030] In some embodiments of the present invention, 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; in some embodiments, ring A may contain a double bond; in some embodiments, 1 or 2 ring atoms on ring A may be optionally replaced by -C(=O), -N(=O), -S(=O), -S(=O)2, and ring A may also be optionally replaced by one or more R x Group substituted, wherein the R x Selected from H, -OH, -CN, -NH2, halogen, C 1-6 Alkylcarbonyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 said 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 substituted; said R ySelected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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.

[0031] In some embodiments of the present invention, ring B is an aryl group or a 5-6 membered heteroaryl group optionally substituted by one or more R2; the aryl group or the 5-6 membered heteroaryl group can be pyrrolyl, furyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, triazolyl, phenyl, pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl or triazinyl.

[0032] In some embodiments of the present invention, R2 is independently selected from H, halogen, -CN, -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 Halogenated alkyl, 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 -(CH2) r NR c R d , r is arbitrarily selected from 0, 1, 2 or 3; wherein 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.

[0033] In some embodiments of the present invention, R3 and R4 are independently selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C1-6 Halogenated alkoxy, C 3-6 Cycloalkyl; or, R3 and R4 are cyclized to form phenyl, C 4-7 cycloalkyl, a 5-7 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from O, S and N, or a 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.

[0034] 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 ; Or, R5 and R6 are cyclized to form a -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 membered ring.

[0035] In some embodiments of the present invention, R b 、R c 、Rd Each independently selected from H, C 1-3 Alkyl, C 1-3 Halogenated alkyl, 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.

[0036] In some embodiments of the present invention, R6 and R7 are independently selected from H, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, 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, R6 and R7 are cyclized to form 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.

[0037] In some embodiments of the present invention, R8 is H.

[0038] The present invention provides a compound represented by formula (I") or a stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, or isotope-labeled derivative thereof.

[0039]

[0040] in,

[0041] R1 is selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, 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 2-6Alkynyloxy, 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;

[0042] M is selected from N or CR a ; R a H, halogen, C 1-3 Alkyl, C 3-6 Cycloalkyl or C 1-3 alkyl halide;

[0043] Z is selected from N or CR6;

[0044] Z1 is selected from N or CR7;

[0045] Or, R a Cyclize with R1 to form a substituted or unsubstituted 5-8 membered heterocyclic group;

[0046] Ring A is selected from substituted or unsubstituted 5-8 membered heterocyclic group or 5-8 membered carbocyclic group;

[0047] Ring B is an aryl or 5-6 membered heteroaryl group optionally substituted by one or more R2; the aryl or 5-6 membered heteroaryl group may be pyrrolyl, furyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, triazolyl, phenyl, pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl or triazinyl;

[0048] R2 is independently selected from H, halogen, -CN, -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 Halogenated alkyl, 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 -(CH2) r NRc R d , r is arbitrarily selected from 0, 1, 2 or 3;

[0049] R3 and R4 are each independently selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, 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;

[0050] Alternatively, R3 and R4 are cyclized to form an aryl group, C 4-7 Cycloalkyl, 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl;

[0051] 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)R c ;

[0052] R b 、Rc 、R d Each independently selected from H, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, C 4-6 Heterocycloalkyl, C 5-10 Aryl or 5-10 membered heteroaryl;

[0053] Or, R b 、R c The atoms commonly connected thereto are cyclized to form a 5-6 membered heterocycloalkyl group;

[0054] R6, R7, R8 are each independently selected from H, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, 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;

[0055] Alternatively, R5 and R6 are cyclized to form a -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 membered ring;

[0056] Alternatively, R6 and R7 are cyclized to form C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl;

[0057] Alternatively, R7 and R8 are cyclized to form C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl.

[0058] The present invention provides a compound represented by formula (I') or a stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, or isotope-labeled derivative thereof.

[0059]

[0060] in,

[0061] R1 is selected from H, halogen, -CN, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, 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;

[0062] M is selected from N or CR a ; R a H, halogen, C 1-3 Alkyl, C 3-6 Cycloalkyl or C 1-3 alkyl halide;

[0063] Z is selected from N or CR6;

[0064] Or, R a Cyclize with R1 to form a substituted or unsubstituted 5-8 membered heterocyclic group;

[0065] Ring A is selected from substituted or unsubstituted 5-8 membered heterocyclic group or 5-8 membered carbocyclic group;

[0066] Ring B is an aryl or 5-6 membered heteroaryl group optionally substituted by one or more R2; the aryl or 5-6 membered heteroaryl group may be pyrrolyl, furyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, triazolyl, phenyl, pyrimidinyl, pyridyl, pyrazinyl or pyridazinyl;

[0067] R2 is independently selected from H, halogen, -CN, -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 Halogenated alkyl, 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, C2-6 Alkenyloxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino and C 2-6 alkenylamino;

[0068] R3 and R4 are each independently selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, 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;

[0069] Alternatively, R3 and R4 are cyclized to form an aryl group, C 4-7 Cycloalkyl, 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl;

[0070] 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 )-;

[0071] R b 、R c 、R d Each independently selected from H, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, C 4-6 Heterocycloalkyl, C 5-10 Aryl or 5-10 membered heteroaryl;

[0072] R6, R7, R8 are each independently selected from H, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, 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;

[0073] Alternatively, R5 and R6 are cyclized to form a -P(=O)R b -4-7 membered ring;

[0074] Alternatively, R6 and R7 are cyclized to form C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl;

[0075] Alternatively, R7 and R8 are cyclized to form C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl.

[0076] The present invention provides a compound represented by formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt, prodrug, hydrate, solvate, or isotope-labeled derivative thereof.

[0077]

[0078] in,

[0079] R1 is selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocycloalkyloxy, C2-6 Alkenyloxy, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 3-6 Cycloalkylamino, 3-6 membered heterocycloalkylamino and C 2-6 alkenylamino;

[0080] M is selected from N or CR a ;

[0081] R a H, halogen, C 1-3 Alkyl, C 3-6 Cycloalkyl or C 1-3 alkyl halide;

[0082] Or, R a Cyclize with R1 to form a substituted or unsubstituted 5-8 membered heterocyclic group;

[0083] Ring A is selected from substituted or unsubstituted 4-8 membered heterocyclic group or 5-8 membered carbocyclic group;

[0084] Ring B is an aryl or 5-6 membered heteroaryl group optionally substituted by one or more R2; the aryl or 5-6 membered heteroaryl group may be pyrrolyl, furyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, triazolyl, phenyl, pyrimidinyl, pyridyl, pyrazinyl or pyridazinyl;

[0085] R2 is independently selected from H, halogen, -CN, -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 Halogenated alkyl, 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;

[0086] R3 and R4 are each independently selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6Halogenated 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;

[0087] Alternatively, R3 and R4 are cyclized to form an aryl group, C 4-7 Cycloalkyl, 5-7 membered heterocycloalkyl or 5-6 membered heteroaryl;

[0088] 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 )-;

[0089] R b 、R c 、R d Each independently selected from H, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, C 4-6 Heterocycloalkyl, C 5-10 Aryl or 5-10 membered heteroaryl;

[0090] R6, R7, R8 are each independently selected from H, halogen, -CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, 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 2-6alkenylamino;

[0091] Alternatively, R5 and R6 are cyclized to form a -P(=O)R b -4-7 membered ring;

[0092] Alternatively, R6 and R7 are cyclized to form C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl;

[0093] Alternatively, R7 and R8 are cyclized to form C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl.

[0094] In the compounds of the above formula (I'), formula (I"), formula (I'), and formula (I) of the present invention,

[0095] R1 is selected from H, halogen, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 haloalkoxy;

[0096] M is selected from N or CH;

[0097] Ring A is selected from substituted or unsubstituted 5-8 membered heterocyclic group or 5-8 membered carbocyclic group;

[0098] Ring B is a 5-6 membered heteroaryl group optionally substituted by one or more R2; the 5-6 membered heteroaryl group is pyrrolyl, furyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, triazolyl, phenyl, pyrimidinyl, pyridyl, pyrazinyl or pyridazinyl;

[0099] R2 are each independently selected from H, C 1-4 Alkyl, C 1-4 Haloalkyl, -(CH2) 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;

[0100] R3 and R4 are each independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl;

[0101] Alternatively, R3 and R4 are cyclized to form a 5-6 membered heteroaryl; the 5-6 membered heteroaryl is pyrrolyl, furyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, triazolyl, phenyl, pyrimidinyl, pyridyl, pyrazinyl or pyridazinyl;

[0102] 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 ;

[0103] R b 、R c 、R d Each independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl;

[0104] 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;

[0105] Alternatively, R5 and R6 are cyclized to form a -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 membered ring;

[0106] R6, R7, R8 are each independently selected from H, halogen, C 1-3 alkyl;

[0107] Alternatively, R8 is selected from H, and R6 and R7 are cyclized to form a 5-6 membered heteroaryl; the 5-6 membered heteroaryl is pyrrolyl, furyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, triazolyl, phenyl, pyrimidinyl, pyridyl, pyrazinyl or pyridazinyl.

[0108] In the compounds of the above formula (I'), formula (I"), formula (I'), and formula (I) of the present invention, R1 is selected from H, halogen, -CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy; preferably, the above 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 above R1 is selected from methoxy.

[0109] In the compounds of the above 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.

[0110] 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,

[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, and trifluoromethyl; preferably, the above R2 is selected from methyl.

[0112] In the compounds of the above-mentioned 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.

[0113] 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.

[0114] In the compounds of the above 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.

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

[0116] In the compounds of the above formula (I'), formula (I"), formula (I'), and formula (I) of the present invention, R3 and R4 are cyclized to form a thiophene ring or a pyrrole ring, wherein the thiophene ring and the pyrrole ring may be optionally C 1-4 Alkyl substituted.

[0117] In the compounds of the above formula (I'), formula (I"), formula (I'), and formula (I) of the present invention, R5 is selected from

[0118] In the compounds of the above formula (I'), formula (I"), formula (I'), and formula (I) of the present invention, R5 is selected from

[0119] In the compounds of the above formula (I'), formula (I"), formula (I'), and formula (I) of the present invention, R5 is selected from

[0120] Preferably, R5 is selected from

[0121] Preferably, wherein said R5 is selected from

[0122] In the compounds of the above formula (I'), formula (I"), formula (I'), and formula (I) of the present invention, R5 and R6 are cyclized to form

[0123] 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, each independently selected from H or methyl.

[0124] In the compounds of the above formula (I''), formula (I"), formula (I'), and formula (I) of the present invention, R6, R7, and R8 are selected from H.

[0125] In the compounds of the above 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.

[0126] In the compounds of the above-mentioned formula (I'), formula (I"), formula (I'), and formula (I) of the present invention, R6 and R7 or R7 and R8 are independently cyclized to form 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, or pyrazine ring; preferably, R6 and R7 or R7 and R8 are independently cyclized to form cyclobutane, pyridine ring, or pyrazine ring; more preferably, R6 and R7 are independently cyclized to form a pyrazine ring.

[0127] In the compounds of the above formula (I'), formula (I"), formula (I'), and formula (I) of the present invention, the structural unit Selected from

[0128] R1, M, R2 are as defined above; x Selected from H, -OH, -CN, -NH2, halogen, C 1-6 Alkylcarbonyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 said 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 substituted; said R y Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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.

[0129] When R x When directly connected to the N atom, Rx Not -OH, -NH2 and halogen.

[0130] In the compounds of the above formula (I'), formula (I"), formula (I'), and formula (I) of the present invention, R x Selected from H, -OH, -CN, -NH2, halogen, C 1-6 Alkylcarbonyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 by one or more R y substituted; said R y Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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.

[0131] In the compounds of the above formula (I'), formula (I"), formula (I'), and formula (I) of the present invention, R x Selected from H, -OH, -CN, -NH2, halogen, C 1-6 Alkylcarbonyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 replaced by one or more Ry substituted; said R y Selected from H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, 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 the above formula (I'), formula (I"), formula (I'), and formula (I) of the present invention, R x Selected from H, -OH, -CN, -NH2, F, methyl, ethyl, isopropyl, trifluoroethyl, methylcarbonyl, Ring C is a 4-8 membered heterocycloalkyl, and Ring D is an oxygen-containing 4-8 membered heterocycloalkyl; m and n are independently 0, 1, 2 or 3; R y As defined above.

[0133] In the compounds of the above formula (I'), formula (I"), formula (I'), and formula (I) of the present invention, R x Selected from H, -OH, -CN, -NH2, methyl, ethyl, isopropyl, methylcarbonyl, Ring C is a 4-8 membered heterocycloalkyl group; m and n are independently 0, 1, 2 or 3.

[0134] In the compounds of the above formula (I'), formula (I"), formula (I'), and formula (I) of the present invention, R x Selected from H, -OH, -CN, -NH2, F, methyl, ethyl, isopropyl, trifluoroethyl, methylcarbonyl,

[0135] In the compounds of the above formula (I'), formula (I"), formula (I'), and formula (I) of the present invention, R x Selected from H, methyl, ethyl, isopropyl,

[0136] In the compounds of the above formula (I'), formula (I"), formula (I'), and formula (I) of the present invention, R x Selected from H, methyl, ethyl, isopropyl,

[0137] In the compounds of the above formula (I'), formula (I"), formula (I'), and formula (I) of the present invention, R x is selected from H, methyl, ethyl or isopropyl.

[0138] In the compounds of the above formula (I'), formula (I"), formula (I'), and formula (I) of the present invention, R x is selected from methyl or isopropyl.

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

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

[0141] In the compounds of the above formula (I'), formula (I"), formula (I'), and formula (I) of the present invention, the structural unit Selected from R1, M, R x 、R b 、R c , R2 are as defined above.

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

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

[0144]

[0145] in,

[0146] X and Y are each independently selected from -C(=O)-, -C=C-, -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, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl;

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

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

[0151]

[0152] in,

[0153] X and Y are each independently selected from -C(=O)-, -NR 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, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl;

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

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

[0158]

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

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

[0161]

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

[0163] Further preferably, the above compound or its stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotope-labeled derivatives are selected from:

[0164]

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

[0166] Further preferably, the above compound or its stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotope-labeled derivatives are selected from:

[0167]

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

[0169] Further preferably, the above compound or its stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotope-labeled derivatives are selected from:

[0170]

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

[0172] Further preferably, the above compound or its stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotope-labeled derivatives are selected from:

[0173]

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

[0175] Further preferably, the above compound or its stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotope-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'') or its stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotope-labeled derivatives are selected from (I''-A),

[0179]

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

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

[0182]

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

[0184] R w 、R z Each independently selected from H, -OH, -CN, -NH2, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Halogenated alkyl, 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.

[0185] Most preferably, the compound or its stereoisomers, tautomers or pharmaceutically acceptable salts, prodrugs, hydrates, solvates, isotope-labeled derivatives, include but are 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 above-mentioned compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent and excipient. The pharmaceutical composition provided by the present invention can be formulated for specific routes of administration, such as oral administration, parenteral administration and rectal administration. Oral administration, such as tablets, capsules (including sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions; sublingual administration; buccal administration; parenteral administration, such as by subcutaneous, intravenous, intramuscular or intrasternal injection, or infusion technology (such as as a sterile injectable aqueous solution or non-aqueous solution or suspension); nasal administration, including administration to the nasal mucosa, such as by inhalation spray; topical administration, such as in the form of a cream or ointment; or rectal administration, such as in the form of a suppository. They can be administered alone, but are usually administered together with a pharmaceutical carrier selected according to the selected route of administration and standard pharmaceutical operations.

[0197] A "pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering a biologically active agent to an animal, particularly a mammal, and includes, for example, adjuvants, excipients, or vehicles, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the mode of administration and the nature of the dosage form. Pharmaceutically acceptable carriers are formulated within the purview of those skilled in the art based on a number of factors. These include, but are not limited to, the type and nature of the active agent being formulated, the subject to whom the composition containing the agent is to be administered, the intended route of administration of the composition, and the intended therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media, as well as a variety of solid and semisolid dosage forms. In addition to the active agent, such carriers include many different ingredients and additives, and the inclusion of such additional ingredients in a formulation for various reasons (e.g., stabilization of the active agent, binders, etc.) is well known to those skilled in the art.

[0198] As a general guide, when used for the indicated effects, the daily oral dosage of each active ingredient is in the range of about 0.001-5000 mg, 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 active ingredient per day; the most preferred dosage is in the range of about 0.01-10 mg / kg / minute intravenously during a constant rate infusion. The compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of 2, 3 or 4 times daily.

[0199] The dosage regimen for the compounds of the present invention can of course vary depending on known factors, such as the pharmacodynamic characteristics of the specific agent and its mode and route of administration, the species, age, sex, health, medical condition and weight of the recipient, the nature and extent of symptoms, the type of coexisting treatment, 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 condition of the subject, the condition or disease being treated or its severity. A physician, clinician or veterinarian of ordinary skill 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 use of the above-mentioned compound or its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in the preparation of a drug for treating cancer.

[0201] The 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 mutations are also the most common type of mutation in NSCLC patients, particularly in Asian populations, accounting for 40% to 50%. Therefore, in some approaches, the compounds of the present invention can be used to treat cancers caused by overexpression of EGFR. 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), bile duct cancer, 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 the above-mentioned formula (I''), formula (I"), formula (I') or formula (I) or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition. The above-mentioned 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), bile duct cancer, renal cancer, thyroid cancer, anaplastic large cell lymphoma, mesothelioma, multiple myeloma, and melanoma.

[0203] The compounds of the above-mentioned formula (I''), formula (I"), formula (I') or formula (I) or their pharmaceutically acceptable salts or the above-mentioned pharmaceutical compositions provided by the present invention are used to treat cancer, and the above-mentioned 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), bile duct cancer, renal cancer, thyroid cancer, anaplastic large cell lymphoma, mesothelioma, multiple myeloma, and melanoma.

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

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

[0206]

[0207] Among them, R 11 is -NH2 or -NO2;

[0208] Structural unit As defined above;

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

[0210]

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

[0212] Further preferably, the intermediate compound represented by formula (V), the intermediate compound or a pharmaceutically acceptable salt thereof, is selected from:

[0213]

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

[0215] Technical Effects

[0216] The compounds of the present invention have a good inhibitory effect on EGFR (L858R / T790M / C797S) kinase, but a weaker inhibitory effect on wild-type EGFR kinase, indicating that the compounds of the present invention have good kinase activity and selectivity.

[0217] The compounds of the present invention have a strong inhibitory effect on the cell proliferation of the Ba / F3 Del19 / T790M / C797S EGFR triple mutant cell line and the Ba / F3 L858R / T790M / C797S EGFR triple mutant cell line; the inhibitory effect on the EGFR wild-type cell line A431 is weaker, indicating that the compounds of the present invention have good cell activity and selectivity. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0219] Figure 2 Figure 2 is the body weight curve of each group of animals in the in vivo efficacy study experiment (g).

[0220] Description and Definition

[0221] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered ambiguous or unclear without a specific definition, but should be understood according to its ordinary meaning.

[0222] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0223] The term "pharmaceutically acceptable salt" refers to derivatives of the compounds of the present invention prepared with relatively nontoxic acids or bases. These salts can be prepared during compound synthesis, isolation, or purification, or by reacting the purified free form of the compound with a suitable acid or base. When the compound contains relatively acidic functional groups, base addition salts are obtained by reaction with alkali metal or alkaline earth metal hydroxides or organic amines. These salts include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations. When the compound contains relatively basic functional groups, acid addition salts are obtained by reaction with organic or inorganic acids.

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

[0225] The compounds of the present invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are also encompassed within the scope of the present invention.

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

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

[0228] The term "diastereomer" refers to stereoisomers that have two or more chiral centers and are not mirror images of each other.

[0229] The term "cis-trans isomers" refers to configurations in which a molecule cannot rotate freely about a double bond or a single bond of a ring-forming carbon atom.

[0230] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicates the relative configuration of a stereocenter.

[0231] It indicates that the carbon atom is a chiral carbon atom, and the structure represents an optically pure compound and a mixture thereof in which the stereo configuration of the carbon atom is (R) configuration or (S) configuration.

[0232] Stereoisomers of the compounds of the present invention can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. For example, one enantiomer of a compound of the present invention can be prepared by asymmetric catalysis or chiral auxiliary derivatization. Alternatively, a single stereoisomer of the compound can be obtained from a mixture by chiral resolution techniques. Alternatively, the enantiomers can be prepared directly using chiral starting materials. Separation of optically pure compounds in the present invention is typically accomplished by preparative chromatography using chiral chromatographic columns to achieve the purpose of separating chiral compounds.

[0233] The term "optically pure" or "enantiomerically enriched" means that the content of the isomer or enantiomer is 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 stereo configuration of a compound can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction can be used. Alternatively, the absolute configuration of a compound can be confirmed based on the chiral structure of the starting materials and the reaction mechanism of asymmetric synthesis. Compounds marked "absolute configuration not determined" herein are typically separated from racemates by chiral preparative HPLC or SFC into individual isomers, which are then characterized and tested.

[0235] For example, the following formula represents that compounds 117A and 117B are separated from compound 84 and are enantiomers of each other, but the absolute stereo configurations of 117A and 117B have not been determined.

[0236]

[0237] The present invention also includes isotopically labeled compounds, including isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 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 Compounds of the present invention that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention.

[0238] The term "pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering biologically active agents to animals, particularly mammals, and includes, for example, adjuvants, excipients, or vehicles, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the mode of administration and the nature of the dosage form. Pharmaceutically acceptable carriers are formulated within the purview of those skilled in the art based on a wide range of factors. These include, but are not limited to, the type and nature of the active agent being formulated, the subject to whom the composition containing the agent is to be administered, the intended route of administration of the composition, and the intended therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media, as well as a variety of solid and semisolid dosage forms. In addition to the active agent, such carriers include a variety of different ingredients and additives, and the inclusion of such additional ingredients in a formulation for various reasons (e.g., to stabilize the active agent, binders, etc.) is well known to those skilled in the art.

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

[0240] The term "effective prophylactic or therapeutic amount" refers to a sufficient amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, to treat a disorder at a reasonable benefit / risk ratio applicable to any medical treatment and / or prevention. However, it should be understood that the total daily dosage of the compound of Formula I, or a pharmaceutically acceptable salt thereof, and the composition of the present invention must be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dosage level must be determined based on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound being used; the specific composition being used; the patient's age, weight, general health, sex, and diet; the administration time, route of administration, and excretion rate of the specific compound being used; the duration of treatment; drugs used in combination with or concurrently with the specific compound being used; and similar factors well known in the medical field. For example, it is common practice in the art to start the dose of the compound at a level below that 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 represented by formula I of the present invention or a pharmaceutically acceptable salt thereof for mammals, especially 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 be substituted or not substituted. Unless otherwise specified, the type and number of substituents can be any on the basis of chemical feasibility. For example, the term "optionally substituted with one or more R2" means that it may be substituted with one or more R2 or not substituted with R2.

[0242] When any variable (e.g., R2) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. For example, if a group is substituted with 0-2 R2, the group may optionally be substituted with up to two R2, and each occurrence of R2 has independent options.

[0243] When the number of a linking group is 0, such as -O(CH2) n CH3, n=0 means that the connecting group is a single bond, ie -OCH3.

[0244] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that the substituent R1 can be substituted at any position on the benzene ring.

[0245] When a substituent is listed without specifying the atom through which it is bonded to the compound included in the general chemical formula but not specifically mentioned, the substituent may be bonded through any atom thereof. For example, pyrazole as a substituent means that any carbon atom on the pyrazole ring is bonded to the substituted group; when or , it indicates that the atom is a bonding atom, for example and Both indicate that the nitrogen atom on the morpholine ring is a bonding atom.

[0246] Unless otherwise specified, "ring" refers to saturated, partially saturated or unsaturated monocyclic and polycyclic rings, and "polycyclic" includes linked, spirocyclic, fused or bridged rings. Representative "rings" include substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. The term "hetero" refers to substituted or unsubstituted heteroatoms and oxidized forms of heteroatoms, wherein the heteroatoms are generally selected from N, O, and S, and the oxidized forms generally include NO, SO, and S(O)2. The nitrogen atom may be substituted, i.e., NR (R is H or other substituents defined herein); the number of atoms in the ring is generally defined as the number of ring members, for example, "3-6 membered heterocycloalkyl" refers to a ring of 3-6 atoms, each ring optionally containing 1 to 3 heteroatoms, i.e., N, O, S, NO, SO, S(O)2 or NR, each ring optionally substituted with an R group, where R is a group defined herein.

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

[0248] Unless otherwise specified, the term "heterocycle" or "heterocyclyl" means a stable monocyclic, bicyclic or tricyclic ring containing heteroatoms or heteroatom groups, which may be saturated, partially unsaturated or unsaturated (aromatic), and which contains carbon atoms and 1, 2, or 3 ring heteroatoms independently selected from N, O, S, NO, SO, S(O)2 or NR, wherein any of the above heterocycles may be fused to one or more aromatic rings or aromatic heterocycles to form a bicyclic, tricyclic or other polycyclic ring. For example, the structural unit In the embodiment, 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 radical which may be a single ring or multiple rings fused together. 5-10 Aryl, more preferably C 5-8 Aryl, most preferably a monocyclic C 5-6 Aryl; examples of aryl include, but are not limited to, phenyl, naphthyl.

[0250] Unless otherwise specified, the term "heteroaryl" means a stable monocyclic or polycyclic aromatic hydrocarbon containing at least one heteroatom (N, O, S, NO, SO, S(O)2 or NR). Preferably, the heteroaryl is a 5-membered or 6-membered monocyclic ring. Examples of heteroaryl include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, and pyrimidinyl.

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

[0252] Unless otherwise specified, the term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced by a heteroatom selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized, including but not limited to "alkoxy", "alkylamino" and "alkylthio"; 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. 2-8 Alkenyl. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like.

[0254] Unless otherwise specified, "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds. 2-8Alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.

[0255] Unless otherwise specified, the term "halogen" means 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 a halogen atom. 1-6 Halogenated alkyl, more preferably C 1-3 Haloalkyl, examples of which include but are not limited to monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl and the like.

[0257] Unless otherwise specified, the term "alkoxy" refers to an alkyl group connected through an oxygen bridge, that is, a group obtained by replacing the hydrogen atom of a hydroxy group with an alkyl group. 1-6 Alkoxy, more preferably C 1-3 Alkoxy. Examples of alkoxy 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 attached through an oxygen bridge, i.e., a group resulting from the substitution of a hydrogen atom of a hydroxyl group with a cycloalkyl group. Cycloalkyloxy groups are preferably 3-7 membered, 4-7 membered, or 5-7 membered cycloalkyloxy groups. Examples of cycloalkyloxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy groups.

[0259] Unless otherwise specified, the term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by a halogen atom. 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 membered monocyclic alkyl, more preferably a 3-6 membered monocyclic alkyl. Examples of these monocyclic alkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0261] Unless otherwise specified, "heterocycloalkyl" refers to mono- and polyheterocycloalkyl groups containing a certain number of heteroatoms in the ring, and the heteroatoms are generally selected from N, O, S, NO, SO, S(O)2, and NR. The heterocycloalkyl group is preferably a 3- to 8-membered monoheterocycloalkyl group, more preferably a 3- to 6-membered monoheterocycloalkyl group. Examples of these monoheterocycloalkyl groups include, but are not limited to, oxiranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, 1,3-dioxolane, 1,4-dioxane, and the like.

[0262] Unless otherwise specified, "spirocyclyl" refers to a bicyclic or polycyclic hydrocarbon group in which two monocyclic rings share one carbon atom. Spirocyclyl is preferably a 5-13 membered spirocyclyl, a 6-12 membered spirocyclyl, or a 7-11 membered spirocyclyl. The 6-12 membered spirocyclyl refers to a hydrocarbon group in which the spirocyclic skeleton structure consists of 6-12 atoms. Examples of spirocyclyl 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, "spiroheterocyclyl" refers to a spiroheterocyclyl group in which one or more carbon atoms in the spiro ring skeleton structure are replaced by a heteroatom, wherein the heteroatom is selected from N, O, and S. The spiroheterocyclyl group is preferably a 5-13 membered spiroheterocyclyl group, a 6-12 membered spiroheterocyclyl group, or a 7-11 membered spiroheterocyclyl group. Examples of spiroheterocyclyl groups include, but are not limited to, 2-oxa-7-azaspiro[5.3]nonan-7-yl, 2-oxa-7-azaspiro[4.4]nonan-7-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 2-oxa-8-azaspiro[4.5]decan-8-yl, 1,4,9-triazaspiro[5.5]undec-9-yl, 3-oxa-9-azaspiro[5.5]undec-9-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2,7-diazaspiro[5.3]nonan-7-yl, 2,7-dioxaspiro[5.3]nonan-3,9-diazaspiro[5.5 ]undecan-3-yl, 1-oxa-4,9-diazaspiro[5.5]undecan-9-yl, 1-oxa-4,8-diazaspiro[5.4]decan-8-yl, 3-azaspiro[5.5]undecan-3-yl, 7-azaspiro[3.5]decan-7-yl, 1-oxa-4,9-diazaspiro[5.5]undecan-4-yl, 6-oxa-2,9-diazaspiro[4.5]decan-9-yl, 9-oxa-2,6-diazaspiro[4.5]decan-6-yl, 3-azaspiro[5.5]undecan-3-yl, 4-oxa-1,9-diazaspiro[5.5]undecan-9-yl.

[0264] The term "containing P(=O)R b The 4-7 membered ring is a ring having A group of structure, n is 0, 1, 2 or 3; R b is a group defined herein, containing -P(=S)(R b )-、-N(R b)S(=O)2-、-S(=O)2N(R b )- or -S(=O)2 4-7 membered rings represent The structure of n is 0, 1, 2 or 3; R b is a group as defined herein.

[0265] Specifically, all combinations of substituents and / or variations thereof are permissible only if such combinations result in stable compounds.

[0266] In the examples of this invention, the title compound names were derived from the compound structures using ChemDraw. If the compound name and structure are inconsistent, the structure can be determined by integrating relevant information and reaction routes. If other methods are unavailable for confirmation, the given compound structure will prevail.

[0267] The preparation methods of some compounds in the present invention refer to the preparation methods of the aforementioned similar compounds. Those skilled in the art should be aware that when using or referring to the preparation methods cited, the feed ratio of reactants, reaction solvent, reaction temperature, 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 well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

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

[0270]

[0271] DETAILED DESCRIPTION

[0272] The structures of the compounds of the present invention are 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 are performed using a Bruker AVANCE III HD 400 or Bruker AVANCE III HD 300 NMR instrument, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the solvents, with tetramethylsilane (TMS) as the internal standard.

[0273] Liquid chromatography-mass spectrometry (LC-MS) was performed using a SHIMADZU LCMS-2020 mass spectrometer (electrospray ionization as the ion source). HPLC was performed using a SHIMADZU LC-20 AP XR and SPD-M20A high pressure liquid chromatography.

[0274] The thin layer chromatography silica gel plate uses Yantai Xinnuo Chemical GF254 silica gel plate, the specification used by TLC is 0.15mm~0.20mm, and column chromatography generally uses Chenghua 200~300 mesh silica gel as the carrier.

[0275] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to 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 portionwise to the reaction mixture and stirred at this temperature for 30 minutes. After TLC monitoring showed the disappearance of the starting material, the reaction mixture was slowly poured into ice water (500 g) to quench the mixture. The mixed solution was extracted with ethyl acetate (200 mL × 3 times), and the organic phases were combined and washed with saturated brine (200 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting 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) δ 8.19 (d, J=7.2Hz, 1H), 6.91 (d, J=9.9Hz, 1H), 3.99 (s, 3H).

[0282] Intermediate 1A:

[0283] At room temperature and under a nitrogen atmosphere, compound 1A-1 (3 g, 12 mmol) was dissolved in 1,4-dioxane (20 mL). Subsequently, bis-pinacol borate (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 to the reaction solution in sequence. The reaction system was heated to 80°C and stirred for 16 hours. After TLC monitoring showed the disappearance of the starting material, the reaction solution was cooled to room temperature and quenched by the addition of water (100 mL). The mixture was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined, washed with saturated brine (100 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 1.5 g of compound 1A.

[0284] 1 H NMR (300MHz, CDCl3) δ 8.36 (d, J=6.0Hz, 1H), 6.76 (d, J=10.5Hz, 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 system was stirred at room temperature for 1 hour. After LCMS monitoring showed the disappearance of the starting material, water (3000 mL) was added to the reaction solution to quench the reaction. The mixed solution was extracted with ethyl acetate (1000 mL × 3 times), and the organic phases were combined, washed with saturated brine (500 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure; the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2) to obtain 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 under nitrogen. Dimethylphosphine oxide (17.3 g, 221.4 mmol), palladium acetate (3.3 g, 14.7 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12.8 g, 22.1 mmol), and N,N-diisopropylethylamine (38.1 g, 295.1 mmol) were then 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 and filtered. The filter cake was washed with ethanol (100 mL x 3 times). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain 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 under nitrogen. Sodium hydride (60%, 1.99 g, 49.8 mmol) was then added portionwise to the reaction mixture at 0°C and stirred for 30 minutes. 2,4-dichloro-5-bromopyrimidine (6.18 g, 27.1 mmol) was then added to the reaction mixture at 0°C, and the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. After LCMS monitoring showed the disappearance of the starting material, saturated aqueous ammonium chloride (600 mL) was added to the reaction mixture to quench the mixture. The mixture was extracted with ethyl acetate (200 mL x 3 times), and the organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate) to yield 3 g of compound 1B.

[0295] Preparation of intermediate 1C

[0296]

[0297] Compound 1C-1:

[0298] Triethyl phosphinoacetate (61.1 g, 273 mmol) was dissolved in tetrahydrofuran (120 mL). Subsequently, sodium hydride (60%, 10.9 g, 273 mmol) was added to the reaction solution under a nitrogen atmosphere at 0°C and stirring was continued at this temperature for 30 minutes. A solution of 1-methyl-1H-pyrazole-5-carboxaldehyde (20 g, 182 mmol) in tetrahydrofuran (100 mL) was added to the reaction solution. The reaction system was warmed to room temperature and stirred for 1.5 hours. After LCMS monitoring showed that the starting material disappeared, saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution to quench the mixture. The mixed solution was extracted with ethyl acetate (300 mL × 3 times), the organic phases were combined, washed with saturated brine (100 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain 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 solution. The reaction system was purged with hydrogen three times, and the reaction solution was stirred at room temperature for 1 hour. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered through celite, and the filter cake was washed with ethyl acetate (30 mL × 3 times). The resulting filtrate was concentrated under reduced pressure to obtain 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). Subsequently, sodium hydroxide (1 N, 352 mL) was added to the reaction solution. The reaction system was heated to 70 ° C and continued to stir for 1 hour. After LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove ethanol. The pH of the aqueous phase was adjusted to 3 with dilute hydrochloric acid (1 N) and ethyl acetate (100 mL × 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (100 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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 diphenylphosphoryl azide (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 solution and stirred at room temperature for 1 hour. 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 solution was cooled to room temperature and quenched by the addition of 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 resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain 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. 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 warmed to room temperature and stirred for 2 hours. After LCMS monitoring showed the disappearance of the starting material, saturated aqueous ammonium chloride solution (20 mL) was added to the reaction mixture to quench the mixture. The mixture was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined. The organic phases were first washed with saturated brine (50 mL × 3 times), then 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 = 15 / 1) to obtain 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). N-iodosuccinimide (451 mg, 2.0 mmol) was then added to the reaction mixture at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. After LCMS monitoring indicated the disappearance of the starting material, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to afford 600 mg of compound 1C-6.

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

[0315] Compound 1C-7:

[0316] Under a nitrogen atmosphere, compound 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(diphenylphosphino)ferrocene] palladium dichloride (124 mg, 0.15 mmol) and sodium carbonate (321 mg, 3.0 mmol) were added to the reaction solution. The reaction system was heated to 80°C and stirred for 2 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature and quenched by adding water (20 mL). The mixed solution was extracted with ethyl acetate (30 mL × 3 times), the organic phases were combined, the organic phases were washed with saturated brine (30 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting 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 solution of hydrochloric acid in dioxane (4 M, 4 mL) and stirred at room temperature for 1 hour. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure to obtain 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 system was heated to 100°C and stirred for 1 hour. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was cooled to room temperature and directly purified 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 increased from 40% to 80% within 30 minutes; detection wavelength: 254 nm. The product was collected and 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). Iron powder (48 mg, 0.9 mmol) and ammonium chloride (14 mg, 0.26 mmol) were then added to the reaction mixture. The reaction system was heated to 80°C and stirred for 2 hours. After LCMS monitoring indicated the disappearance of the starting material, the reaction mixture was cooled to room temperature and filtered. The filter cake was washed with ethanol (10 mL x 5 times), and the filtrate was concentrated under reduced pressure to yield 50 mg of intermediate compound 1C.

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

[0327] Preparation of compound 1

[0328]

[0329] Compound 1C (40 mg, 0.16 mmol) and 1B (64 mg, 0.16 mmol) were dissolved in N-methylpyrrolidone (2 mL). Subsequently, methanesulfonic acid (45 mg, 0.47 mmol) was added to the above reaction solution. The reaction system was heated to 100°C and stirred for 3 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature and purified by reverse phase C18 column. Purification conditions: chromatographic column 40g C18 reverse phase column; mobile phase water (containing 0.1% formic acid) and acetonitrile; flow rate 35 mL / min; gradient acetonitrile increased from 10% to 50% within 20 minutes; detection wavelength 254 nm. The product was collected and lyophilized under reduced pressure to obtain 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), and anhydrous potassium carbonate (3.64 g, 26.3 mmol) and 2-(dimethylphosphinoyl)aniline (1.48 g, 8.8 mmol) were added sequentially. The reaction solution was heated to 60°C and stirred for 12 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was cooled to room temperature and quenched by adding water (150 mL). The mixture was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined, washed with saturated brine (80 mL × 3 times), then 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 obtain 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 starting material was 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] Methylamine in tetrahydrofuran (2M, 106.7mL, 213.4mmol) and triethylamine (10.8g, 106.7mmol) were dissolved in dichloromethane (80mL). Subsequently, cyclopropylsulfonyl chloride (10g, 71.1mmol) was added dropwise to the reaction solution at 0°C. The reaction system was warmed to room temperature and stirred for 24 hours. After TLC monitoring showed that the raw material disappeared, the reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (100mL). Subsequently, cesium carbonate (31.1g, 95.4mmol) and o-nitrofluorobenzene (15.5g, 95.4mmol) were added to the reaction solution and stirred at room temperature for 16 hours. After LCMS monitoring showed that the raw material disappeared, water (100mL) was added to the reaction solution to quench the product. The mixture was extracted with ethyl acetate (100 mL x 3 times), and the organic phases were combined, washed with saturated brine (100 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: petroleum ether / ethyl acetate = 1 / 1) to obtain 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). Subsequently, wet palladium on carbon (10%, 600 mg) was added to the reaction solution. The reaction system was replaced with hydrogen (1 atm) three times, and the reaction solution was stirred at room temperature for 16 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution 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 obtain 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 (12 g, 53 mmol) to prepare 9 g 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 starting material was replaced with 3A (80 mg, 0.3 mmol) to obtain 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). Subsequently, cesium carbonate (138.6 g, 425 mmol) was added to the reaction solution and continued to stir at room temperature for 16 hours. After LCMS monitoring showed that the raw material disappeared, water (300 mL) was added to the reaction solution to quench the mixture. The mixed solution 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 resulting 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 of preparing 3A-2 from 3A-1 in Example 3, the raw material was replaced with 4A-1 (15 g, 65 mmol) to prepare 12 g 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 starting material was replaced with 4A-2 (5 g, 25 mmol) to prepare 3 g 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 starting material was 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 from 1B-2 in Example 1, 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 starting material was 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 of preparing 1C-6 from 1C-5 in Example 1, the raw material was replaced with 1C-4 (3.5 g, 15.5 mmol) to prepare 3.57 g of compound 6A-1.

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

[0390] Compound 6A-2:

[0391] According to the method of 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] According to the method of 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] According to the method of 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). Subsequently, iodoisopropyl (1.86 g, 10.9 mmol) was added to the above reaction solution. The reaction system was heated to 80 ° C and stirred for 16 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature and quenched by adding water (30 mL). The mixed solution was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined. The organic phases were first washed with saturated brine (50 mL × 3 times), then 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 = 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 of preparing 1C from 1C-9 in Example 1, the starting material was 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 starting material was 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 from 1B-2 in Example 1, the raw materials were replaced with 2,4-dichloro-5-methylpyrimidine (578 mg, 3.55 mmol) and 2-(dimethylphosphinyl)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 starting material was replaced with 7A (80 mg, 0.27 mmol) to prepare 111 mg of the formate salt 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-carbaldehyde (10 g, 90.8 mmol) to prepare 16 g of compound 8A-1.

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

[0425] Compound 8A-2:

[0426] According to the method of preparing 1C-2 from 1C-1 in Example 1, the raw material was replaced with 8A-1 (16.8 g, 93.2 mmol) to prepare 16 g 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). Subsequently, N-iodosuccinimide (7.4 g, 32.9 mmol) was added to the above reaction solution and continued to stir at room temperature for 1 hour. After LCMS monitoring showed that the starting material disappeared, the reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in water (100 mL), and the mixed solution was extracted with dichloromethane (3×100 mL). The organic phases were combined, and the organic phases were first washed with saturated brine (150 mL x 3 times), then 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 of 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). Subsequently, lithium hydroxide (130 mg, 5.4 mmol) was added to the reaction solution and continued to stir at room temperature for 2 hours. After LCMS monitoring showed that the starting material disappeared, water (20 mL) was added to the reaction solution for dilution, and the pH was adjusted to 2 with 1N hydrochloric acid. The mixed solution 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 give 330 mg of compound 8A-5.

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

[0437] Compound 8A-6:

[0438] According to the method of 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 solution at 0°C. The reaction system was warmed to room temperature and stirred for 2 hours. After LCMS monitoring showed that the starting material disappeared, water (30 mL) was added to the reaction solution to quench the mixture. The mixed solution was extracted with ethyl acetate (50 mL x 3 times), and the organic phases were combined. The organic phases were first washed with saturated brine (50 mL x 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting 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 of 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). Sodium hydride (60%, 350 mg, 8.75 mmol) was then added to the reaction mixture at 0°C and stirred for 30 minutes. Methyl iodide (1.2 g, 8.5 mmol) was then added to the reaction mixture. The reaction mixture was warmed to room temperature and stirred for 1 hour. After LCMS monitoring showed the disappearance of the starting material, water (30 mL) was added to the reaction mixture to quench the mixture. The mixture was extracted with ethyl acetate (50 mL x 3 times), and the organic phases were combined, washed with saturated brine (50 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 = 20 / 1) to obtain 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). Subsequently, platinum dioxide (20 mg) was added to the reaction solution. After the reaction system was replaced with hydrogen three times, the reaction solution was stirred at room temperature for 16 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was filtered through celite, 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 starting material was replaced with 8A (70 mg, 0.17 mmol) to obtain 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 (10 g, 40.8 mmol) to prepare 10 g of compound 9A-1.

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

[0463] Compound 9A-2:

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

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

[0466] Compound 9A-3:

[0467] At 0 ° C, compound 9A-2 (2.4 g, 8.75 mmol) was dissolved in concentrated sulfuric acid (25 mL). Subsequently, potassium nitrate (973 mg, 9.63 mmol) was added to the reaction solution in batches and stirred at this temperature for 10 minutes. After TLC monitoring showed that the starting material disappeared, the reaction solution was slowly poured into ice water (100 g) to quench. The mixed solution was extracted with ethyl acetate (100 mL x 3 times), and the organic phases were combined. The organic phases were first washed with saturated brine (100 mL x 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting 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). Subsequently, glacial acetic acid (276 mg, 4.6 mmol) was added to the reaction solution and stirring was continued at room temperature for 16 hours. Sodium borohydride (332 mg, 8.77 mmol) was added to the reaction solution and stirring was continued at room temperature for 2 hours. After LCMS monitoring showed that the starting material disappeared, water (50 mL) was added to the reaction solution to quench the mixture. The mixed solution was extracted with ethyl acetate (50 mL x 3 times), and the organic phases were combined. The organic phases were first washed with saturated brine (50 mL x 3 times), then 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 = 10 / 1) to give 540 mg of compound 9A-4.

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

[0472] Intermediate 9A:

[0473] According to the method of 1C-9 to 1C in Example 1, the starting 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 starting material was 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 of preparing 1C-8 from 1C-7 in Example 1, the starting 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-azetidinone (95 mg, 1.12 mmol) were dissolved in dichloromethane (7 mL). Subsequently, triethylamine (453 mg, 4.48 mmol) and tetraisopropyl titanate (636 mg, 2.24 mmol) were added to the reaction solution and continued to stir at room temperature for 1 hour. Sodium borohydride (85 mg, 2.24 mmol) was added to the reaction solution and continued to stir at room temperature for 1 hour. After LCMS monitoring showed that the raw material disappeared, the reaction solution was purified using a reverse phase C18 column under the following conditions: 40 g C18 reverse phase column; mobile phase, water (containing 10 mM ammonium bicarbonate) and acetonitrile; flow rate, 35 mL / min; gradient, acetonitrile increased from 5% to 40% in 20 minutes; detection wavelength, 254 nm. The product was collected and lyophilized under reduced pressure to obtain 70 mg of compound 10A-2.

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

[0490] Compound 10A-3:

[0491] According to the method of 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 IC from 1C-9 in Example 1, the starting 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 starting material was 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, 2H), 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). Subsequently, borane-dimethyl sulfide solution (251 mg, 3.31 mmol) was added to the reaction solution and stirred at room temperature for 16 hours. After the disappearance of the starting material by LCMS monitoring, methanol (5 mL) was added to the reaction solution to quench the mixture. The mixture was heated to 60°C and stirred for 1 hour, then cooled to 0°C. The precipitated white solid was filtered and dried to obtain 60 mg of compound 11A-1.

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

[0507] Intermediate 11A:

[0508] According to the method of preparing 1C from 1C-9 in Example 1, the starting 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 starting material was 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 of 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 of preparing 1C from intermediate 1C-9 in Example 1, the starting 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 starting material was replaced with 12A (70 mg, 0.24 mmol) to obtain 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 from 1B-2 in Example 1, the starting 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 starting material was replaced with 13A (100 mg, 0.27 mmol) to obtain 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 starting materials were replaced with 2,4,5-trichloropyrimidine (13 g, 71 mmol) and 2-(dimethylphosphinyl)aniline (10 g, 59 mmol) to prepare 14.4 g 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 starting material was replaced with 14A (80 mg, 0.25 mmol) to obtain 80 mg of compound 14.

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

[0548] 1 H 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, 3H).

[0549] Example 15:

[0550] Preparation of intermediate 15A

[0551]

[0552] Compound 15A-1:

[0553] 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 LCMS monitoring showed the disappearance of the starting material, the reaction mixture 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 obtain 90 mg of compound 15A-1.

[0554] MS (ESI, m / z): 317.2 [M+H] + .

[0555] Intermediate 15A:

[0556] According to the method of preparing 1C from intermediate 1C-9 in Example 1, the starting material was replaced with 15A-1 (80 mg, 0.25 mmol) to prepare 66 mg of compound 15A.

[0557] MS (ESI, m / z): 287.1 [M+H] + .

[0558] Preparation of compound 15

[0559]

[0560] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting material was replaced with 15A (50 mg, 0.17 mmol) to obtain 17 mg of compound 15.

[0561] MS (ESI, m / z): 662.2, 664.2[M+H] + .

[0562] 1H 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).

[0563] Example 16:

[0564] Preparation of intermediate 16A

[0565]

[0566] According to the method of 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.

[0567] MS (ESI, m / z): 245.2 [M+H] + .

[0568] Preparation of compound 16

[0569]

[0570] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting material was replaced with 16A (60 mg, 0.25 mmol) to prepare 13 mg of compound 16.

[0571] MS (ESI, m / z): 620.2, 622.2[M+H] + .

[0572] 1 H 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).

[0573] Example 17:

[0574] Preparation of compound 17

[0575]

[0576] Compound 17A:

[0577] According to the method for preparing 2A in Example 2, the starting materials were replaced with 2,4-dichloro-5-fluoropyrimidine (2 g, 11.98 mmol) and 2-(dimethylphosphinyl)aniline (2.03 g, 11.98 mmol) to prepare 1.9 g of compound 17A.

[0578] MS (ESI, m / z): 300.0, 302.0[M+H] + .

[0579] Compound 17:

[0580] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting material was replaced with 17A (60 mg, 0.2 mmol) to obtain 21 mg of compound 17.

[0581] MS (ESI, m / z): 522.3 [M+H] + .

[0582] 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).

[0583] 19F NMR (282MHz, CDCl3) δ-164.46.

[0584] Example 18:

[0585] Preparation of Intermediate 18A

[0586]

[0587] Compound 18A-1

[0588] Under nitrogen atmosphere and 0 ° C, compound 1C-9 (100 mg, 0.35 mmol) was dissolved in dichloromethane (2 mL). Subsequently, boron tribromide (174 mg, 0.69 mmol) was added to the above reaction solution. The reaction system was warmed to room temperature and continued to stir for 16 hours. After LCMS monitoring showed that the starting material disappeared, water (10 mL) was added to the reaction solution to quench the mixture. The mixed solution was extracted with ethyl acetate (10 mL x 3 times), and the organic phases were combined. The organic phases were first washed with saturated brine (30 mL x 3 times), then 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 = 20 / 1) to give 50 mg of compound 18A-1.

[0589] MS (ESI, m / z): 275.1 [M+H] + .

[0590] Compound 18A-2:

[0591] Compound 18A-1 (75 mg, 0.27 mmol) and potassium carbonate (113 mg, 0.82 mmol) were dissolved in N,N-dimethylformamide (20 mL). Isopropyl iodide (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 LCMS monitoring showed the disappearance of the starting material, the reaction solution was cooled to room temperature and quenched by adding water (10 mL). The mixed solution was extracted with ethyl acetate (20 mL x 3 times), and the organic phases were combined, washed with saturated brine (30 mL x 3 times), then 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 = 20 / 1) to obtain 70 mg of compound 18A-2.

[0592] MS (ESI, m / z): 317.1 [M+H] + .

[0593] Intermediate 18A:

[0594] According to the method of preparing 1C from intermediate 1C-9 in Example 1, the starting material was replaced with 18A-2 (70 mg, 0.22 mmol) to prepare 55 mg of compound 18A.

[0595] MS (ESI, m / z): 287.1 [M+H] +

[0596] Preparation of compound 18

[0597]

[0598] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 18A (50 mg, 0.18 mmol) and 7A (52 mg, 0.18 mmol) to prepare 20 mg of compound 18.

[0599] MS (ESI, m / z): 546.0 [M+H] + .

[0600] 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).

[0601] Example 19:

[0602] Preparation of intermediate 19A

[0603]

[0604] Compound 19A-1:

[0605] According to the method of 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.

[0606] MS (ESI, m / z): 303.2 [M+H] + .

[0607] Intermediate 19A:

[0608] According to the method of preparing 1C from intermediate 1C-9 in Example 1, the starting material was replaced with 19A-1 (150 mg, 0.5 mmol) to prepare 100 mg of compound 19A.

[0609] MS (ESI, m / z): 273.1 [M+H] + .

[0610] Preparation of compound 19

[0611]

[0612] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 19A (60 mg, 0.22 mmol) and 7A (65 mg, 0.22 mmol) to obtain 33 mg of compound 19.

[0613] MS (ESI, m / z): 532.2 [M+H] + .

[0614] 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).

[0615] Example 20:

[0616] Preparation of compound 20

[0617]

[0618] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 19A (60 mg, 0.22 mmol) and 2A (79 mg, 0.22 mmol) to prepare 33 mg of compound 20.

[0619] MS (ESI, m / z): 596.2, 598.2[M+H] + .

[0620] 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).

[0621] Example 21:

[0622] Preparation of Intermediate 21A

[0623]

[0624] Compound 21A-1:

[0625] 4-Bromo-3-nitro-1,2-phenylenediamine (10 g, 43 mmol) and a 40% aqueous solution of glyoxal (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 TLC monitoring showed the disappearance of the starting material, the reaction solution was cooled to room temperature. The precipitated solid was filtered, washed with water (3 times with 20 mL), and dried to obtain 13.4 g of crude compound 21A-1.

[0626] 1 H NMR (300 MHz, DMSO-d6) δ 8.16 (d, J = 1.8 Hz, 1H), 9.11 (d, J = 2.1 Hz, 1H), 8.30 (d, J = 5.4 Hz, 2H).

[0627] Compound 21A-2:

[0628] According to the method of preparing 1C from intermediate 1C-9 in Example 1, the raw material was replaced with 21A-1 (11 g, 43.3 mmol) to prepare 5.3 g of compound 21A-2.

[0629] MS (ESI, m / z): 223.8, 225.8[M+H] + .

[0630] Compound 21A-3:

[0631] Under nitrogen, compound 21A-2 (3.7 g, 17 mmol) was dissolved in N,N-dimethylformamide (50 mL). Sodium hydride (60%, 2.6 g, 66 mmol) was then added to the reaction mixture at 0°C and stirred for 30 minutes. Cyclopropanesulfonyl chloride (7 g, 50 mmol) was then added dropwise to the reaction mixture. The reaction mixture was warmed to room temperature and stirred for 2 hours. After LCMS monitoring showed the disappearance of the starting material, saturated aqueous ammonium chloride (50 mL) was added to the reaction mixture to quench the mixture. The mixture was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined, washed with saturated brine (80 mL × 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: petroleum ether / ethyl acetate = 1 / 1) to obtain 1.5 g of compound 21A-3.

[0632] MS (ESI, m / z): 431.8, 433.8[M+H] + .

[0633] Compound 21A-4:

[0634] Compound 21A-3 (2.2 g, 5.1 mmol) was dissolved in methanol (25 mL), and sodium hydroxide (8.1 g, 102 mmol) was added to the reaction solution. The reaction system was heated to 90°C and stirred for 2 hours. After the disappearance of the starting material by LCMS monitoring, the reaction solution 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 phases were first washed with saturated brine (80 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure; the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain 0.94 g of compound 21A-4.

[0635] MS (ESI, m / z): 327.9, 329.9[M+H] + .

[0636] Compound 21A-5:

[0637] 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 solution at 0°C. The reaction system was warmed to room temperature and stirred for 2 hours. After LCMS monitoring showed the disappearance of the starting material, water (50 mL) was added to the reaction solution to quench the reaction. The mixed solution was extracted with ethyl acetate (80 mL × 3 times), and the organic phases were combined, washed with saturated brine (80 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure; the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain 930 mg of compound 21A-5.

[0638] MS (ESI, m / z): 341.9, 343.9[M+H] + .

[0639] Compound 21A-6:

[0640] Under nitrogen, 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-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (132 mg, 0.28 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction system was heated to 90° C. and stirred for 4 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: petroleum ether / ethyl acetate = 1 / 1) to obtain 810 mg of compound 21A-6.

[0641] MS (ESI, m / z): 379.0 [M+H] + .

[0642] Compound 21A-7:

[0643] Compound 21A-6 (810 mg, 2.1 mmol) was dissolved in a 4 M solution of hydrogen chloride in ethyl acetate (10 mL) and stirred at room temperature for 2 hours. After LCMS monitoring indicated the disappearance of the starting material, the reaction solution was concentrated under reduced pressure, diluted with water (10 mL), and the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined, washed with saturated brine (80 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. 660 mg of crude compound 21A-7 was obtained.

[0644] MS (ESI, m / z): 279.2 [M+H] + .

[0645] Intermediate 21A:

[0646] According to the method of preparing 1B from 1B-2 in Example 1, the raw material was replaced with compound 21A-7 (620 mg, 2.2 mmol) to prepare 700 mg of compound 21A.

[0647] MS (ESI, m / z): 468.9, 470.9[M+H] + .

[0648] Preparation of compound 21

[0649]

[0650] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting material was replaced with 21A (110 mg, 0.23 mmol) to prepare 29 mg of compound 21.

[0651] MS (ESI, m / z): 691.3, 693.3[M+H] + .

[0652] 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).

[0653] Example 22:

[0654] Preparation of compound 22

[0655]

[0656] 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 stirred at room temperature for 3 hours. After LCMS monitoring showed the disappearance of the starting material, the palladium on carbon was filtered out, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain 27 mg of compound 22.

[0657] MS (ESI, m / z): 504.3 [M+H] + .

[0658] 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).

[0659] Example 23:

[0660] Preparation of intermediate 23A

[0661]

[0662] Compound 23A-1:

[0663] Under nitrogen, compound 6A-4 (100 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (3 mL). Sodium hydride (60%, 22 mg, 0.5 mmol) was then added to the reaction mixture at 0°C and stirred for 30 minutes. Cyanogen bromide (386 mg, 3.6 mmol) was then added to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. After LCMS monitoring indicated the disappearance of the starting material, the reaction mixture was purified by reverse-phase C18 column. Purification conditions: Column: 40 g C18 reverse-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 yield 65 mg of compound 23A-1.

[0664] MS (ESI, m / z): 300.2 [M+H] + .

[0665] Intermediate 23A:

[0666] According to the method of preparing 1C from intermediate 1C-9 in Example 1, the starting material was replaced with 23A-1 (55 mg, 0.18 mmol) to prepare 50 mg of compound 23A.

[0667] MS (ESI, m / z): 270.2 [M+H] + .

[0668] Preparation of compound 23:

[0669]

[0670] Under nitrogen, compound 23A (50 mg, 0.18 mmol), 7A (38 mg, 0.13 mmol), cesium carbonate (121 mg, 0.37 mmol), tris(dibenzylideneindeneacetone)dipalladium(0) (17 mg, 0.019 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (11 mg, 0.019 mmol) were dissolved in 1,4-dioxane (1 mL). The reaction system was heated to 90° C. and stirred for 4 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 17 mg of compound 23.

[0671] MS (ESI, m / z): 529.3 [M+H] + .

[0672] 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).

[0673] Example 24:

[0674] Preparation of intermediate 24A

[0675]

[0676] According to the method of preparing 1A from intermediate 1A-1 in Example 1, the starting material was replaced with 4-bromo-2-nitroanisole (20 g, 86.16 mmol) to prepare 19.7 g of compound 24A.

[0677] 1 H NMR (300MHz, CDCl3) δ 8.27 (d, J=1.5Hz, 1H), 7.96 (dd, J=8.4, 1.8Hz, 1H), 7.08 (d, J=8.4Hz, 1H), 4.00 (s, 3H), 1.36 (s, 12H).

[0678] Preparation of intermediate 24B

[0679]

[0680] Compound 24B-1:

[0681] Compound 1C-2 (6 g, 32.9 mmol) was dissolved in dichloromethane (100 mL). N-bromosuccinimide (8.8 g, 49.4 mmol) was then added to the reaction solution at 0°C. The reaction system was warmed to room temperature and stirred for 1 hour. After LCMS monitoring showed that the starting material disappeared, the reaction solution was poured into water (100 mL) for secondary quenching. The mixed solution was extracted with dichloromethane (100 mL × 3 times), and the organic phases were combined. The organic phases were first washed with saturated brine (80 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure; the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain 8.5 g of compound 24B-1.

[0682] MS(ESI)M / Z: 261.1, 263.1[M+H] + .

[0683] Compound 24B-2:

[0684] According to the method of preparing 1C-7 from 1C-6 in Example 1, the raw materials were replaced with 24B-1 (2 g, 7.6 mmol) and 24A (2.57 g, 9.2 mmol) to prepare 2 g of compound 24B-2.

[0685] MS (ESI, m / z): 334.1 [M+H] + .

[0686] Compound 24B-3:

[0687] Compound 24B-2 (2 g, 6.0 mmol) was dissolved in ethanol (20 mL). Aqueous sodium hydroxide (2 N, 9 mL) was then added to the reaction mixture. The reaction system was stirred at room temperature for 1 hour. After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was concentrated under reduced pressure and the pH was adjusted to 2 with 1 N aqueous hydrochloric acid. The precipitated solid was filtered and dried to obtain 1.5 g of compound 24B-3.

[0688] MS (ESI, m / z): 306.2 [M+H] + .

[0689] Compound 24B-4:

[0690] Compound 24B-3 (1.1 g, 3.6 mmol) was dissolved in a mixed solvent of ethanol (25 mL) and tetrahydrofuran (25 mL). Subsequently, platinum dioxide (221 mg, 0.97 mmol) was added to the reaction solution. After the reaction system was replaced with hydrogen three times, the reaction solution was stirred at room temperature for 2 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was filtered through celite, the filter cake was washed with dichloromethane (30 ml × 3 times), and the resulting filtrate was concentrated under reduced pressure to obtain 0.95 g of compound 24B-4.

[0691] MS (ESI, m / z): 276.2 [M+H] + .

[0692] Intermediate 24B:

[0693] Compound 24B-4 (1 g, 3.6 mmol) was dissolved in polyphosphoric acid (15 mL). The reaction system was heated to 100°C and stirred for 48 hours. After the disappearance of the starting material as monitored by LCMS, the reaction solution was poured into ice water (80 g). The mixture was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined and washed with saturated brine (80 mL × 3 times), then 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 obtain 0.65 g of compound 24B.

[0694] MS (ESI) M / Z: 258.2 [M+H] + .

[0695] Preparation of compound 24

[0696]

[0697] Compound 24C:

[0698] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting material was replaced with 24B (250 mg, 0.97 mmol) to prepare 200 mg of compound 24C.

[0699] MS (ESI, m / z): 633.3, 635.2[M+H] + .

[0700] Compound 24:

[0701] 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 warmed to room temperature and stirred for 2 hours. After LCMS monitoring showed the disappearance of the starting material, saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution. The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined, washed with saturated brine (20 mL × 3 times), then 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 obtain 60 mg of compound 24.

[0702] MS(ESI)M / Z: 634.9, 636.9[M+H] + .

[0703] 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).

[0704] Example 25:

[0705] Preparation of compound 25

[0706]

[0707] Compound 25A:

[0708] Under nitrogen, compound 2 (120 mg, 0.21 mmol), vinylboronic acid pinacol ester (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 system was heated to 85° C. and stirred for 4 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 obtain 70 mg of compound 25A.

[0709] MS (ESI, m / z): 530.3 [M+H] + .

[0710] Compound 25:

[0711] 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 solution. The reaction system was replaced with hydrogen three times, and the reaction solution was stirred at room temperature for 2 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered through celite, the filter cake was washed with ethanol (5 mL × 3 times), and the resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain 53 mg of compound 25.

[0712] MS (ESI, m / z): 532.3 [M+H] + .

[0713] 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).

[0714] Example 26:

[0715] Preparation of compound 26

[0716]

[0717] Compound 26A:

[0718] 2,4-Dichloro-5-trifluoromethylpyrimidine (2 g, 9.2 mmol) was dissolved in N,N-dimethylformamide (20 mL), and anhydrous potassium carbonate (1.5 g, 11.1 mmol) and 2-(dimethylphosphinoyl)aniline (1.6 g, 9.2 mmol) were added sequentially. The reaction solution was heated to 80°C and stirred for 12 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was cooled to room temperature and quenched by adding water (150 mL). The mixture was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined, washed with saturated brine (80 mL × 3 times), then 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 obtain 0.35 g of compound 26A.

[0719] MS(ESI)M / Z: 350.1, 352.1[M+H] + .

[0720] Compound 26:

[0721] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting material was replaced with 26A (108 mg, 0.31 mmol) to prepare 41 mg of compound 26.

[0722] MS (ESI, m / z): 572.3 [M+H] + .

[0723] 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).

[0724] 19 F NMR (282MHz, CDCl3) δ-60.82.

[0725] Example 27:

[0726] Preparation of compound 27

[0727]

[0728] Compound 6A (80 mg, 0.28 mmol) and 2A (101 mg, 0.28 mmol) were dissolved in N-methylpyrrolidone (2 mL). Subsequently, methanesulfonic acid (81 mg, 0.84 mmol) was added to the above reaction solution. 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 solution was cooled to room temperature and purified by reverse phase C18 column. Purification conditions: chromatographic column 80 g C18 reverse phase column; mobile phase water (containing 0.1% formic acid) and acetonitrile; flow rate 50 mL / min; gradient of acetonitrile from 15% to 55% within 25 minutes; detection wavelength 254 nm. The product was collected and concentrated under reduced pressure to obtain 60 mg of compound 27.

[0729] MS (ESI, m / z): 610.2, 612.2[M+H] + .

[0730] 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(brs, 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).

[0731] Example 28:

[0732] Preparation of compound 28

[0733]

[0734] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 2A (162 mg, 0.45 mmol) and 16A (110 mg, 0.45 mmol) to prepare 15 mg of compound 28.

[0735] MS (ESI, m / z): 568.2, 570.2[M+H] + .

[0736] 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).

[0737] Example 29:

[0738] Preparation of intermediate 29A

[0739]

[0740] Compound 29A-1:

[0741] 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 system 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 poured into water (100 mL) for quenching. The mixed solution was extracted with ethyl acetate (80 mL × 3 times), and the organic phases were combined and washed with saturated brine (80 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure; the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 1 g of compound 29A-1.

[0742] MS(ESI)M / Z: 305.0, 307.0[M+H] + .

[0743] Compound 29A-2:

[0744] According to the method of preparing 1C-7 from 1C-6 in Example 1, the raw materials were replaced with 29A-1 (1 g, 3.3 mmol) and 1-(2-tetrahydropyranyl)-1H-pyrazole-5-boronic acid pinacol ester (1.37 g, 4.92 mmol) to prepare 0.15 g of compound 29A-2.

[0745] MS (ESI, m / z): 377.3 [M+H] + .

[0746] Compound 29A-3:

[0747] 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 solution and stirred at room temperature for 5 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 90 mg of compound 29A-3.

[0748] MS (ESI) M / Z: 292.9 [M+H] + .

[0749] Compound 29A-4:

[0750] Under nitrogen, triphenylphosphine (129 mg, 0.5 mmol) was dissolved in tetrahydrofuran (2 mL). Diethyl azodicarboxylate (97 mg, 0.56 mmol) was added to the reaction solution at 0°C and stirred at 0°C for 1 hour (until a milky white turbid solution was formed). Compound 29A-3 (90 mg, 0.31 mmol) was added to the reaction solution and stirred at room temperature for 4 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to give 35 mg of compound 29A-4.

[0751] MS (ESI) M / Z: 275.1 [M+H] + .

[0752] Intermediate 29A:

[0753] According to the method of preparing 1C from intermediate 1C-9 in Example 1, the starting material was replaced with 29A-4 (35 mg, 0.13 mmol) to prepare 20 mg of compound 29A.

[0754] MS (ESI, m / z): 245.2 [M+H] + .

[0755] Preparation of compound 29

[0756]

[0757] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 2A (51.66 mg, 0.14 mmol) and 29A (35 mg, 0.14 mmol) to obtain 7.6 mg of compound 29.

[0758] MS (ESI, m / z): 568.2, 570.2[M+H] + .

[0759] 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).

[0760] Example 30:

[0761] Preparation of compound 30

[0762]

[0763] Under nitrogen, 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 system was heated to 100°C and stirred for 24 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was added to water (10 mL). The mixture was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined, washed with saturated brine (20 mL × 3 times), then 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 obtain 91 mg of compound 30.

[0764] MS (ESI) M / Z: 544.3 [M+H] + .

[0765] 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).

[0766] Example 31:

[0767] Preparation of intermediate 31A

[0768]

[0769] Compound 31A-1:

[0770] 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 solution and stirred at room temperature for 16 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain 550 mg of compound 31A-1.

[0771] MS (ESI) M / Z: 294.1 [M+H] + .

[0772] Compound 31A-2:

[0773] Under nitrogen, compound 31A-1 (850 mg, 2.9 mmol) and carbon tetrabromide (3.84 g, 11.59 mmol) were dissolved in tetrahydrofuran (10 mL). Triphenylphosphine (3.04 g, 11.59 mmol) was then added to the reaction solution and stirred at room temperature for 5 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give 130 mg of compound 31A-2.

[0774] MS(ESI)M / Z: 418.0, 420.0, 422.0[M+H] + .

[0775] Compound 31A-3:

[0776] Compound 31A-2 (880 mg, 2.1 mmol), tetrabutylammonium bromide (162 mg, 0.5 mmol), and p-methylsulfonylmethyl isocyanide (451 mg, 2.3 mmol) were dissolved in dichloromethane (24 mL). A solution of sodium hydroxide (428 mg, 10.71 mmol) in water (6 mL) was then added to the reaction mixture at 0°C. The reaction system was warmed to room temperature and stirred for 16 hours. After LCMS monitoring showed the disappearance of the starting material, the two phases were separated, and the aqueous phase was extracted with dichloromethane (20 mL). The organic phases were combined and aqueous hydrochloric acid (7 mL, 37%) was added, and stirring was continued at room temperature for 3 hours. The two phases were separated, and the organic phase was washed sequentially 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 resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 360 mg of compound 31A-3.

[0777] MS (ESI) M / Z: 288.1 [M+H] + .

[0778] Compound 31A-4:

[0779] 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 solution at 0°C. The reaction system was warmed to room temperature and stirred for 1 hour. After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added to the reaction solution to quench the mixture. The mixed solution was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined. The organic phases were first washed with saturated brine (20 mL × 3 times), then 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 85 mg of compound 31A-4.

[0780] MS (ESI) M / Z: 290.1 ​​[M+H] + .

[0781] Intermediate 31A:

[0782] According to the method of preparing 1C from intermediate 1C-9 in Example 1, the starting material was replaced with 31A-4 (85 mg, 0.29 mmol) to prepare 65 mg of compound 31A.

[0783] MS (ESI, m / z): 260.1 [M+H] + .

[0784] Preparation of compound 31

[0785]

[0786] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting material was replaced with 31A (65 mg, 0.25 mmol) to prepare 30 mg of compound 31.

[0787] MS (ESI, m / z): 635.1, 637.1[M+H] + .

[0788] 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).

[0789] Example 32:

[0790] Preparation of intermediate 32A

[0791]

[0792] According to the method of preparing 1B from 1B-2 in Example 1, the starting material was replaced with 2-nitroaniline (5.0 g, 36.2 mmol) to prepare 3.2 g of compound 32A.

[0793] MS (ESI, m / z): 328.8, 330.8[M+H] + .

[0794] Preparation of compound 32

[0795]

[0796] Compound 32B:

[0797] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting material was replaced with 32A (200 mg, 0.61 mmol) to prepare 270 mg of compound 32B.

[0798] MS (ESI, m / z): 551.0, 553.0[M+H] + .

[0799] Compound 32C:

[0800] According to the method of preparing 1C from intermediate 1C-9 in Example 1, the starting material was replaced with 32B (130 mg, 0.24 mmol) to prepare 80 mg of compound 32C.

[0801] MS (ESI, m / z): 521.2, 523.2[M+H] + .

[0802] Compound 32:

[0803] 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 solution. The reaction system was warmed to room temperature and stirred for 3 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was purified by C18 reverse phase column. Purification conditions: 80 g C18 reverse phase column; mobile phase: water (containing 0.1% formic acid) and acetonitrile; flow rate: 50 mL / min; gradient: acetonitrile increased from 5% to 40% in 30 minutes; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure to obtain 21 mg of compound 32.

[0804] MS(ESI, m / z): 599.0, 601.0[M+H] + .

[0805] 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(brs, 5H), 2.91(s, 3H).

[0806] Example 33:

[0807] Preparation of intermediate 33A

[0808]

[0809] Compound 33A-1:

[0810] According to the method of preparing 24B-1 from intermediate 1C-2 in Example 24, the raw material was replaced with 1-methyl-1H-pyrazole-5-carbaldehyde (59.7 g, 542 mmol) to prepare 80 g of compound 33A-1.

[0811] 1H NMR (300MHz, CDCl3) δ9.91 (s, 1H), 7.54 (s, 1H), 4.18 (s, 3H).

[0812] Compound 33A-2:

[0813] At 0°C, compound 33A-1 (60 g, 317.4 mmol) was dissolved in ethanol (500 mL). Sodium borohydride (6 g, 158.7 mmol) was then added to the reaction solution in batches. The reaction system was warmed to room temperature and stirred for 1 hour. After LCMS monitoring showed that the starting material disappeared, the reaction solution was concentrated under reduced pressure. Water (300 mL) was added to the mixture for dilution, and the pH was adjusted to 6 with concentrated hydrochloric acid. The mixed solution was extracted with ethyl acetate (300 mL × 3 times), and the organic phases were combined. The organic phases were first washed with saturated brine (200 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 60 g of compound 33A-2.

[0814] MS(ESI)M / Z: 191.2, 193.2[M+H] + .

[0815] Compound 33A-3:

[0816] At 0°C, compound 33A-2 (60 g, 314 mmol) was dissolved in dichloromethane (500 mL). Dichlorothionyl (18.68 g, 157 mmol) was then added dropwise to the reaction solution. The reaction system was warmed to room temperature and stirred for 16 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was concentrated under reduced pressure. Dichloromethane (300 mL) was added to the mixture to dilute it and slowly added dropwise to a saturated aqueous sodium bicarbonate solution (300 mL). The mixed solution was extracted with dichloromethane (300 mL × 2 times), and the organic phases were combined. The organic phases were first washed with saturated brine (300 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 62 g of compound 33A-3 was obtained.

[0817] MS(ESI)M / Z: 209.0, 211.0[M+H] + .

[0818] Compound 33A-4:

[0819] Compound 33A-3 (62 g, 296 mmol) and sodium cyanide (17.41 g, 355 mmol) were dissolved in dimethyl sulfoxide (300 mL). The reaction system was heated to 50°C and stirred for 16 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was poured into saturated sodium bicarbonate (500 mL). The mixed solution was extracted with ethyl acetate (300 mL × 2 times), and the organic phases were combined, washed with saturated brine (300 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain 15 g of compound 33A-4.

[0820] MS(ESI)M / Z: 200.0, 202.0[M+H] + .

[0821] Compound 33A-5:

[0822] Dissolve compound 33A-4 (5 g, 25 mmol) and sodium hydroxide (10 g, 250 mmol) in water (100 mL). Heat the reaction system to 100°C and continue stirring for 16 hours. After LCMS monitoring shows the disappearance of the starting material, cool the reaction solution to room temperature and adjust its pH to 1 with concentrated hydrochloric acid. The mixture is extracted with ethyl acetate (200 mL x 2). The organic phases are combined and washed with saturated brine (150 mL x 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 5 g of compound 33A-5 is obtained.

[0823] MS(ESI)M / Z: 218.7, 220.7[M+H] + .

[0824] Compound 33A-6:

[0825] Under nitrogen, compound 33A-5 (1 g, 4.6 mmol) was dissolved in tetrahydrofuran (10 mL). Borane tetrahydrofuran solution (1 M, 10 mL) was then added to the reaction solution. The reaction system was heated to 40°C and stirred for 16 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was cooled to room temperature and slowly added to methanol (40 mL). The reaction solution was heated to 60°C and stirred for 30 minutes. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 0.8 g of compound 33A-6.

[0826] MS(ESI)M / Z: 205.0, 207.0[M+H] + .

[0827] Compound 33A-7:

[0828] Compound 33A-6 (300 mg, 1.46 mmol) and imidazole (120 mg, 1.76 mmol) were dissolved in N,N-dimethylformamide (3 mL). Tert-butyldimethylsilyl chloride (265 mg, 1.76 mmol) was then added to the reaction solution at 0°C. The reaction system was warmed to room temperature and stirred for 2 hours. After LCMS monitoring showed the disappearance of the starting material, water (10 mL) was added to the reaction solution to quench the mixture. The mixed solution was extracted with ethyl acetate (20 mL × 2 times), and the organic phases were combined, washed with saturated brine (10 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / methyl tert-butyl ether = 2 / 1) to obtain 140 mg of compound 33A-7.

[0829] MS(ESI)M / Z: 319.1, 321.1[M+H] + .

[0830] Compound 33A-8:

[0831] Under nitrogen, compound 33A-7 (330 mg, 1.03 mmol) was dissolved in tetrahydrofuran (5 mL). Then, n-butyl lithium (2.5 M, 0.6 mL, 1.5 mmol) was added to the reaction solution at -78°C and stirring continued at this temperature for 1 hour. Isopropyl alcohol pinacol borate (230 mg, 1.2 mmol) was added to the reaction solution and stirring continued at this temperature for 1 hour. After LCMS monitoring showed the disappearance of the starting material, saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution to quench the mixture. The mixture was extracted with ethyl acetate (20 mL × 2 times), and the organic phases were combined, washed with saturated brine (10 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / methyl tert-butyl ether = 1 / 1) to obtain 300 mg of compound 33A-8.

[0832] MS (ESI) M / Z: 367.2 [M+H] + .

[0833] Compound 33A-9:

[0834] According to the method of 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.

[0835] MS (ESI, m / z): 410.2 [M+H] + .

[0836] Compound 33A-10:

[0837] Compound 33A-9 (100 mg, 0.24 mmol) was dissolved in tetrahydrofuran (2 mL). A solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 1 mL) was then added to the reaction mixture, and stirring was continued at room temperature for 5 hours. After LCMS monitoring indicated the disappearance of the starting material, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to afford 40 mg of compound 33A-10.

[0838] MS (ESI) M / Z: 276.1 [M+H] + .

[0839] Intermediate 33A:

[0840] According to the method of preparing 1C from intermediate 1C-9 in Example 1, the starting material was replaced with 33A-10 (40 mg, 0.15 mmol) to prepare 30 mg of compound 33A.

[0841] MS (ESI, m / z): 246.1 [M+H] + .

[0842] Preparation of compound 33

[0843]

[0844] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting material was replaced with 33A (25 mg, 0.1 mmol) to prepare 20 mg of compound 33.

[0845] MS (ESI, m / z): 621.1, 623.1[M+H] + .

[0846] 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).

[0847] Example 34:

[0848] Preparation of intermediate 34A

[0849]

[0850]

[0851] Compound 34A-1:

[0852] 1H-pyrazole-5-carboxaldehyde (3.7 g, 38 mmol) and potassium phosphate (16 g, 77 mmol) were dissolved in N,N-dimethylformamide (50 mL). p-Methoxybenzyl chloride (PMB-Cl, 6 g, 38 mmol) was then added to the reaction solution. The reaction system was heated to 80°C and stirred for 3 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was poured into water (150 mL). The mixture was extracted with ethyl acetate (100 mL x 2), and the organic phases were combined, washed with saturated brine (100 mL x 3), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain 4 g of compound 34A-1.

[0853] MS (ESI) M / Z: 217.2 [M+H] + .

[0854] Compound 34A-2:

[0855] According to the method for preparing compound 1C-1 in Example 1, the raw material was replaced with 34A-1 (2 g, 9 mmol) to prepare 2.6 g of compound 34A-2.

[0856] MS (ESI, m / z): 287.1 [M+H] + .

[0857] Compound 34A-3:

[0858] According to the method of preparing compound 1C-2 from 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.

[0859] MS (ESI, m / z): 289.1 [M+H] + .

[0860] Compound 34A-4:

[0861] According to the method of 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.

[0862] MS (ESI, m / z): 259.1 [MH]- .

[0863] Compound 34A-5:

[0864] According to the method for preparing compound 1C-4 from 1C-3 in Example 1, the raw material was replaced with 34A-4 (2 g, 7.7 mmol) to prepare 1.8 g of compound 34A-5.

[0865] MS (ESI, m / z): 332.2 [M+H] + .

[0866] Compound 34A-6:

[0867] According to the method for preparing compound 1C-5 from 1C-4 in Example 1, the raw material was replaced with 34A-5 (1.8 g, 5.4 mmol) to prepare 1.6 g of compound 34A-6.

[0868] MS (ESI, m / z): 346.3 [M+H] + .

[0869] Compound 34A-7:

[0870] According to the method for preparing compound 1C-6 from 1C-5 in Example 1, the raw material was replaced with 34A-6 (2 g, 5.8 mmol) to prepare 2.1 g of compound 34A-7.

[0871] MS (ESI, m / z): 472.0 [M+H] + .

[0872] Compound 34A-8:

[0873] According to the method for preparing compound 1C-7 from 1C-6 in Example 1, the raw material was replaced with 34A-7 (1.3 g, 4.2 mmol) to prepare 1.9 g of compound 34A-8.

[0874] MS (ESI, m / z): 515.3 [M+H] + .

[0875] Compound 34A-9:

[0876] According to the method for preparing compound 1C-8 from 1C-7 in Example 1, the raw material was replaced with 34A-8 (1.9 g, 3.7 mmol) to prepare 1 g of compound 34A-9.

[0877] MS (ESI, m / z): 415.2 [M+H] + .

[0878] Compound 34A-10:

[0879] According to the method for preparing compound 1C-9 from 1C-8 in Example 1, the raw material was replaced with 34A-9 (1 g, 2.4 mmol) to prepare 0.8 g of compound 34A-10.

[0880] MS (ESI, m / z): 395.3 [M+H] + .

[0881] Compound 34A:

[0882] According to the method for preparing compound 1C from 1C-9 in Example 1, the starting material was replaced with 34A-10 (300 mg, 0.76 mmol) to prepare 200 mg of compound 34A.

[0883] MS (ESI, m / z): 365.2 [M+H] + .

[0884] Preparation of compound 34

[0885]

[0886] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 34A (202 mg, 0.56 mmol) and 2A (200 mg, 0.56 mmol) to obtain 200 mg of compound 34.

[0887] MS (ESI, m / z): 688.3, ​​690.3[M+H] + .

[0888] 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).

[0889] Example 35:

[0890] Preparation of intermediate 35A

[0891]

[0892] Compound 35A-1:

[0893] 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 to the reaction mixture in portions at 0°C and stirred at this temperature for 30 minutes. After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was poured into ice water (100 g). The pH was adjusted to 8 with a 1 M aqueous sodium hydroxide solution. The mixed solution was extracted with ethyl acetate (200 mL × 2 times), and the organic phases were combined and washed with saturated brine (100 mL × 3 times), then 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 2 g of compound 35A-1.

[0894] MS (ESI) M / Z: 191.2 [M+H] + .

[0895] Intermediate 35A:

[0896] According to the method of preparing 1B from 1B-2 in Example 1, the starting material was replaced with 35A-1 (50 mg, 0.26 mmol) to prepare 40 mg of compound 35A.

[0897] MS (ESI, m / z): 381.0, 383.0[M+H] + .

[0898] Preparation of compound 35

[0899]

[0900] Compound 35B:

[0901] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting material was replaced with 35A (200 mg, 0.52 mmol) to prepare 130 mg of compound 35B.

[0902] MS (ESI, m / z): 603.0, 605.0[M+H] + .

[0903] Compound 35C:

[0904] According to the method of preparing 1C from intermediate 1C-9 in Example 1, the starting material was replaced with 35B (130 mg, 0.22 mmol) to prepare 76 mg of compound 35C.

[0905] MS (ESI, m / z): 573.1, 575.1[M+H] + .

[0906] Compound 35:

[0907] According to the method of preparing 32 from intermediate 32C in Example 32, the starting material was replaced with 35C (65 mg, 0.11 mmol) to prepare 33 mg of compound 35.

[0908] MS (ESI, m / z): 650.9, 652.9[M+H] + .

[0909] 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 (brs, 5H), 2.96 (s, 3H).

[0910] Example 36:

[0911] Preparation of intermediate 36A

[0912]

[0913] Compound 36A-1:

[0914] Under nitrogen, 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 13.3 mmol) was dissolved in N,N-dimethylformamide (25 mL). Sodium hydride (60%, 0.69 g, 17.3 mmol) was then added portionwise to the reaction mixture at 0°C and stirred for 30 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (2.88 g, 17.3 mmol) was added to the reaction mixture. The reaction system was warmed to room temperature and stirred for 1 hour. After LCMS monitoring showed the disappearance of the starting material, water (100 mL) was added to the reaction mixture to quench the mixture. The mixture was extracted with ethyl acetate (100 mL x 2 times), and the organic phases were combined, washed with saturated brine (100 mL x 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 3.9 g of compound 36A-1.

[0915] MS(ESI)M / Z: 318.1, 320.1[M+H] + .

[0916] Intermediate 36A:

[0917] According to the method of preparing 1B from 1B-2 in Example 1, the raw materials were replaced with 36A-1 (1.1 mg, 3.55 mmol) and 2-(dimethylphosphinyl)aniline (0.5 g, 2.96 mmol) to prepare 1.1 g of compound 36A.

[0918] MS (ESI, m / z): 451.2, 452.2[M+H] + .

[0919] Preparation of compound 36

[0920]

[0921] Compound 36B:

[0922] Under nitrogen, compound 36A (200 mg, 0.44 mmol), 1C (126 mg, 0.49 mmol), trisdibenzylideneacetone dipalladium (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 system was heated to 110° 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 260 mg of compound 36B.

[0923] MS (ESI) M / Z: 673.4 [M+H] + .

[0924] Compound 36:

[0925] Compound 36B (260 mg, 0.39 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (1.5 mL) was subsequently added to the reaction solution and stirring continued at room temperature for 1.5 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was concentrated under reduced pressure. Methanol (5 mL) and potassium carbonate (300 mg) were added to the residue and stirring continued at room temperature for 30 minutes. The reaction solution 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 36.

[0926] MS (ESI) M / Z: 543.3 [M+H] + .

[0927] 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).

[0928] Example 37:

[0929] Preparation of compound 37

[0930]

[0931] Compound 34 (40 mg, 0.06 mmol) was dissolved in trifluoroacetic acid (1 mL). The reaction system was heated to 100°C and stirred for 6 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 subjected to high pressure chromatography (preparation conditions: reverse phase column XBridge Shield RP18 OBD Column 30x150 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.

[0932] MS(ESI)M / Z: 568.0, 570.0[M+H] + .

[0933] 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).

[0934] Example 38:

[0935] Preparation of intermediate 38A

[0936]

[0937] Compound 24B (100 mg, 0.39 mmol) and triethylsilane (226 mg, 1.9 mmol) were dissolved in trifluoroacetic acid (4 mL). The reaction system was heated to 60°C and stirred for 5 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 C18 reverse phase column. Purification conditions: chromatographic column 40 g C18 reverse phase column; mobile phase water (containing 0.1% formic acid) and acetonitrile; flow rate 35 mL / min; gradient acetonitrile from 5% to 95% within 20 minutes; detection wave 254 nm. The product was collected and lyophilized under reduced pressure to obtain 90 mg of compound 38A.

[0938] MS (ESI, m / z): 244.2 [M+H] + .

[0939] Preparation of compound 38

[0940]

[0941] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 38A (90 mg, 0.37 mmol) and 2A (133 mg, 0.37 mmol) to prepare 10 mg of compound 38.

[0942] MS (ESI, m / z): 567.2, 569.2[M+H] + .

[0943] 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).

[0944] Example 39:

[0945] Preparation of compound 39

[0946]

[0947] Compound 37 (100 mg, 0.18 mmol) and potassium carbonate (49 mg, 0.35 mmol) were dissolved in N,N-dimethylformamide (2 mL). Ethyl iodide (41 mg, 0.26 mmol) was added to the reaction solution. The reaction system was heated to 50°C and stirred for 2 hours. After the disappearance of the starting material by LCMS monitoring, the reaction solution was cooled to room temperature and water (10 mL) was added. The mixed solution was extracted with ethyl acetate (10 mL × 2 times), and the organic phases were combined. The organic phases were first washed with saturated brine (10 mL × 3 times), then 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 10 mg of compound 39.

[0948] MS(ESI)M / Z: 595.9, 597.9[M+H] + .

[0949] 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 (brs, 2H), 3.15 (brs, 2H), 3.03 (s, 3H), 1.87 (s, 3H), 1.82 (s, 3H), 1.37 (t, J=7.2Hz, 3H).

[0950] Example 40:

[0951] Preparation of intermediate 40A

[0952]

[0953] Compound 40A-1:

[0954] According to the method for preparing compound 24 from 24C in Example 24, the starting material was replaced with 24B (700 mg, 2.72 mmol) to prepare 400 mg of compound 40A-1.

[0955] MS (ESI, m / z): 260.1 [M+H] + .

[0956] Compound 40A-2:

[0957] Compound 40A-1 (400 mg, 1.54 mmol) was dissolved in 1,2-dichloroethane (8 mL). Meta-chloroperbenzoic acid (799 mg, 4.63 mmol) was then added to the reaction solution. The reaction system was heated to 80°C and stirred for 1 hour. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was cooled to room temperature and water (20 mL) was added. The mixed solution was extracted with dichloromethane (20 mL × 2 times), and the organic phases were combined. The organic phases were first washed with saturated brine (20 mL × 3 times), then 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 obtain 160 mg of compound 40A-2.

[0958] MS (ESI, m / z): 290.1 ​​[M+H] + .

[0959] Compound 40A-3:

[0960] Under nitrogen, compound 40A-2 (75 mg, 0.26 mmol) was added to N,N-dimethylformamide (2 mL). Sodium hydride (60%, 31 mg, 0.78 mmol) was then added portionwise to the reaction mixture at 0°C and stirred for 30 minutes. Iodomethane (110 mg, 0.78 mmol) was added to the reaction mixture. The reaction system was warmed to room temperature and stirred for 2 hours. After LCMS monitoring showed the disappearance of the starting material, water (20 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 2 times), and the organic phases were combined, washed with saturated brine (20 mL × 3 times), then 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 obtain 75 mg of compound 40A-3.

[0961] MS (ESI) M / Z: 304.1 [M+H] + .

[0962] Intermediate 40A:

[0963] According to the method for preparing compound 8A from 8A-9 in Example 8, the starting material was replaced with 40A-3 (75 mg, 0.25 mmol) to prepare 65 mg of compound 40A.

[0964] MS (ESI, m / z): 274.1 [M+H] + .

[0965] Preparation of compound 40

[0966]

[0967] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 40A (65 mg, 0.24 mmol) and 2A (86 mg, 0.24 mmol) to prepare 10 mg of compound 40.

[0968] MS (ESI, m / z): 564.9, 566.9[M+H] + .

[0969] 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).

[0970] Example 41:

[0971] Preparation of Intermediate 41A

[0972]

[0973] Compound 41A-1:

[0974] Compound 6A-4 (500 mg, 1.8 mmol) and triethylamine (553 mg, 5.5 mmol) were dissolved in dichloromethane (10 mL). Bromoacetyl bromide (736 mg, 3.65 mmol) was then added to the reaction solution at 0°C. The reaction system was warmed to room temperature and stirred for 16 hours. After LCMS monitoring showed the disappearance of the starting material, water (50 mL) was added to the reaction solution to quench the mixture. The mixed solution was extracted with ethyl acetate (50 mL × 2 times), and the organic phases were combined, washed with saturated brine (30 mL × 3 times), then 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 obtain 720 mg of compound 41A-1.

[0975] MS(ESI)M / Z: 395.0, 397.0[M+H] + .

[0976] Compound 41A-2:

[0977] Compound 41A-1 (670 mg, 1.7 mmol) and diisopropylethylamine (657 mg, 5.09 mmol) were dissolved in N,N-dimethylformamide (15 mL). 4-Fluoropiperidine hydrochloride (355 mg, 2.54 mmol) was then added to the reaction solution and stirred at room temperature for 16 hours. After LCMS monitoring showed the disappearance of the starting material, water (50 mL) was added to the reaction solution to quench the mixture. The mixed solution was extracted with ethyl acetate (50 mL × 2 times), and the organic phases were combined. The organic phases were first washed with saturated brine (50 mL × 3 times), then 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 690 mg of compound 41A-2.

[0978] MS (ESI) M / Z: 417.9 [M+H] + .

[0979] Compound 41A-3:

[0980] According to the method of preparing 11A-1 from 9A-4 in Example 11, the starting material was replaced with 41A-2 (450 mg, 1.08 mmol) to prepare 298 mg of compound 41A-3.

[0981] MS (ESI, m / z): 404.1 [M+H] + .

[0982] Intermediate 41A:

[0983] According to the method for preparing compound 1C from 1C-9 in Example 1, the starting material was replaced with 41A-3 (100 mg, 0.25 mmol) to prepare 90 mg of compound 41A.

[0984] MS (ESI, m / z): 374.1 [M+H] + .

[0985] Preparation of compound 41

[0986]

[0987] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 41A (90 mg, 0.24 mmol) and 2A (87 mg, 0.24 mmol) to obtain 64 mg of compound 41.

[0988] MS (ESI, m / z): 697.1, 699.1[M+H] + .

[0989] 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).

[0990] Example 42:

[0991] Preparation of Intermediate 42A

[0992]

[0993] Compound 42A-1:

[0994] Under nitrogen, ethyl 5-bromothiazole-4-carboxylate (10 g, 42.36 mmol) was dissolved in dichloromethane (80 mL). A toluene solution of diisobutylaluminum hydride (1.5 M, 56.5 mL, 84.74 mmol) was then added to the reaction mixture at -78°C and stirred for 3 hours. After LCMS monitoring showed the disappearance of the starting material, saturated sodium potassium tartrate aqueous solution (200 mL) and dichloromethane (100 mL) were added to the reaction mixture and stirred at room temperature for 1 hour. The mixture was extracted with dichloromethane (100 mL x 2), and the organic phases were combined, washed with saturated brine (100 mL x 3), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain 6 g of compound 42A-1.

[0995] MS (ESI, m / z): 191.9, 193.9[M+H] + .

[0996] Compound 42A-2:

[0997] According to the method for preparing compound 1C-1 in Example 1, the raw material was replaced with 42A-1 (6 g, 31.25 mmol) to prepare 7.4 g of compound 42A-2.

[0998] MS (ESI, m / z): 261.7, 263.7[M+H] + .

[0999] Compound 42A-3:

[1000] Compound 42A-2 (7.4 g, 28.23 mmol), sodium acetate (4.63 g, 56.46 mmol) and p-methylbenzenesulfonyl hydrazide (21.03 g, 112.9 mmol) were dissolved in ethanol (80 mL). The reaction system was heated to 90°C and stirred for 3 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was cooled to room temperature and concentrated under reduced pressure. Water (100 mL) was added to the residue. The mixed solution was extracted with ethyl acetate (100 mL × 2 times), and the organic phases were combined. The organic phases were first washed with saturated brine (100 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 6.4 g of compound 42A-3.

[1001] MS(ESI)M / Z: 263.9, 265.9[M+H] + .

[1002] Compound 42A-4:

[1003] 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 solution. The reaction system was heated to 50 ° C and continued to stir for 5 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature and concentrated under reduced pressure. Water (20 mL) was added to the reaction solution to dilute it, and its pH was adjusted to 4 with 1M hydrochloric acid. The mixed solution was extracted with ethyl acetate (100 mL × 2 times), and the organic phases were combined. The organic phases were first washed with saturated brine (50 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 2.5 g of compound 42A-4 was obtained.

[1004] MS(ESI)M / Z: 234.0, 236.0[MH] - .

[1005] Compound 42A-5:

[1006] According to the method for preparing compound 1C-4 from 1C-3 in Example 1, the raw material was replaced with 42A-4 (3 g, 12.7 mmol) to prepare 2.5 g of compound 42A-5.

[1007] MS (ESI, m / z): 306.8, 308.8[M+H] + .

[1008] Compound 42A-6:

[1009] According to the method for preparing compound 1C-7 from 1C-6 in Example 1, the raw material was replaced with 42A-5 (2.5 g, 8.14 mmol) to prepare 2.8 g of compound 42A-6.

[1010] MS (ESI, m / z): 398.1 [M+H] + .

[1011] Compound 42A-7:

[1012] Compound 42A-6 (1 g, 2.52 mmol) was dissolved in dichloromethane (10 mL). A solution of hydrogen chloride in ethyl acetate (4 M, 5 mL) was then added to the reaction solution and stirring continued at room temperature for 1 hour. After LCMS monitoring showed the disappearance of the starting material, the reaction solution 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 system was heated to 90°C and stirred for 1 hour. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was cooled to room temperature and water (50 mL) was added. The mixed solution was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined, washed with saturated brine (50 mL × 3 times), then 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 obtain 0.4 g of compound 42A-7.

[1013] MS (ESI) M / Z: 277.9 [M+H] + .

[1014] Compound 42A-8:

[1015] According to the method for preparing compound 8A-9 from 8A-8 in Example 8, the starting material was replaced with 42A-7 (150 mg, 0.54 mmol) to prepare 117 mg of compound 42A-8.

[1016] MS (ESI, m / z): 292.2 [M+H] + .

[1017] Intermediate 42A:

[1018] According to the method for preparing compound 1C from 1C-9 in Example 1, the starting material was replaced with 42A-8 (117 mg, 0.4 mmol) to prepare 92 mg of compound 42A.

[1019] MS (ESI, m / z): 262.3 [M+H] + .

[1020] Preparation of compound 42

[1021]

[1022] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 42A (70 mg, 0.27 mmol) and 2A (96 mg, 0.27 mmol) to obtain 35 mg of compound 42.

[1023] MS (ESI, m / z): 585.1, 587.1[M+H] + .

[1024] 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, 1 H), 7.15-7.09(m, 1H), 6.97-6.92(m, 1H), 6.54(s, 1H), 3.93(s, 3H), 3.36(brs, 4H), 3.08(s, 3H), 1.89(s, 3H), 1.85(s, 3H).

[1025] Example 43:

[1026] Preparation of intermediate 43A

[1027]

[1028] Compound 43A-1

[1029] Under nitrogen, 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(diphenylphosphino)-9,9-dimethylxanthene (549 mg, 0.95 mmol), and diisopropylethylamine (3.27 g, 25.32 mmol) were dissolved in N,N-dimethylformamide (30 mL). The reaction system was heated to 120° C. and stirred for 16 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 0.65 g of compound 43A-1.

[1030] MS (ESI) M / Z: 187.9 [M+H] + .

[1031] Intermediate 43A:

[1032] According to the method for preparing 2A in Example 2, the starting material was replaced with 43A-1 (450 mg, 2.4 mmol) to prepare 200 mg of compound 43A.

[1033] MS (ESI, m / z): 377.6, 379.6[M+H] + .

[1034] Preparation of compound 43

[1035]

[1036] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting material was replaced with 43A (33 mg, 0.087 mmol) to prepare 10 mg of compound 43.

[1037] MS (ESI, m / z): 600.2, 602.2[M+H] + .

[1038] 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 (brs, 2H), 3.06 (brs, 5H), 1.89 (s, 3H), 1.85 (s, 3H).

[1039] Example 44:

[1040] Preparation of intermediate 44A

[1041]

[1042] Compound 44A-1:

[1043] 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.

[1044] MS (ESI, m / z): 171.1 [M+H] + .

[1045] Intermediate 44A:

[1046] According to the method for preparing 2A in Example 2, the starting material was replaced with 44A-1 (800 mg, 4.7 mmol) to prepare 730 mg of compound 44A.

[1047] MS (ESI, m / z): 360.9, 362.9[M+H] + .

[1048] Preparation of compound 44

[1049]

[1050] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting material was replaced with 44A (80 mg, 0.22 mmol) to prepare 33 mg of compound 44.

[1051] MS (ESI, m / z): 583.1, 585.1[M+H] + .

[1052] 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 (brs, 2H), 3.07 (brs, 5H), 1.91 (s, 3H), 1.86 (s, 3H).

[1053] Example 45:

[1054] Preparation of compound 45

[1055]

[1056] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 14A (60 mg, 0.19 mmol) and 6A (49 mg, 0.19 mmol) to prepare 49 mg of compound 45.

[1057] MS (ESI, m / z): 566.1, 568.1[M+H] + .

[1058] 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 (brs, 4H), 3.82 (s, 3H), 3.30 (brs, 2H), 2.95 (brs, 2H), 1.87 (s, 3H), 1.83 (s, 3H), 1.33 (s, 3H), 1.27 (s, 3H).

[1059] Example 46:

[1060] Preparation of intermediate 46A

[1061]

[1062] Compound 46A-1:

[1063] Compound 31A-1 (180 mg, 0.61 mmol) was dissolved in 50% aqueous sulfuric acid (5 mL). The reaction system was heated to 85°C and stirred for 4 hours. After the disappearance of the starting material as monitored by LCMS, the reaction solution was cooled to room temperature and its pH was adjusted to 8 with 1 M sodium hydroxide. The mixed solution was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined and washed with saturated brine (30 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 35 mg of compound 46A-1.

[1064] MS (ESI) M / Z: 276.0 [M+H] + .

[1065] Intermediate 46A:

[1066] According to the method for preparing compound 1C from 1C-9 in Example 1, the starting material was replaced with 46A-1 (45 mg, 0.16 mmol) to prepare 35 mg of compound 46A.

[1067] MS (ESI, m / z): 246.1 [M+H] + .

[1068] Preparation of compound 46

[1069]

[1070] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 46A (35 mg, 0.14 mmol) and 2A (51 mg, 0.14 mmol) to obtain 19 mg of compound 46.

[1071] MS (ESI, m / z): 569.2, 571.2[M+H] + .

[1072] 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).

[1073] Example 47:

[1074] Preparation of intermediate 47A

[1075]

[1076] Compound 47A-1:

[1077] Compound 10A-1 (200 mg, 0.61 mmol), N-methyl-4-piperidone (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 solution. The reaction system was stirred at room temperature for 16 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution 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 solution was heated to 110 ° C and stirred for 3 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature and poured into water (30 mL). The mixture was extracted with ethyl acetate (50 mL x 3 times), and the organic phases were combined, washed with saturated brine (50 mL x 3 times), then 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 obtain 160 mg of compound 47A-1.

[1078] MS (ESI) M / Z: 372.2 [M+H] + .

[1079] Intermediate 47A:

[1080] According to the method for preparing compound 1C from 1C-9 in Example 1, the starting material was replaced with 47A-1 (160 mg, 0.43 mmol) to prepare 130 mg of compound 47A.

[1081] MS (ESI, m / z): 342.2 [M+H] + .

[1082] Preparation of compound 47

[1083]

[1084] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 47A (130 mg, 0.38 mmol) and 2A (137 mg, 0.38 mmol) to obtain 44 mg of compound 47.

[1085] MS (ESI, m / z): 665.0, 667.0[M+H] + .

[1086] 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).

[1087] Example 48:

[1088] Preparation of intermediate 48A

[1089]

[1090] Compound 48A-1:

[1091] Under nitrogen, compound 1A-1 (2 g, 8.0 mmol), trimethylsilyl acetylene (2.36 g, 24 mmol), tetrakistriphenylphosphine palladium (1.85 g, 1.6 mmol), and cuprous iodide (0.15 g, 0.8 mmol) were dissolved in triethylamine (20 mL). 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 solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 15 / 1) to give 1.73 g of compound 48A-1.

[1092] 1 H NMR (400MHz, CDCl3) δ 8.07 (d, J=7.2Hz, 1H), 6.79 (d, J=10.4Hz, 1H), 3.97 (s, 3H), 0.26 (s, 9H).

[1093] Compound 48A-2:

[1094] Compound 48A-1 (2.6 g, 9.7 mmol) and ethyl azidoacetate (1.26 g, 9.7 mmol) were dissolved in toluene (30 mL). The reaction system was heated to 100°C and stirred for 2 days. 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: petroleum ether / ethyl acetate = 2 / 1) to obtain 2.8 g of compound 48A-2.

[1095] MS (ESI, m / z): 397.2 [M+H] + .

[1096] 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).

[1097] Compound 48A-3:

[1098] 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 warmed to room temperature and stirred for 2 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain 1 g of compound 48A-3.

[1099] MS (ESI, m / z): 325.1 [M+H] + .

[1100] Compound 48A-4:

[1101] According to the method for preparing compound 42A-4 from 42A-3 in Example 42, the starting material was replaced with 48A-3 (300 mg, 0.9 mmol) to prepare 200 mg of compound 48A-4.

[1102] MS (ESI, m / z): 297.1 [M+H] + .

[1103] Compound 48A-5:

[1104] Compound 48A-4 (300 mg, 1.0 mmol) and 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (501 mg, 1.3 mmol) were dissolved in N,N-dimethylformamide (5 mL) and stirred at room temperature for 30 minutes. Methylamine hydrochloride (137 mg, 2.0 mmol) and diisopropylethylamine (524 mg, 4.1 mmol) were then added to the reaction solution and stirred at room temperature for 16 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was purified by C18 reverse phase column. Purification conditions: 40 g C18 reverse phase column; mobile phase: water (containing 10 mM ammonium bicarbonate) and acetonitrile; flow rate: 35 mL / min; gradient: acetonitrile from 20% to 70% in 20 minutes; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure to obtain 100 mg of compound 48A-5.

[1105] MS (ESI, m / z): 310.1 [M+H] + .

[1106] Compound 48A-6:

[1107] 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 system was heated to 80°C and stirred for 1 hour. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was cooled to room temperature. The reaction solution was purified by C18 reverse phase column. Purification conditions: chromatographic column 40g C18 reverse phase column; mobile phase water (containing 10 mM ammonium bicarbonate) and acetonitrile; flow rate 35 mL / min; gradient acetonitrile increased from 20% to 60% within 20 minutes; detection wavelength 254 nm. The product was collected and lyophilized under reduced pressure to obtain 45 mg of compound 48A-6.

[1108] MS (ESI, m / z): 290.1 ​​[M+H] + .

[1109] Intermediate 48:

[1110] Compound 48A-6 (45 mg, 0.17 mmol) was dissolved in tetrahydrofuran (2 mL). Borane dimethyl sulfide (59 mg, 0.78 mmol) was subsequently added to the reaction solution and continued to stir at room temperature for 2 hours. After LCMS monitoring showed that the raw material disappeared, methanol (1 mL) was slowly added to the reaction solution to quench the product and the product 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 subsequently added. The reaction system was heated to 80 ° C and continued to stir for 2 hours. After LCMS monitoring showed that the raw material disappeared, the reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. 40 mg of crude compound 48A was obtained.

[1111] MS (ESI, m / z): 246.2 [M+H] + .

[1112] Preparation of compound 48

[1113]

[1114] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 48A (40 mg, 0.16 mmol) and 2A (41 mg, 0.1 mmol) to obtain 25 mg of compound 48.

[1115] MS (ESI, m / z): 568.9, 570.9[M+H] + .

[1116] 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).

[1117] Example 49:

[1118] Preparation of intermediate 49A

[1119]

[1120] Compound 49A-1:

[1121] 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.

[1122] MS (ESI, m / z): 439.1 [M+H] + .

[1123] Compound 49A-2:

[1124] 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.

[1125] MS (ESI, m / z): 409.2 [M+H] + .

[1126] Intermediate 49A:

[1127] According to the method for preparing compound 11A-1 from 9A-4 in Example 11, the starting material was replaced with 49A-1 (250 mg, 0.61 mmol) to prepare 212 mg of compound 49A.

[1128] MS (ESI, m / z): 395.2 [M+H] + .

[1129] Preparation of compound 49

[1130]

[1131] Compound 49B:

[1132] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 49A (100 mg, 0.25 mmol) and 2A (91 mg, 0.25 mmol) to prepare 117 mg of compound 49B.

[1133] MS (ESI, m / z): 718.1, 720.1[M+H] + .

[1134] Compound 49:

[1135] According to the method of preparing compound 37 in Example 34, the starting material was replaced with 49B (100 mg, 0.14 mmol) to prepare 26 mg of compound 49.

[1136] MS (ESI, m / z): 568.1.1, 570.1[M+H] + .

[1137] 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).

[1138] Example 50:

[1139] Preparation of Intermediate 50A

[1140]

[1141] Compound 50A-1:

[1142] Under nitrogen, compound 40A-2 (150 mg, 0.52 mmol) and triphenylphosphine (204 mg, 0.78 mmol) were dissolved in tetrahydrofuran (5 mL). Diethyl azodicarboxylate (135 mg, 0.78 mmol) was then added to the reaction mixture at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 70 mg of compound 50A-1.

[1143] MS (ESI, m / z): 419.0 [M+1] + .

[1144] Intermediate 50A:

[1145] According to the method for preparing compound 1C from 1C-9 in Example 1, the starting material was replaced with 50A-1 (65 mg, 0.16 mmol) to prepare 56 mg of compound 50A.

[1146] MS (ESI, m / z): 389.2 [M+H] + .

[1147] Preparation of compound 50

[1148]

[1149] Compound 50B:

[1150] According to the method for preparing compound 1 from 1B and 1C in Example 1, the starting materials were replaced with 50A (56 mg, 0.14 mmol) and 2A (52 mg, 0.14 mmol) to prepare 38 mg of compound 50B.

[1151] MS (ESI, m / z): 712.1, 714.1[M+H] + .

[1152] Compound 50:

[1153] 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 solution and stirring continued at room temperature for 2 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by C18 reverse phase column. Purification conditions: chromatographic column 40 g C18 reverse phase column; mobile phase water (containing 0.1% formic acid) and acetonitrile; flow rate 35 mL / min; gradient acetonitrile increased from 15% to 55% within 25 minutes; detection wavelength 254 nm. The product was collected and lyophilized under reduced pressure to obtain 8 mg of compound 50.

[1154] MS (ESI, m / z): 582.1, 584.1[M+H] + .

[1155] 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), 222 (br s, 2H), 2.24 (br s, 2H), 1.88 (s, 3H).

[1156] Example 51:

[1157] Preparation of Intermediate 51A

[1158]

[1159] Compound 33-5 (4.9 g, 22.37 mmol) was dissolved in methanol (50 mL). Thionyl chloride (3.99 g, 33.56 mmol) was then added dropwise to the reaction solution at 0°C. The reaction solution was warmed to room temperature and stirred for 16 hours. After the disappearance of the starting material 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 mixed solution was extracted with dichloromethane (50 mL × 3 times), and the organic phases were combined. The organic phases were first washed with saturated brine (50 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 4.4 g of compound 51A was obtained.

[1160] MS(ESI)M / Z: 233.1, 235.1[M+H] + .

[1161] Preparation of intermediate 51B

[1162]

[1163] Compound 51B-1:

[1164] Compound 2-methoxy-3-nitro-6-chloropyridine (5 g, 26.5 mmol) and 2,4-dimethoxybenzylamine (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 solution and stirred at room temperature for 5 hours. After LCMS monitoring showed that the starting material had disappeared, water (200 mL) was added to the reaction solution to quench the mixture. The mixed solution was extracted with ethyl acetate (100 mL × 3 times), and the organic phases were combined. The organic phases were first washed with saturated brine (80 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain 6 g of compound 51B-1.

[1165] MS (ESI) M / Z: 320.1 [M+H] + .

[1166] Compound 51B-2:

[1167] 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 solution and stirring continued at room temperature for 16 hours. After LCMS monitoring showed that the starting material disappeared, water (300 mL) was added to the reaction solution to quench the mixture. The mixed solution was extracted with ethyl acetate (300 mL × 3 times), and the organic phases were combined. The organic phases were first washed with saturated brine (200 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 7 g of compound 51B-2.

[1168] MS(ESI)M / Z: 475.9, 477.9, 479.9[M+H] + .

[1169] Compound 51B-3:

[1170] According to the method of preparing compound 37 in Example 34, the raw material was replaced with 51B-2 (6.5 g, 13.63 mmol) to prepare 3 g of compound 51B-3.

[1171] MS (ESI, m / z): 248.1, 250.1[M+H] + .

[1172] Compound 51B-4:

[1173] According to the method for preparing compound 1A from 1A-1 in Example 1, the starting material was replaced with 51B-3 (3 g, 12.1 mmol) to prepare 1.5 g of compound 51B-4.

[1174] MS (ESI, m / z): 296.1 [M+H] + .

[1175] Compound 51B-5:

[1176] Under nitrogen, 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 system was heated to 60° C. and stirred for 16 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 3) to give 760 mg of compound 51B-5.

[1177] MS (ESI) M / Z: 322.2 [M+H] + .

[1178] Compound 51B-6:

[1179] 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 solution and stirring was continued at room temperature for 2 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure and its pH was adjusted to 3 with 1N hydrochloric acid. The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined, washed with saturated brine (20 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 170 mg of crude compound 51B-6 was obtained.

[1180] MS (ESI) M / Z: 308.1 [M+H] + .

[1181] Compound 51B-7:

[1182] Compound 51B-6 (400 mg, 1.3 mmol) was dissolved in N,N-dimethylformamide (5 mL). 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (594 mg, 1.56 mmol) and N,N-diisopropylethylamine (505 mg, 3.91 mmol) were added to the reaction solution and stirred at room temperature for 16 hours. After LCMS monitoring showed that the starting material disappeared, water (20 mL) was added to the reaction solution to quench the mixture. The mixed solution was extracted with ethyl acetate (20 mL × 3 times), and the organic phases were combined. The organic phases were first washed with saturated brine (20 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 300 mg of crude compound 51B-7 was obtained.

[1183] MS (ESI) M / Z: 290.1 ​​[M+H] + .

[1184] Compound 51B-8:

[1185] According to the method of preparing compound 11A-1 using 9A-4 in Example 11, the starting material was replaced with 51B-7 (170 mg, 0.59 mmol) to prepare 140 mg of compound 51B-8.

[1186] MS (ESI, m / z): 276.1 [M+H] + .

[1187] Compound 51B:

[1188] According to the method for preparing compound 1C from 1C-9 in Example 1, the starting material was replaced with 51B-8 (140 mg, 0.51 mmol) to prepare 53 mg of compound 51B.

[1189] MS (ESI, m / z): 246.1 [M+H] + .

[1190] Preparation of compound 51

[1191]

[1192] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 51B (57 mg, 0.23 mmol) and 2A (84 mg, 0.23 mmol) to prepare 14 mg of compound 51.

[1193] MS (ESI, m / z): 569.1, 571.1[M+H] + .

[1194] 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).

[1195] Example 52:

[1196] Preparation of compound 52

[1197]

[1198] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting material was replaced with 51B (80 mg, 0.33 mmol) to prepare 25 mg of compound 52.

[1199] MS (ESI, m / z): 621.1, 623.1[M+H] + .

[1200] 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).

[1201] Example 53:

[1202] Preparation of compound 53

[1203]

[1204] Compound 53A:

[1205] Compound 6A (2.7 g, 9.43 mmol) and 35A (3.6 g, 9.43 mmol) were dissolved in N-methylpyrrolidone (30 mL). Subsequently, methanesulfonic acid (2.72 g, 28.28 mmol) was added to the above reaction solution. The reaction system was heated to 95°C and stirred for 3 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was cooled to room temperature and purified by reverse phase C18 column. Purification conditions: chromatographic column 330 g C18 reverse phase column; mobile phase water (containing 0.1% formic acid) and acetonitrile; flow rate 70 mL / min; gradient of acetonitrile from 10% to 50% within 20 minutes; detection wavelength 254 nm. The product was collected and concentrated under reduced pressure to obtain 3.4 g of compound 53A.

[1206] MS (ESI, m / z): 631.2, 633.2[M+H] + .

[1207] Compound 53B:

[1208] Compound 53A (3.4 g, 5.38 mmol) was dissolved in a mixed solvent of ethanol (40 mL) and water (8 mL). Iron powder (1.50 g, 26.92 mmol) and ammonium chloride (0.86 g, 16.15 mmol) were then added to the reaction mixture, and the reaction system was heated to 80° C. and stirred for 2 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction mixture 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 obtain 2.8 g of compound 53B.

[1209] MS (ESI, m / z): 601.2, 603.2[M+H] + .

[1210] Compound 53:

[1211] 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 solution. The reaction system was heated to 50°C and stirred for 1 hour. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was cooled to room temperature and quenched by the addition of water (3 mL). The reaction solution was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1), and the resulting crude product was purified by C18 reverse-phase column. Purification conditions: 330 g C18 reverse-phase column; mobile phase: water (containing 0.1% formic acid) and acetonitrile; flow rate: 70 mL / min; gradient: acetonitrile from 5% to 60% over 30 minutes; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure to obtain 2.2 g of compound 53.

[1212] MS (ESI, m / z): 679.2, 681.2[M+H] + .

[1213] 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).

[1214] 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).

[1215] Example 54:

[1216] Preparation of compound 54

[1217]

[1218] Compound 54A:

[1219] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 6A (130 mg, 0.46 mmol) and 32A (150 mg, 0.46 mmol) to obtain 110 mg of compound 54A.

[1220] MS (ESI, m / z): 579.3, 581.3[M+H] + .

[1221] Compound 54B:

[1222] According to the method of preparing 1C from intermediate 1C-9 in Example 1, the starting material was replaced with 54A (100 mg, 0.17 mmol) to prepare 89 mg of compound 54B.

[1223] MS (ESI, m / z): 549.3, 551.3[M+H] + .

[1224] Compound 54:

[1225] According to the method of preparing 32 from intermediate 32C of Example 32, the starting material was replaced with 54B (80 mg, 0.15 mmol) to prepare 47 mg of compound 54.

[1226] MS (ESI, m / z): 627.2, 629.2[M+H] + .

[1227] 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).

[1228] Example 55:

[1229] Preparation of intermediate 55A

[1230]

[1231] Compound 55A-1:

[1232] 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 solution. The reaction system was heated to 70°C and stirred for 16 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 a reverse phase C18 column under the following purification conditions: chromatographic column 120 g C18 reverse phase column; mobile phase water (containing 10 mM ammonium bicarbonate) and acetonitrile; flow rate 60 mL / min; gradient acetonitrile from 30% to 80% within 30 minutes; detection wavelength 220 nm. The product was collected and lyophilized under reduced pressure to obtain 1.7 g of compound 55A-1.

[1233] MS (ESI) M / Z: 226.3 [M+H] + .

[1234] Compound 55A-2:

[1235] 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 solution. The reaction solution was heated to 120°C using a microwave reactor and continued to stir for 4 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by a reverse phase C18 column under the following purification conditions: chromatographic column 120 g C18 reverse phase column; mobile phase water (containing 10 mM ammonium bicarbonate) and acetonitrile; flow rate 60 mL / min; gradient acetonitrile increased from 30% to 80% within 30 minutes; detection wavelength 220 nm. The product was collected and lyophilized under reduced pressure to obtain 1.1 g of compound 55A-2.

[1236] MS (ESI) M / Z: 352.1 [M+H] + .

[1237] Compound 55A-3:

[1238] 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). 1,1′-bis(di-tert-butylphosphino)ferrocenedichloropalladium (167 mg, 0.26 mmol) was then added to the reaction solution. The reaction system 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 quenched by the addition of water (10 mL). The mixed solution was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined, washed with saturated brine (30 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain 300 mg of compound 55A-3.

[1239] MS (ESI) M / Z: 395.2 [M+H] + .

[1240] Compound 55A-4:

[1241] 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.

[1242] MS (ESI, m / z): 274.8 [M+H] + .

[1243] Compound 55A-5:

[1244] According to the method of preparing compound 8A-9 from 8A-8 in Example 8, the starting material was replaced with 55A-4 (130 mg, 0.47 mmol) to prepare 90 mg of compound 55A-5.

[1245] MS (ESI, m / z): 289.1 [M+H] + .

[1246] Intermediate 55A:

[1247] According to the method for preparing compound 1C from 1C-9 in Example 1, the starting material was replaced with 55A-5 (90 mg, 0.31 mmol) to prepare 70 mg of compound 55A.

[1248] MS (ESI, m / z): 259.2 [M+H] + .

[1249] Preparation of compound 55

[1250]

[1251] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 55A (72 mg, 0.28 mmol) and 2A (101 mg, 0.28 mmol) to obtain 37 mg of compound 55.

[1252] MS (ESI, m / z): 582.0, 584.0[M+H] + .

[1253] 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).

[1254] Example 56:

[1255] Preparation of intermediate 56A

[1256]

[1257] Compound 56A-1:

[1258] According to the method of preparing compound 1C-6 from 1C-5 in Example 1, the raw material was replaced with 34A-5 (10 g, 30.2 mmol) to prepare 12.5 g of compound 56A-1.

[1259] MS (ESI, m / z): 458.1 [M+H] + .

[1260] Compound 56A-2:

[1261] According to the method of preparing compound 1C-7 from 1C-6 in Example 1, the raw material was replaced with 56A-1 (12.1 g, 26.5 mmol) to prepare 10 g of compound 56A-2.

[1262] MS (ESI, m / z): 501.2 [M+H] + .

[1263] Compound 56A-3:

[1264] According to the method of preparing compound 1C-9 from 1C-8 in Example 1, the raw material was replaced with 56A-2 (3 g, 6.0 mmol) to prepare 2.4 g of compound 56A-3.

[1265] MS (ESI, m / z): 401.0 [M+H] + .

[1266] Compound 56A-4:

[1267] 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 subsequently added to the reaction solution and stirring continued 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 subsequently added to the reaction solution. The reaction system was stirred for 2 hours at room temperature. After LCMS monitoring showed that the raw material disappeared, the reaction solution was concentrated under reduced pressure. The obtained residue was dissolved in N, N-dimethylformamide (30 mL), and anhydrous potassium carbonate (4.2 g, 30.5 mmol) was subsequently added to the reaction solution. The reaction system was heated to 110 ° C and stirred for 4 hours. After LCMS monitoring showed that the raw material disappeared, the reaction solution was cooled to room temperature and quenched by adding water (150 mL). The mixture was extracted with ethyl acetate (100 mL x 3 times), and the organic phases were combined, washed with saturated brine (80 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: petroleum ether / ethyl acetate = 1 / 1) to obtain 2.12 g of compound 56A-4.

[1268] MS (ESI) M / Z: 423.2 [M+H] + .

[1269] Intermediate 56A:

[1270] According to the method for preparing compound 1C from 1C-9 in Example 1, the starting material was replaced with 56A-4 (2.12 g, 5.02 mmol) to prepare 1.67 g of compound 56A.

[1271] MS (ESI, m / z): 393.3 [M+H] + .

[1272] Preparation of compound 56

[1273]

[1274] Compound 56B:

[1275] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting 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.

[1276] MS (ESI, m / z): 716.3, 718.3[M+H] + .

[1277] Compound 56C:

[1278] According to the method for preparing compound 37 in Example 37, 1.2 g of compound 56C was prepared by replacing the starting material with 56B (2.88 g, 4.02 mmol).

[1279] MS (ESI, m / z): 596.2, 598.2[M+H] + .

[1280] Compound 56:

[1281] Compound 56C (100 mg, 0.17 mmol) and anhydrous potassium carbonate (232 mg, 1.68 mmol) were dissolved in N,N-dimethylformamide (2 mL). 2-Bromo-N,N-dimethylethylamine hydrobromide (195 mg, 0.84 mmol) was then added to the reaction mixture. The reaction mixture was heated to 120°C and stirred for 2 days. After LCMS monitoring indicated the disappearance of the starting material, the reaction mixture was cooled to room temperature and subjected to high pressure preparative chromatography. The preparative conditions were: 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 yield 3 mg of compound 56.

[1282] MS (ESI, m / z): 667.2, 669.2[M+H] + .

[1283] 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).

[1284] Example 57:

[1285] Preparation of compound 57

[1286]

[1287] Compound 57:

[1288] According to the method of preparing compound 1 according to 1B and 1C in Example 1, the starting material was replaced with 49A (100 mg, 0.25 mmol) to prepare 133 mg of compound 57.

[1289] MS (ESI, m / z): 770.3, 772.3[M+H] + .

[1290] 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).

[1291] Example 58:

[1292] Preparation of compound 58

[1293]

[1294] Compound 58A:

[1295] Compound 2-(dimethylphosphinyl)aniline (1.37 g, 8.1 mmol) and 2,4-dichlorothienyl[3,2-d]pyrimidine (1.99 g, 9.72 mmol) were dissolved in N,N-dimethylformamide (20 mL), and diisopropylethylamine (2.09 g, 16.2 mmol) was added to the reaction solution. The reaction system was heated to 110°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 quenched by adding water (100 mL). The mixture was extracted with ethyl acetate (80 mL × 3 times), and the organic phases were combined, washed with saturated brine (80 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain 1.82 g of compound 58A.

[1296] MS(ESI)M / Z: 338.1, 340.1[M+H] + .

[1297] Compound 58:

[1298] 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(dibenzylideneacetone)dipalladium (27 mg, 0.03 mmol) and 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl (21 mg, 0.04 mmol) were then added to the reaction solution. The reaction system was heated to 110° 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 103 mg of compound 58.

[1299] MS (ESI) M / Z: 560.2 [M+H] + .

[1300] 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).

[1301] Example 59:

[1302] Preparation of compound 59

[1303]

[1304] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 10A (71 mg, 0.23 mmol) and 2A (65 mg, 0.18 mmol) to obtain 12 mg of compound 59.

[1305] MS (ESI, m / z): 637.2, 639.2[M+H] + .

[1306] 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).

[1307] Example 60:

[1308] Preparation of intermediate 60A

[1309]

[1310] Compound 60A-1:

[1311] 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). 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 13.3 mmol) was then added portionwise to the reaction solution and stirred at the same temperature for 10 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (2.88 g, 17.29 mmol) was then added to the reaction solution and stirred at the same temperature for 10 minutes. The reaction system was then warmed to room temperature and stirred for 1 hour. After LCMS monitoring showed the disappearance of the starting material, water (100 mL) was added to the reaction solution to quench the mixture. The mixture was extracted with ethyl acetate (80 mL × 3 times), and the organic phases were combined, washed with saturated brine (80 mL × 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: petroleum ether / ethyl acetate = 5 / 1) to obtain 3.9 g of compound 60A-1.

[1312] MS(ESI)M / Z: 318.1, 320.1[M+H] + .

[1313] Intermediate 60A:

[1314] According to the method for preparing compound 1B from 1B-2 in Example 1, the starting material was replaced with 60A-1 (5.76 g, 18.08 mmol) to prepare 3 g of compound 60A.

[1315] MS (ESI, m / z): 503.3, 505.3[M+H] + .

[1316] Preparation of Compound 60

[1317]

[1318] Compound 60B:

[1319] According to the method for preparing compound 58 from 58A and 1C in Example 58, the starting material was replaced with 60A (80 mg, 0.16 mmol) to prepare 70 mg of compound 60B.

[1320] MS (ESI, m / z): 725.4 [M+H] + .

[1321] Compound 60:

[1322] According to the method for preparing compound 36 from 36B in Example 36, the starting material was replaced with 60B (148 mg, 0.2 mmol) to prepare 21 mg of compound 60.

[1323] MS (ESI, m / z): 595.2 [M+H] + .

[1324] 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).

[1325] Example 61:

[1326] Preparation of compound 61

[1327]

[1328] Compound 61A:

[1329] According to the method for preparing compound 1B in 1B-2 in Example 1, replacing the starting material with 2,4-dichlorothienyl[3,2-d]pyrimidine (1.85 g, 9.04 mmol), 1 g of compound 61A was prepared.

[1330] MS (ESI, m / z): 390.0, 392.0[M+H] + .

[1331] Compound 61:

[1332] According to the method of preparing compound 58 using 58A and 1C in Example 58, the starting material was replaced with 61A (100 mg, 0.26 mmol) to prepare 46 mg of compound 61.

[1333] MS (ESI, m / z): 612.2 [M+H] + .

[1334] 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).

[1335] Example 62:

[1336] Preparation of compound 62

[1337]

[1338] Compound 62:

[1339] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 47A (100 mg, 0.29 mmol) and 1B (100 mg, 0.24 mmol) to obtain 42 mg of compound 62.

[1340] MS (ESI, m / z): 717.3, 719.3[M+H] + .

[1341] 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).

[1342] Example 63:

[1343] Preparation of intermediate 63A

[1344]

[1345] Compound 63A-1:

[1346] According to the method for preparing compound 47A-1 from 10A-1 in Example 47, the raw material was replaced with tert-butyl 3-oxoazetidine-1-carboxylate (2.2 g, 12.9 mmol) to prepare 0.9 g of compound 63A-1.

[1347] MS (ESI, m / z): 430.2 [M+H] + .

[1348] Compound 63A-2:

[1349] Compound 63A-1 (300 mg, 0.7 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was subsequently added to the reaction solution and stirred at room temperature for 2 hours. After LCMS monitoring showed that the starting material 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 solution and stirred at room temperature for 30 minutes. Sodium cyanoborohydride (88 mg, 1.4 mmol) was added to the reaction solution and stirred at room temperature for 2 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution 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.

[1350] MS (ESI) M / Z: 372.2 [M+H] + .

[1351] Intermediate 63:

[1352] According to the method for preparing compound 1C from 1C-9 in Example 1, the starting material was replaced with 63A-2 (150 mg, 0.4 mmol) to prepare 87 g of compound 63A.

[1353] MS (ESI, m / z): 342.2 [M+H] + .

[1354] Preparation of compound 63

[1355]

[1356] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting material was replaced with 63A (87 mg, 0.26 mmol) to prepare 64 mg of compound 63.

[1357] MS (ESI, m / z): 717.2, 719.2[M+H] + .

[1358] 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).

[1359] Example 64:

[1360] Preparation of compound 64

[1361]

[1362] Compound 28 (100 mg, 0.18 mmol) and 3-oxetanone (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 solution. The reaction system was stirred at room temperature for 2 hours. After LCMS monitoring showed that the starting material disappeared, water (10 mL) was added to the reaction solution to quench the mixture. The mixed solution was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined. The organic phases were first washed with saturated brine (30 mL × 3 times), then 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 obtain 64 mg of compound 64A.

[1363] MS (ESI, m / z): 624.2, 626.2[M+H] + .

[1364] 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).

[1365] Example 65:

[1366] Preparation of intermediate 65A

[1367]

[1368] Compound 65A-1:

[1369] 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-oxopiperidine-1-carboxylate (828 mg, 3.81 mmol) to prepare 50 mg of compound 65A-1.

[1370] MS (ESI, m / z): 476.2 [M+H] + .

[1371] Compound 65A-2:

[1372] According to the method of preparing compound 63A-2 using 63A-1 in Example 63, the raw material was replaced with formaldehyde aqueous solution (40%, 200 mg, 2.67 mmol) to prepare 200 mg of compound 65A-2.

[1373] MS (ESI, m / z): 390.2 [M+H] + .

[1374] Intermediate 65A:

[1375] According to the method for preparing compound 1C from 1C-9 in Example 1, the starting material was replaced with 65A-2 (110 mg, 0.28 mmol) to prepare 64 mg of compound 65A.

[1376] MS (ESI, m / z): 360.2 [M+H] + .

[1377] Preparation of compound 65

[1378]

[1379] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 65A (30 mg, 0.08 mmol) and 2A (30 mg, 0.08 mmol) to obtain 11 mg of compound 65.

[1380] MS (ESI, m / z): 683.2, 685.2[M+H] + .

[1381] 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).

[1382] 19 F NMR (282MHz, CDCl3) δ-196.73.

[1383] Example 66:

[1384] Preparation of compounds 66A and 66B

[1385]

[1386] Compound 65 (168 mg, 0.25 mmol) was separated using a chiral column. Preparative conditions: chiral column: Lux 5μm Cellulose-4, 2.12 x 25 cm, 5μm; mobile phase A: n-hexane (10 mM ammonia in methanol), mobile phase B: ethanol; flow rate: 20 mL / min; isocratic elution with 50% B over 51 minutes; detection wavelength: 205 / 260 nm; RT1: 22 minutes; RT2: 34.5 minutes. The product was 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.

[1387] Compounds 66A and 66B are enantiomers, and their absolute configurations have not been determined.

[1388] 66A: MS (ESI, m / z): 683.3, 685.3[M+H] + .

[1389] 66B: MS (ESI, m / z): 683.2, 685.2[M+H] + .

[1390] 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).

[1391] 19 F NMR (282MHz, CDCl3) δ-196.86.

[1392] 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).

[1393] 19 F NMR (282MHz, CDCl3) δ-196.86.

[1394] Example 67:

[1395] Preparation of compound 67

[1396]

[1397] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting material was replaced with 65A (30 mg, 0.08 mmol) to prepare 19 mg of compound 67.

[1398] MS (ESI, m / z): 735.2, 737.2[M+H] + .

[1399] 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).

[1400] 19 F NMR (282MHz, CDCl3) δ-196.72.

[1401] Example 68:

[1402] Preparation of compound 68

[1403]

[1404] Compound 67 (50 mg, 0.07 mmol) was prepared using a 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 in methanol), mobile phase B: ethanol; flow rate: 20 mL / min; isocratic elution with 30% B over 25 minutes; detection wavelength: 260 / 210 nm; RT: 23.47 minutes. The product was collected and lyophilized under reduced pressure to yield 11 mg of compound 68 (one of the four possible enantiomers was isolated; 100% ee) at a retention time of 23.47 minutes.

[1405] MS (ESI, m / z): 735.2, 737.2[M+H] + .

[1406] 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).

[1407] Example 69:

[1408] Preparation of intermediate 69A

[1409]

[1410] Compound 69A-1:

[1411] 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 solution and stirring continued at room temperature for 2 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in N, N-dimethylformamide (3 mL), and anhydrous potassium carbonate (482 mg, 3.5 mmol) and 1-bromo-2-fluoroethane (370 mg, 2.9 mmol) were subsequently added to the reaction solution. The reaction system was heated to 80 ° C and continued to stir for 2 hours. After LCMS monitoring showed that the starting material disappeared, the reaction solution was cooled to room temperature and quenched by adding water (20 mL). The mixed solution 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 resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain 100 mg of compound 69A-1.

[1412] MS (ESI, m / z): 376.2 [M+H] + .

[1413] Intermediate 69A:

[1414] According to the method for preparing compound 1C from 1C-9 in Example 1, the starting material was replaced with 69A-1 (100 mg, 0.27 mmol) to prepare 60 mg of compound 69A.

[1415] MS (ESI, m / z): 346.2 [M+H] + .

[1416] Preparation of compound 69

[1417]

[1418] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 69A (60 mg, 0.17 mmol) and 2A (52 mg, 0.15 mmol) to obtain 20 mg of compound 69.

[1419] MS (ESI, m / z): 669.2, 671.2[M+H] + .

[1420] 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).

[1421] Example 70:

[1422] Preparation of intermediate 70A

[1423]

[1424] Compound 70A-1:

[1425] According to the method for preparing compound 63A-2 from 63A-1 in Example 63, the raw material was replaced with cyclopropylcarboxaldehyde (230 mg, 3.3 mmol) to prepare 430 mg of compound 70A-1.

[1426] MS (ESI, m / z): 384.2 [M+H] + .

[1427] Intermediate 70A:

[1428] According to the method for preparing compound 1C from 1C-9 in Example 1, the starting material was replaced with 70A-1 (150 mg, 0.39 mmol) to prepare 120 mg of compound 70A.

[1429] MS (ESI, m / z): 354.2 [M+H] + .

[1430] Preparation of compound 70

[1431]

[1432] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting material was replaced with 70A (120 mg, 0.34 mmol) to prepare 55 mg of compound 69.

[1433] MS (ESI, m / z): 729.2, 731.2[M+H] + .

[1434] 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).

[1435] Example 71:

[1436] Preparation of compound 71

[1437]

[1438] Compound 71:

[1439] According to the method of preparing compound 37 in Example 34 in Example 37, the starting material was replaced with 57 (133 mg, 0.17 mmol) to prepare 12 mg of compound 71.

[1440] MS (ESI, m / z): 620.1.1, 622.1[M+H] + .

[1441] 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).

[1442] Example 72:

[1443] Preparation of compound 72

[1444]

[1445] 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 solution and stirred at room temperature for 2 hours. After LCMS monitoring showed that the starting material disappeared, water (10 mL) was added to the reaction solution to quench the mixture. The mixed solution was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined. The organic phases were first washed with saturated brine (30 mL × 3 times), then 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 98 mg of compound 72.

[1446] MS (ESI, m / z): 662.2, 664.2[M+H] + .

[1447] 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).

[1448] Example 73:

[1449] Preparation of intermediate 73A

[1450]

[1451] Compound 73A-1:

[1452] Compound 6A-4 (200 mg, 0.73 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic anhydride (766 mg, 3.65 mmol) was added to the reaction solution and stirred at room temperature for 1 hour. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain 250 mg of compound 73A-1.

[1453] MS (ESI, m / z): 371.2 [M+H] + .

[1454] Compound 73A-2:

[1455] According to the method for preparing compound 11A-1 from 9A-4 in Example 11, the starting material was replaced with 73A-1 (168 mg, 0.45 mmol) to prepare 93 mg of compound 73A-2.

[1456] MS (ESI, m / z): 357.1 [M+H] + .

[1457] Intermediate 73A:

[1458] According to the method for preparing compound 1C from 1C-9 in Example 1, the starting material was replaced with 73A-2 (93 mg, 0.26 mmol) to prepare 70 mg of compound 73A.

[1459] MS (ESI, m / z): 327.2 [M+H] + .

[1460] Preparation of compound 73

[1461]

[1462] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 73A (70 mg, 0.21 mmol) and 2A (77 mg, 0.21 mmol) to obtain 43 mg of compound 73.

[1463] MS (ESI, m / z): 650.2, 652.2[M+H] + .

[1464] 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).

[1465] 19 F NMR (282MHz, CDCl3) δ-70.35.

[1466] Example 74:

[1467] Preparation of intermediate 74A

[1468]

[1469] Compound 74A-1:

[1470] Compound 33A-5 (500 mg, 2.28 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1042 mg, 2.74 mmol) was added to the reaction solution, and stirring was continued at room temperature for 30 minutes. Cyclopropylamine (196 mg, 3.42 mmol) and diisopropylethylamine (738 mg, 5.71 mmol) were added to the reaction solution, and stirring was continued at room temperature for 3 hours. After LCMS monitoring showed the disappearance of the starting material, water (30 mL) was added to the reaction solution to quench the mixture. The mixed solution was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined, washed with saturated brine (30 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1) to obtain 500 mg of compound 74A-1.

[1471] MS (ESI, m / z): 258.0, 260.0[M+H] + .

[1472] Compound 74A-2:

[1473] Under a nitrogen atmosphere, compound 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), and then methanesulfonic acid (tri-tert-butylphosphino) (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 solution. The reaction system was heated to 50°C and stirred for 4 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 = 15 / 1) to give 700 mg of compound 74A-2.

[1474] MS (ESI, m / z): 349.2 [M+H] + .

[1475] Compound 74A-3:

[1476] Compound 74A-2 (680 mg, 1.95 mmol) was dissolved in N,N-dimethylformamide (10 mL), and anhydrous potassium carbonate (1079 mg, 7.81 mmol) was added to the reaction solution. The reaction system was heated to 100°C and stirred for 3 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was cooled to room temperature and quenched by adding water (50 mL). The mixed solution was extracted with ethyl acetate (30 mL × 3 times), and the organic phases were combined, washed with saturated brine (30 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 15 / 1) to obtain 230 mg of compound 74A-3.

[1477] MS (ESI, m / z): 329.2 [M+H] + .

[1478] Compound 74A-4:

[1479] According to the method for preparing compound 11A-1 from 9A-4 in Example 11, the starting material was replaced with 74A-3 (240 mg, 0.73 mmol) to prepare 110 mg of compound 74A-4.

[1480] MS (ESI, m / z): 315.2 [M+H] + .

[1481] Compound 74A:

[1482] According to the method for preparing compound 1C from 1C-9 in Example 1, the starting material was replaced with 74A-4 (110 mg, 0.35 mmol) to prepare 80 mg of compound 74A.

[1483] MS (ESI, m / z): 285.3 [M+H] + .

[1484] Preparation of Compound 74

[1485]

[1486] According to the method of preparing compound 1 using 1B and 1C in Example 1, the starting material was replaced with 74A (70 mg, 0.25 mmol) to prepare 15 mg of compound 74.

[1487] MS (ESI, m / z): 660.2, 662.2[M+H] + .

[1488] 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).

[1489] Example 75:

[1490] Preparation of compound 75

[1491]

[1492] Compound 75A:

[1493] According to the method for preparing compound 56 in Example 56C, the starting material was replaced with tert-butyl 4-methanesulfonyloxypiperidine-1-carboxylate (281 mg, 1.01 mmol) to prepare 250 mg of compound 75A.

[1494] MS (ESI, m / z): 779.4, 781.4[M+H] + .

[1495] Compound 75:

[1496] According to the method for preparing compound 63A-1 in Example 63, the raw material was replaced with formaldehyde aqueous solution (37%, 177 mg, 2.18 mmol) to prepare 7 mg of compound 75.

[1497] MS (ESI, m / z): 693.4, 695.4[M+H] + .

[1498] 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).

[1499] Example 76:

[1500] Preparation of intermediate 76A

[1501]

[1502] Compound 76A-1:

[1503] Under a nitrogen atmosphere, compound 1B-2 (5 g, 22.81 mmol) was dissolved in toluene (125 mL), and then Lawesson reagent (18.45 g, 45.62 mmol) was added to the reaction solution. 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 solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain 3 g of compound 76A-1.

[1504] MS (ESI, m / z): 238.2 [M+H] + .

[1505] Compound 76A:

[1506] According to the method for preparing compound 1B using 1B-2 in Example 1, the starting material was replaced with 76A-1 (3 g, 12.64 mmol) to prepare 2 g of compound 76A.

[1507] MS (ESI, m / z): 428.0, 430.0[M+H] + .

[1508] Preparation of Compound 76

[1509]

[1510] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 76A (109 mg, 0.25 mmol) and 47A (87 mg, 0.25 mmol) to prepare 2 mg of compound 76.

[1511] MS (ESI, m / z): 733.2, 735.2[M+H] + .

[1512] 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).

[1513] Example 77:

[1514] Preparation of compounds 77A and 77B

[1515]

[1516] According to the method for preparing compound 56 in Example 56C, the starting material was replaced with 3-bromobutylene oxide (103 mg, 0.75 mmol) to prepare 6 mg of compound 77A and 4 mg of compound 77B.

[1517] 77A: MS (ESI, m / z): 652.2, 654.2[M+H] + .

[1518] 77B: MS (ESI, m / z): 652.2, 654.2[M+H] + .

[1519] 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), 5.43-5.3 4 (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).

[1520] 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).

[1521] Example 78:

[1522] Preparation of Compound 78

[1523]

[1524] According to the method for preparing compound 72 from 71 in Example 72, the starting 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.

[1525] MS (ESI, m / z): 610.2, 612.2[M+H] + .

[1526] 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).

[1527] Example 79:

[1528] Preparation of compound 79

[1529]

[1530] According to the method for preparing compound 72 from 71 in Example 72, 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.

[1531] MS (ESI, m / z): 583.2, 585.2[M+H] + .

[1532] 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).

[1533] Example 80:

[1534] Preparation of Compound 80

[1535]

[1536] According to the method for preparing compound 72 from 71 in Example 72, 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.

[1537] MS (ESI, m / z): 635.2, 637.2[M+H] + .

[1538] 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).

[1539] Example 81:

[1540] Preparation of Intermediate 81A

[1541]

[1542] Compound 81A-1:

[1543] According to the method for preparing compound 1C from 1C-9 in Example 1, the starting material was replaced with 35A (2.4 g, 6.3 mmol) to prepare 2 g of compound 81A-1.

[1544] MS (ESI, m / z): 351.1, 353.1[M+H] + .

[1545] Compound 81A:

[1546] According to the method for preparing compound 32C in Example 32, the starting material was replaced with 81A-1 (590 mg, 1.68 mmol) to prepare 300 mg of compound 81A.

[1547] MS (ESI, m / z): 429.0, 431.0[M+H] + .

[1548] Preparation of Compound 81

[1549]

[1550] Compound 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 system was heated to 85° C. and stirred for 16 hours. After LCMS 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 obtain 40 mg of compound 81.

[1551] MS (ESI, m / z): 638.1, 640.1[M+H] + .

[1552] 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).

[1553] Example 82:

[1554] Preparation of Compound 82

[1555]

[1556] According to the method for preparing compound 72 from 71 in Example 72, the starting material was replaced with compound 52 (85 mg, 0.14 mmol) to prepare 20 mg of compound 82.

[1557] MS (ESI, m / z): 663.2, 665.2[M+H] + .

[1558] 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), 4.5 9-4.43 (m, 1H), 3.83 (s, 3H), 3.72 (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).

[1559] Example 83:

[1560] Preparation of compound 83

[1561]

[1562] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 44A (126 mg, 0.35 mmol) and 6A (100 mg, 0.35 mmol) to obtain 33 mg of compound 83.

[1563] MS (ESI, m / z): 611.2, 613.2[M+H] + .

[1564] 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).

[1565] Example 84:

[1566] Preparation of intermediate 84A

[1567]

[1568] Compound 84A-1:

[1569] According to the method for preparing compound 47A-1 from 10A-1 in Example 47, the raw material was replaced with tert-butyl 3-oxopiperidine-1-carboxylate (1693 mg, 8.5 mmol) to prepare 500 mg of compound 84A-1.

[1570] MS (ESI, m / z): 458.1 [M+H] + .

[1571] Compound 84A-2:

[1572] According to the method of preparing compound 63A-1 in Example 63, the raw material was replaced with formaldehyde aqueous solution (40%, 82 mg, 1.1 mmol) to prepare 80 mg of compound 84A-2.

[1573] MS (ESI, m / z): 372.2 [M+H] + .

[1574] Intermediate 84A:

[1575] According to the method for preparing compound 1C from 1C-9 in Example 1, the starting material was replaced with 84A-2 (80 mg, 0.22 mmol) to prepare 45 mg of compound 84A.

[1576] MS (ESI, m / z): 342.2 [M+H] + .

[1577] Preparation of compound 84

[1578]

[1579] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting material was replaced with 84A (70 mg, 0.21 mmol) to prepare 8 mg of compound 84.

[1580] MS (ESI, m / z): 717.2, 719.2[M+H] + .

[1581] 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).

[1582] Example 85:

[1583] Preparation of compound 85

[1584]

[1585] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 6A (100 mg, 0.35 mmol) and 5A (109 mg, 0.31 mmol) to obtain 46 mg of compound 85.

[1586] MS (ESI, m / z): 598.3 [M+H] + .

[1587] 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).

[1588] Example 86:

[1589] Preparation of intermediate 86A

[1590]

[1591] Compound 86A-1:91

[1592] 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.

[1593] MS (ESI, m / z): 212.1 [M+H] + .

[1594] Compound 86A-2:

[1595] According to the method of preparing compound 24B-1 from 1C-2 in Example 24, the raw material was replaced with 86A-1 (3 g, 14.2 mmol) to prepare 3.81 g of compound 86A-2.

[1596] MS (ESI, m / z): 290.0, 292.0[M+H] + .

[1597] Compound 86A-3:

[1598] According to the method for preparing compound 1A from 1A-1 in Example 1, the starting material was replaced with 86A-2 (5.3 g, 18.3 mmol) to prepare 3.54 g of compound 86A-3.

[1599] MS (ESI, m / z): 338.3 [M+H] + .

[1600] Compound 86A-4:

[1601] 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.

[1602] MS (ESI, m / z): 364.1 [M+H] + .

[1603] Compound 86A-5:

[1604] According to the method for preparing compound 51B-6 from 51B-5 in Example 51, the raw material was replaced with 86A-4 (1.7 g, 4.68 mmol) to prepare 1.6 g of compound 86A-5.

[1605] MS (ESI, m / z): 350.3 [M+H] + .

[1606] Compound 86A-6:

[1607] According to the method for preparing compound 51B-7 from 51B-6 in Example 51, the raw material was replaced with 86A-5 (1.72 g, 4.92 mmol) to prepare 1.4 g of compound 86A-6.

[1608] MS (ESI, m / z): 332.3 [M+H] + .

[1609] Compound 86A-7:

[1610] According to the method for preparing compound 11A-1 from 9A-4 in Example 11, the starting material was replaced with 86A-6 (1.4 g, 4.23 mmol) to prepare 1.3 g of compound 86A-7.

[1611] MS (ESI, m / z): 318.1 [M+H] + .

[1612] Compound 86A:

[1613] According to the method for preparing compound 1C from 1C-9 in Example 1, the starting material was replaced with 86A-7 (1.35 g, 4.25 mmol) to prepare 0.9 g of compound 86A.

[1614] MS (ESI, m / z): 288.2 [M+H] + .

[1615] Preparation of Compound 86

[1616]

[1617] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 86A (75 mg, 0.26 mmol) and 81A (112 mg, 0.26 mmol) to prepare 56 mg of compound 86.

[1618] MS (ESI, m / z): 680.2, 682.2[M+H] + .

[1619] 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).

[1620] Example 87:

[1621] Preparation of intermediate 87A

[1622]

[1623] Compound 87A-1:

[1624] According to the method for preparing compound 47A-1 from 10A-1 in Example 47, the starting material was replaced with tetrahydropyrone (204 mg, 2.04 mmol) to prepare 163 mg of compound 87A-1.

[1625] MS (ESI, m / z): 359.2 [M+H] + .

[1626] Intermediate 87A:

[1627] According to the method for preparing compound 1C from 1C-9 in Example 1, the starting material was replaced with 87A-1 (163 mg, 0.46 mmol) to prepare 130 mg of compound 87A.

[1628] MS (ESI, m / z): 329.3 [M+H] + .

[1629] Preparation of Compound 87

[1630]

[1631] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 87A (50 mg, 0.15 mmol) and 2A (55 mg, 0.15 mmol) to obtain 26 mg of compound 87.

[1632] MS (ESI, m / z): 652.2, 654.2[M+H] + .

[1633] 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).

[1634] Example 88:

[1635] Preparation of Compound 88

[1636]

[1637] According to the method of preparing compound 1 using 1B and 1C in Example 1, the starting material was replaced with 87A (50 mg, 0.15 mmol) to prepare 45 mg of compound 88.

[1638] MS (ESI, m / z): 704.2, 706.2[M+H] + .

[1639] 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), 3.5 5-3.40(m, 4H), 3.03-2.93(m, 2H), 2.18(s, 3H), 2.13(s, 3H), 2.00-1.83(m, 4H).

[1640] Example 89:

[1641] Preparation of compound 89

[1642]

[1643] Compound 89A:

[1644] According to the method for preparing compound 72 from 71 in Example 72, the raw materials were replaced with compound 52 (150 mg, 0.24 mmol) and tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (102 mg, 0.48 mmol) to prepare 88 mg of compound 89A.

[1645] MS (ESI, m / z): 815.2, 817.2[M+H] + .

[1646] Compound 89:

[1647] According to the method of preparing compound 63A-2 from 63A-1 in Example 63, the starting material was replaced with 89A (50 mg, 0.06 mmol) to prepare 16 mg of compound 89.

[1648] MS (ESI, m / z): 729.2, 731.2[M+H] + .

[1649] 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).

[1650] Example 90:

[1651] Preparation of Compound 90

[1652]

[1653] According to the method of preparing compound 63A-2 from 63A-1 in Example 63, the starting materials were replaced with 89A (50 mg, 0.06 mmol) and acetone (11 mg, 0.14 mmol) to prepare 4 mg of compound 90.

[1654] MS (ESI, m / z): 757.2, 759.2[M+H] + .

[1655] 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).

[1656] Example 91: Preparation of Intermediate 91A

[1657]

[1658] Compound 90A-1:

[1659] 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 solution of vinylmagnesium bromide in tetrahydrofuran (1 M, 68 mL, 68 mmol) was added to the reaction solution and stirred at this temperature for 1 hour. After LCMS monitoring showed the disappearance of the starting material, 1N hydrochloric acid (100 mL) was added to the reaction solution to quench the mixture. The mixed solution was extracted with ethyl acetate (150 mL × 3 times), and the organic phases were combined, washed with saturated brine (150 mL × 3 times), then 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 obtain 1.1 g of compound 90A-1.

[1660] MS (ESI) M / Z: 147.3 [M+H] + .

[1661] Compound 91A-2:

[1662] Compound 91A-1 (1.4 g, 9.58 mmol) was dissolved in ethanol (10 mL), and 2,4-dimethoxybenzylamine (1.92 g, 11.45 mmol) was added to the reaction solution. The reaction system was heated to 90°C and stirred for 4 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 obtain 2 g of compound 91A-2.

[1663] MS (ESI) M / Z: 314.1 [M+H] + .

[1664] Compound 91A-3:

[1665] 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 solution at 0°C and continued to stir at this temperature for 1 hour. After LCMS monitoring showed that the starting material disappeared, water (0.1 mL), 15% aqueous sodium hydroxide solution (0.1 mL) and water (0.3 mL) were added to the reaction solution to quench the mixture. The reaction solution was continued to stir 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.

[1666] MS (ESI) M / Z: 270.1 [M+H]+ .

[1667] Compound 91A-4:

[1668] According to the method for preparing compound 1B-2 from 1B-1 in Example 1, the starting material was replaced with 91A-3 (220 mg, 0.82 mmol) to prepare 200 mg of compound 91A-4.

[1669] MS (ESI, m / z): 413.1 [M+H] + .

[1670] Intermediate 91A:

[1671] According to the method for preparing compound 1B from 1B-2 in Example 1, the starting material was replaced with 91A-4 (150 mg, 0.36 mmol) to prepare 78 mg of compound 91A.

[1672] MS (ESI, m / z): 603.1, 605.1[M+H] + .

[1673] Preparation of Compound 91

[1674]

[1675] Compound 91B:

[1676] According to the method for preparing compound 1 from 1B and 1C in Example 1, the starting materials were replaced with 91A (78 mg, 0.13 mmol) and 6A (37 mg, 0.13 mmol) to prepare 50 mg of compound 91B.

[1677] MS (ESI, m / z): 853.4, 855.4[M+H] + .

[1678] Compound 91C:

[1679] According to the method of preparing compound 37 in Example 34, the starting material was replaced with 91B (50 mg, 0.06 mmol) to prepare 35 mg of compound 91C.

[1680] MS (ESI, m / z): 703.3, 705.3[M+H] + .

[1681] Compound 91:

[1682] According to the method for preparing compound 72 from 71 in Example 72, 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.

[1683] MS (ESI, m / z): 717.2, 719.2[M+H] + .

[1684] 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).

[1685] Example 92:

[1686] Preparation of intermediate 92

[1687]

[1688] Compound 92A-1:

[1689] 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), and copper powder (5.80 g, 91.35 mmol) was then added to the reaction solution. 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 solution was cooled to room temperature and quenched by adding water (500 mL). The mixture was extracted with ethyl acetate (200 mL × 3 times), and the organic phases were combined, washed with saturated brine (200 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / methyl tert-butyl ether = 1 / 1) to obtain 6.22 g of compound 92A-1.

[1690] MS (ESI) M / Z: 205.3 [M+H] + .

[1691] Compound 92A-2:

[1692] Compound 92A-1 (2.95 g, 14.45 mmol) was dissolved in acetonitrile (50 mL), and N-bromosuccinimide (5.66 g, 31.79 mmol) was added to the reaction mixture. The reaction system was heated to 50°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 concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / methyl tert-butyl ether = 1 / 1) to obtain 3.26 g of compound 92A-2.

[1693] MS(ESI)M / Z: 283.0, 285.0[M+H] + .

[1694] Compound 92A-3:

[1695] According to the method for preparing compound 91A-3 from 91A-2 in Example 91, the raw material was replaced with 92A-2 (3.76 g, 13.28 mmol) to prepare 1.6 g of compound 92A-3.

[1696] MS (ESI, m / z): 241.0, 243.0[M+H] + .

[1697] Compound 92A-4:

[1698] Compound 92A-3 (1.8 g, 7.47 mmol) and pyridine (1.3 g, 16.430 mmol) were dissolved in acetonitrile (15 mL), and trifluoromethanesulfonic anhydride (4.21 g, 14.97 mmol) was then added dropwise to the reaction mixture at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 hour before the addition of aqueous ammonia (12 mL). The reaction mixture was heated to 50°C and stirred for 16 hours. LCMS monitoring indicated the disappearance of the starting material. The reaction mixture 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. Water (80 mL) was added to the reaction mixture to quench the mixture. The mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / methyl tert-butyl ether = 1 / 1) to afford 1.6 g of compound 92A-4.

[1699] MS(ESI)M / Z: 340.0, 342.0[M+H] + .

[1700] Compound 92A-5:

[1701] 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.

[1702] MS (ESI, m / z): 431.2 [M+H] + .

[1703] Compound 92A-6:

[1704] According to the method for preparing compound 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.

[1705] MS (ESI, m / z): 311.0 [M+H] + .

[1706] Intermediate 92A:

[1707] According to the method for preparing compound 1C from 1C-9 in Example 1, the starting material was replaced with 92A-6 (120 mg, 0.39 mmol) to prepare 100 mg of compound 92A.

[1708] MS (ESI, m / z): 281.1 [M+H] + .

[1709] Preparation of compound 92

[1710]

[1711] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 92A (100 mg, 0.36 mmol) and 2A (129 mg, 0.36 mmol) to prepare 38 mg of compound 92.

[1712] MS (ESI, m / z): 604.1, 606.1[M+H] + .

[1713] 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).

[1714] 19 F NMR (282MHz, CDCl3) δ-92.73.

[1715] Example 93:

[1716] Preparation of compound 93

[1717]

[1718] Compound 93A:

[1719] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 16A (48 mg, 0.19 mmol) and 76A (100 mg, 0.23 mmol) to prepare 50 mg of compound 93A.

[1720] MS (ESI, m / z): 636.2, 638.2[M+H] + .

[1721] Compound 93B:

[1722] According to the method for preparing compound 72 from 71 in Example 72, the raw materials were replaced with compound 93A (50 mg, 0.08 mmol) and tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (33 mg, 0.16 mmol) to prepare 62 mg of compound 93B.

[1723] MS (ESI, m / z): 831.2, 833.2[M+H] + .

[1724] Compound 93:

[1725] According to the method of preparing compound 63A-2 from 63A-1 in Example 63, the starting material was replaced with 93B (62 mg, 0.08 mmol) to prepare 7 mg of compound 93.

[1726] MS (ESI, m / z): 745.2, 747.2[M+H]+ .

[1727] 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).

[1728] Example 94:

[1729] Preparation of Compound 94

[1730]

[1731] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 6A (70 mg, 0.24 mmol) and 7A (72 mg, 0.24 mmol) to prepare 20 mg of compound 94.

[1732] MS (ESI, m / z): 546.3 [M+H] + .

[1733] 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).

[1734] Example 95:

[1735] Preparation of Compound 95

[1736]

[1737] Compound 95A:

[1738] According to the method for preparing 1B from 1B-2 in Example 1, the starting 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.

[1739] MS (ESI, m / z): 366.9, 368.9[M+H] + .

[1740] Compound 95B:

[1741] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 6A (100 mg, 0.35 mmol) and 95A (128 mg, 0.35 mmol) to prepare 65 mg of compound 95B.

[1742] MS (ESI, m / z): 617.1, 619.1[M+H] + .

[1743] Compound 95:

[1744] According to the method of preparing compound 1B-2 from 1B-1 in Example 1, the starting material was replaced with 95B (60 mg, 0.1 mmol) to prepare 20 mg of compound 95.

[1745] MS (ESI, m / z): 567.2, 569.2[M+H] + .

[1746] 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).

[1747] Example 96:

[1748] Preparation of intermediate 96A

[1749]

[1750] Compound 96A-1:

[1751] According to the method for preparing compound 47A-1 from 10A-1 in Example 47, the raw material was replaced with N-tert-butyloxycarbonyl-4-piperidone (1.35 g, 6.8 mmol) to prepare 0.9 g of compound 96A-1.

[1752] MS (ESI, m / z): 458.3 [M+H] + .

[1753] Compound 96A:

[1754] According to the method for preparing compound 1C from 1C-9 in Example 1, the starting material was replaced with 96A-1 (900 mg, 1.97 mmol) to prepare 750 mg of compound 96A.

[1755] MS (ESI, m / z): 427.1 [M+H] + .

[1756] Preparation of Compound 96

[1757]

[1758] Compound 96B:

[1759] According to the method for preparing compound 81 from 81A and 51B in Example 81, the starting materials were replaced with 96A (100 mg, 0.23 mmol) and 1B (106 mg, 0.26 mmol) to prepare 65 mg of compound 96B.

[1760] MS (ESI, m / z): 803.4, 805.4[M+H] + .

[1761] Compound 96:

[1762] According to the method of preparing compound 63A-2 from 63A-1 in Example 63, the starting 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.

[1763] MS (ESI, m / z): 793.2, 795.2[M+H] + .

[1764] 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).

[1765] Compound 97:

[1766] Preparation of Compound 97

[1767]

[1768] Compound 97A:

[1769] According to the method of preparing 1B from 1B-2 in Example 1, the starting material was replaced with 4-amino-3-iodopyridine (500 mg, 2.27 mmol) to prepare 130 mg of compound 97A.

[1770] MS (ESI, m / z): 410.8, 412.8[M+H] + .

[1771] Compound 97B:

[1772] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 6A (91 mg, 0.32 mmol) and 97A (130 mg, 0.32 mmol) to prepare 71 mg of compound 97B.

[1773] MS (ESI, m / z): 661.0, 663.0[M+H] + .

[1774] Compound 97:

[1775] According to the method of preparing compound 1B-2 from 1B-1 in Example 1, the starting material was replaced with 97B (70 mg, 0.11 mmol) to prepare 23 mg of compound 97.

[1776] MS (ESI, m / z): 611.2, 613.2[M+H] + .

[1777] 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).

[1778] Example 98:

[1779] Preparation of Compound 98

[1780]

[1781] Compound 98A:

[1782] According to the method of preparing compound 1 according to 1B and 1C in Example 1, the starting material was replaced with 56A (300 mg, 0.76 mmol) to prepare 336 mg of compound 98A.

[1783] MS (ESI, m / z): 768.2, 770.2[M+H] + .

[1784] Compound 98B:

[1785] According to the method for preparing compound 37 in Example 37, the starting material was replaced with 98A (326 mg, 0.42 mmol) to prepare 265 mg of compound 98B.

[1786] MS (ESI, m / z): 648.0, 650.0[M+H] + .

[1787] Compound 98:

[1788] According to the method for preparing compound 56 in Example 56C, the starting materials were replaced with compound 98B (260 mg, 0.4 mmol) and 3-bromobutylene oxide (165 mg, 1.2 mmol) to prepare 50 mg of compound 98.

[1789] MS (ESI, m / z): 704.2, 706.2[M+H] + .

[1790] 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).

[1791] Compound 99:

[1792] Preparation of intermediate 99A

[1793]

[1794] Compound 99A-1:

[1795] Under nitrogen atmosphere, 2-methyl-3-bromopyridine (5g, 28.9mmol) is dissolved in tetrahydrofuran (80mL), then under -78 ℃ condition, slowly add diisopropylamine lithium tetrahydrofuran solution (2M, 14.5mmol, 29mmol) to the reaction solution and continue to stir at this temperature for 1 hour. In the reaction solution, N, N-dimethylformamide (2.11g, 28.9mmol) is added dropwise and continues to stir at this temperature for 30 minutes. After LCMS monitoring raw material disappears, methanol (30mL) is added to the reaction solution to quench. Subsequently, glacial acetic acid (1.74g, 28.9mmol) and sodium borohydride (1.31g, 34.68mmol) are added to the reaction solution, the reaction solution is warmed to room temperature and continued to stir for 10 minutes, saturated sodium bicarbonate aqueous solution (100mL) is added to the reaction solution to quench. The mixture was extracted with ethyl acetate (100 mL x 3 times), and the organic phases were combined, washed with saturated brine (100 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: petroleum ether / ethyl acetate = 1 / 1) to obtain 4.5 g of compound 99A-1.

[1796] MS (ESI, m / z): 201.8, 203.8[M+H] + .

[1797] Compound 99A-2:

[1798] According to the method for preparing compound 51A-1 from 40A-2 in Example 51, the starting material was replaced with 99A-1 (2 g, 9.89 mmol) to prepare 2.5 g of compound 99A-2.

[1799] MS (ESI, m / z): 330.9, 332.9[M+H] + .

[1800] Compound 99A-3:

[1801] Compound 99A-2 (2.5 g, 7.55 mmol) was dissolved in ethanol (30 mL), and hydrazine hydrate (1.51 g, 30.19 mmol) was added to the reaction solution. 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 solution was cooled to room temperature, 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 solution and stirred at room temperature for 16 hours. Water (80 mL) was added to the reaction solution to quench the mixture. The mixture was extracted with ethyl acetate (80 mL × 3 times), and the organic phases were combined, washed with saturated brine (80 mL × 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain 2.5 g of compound 99A-3.

[1802] MS (ESI, m / z): 300.9, 302.9[M+H] + .

[1803] Compound 99A-4:

[1804] According to the method of 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.

[1805] MS (ESI, m / z): 392.1 [M+H] + .

[1806] Compound 99A-5:

[1807] According to the method of preparing 42A-7 from 42A-6 in Example 42, the starting material was replaced with 99A-4 (700 mg, 1.78 mmol) to prepare 400 mg of compound 99A-5.

[1808] MS (ESI, m / z): 272.2 [M+H] + .

[1809] Compound 99A-6:

[1810] According to the method of preparing compound 8A-9 by using 8A-8 in Example 8, the starting material was replaced with 99A-5 (400 mg, 1.66 mmol) to prepare 230 mg of compound 99A-6.

[1811] MS (ESI, m / z): 286.3 [M+H] + .

[1812] Intermediate 99A:

[1813] According to the method for preparing compound 1C from 1C-9 in Example 1, the starting material was replaced with 99A-6 (230 mg, 0.81 mmol) to prepare 160 mg of compound 99A.

[1814] MS (ESI, m / z): 256.3 [M+H] + .

[1815] Preparation of Compound 99

[1816]

[1817] According to the method for preparing compound 1 from 1B and 1C in Example 1, the starting materials were replaced with 99A (35 mg, 0.14 mmol) and 2A (50 mg, 0.14 mmol) to prepare 20 mg of compound 99.

[1818] MS (ESI, m / z): 579.1, 581.1[M+H] + .

[1819] 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).

[1820] Example 100:

[1821] Preparation of Compound 100

[1822]

[1823] Compound 100A:

[1824] According to the method for preparing 2A in Example 2, the starting materials were replaced with 44A-1 (1 g, 5.88 mmol) and 2,4,5-trichloropyrimidine (2.16 g, 11.75 mmol) to prepare 75 mg of compound 100A.

[1825] MS (ESI, m / z): 317.2, 319.2[M+H] + .

[1826] Compound 100:

[1827] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 100A (70 mg, 0.22 mmol) and 6A (63 mg, 0.22 mmol) to prepare 20 mg of compound 100.

[1828] MS (ESI, m / z): 567.2, 569.2[M+H] + .

[1829] 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).

[1830] Example 101:

[1831] Preparation of Intermediate 101A

[1832]

[1833] Compound 101A-1:

[1834] According to the method of preparing compound 76A-1 in 1B-2 in Example 76, the raw material was replaced with 2-(dimethylphosphino)aniline (5 g, 29.6 mmol) to prepare 770 mg of compound 101A-1.

[1835] MS (ESI, m / z): 186.2 [M+H] + .

[1836] Intermediate 101A:

[1837] According to the method for preparing compound 2A from 2-(dimethylphosphinooxy)aniline in Example 2, the starting material was replaced with 101A-1 (770 mg, 4.16 mmol) to prepare 330 g of compound 101A.

[1838] MS (ESI, m / z): 376.0, 378.0[M+H] + .

[1839] Preparation of Compound 101

[1840]

[1841] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 101A (80 mg, 0.22 mmol) and 47A (76 mg, 0.22 mmol) to obtain 88 mg of compound 101.

[1842] MS (ESI, m / z): 681.2, 683.2[M+H] + .

[1843] 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).

[1844] Example 102:

[1845] Preparation of Compound 102

[1846]

[1847] According to the method for preparing compound 22 in Example 22, the starting material was replaced with 27 (120 mg, 0.2 mmol) to prepare 30 mg of compound 102.

[1848] MS (ESI, m / z): 532.3 [M+H] + .

[1849] 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).

[1850] Example 103:

[1851] Preparation of Intermediate 103A

[1852]

[1853] According to the method for preparing 1B from 1B-2 in Example 1, the starting 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. MS (ESI, m / z): 337.0, 339.0 [M+H] + .

[1854] Preparation of Compound 103

[1855]

[1856] Compound 103B:

[1857] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 103A (150 mg, 0.46 mmol) and 6A (127 mg, 0.46 mmol) to prepare 100 mg of compound 103B.

[1858] MS (ESI, m / z): 587.0, 589.0[M+H] + .

[1859] Compound 103C:

[1860] According to the method of preparing 1C from intermediate 1C-9 in Example 1, the starting material was replaced with 103B (100 mg, 0.17 mmol) to prepare 80 mg of compound 103C.

[1861] MS (ESI, m / z): 557.3, 559.3[M+H] + .

[1862] Compound 103:

[1863] According to the method of preparing 32 from intermediate 32C in Example 32, the starting material was replaced with 103C (50 mg, 0.09 mmol) to prepare 20 mg of compound 103.

[1864] MS (ESI, m / z): 635.3, 637.3[M+H] + .

[1865] 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).

[1866] Example 104:

[1867] Preparation of Intermediate 104A

[1868]

[1869] According to the method of preparing 1B from 1B-2 in Example 1, the starting 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.

[1870] MS (ESI, m / z): 317.2, 319.2[M+H] + .

[1871] Preparation of Compound 104

[1872]

[1873] Compound 104B:

[1874] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting materials were replaced with 104A (100 mg, 0.32 mmol) and 6A (90 mg, 0.32 mmol) to prepare 80 mg of compound 104B.

[1875] MS (ESI, m / z): 567.3 [M+H] + .

[1876] Compound 104C:

[1877] According to the method of preparing 1C from intermediate 1C-9 in Example 1, the starting material was replaced with 104B (75 mg, 0.13 mmol) to prepare 65 mg of compound 104C.

[1878] MS (ESI, m / z): 536.8 [M+H] + .

[1879] Compound 104:

[1880] According to the method of preparing 32 from intermediate 32C in Example 32, the starting material was replaced with 104C (50 mg, 0.09 mmol) to prepare 20 mg of compound 104.

[1881] MS (ESI, m / z): 615.4 [M+H] + .

[1882] 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).

[1883] Example 105:

[1884] Preparation of compound 105

[1885]

[1886] Compound 105A:

[1887] According to the method for preparing compound 81 using 81A and 51B in Example 81, the starting materials were replaced with 96A (227 mg, 0.53 mmol) and 101A (200 mg, 0.53 mmol) to prepare 146 mg of compound 105A.

[1888] MS (ESI, m / z): 767.2, 769.2[M+H] + .

[1889] Compound 105:

[1890] According to the method of preparing compound 63A-2 from 63A-1 in Example 63, the starting material was replaced with 105A (70 mg, 0.09 mmol) to prepare 8 mg of compound 105.

[1891] MS (ESI, m / z): 709.3, 711.3[M+H] + .

[1892] 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).

[1893] Example 106:

[1894] Preparation of Compound 106

[1895]

[1896] According to the method of preparing 32 from intermediate 32C of Example 32, the starting 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.

[1897] MS (ESI, m / z): 643.2, 645.2[M+H] + .

[1898] 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).

[1899] Example 107:

[1900] Preparation of Compound 107

[1901]

[1902] According to the method for preparing compound 72 from 71 in Example 72, 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.

[1903] MS (ESI, m / z): 652.1, 654.1[M+H] + .

[1904] 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).

[1905] Example 108:

[1906] Preparation of Compound 108

[1907]

[1908] According to the method for preparing compound 1 using 1B and 1C in Example 1, the starting material was replaced with 99A (80 mg, 0.31 mmol) to obtain 40 mg of compound 108.

[1909] MS (ESI, m / z): 631.1, 633.1[M+H] + .

[1910] 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).

[1911] Example 109:

[1912] Preparation of Intermediate 109A

[1913]

[1914] Compound 109A-1:

[1915] Compound 1B-1 (6.9 g, 25.46 mmol) and triethylamine (12.88 g, 127.28 mmol) were dissolved in methanol (100 mL), and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (1.86 g, 2.55 mmol) was added to the reaction solution. The reaction solution was charged with carbon monoxide (50 atm) and heated to 70°C and stirred for 16 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was cooled to room temperature and degassed, then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 10) to give 1.5 g of compound 109A-1.

[1916] MS (ESI) M / Z: 204.3 [M+H] + .

[1917] Intermediate 109A:

[1918] According to th...

Claims

1. A compound represented by formula (I'') or a pharmaceutically acceptable salt thereof, in, R1 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy; M is selected from N or CR a ; Z is selected from N or CR6; Z1 is selected from N or CR7; R a H, C 1-6 alkyl; Selected from R2 are each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C6 aryl 1-6 Alkyl or -(CH2) r NR c R d , r is arbitrarily selected from 1, 2 or 3; wherein, C in R2 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C6 aryl 1-6 Alkyl, optionally substituted with one or more C 1-3 Alkyl or C 1-3 Alkoxy substitution; R x Selected from H, -OH, -CN, -NH2, halogen, C 1-6 Alkylcarbonyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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; when R x When directly connected to a N atom, R x is not -OH, -NH2 or halogen; said 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-; R3 and R4 are each independently 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; Alternatively, R3 and R4 are cyclized to form a thienyl group; R5 is selected from substituted or unsubstituted -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(=S)R b R c 、-S(=O)2NR b R c , R b S(=O)2NR c -or-NR b C(O)R c ; R b , R c , R d Each independently selected from H, C 1-3 Alkyl, C 3-6 Cycloalkyl; R6, R7, R8 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy; Alternatively, R5 and R6 are cyclized to form Alternatively, R6 and R7 are cyclized to form a pyridine ring, a pyrimidine ring, a pyridazine ring or a pyrazine ring; Alternatively, R7 and R8 are cyclized to form an imidazole ring, a pyrazole ring or a pyrrole ring.

2. A compound as described in formula (I'') of claim 1 or a pharmaceutically acceptable salt thereof, wherein: M is selected from N or CR a , where R a H, C 1-3 alkyl.

3. A compound as described in formula (I'') of claim 1 or a pharmaceutically acceptable salt thereof, wherein: R b , R c , R d Each independently selected from H, C 1-3 alkyl.

4. A compound as described in formula (I'') of claim 1 or a pharmaceutically acceptable salt thereof, wherein: R8 is H.

5. A compound represented by formula (I') or a pharmaceutically acceptable salt thereof, in, R1 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy; M is selected from N or CR a ; Z is selected from N or CR6; R a H, C 1-3 alkyl; Selected from R2 are each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C6 aryl 1-6 alkyl; R x Selected from H, -OH, -CN, -NH2, halogen, C 1-6 Alkylcarbonyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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; when R x When directly connected to a N atom, R x is not -OH, -NH2 or halogen; said 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-; R3 and R4 are each independently 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; Alternatively, R3 and R4 are cyclized to form a thienyl group; R5 is selected from substituted or unsubstituted -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(=S)R b R c 、-S(=O)2NR b R c , R b S(=O)2NR c -; R b , R c , R d Each independently selected from H, C 1-3 Alkyl, C 3-6 Cycloalkyl; R6, R7, R8 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy; Alternatively, R6 and R7 are cyclized to form a pyridine ring, a pyrimidine ring, a pyridazine ring or a pyrazine ring; Alternatively, R7 and R8 are cyclized to form an imidazole ring, a pyrazole ring or a pyrrole ring.

6. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in, R1 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy; M is selected from N or CR a ; R a H, C 1-3 alkyl; Selected from R2 are each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; R x Selected from H, -OH, -CN, -NH2, halogen, C 1-6 Alkylcarbonyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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; when R x When directly connected to a N atom, R x is not -OH, -NH2 or halogen; said 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-; R3 and R4 are each independently 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; Alternatively, R3 and R4 are cyclized to form a thienyl group; R5 is selected from substituted or unsubstituted -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 - or R b N=S(=O)R c -; R b , R c , R d Each independently selected from H, C 1-3 Alkyl, C 3-6 Cycloalkyl; R6, R7, R8 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy; Alternatively, R6 and R7 are cyclized to form a pyridine ring, a pyrimidine ring, a pyridazine ring or a pyrazine ring; Alternatively, R7 and R8 are cyclized to form an imidazole ring, a pyrazole ring or a pyrrole ring.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from H, C 1-3 Alkyl, C 1-3 Alkoxy; M is selected from N or CH; R2 are each independently selected from H, C 1-4 Alkyl, -(CH2) r NR c R d , 3-6 membered heterocycloalkyl, C6 aryl 1-6 wherein r is arbitrarily selected from 1, 2 or 3, the 3-6 membered heterocycloalkyl, C6 aryl C 1-6 The alkyl group is optionally substituted with one or more C 1-3 Alkyl or C 1-3 Alkoxy substitution; R3 and R4 are each independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl; Alternatively, R3 and R4 are cyclized to form a thienyl group; 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 ; R b , R c , R d Each independently selected from H, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl; Alternatively, R5 and R6 are cyclized to form R6, R7, R8 are each independently selected from H, halogen, C 1-3 alkyl; Alternatively, R8 is selected from H, and R6 and R7 are cyclized to form a pyrimidinyl, pyridinyl, pyrazinyl or pyridazinyl group.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R1 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein said R1 is selected from methoxy.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R2 is selected from H, methyl, ethyl, isopropyl, -CH2CH2N(CH3)CH3, 11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein said R2 is selected from methyl.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R3 and R4 are each independently selected from H, F, Cl, Br, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and cyclopropyl.

13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R3 is selected from H, and R4 is selected from Br.

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R3 and R4 are cyclized to form a thiophene ring.

15. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R5 is selected from 16. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein said R5 is selected from 17. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R6, R7, and R8 are each independently selected from H, methyl or halogen; or, R6 and R8 are selected from H, and R7 is selected from F.

18. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R6 and R7 are independently cyclized to form a pyrazine ring.

19. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R y is selected from H, F, methyl, ethyl, isopropyl, methoxy, FCH2CH2-; in, When R x When directly connected to a N atom, R x Not -OH, -NH2 and halogen.

20. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein: R x Selected from H, -OH, -CN, -NH2, 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 1, or R y is selected from H, F, methyl, ethyl, isopropyl, methoxy, FCH2CH2-.

21. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R x Selected from H, -OH, -CN, -NH2, methyl, ethyl, isopropyl, methylcarbonyl, in, Ring C is a 4-8 membered heterocycloalkyl; m and n are independently 0, 1, 2 or 3; R y As defined in claim 1, or R y is selected from H, F, methyl, ethyl, isopropyl, methoxy, FCH2CH2-.

22. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R x Selected from H, -OH, -CN, -NH2, F, methyl, ethyl, isopropyl, trifluoroethyl, methylcarbonyl, 23. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R x Selected from methyl or isopropyl.

24. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from R1, M, R x as defined in claim 1; or The structural unit Selected from Among them, R1, M, R x , R b , R c , R2 as defined in claim 1; or The structural unit Selected from in, M, R1, R2, R x As defined in claim 1.

25. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from or in, R1, R2, R4, R5, R6, R7, R x As defined in claim 1; M, if present, is as defined in claim 1.

26. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from or in, R1, R2, R4, R5, R x As defined in claim 1; M, if present, is as defined in claim 1.

27. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from or in, R4, R5, R x As defined in claim 1; M, if present, is as defined in claim 1.

28. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from in, R5, R x As defined in claim 1.

29. A compound as shown below or a pharmaceutically acceptable salt thereof, selected from:

30. A pharmaceutical composition comprising the compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

31. Use of the compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 30 in the preparation of a drug for treating cancer.

32. The method of claim 31, wherein the cancer is selected from the group consisting of lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, melanoma, leukemia, gastric cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), bile duct cancer, renal cancer, thyroid cancer, mesothelioma, and multiple myeloma.

33. The use according to claim 31, wherein the cancer is lung cancer, non-Hodgkin's lymphoma, glioblastoma, acute myeloid leukemia (AML), anaplastic large cell lymphoma.

34. A compound represented by formula (V) or a pharmaceutically acceptable salt thereof, in, R 11 is -NH2 or -NO2; R1 is as defined in claim 1; M as defined in claim 1; Structural unit As defined in claim 5.

35. The compound of claim 34 or a pharmaceutically acceptable salt thereof, selected from, in, R1 is as defined in claim 1; R 11 As defined in claim 34; R2 as defined in claim 1; R x As defined in claim 1.

36. The compound of claim 35 or a pharmaceutically acceptable salt thereof, selected from, in, R 11 , R x As defined in claim 35.

37. Use of the compound according to any one of claims 34 to 36 or a pharmaceutically acceptable salt thereof in the preparation of the compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

Images