Compound with SMARCA2 inhibition effect and application thereof

Abstract

The present disclosure provides SMARCA2 inhibitors, pharmaceutical compositions and uses thereof, the compounds having a structure of formula (I), the compounds and pharmaceutical compositions may be used to prevent or treat diseases, conditions or disorders associated with SMARCA2. # imgabs0 #

Description

Technical Field

[0001] The present disclosure relates to compounds that inhibit SMARCA2 or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs thereof, methods for preparing the same and pharmaceutical compositions comprising the same, and the use of the compounds and pharmaceutical compositions for preventing or treating diseases, conditions or disorders associated with SMARCA2. Background Art

[0002] The SWI / SNF complex is one of the four major chromatin regulatory factor families. It uses the hydrolysis of ATP to regulate the sliding of DNA on histones, making the DNA compact and hindering transcription, or making the DNA loose and promoting transcription. Mutations in the subunits of SWI / SNF occur in various cancers.

[0003] SMARCA2 is a core member of the SWI / SNF complex and an ATPase subunit that can hydrolyze ATP to obtain energy to change and reshape the interaction between histones and DNA in nucleosomes, thereby affecting the degree of chromatin openness in specific regions of the genome, thereby regulating gene expression. SMARCA2 and SMARCA4 have independent functions. When SMARCA4 undergoes a LOF mutation, the gene transcription of SMARCA2 increases significantly. Under normal physiological functions, SMARCA2 participates in regulating DNA repair, replication, cell differentiation and other functions. When SMARCA4 LOF occurs, the genome becomes unstable and causes abnormal cell proliferation; SMARCA4 LOF mutation induces increased expression of proto-oncogenes and their target genes, which can promote the occurrence and development of tumors; when a single gene mutation occurs in SMARCA4, it will directly cause multiple types of tumors.

[0004] Targeting SMARCA2 has a clear mechanism of synthetic lethality for SMARCA4 LOF mutant cells and has high unmet clinical needs. It is necessary to develop new SMARCA2 inhibitors. SUMMARY OF THE INVENTION

[0006] The present disclosure provides new SMARCA2 inhibitors with the potential to prevent and treat related diseases, disorders or conditions. The compounds disclosed herein have improved pharmacokinetic properties (e.g., improved bioavailability, improved metabolic stability, suitable half-life and duration of action), improved safety (lower toxicity (e.g., reduced cardiotoxicity) and / or fewer side effects), less prone to drug resistance and other more excellent properties.

[0007] In one aspect, the present disclosure provides a compound of formula (I) as defined below:

[0008]

[0009] or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof.

[0010] In another aspect, the present disclosure provides the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof for use as a medicament, preferably a SMARCA2 inhibitor.

[0011] In another aspect, the present disclosure provides use of the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof in the preparation of a drug, preferably a SMARCA2 inhibitor.

[0012] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier.

[0013] In another aspect, the present disclosure provides a method for preventing or treating a disease, disorder or condition associated with SMARCA2 in an individual, wherein the method comprises: administering to the individual a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof; or administering to the individual a therapeutically effective amount of the pharmaceutical composition.

[0014] In another aspect, the present disclosure provides the use of the compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, or the pharmaceutical composition in the preparation of a medicament for preventing or treating a disease, disorder or condition associated with SMARCA2 in an individual.

[0015] In some embodiments, the disease, disorder or condition is a tumor (e.g., cancer), including solid tumors and hematological tumors. In some embodiments, the tumor or cancer is selected from non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal-gastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, hematological cancer, non-Hodgkin's lymphoma, small cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, central nervous system cancer, thymic tumor, adrenocortical carcinoma, appendix cancer, small intestine cancer, or penile cancer. DETAILED DESCRIPTION OF THE INVENTION

[0017] Compound

[0018] In one aspect, the present disclosure provides compounds of formula (I):

[0019]

[0020] or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof,

[0021] in,

[0022] Dashed lines indicate the presence or absence of a bond;

[0023] Indicates cis-trans, include

[0024] X 1 Selected from CH 2 , NH, O or S;

[0025] R 1 Selected from -C 1～8 Alkyl, -C 0～4 Alkylene-NHC 0～4 Alkyl, -C 0～4 Alkylene-C 3～8 Cycloalkyl, -C 0～4 Alkylene-3 to 8-membered heterocyclic group, -C 0～4 Alkylene-9-12 membered heterocyclic group; said R 1 The alkyl, heterocyclic, cycloalkyl and amino groups in the x Replace 1 to 3 times;

[0026] R 2 Selected from hydrogen, -C 1～6 Alkyl, -C0～3 Alkylene-C 3～6 Cycloalkyl, -C 0～3 Alkylene-3- to 6-membered heterocyclic group, aryl group and 5- to 6-membered heteroaryl group; the R 2 The alkyl, heterocyclic, cycloalkyl, aryl and heteroaryl groups in the x Replace 1 to 3 times;

[0027] R 3 are independently selected from halogen, cyano, oxo, hydroxyl, C 1～3 Alkyl, C 1～3 Alkoxy and C 1～3 Haloalkyl;

[0028] R 4 are independently selected from hydrogen, C 1～6 Alkyl, C 1～6 Haloalkyl, C 3～6 Cycloalkyl, 3-6 membered heterocyclic group, aryl and 5-6 membered heteroaryl; said R 4 The alkyl, heterocyclic, cycloalkyl, aryl and heteroaryl groups in the x Replace 1 to 3 times;

[0029] n is 0, 1, 2 or 3;

[0030] m is 0, 1, 2 or 3;

[0031] R x are independently selected from halogen, cyano, oxo, hydroxyl, amine, C 1～3 Alkyl, C 1～3 Alkoxy, -(C=O)OC 1～3 Alkyl and C 3～6 Cycloalkyl; said R x The alkyl, alkoxy and cycloalkyl groups in the above-mentioned groups may be optionally substituted by halogen for 1 to 3 times.

[0032] In some embodiments, R 1 Selected from -C 1～8 Alkyl, -C 0～4 Alkylene-NHC 0～4 Alkyl, -C 0～4 Alkylene-C 3～8 Cycloalkyl, -C 0～4 Alkylene-3 to 8-membered heterocyclic group, -C 0～4 Alkylene-9-12 membered heterocyclic group; said R 1 The alkyl, heterocyclic, cycloalkyl and amino groups in the x Replace 1 to 3 times.

[0033] In some embodiments, the present disclosure provides a compound of formula (I) as described above, wherein the compound of formula (I) is a compound of formula (Ii):

[0034]

[0035] or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof,

[0036] in,

[0037] represents a single or double bond;

[0038] Dashed lines indicate the presence or absence of a bond;

[0039] Indicates cis-trans, include

[0040] X 1 Selected from CH 2 , NH or S;

[0041] R 1 Selected from -C 1～8 Alkyl, -C 0～4 Alkylene-NHC 0～4 Alkyl, -C 0～4 Alkylene-C 3～8 Cycloalkyl, -C 0～4 Alkylene-3 to 8-membered heterocyclic group, -C 0～4 Alkylene-9-12 membered heterocyclic group; said R 1 The alkyl, heterocyclic, cycloalkyl and amino groups in the x Replace 1 to 3 times;

[0042] R 2 Selected from hydrogen, -C 1～6 Alkyl, -C 0～3 Alkylene-C 3～6 Cycloalkyl, -C 0～3 Alkylene-3 to 6-membered heterocyclic group; the R 2 The alkyl, heterocyclic and cycloalkyl groups in x Replace 1 to 3 times;

[0043] R 3 are independently selected from halogen, cyano, oxo, C 1～3 Alkyl and C 1～3 Haloalkyl;

[0044] R 4 are independently selected from hydrogen, C 1～3Alkyl, C 1～3 haloalkyl and cyclopropyl;

[0045] n is 0, 1, 2 or 3;

[0046] m is 0, 1, 2 or 3;

[0047] R x are independently selected from halogen, cyano, hydroxyl, amine, C 1～3 Alkyl, C 1～3 Alkoxy and C 3～6 Cycloalkyl; said R x The alkyl, alkoxy and cycloalkyl groups in the above-mentioned groups may be optionally substituted by halogen for 1 to 3 times.

[0048] In some preferred embodiments, R 1 Selected from -C 1～8 Alkyl, -C 0～4 Alkylene-NHC 0～4 Alkyl, -C 0～4 Alkylene-C 3～8 Cycloalkyl, -C 0～4 Alkylene-3 to 8-membered heterocyclic group; the R 1 The alkyl, heterocyclic, cycloalkyl and amino groups in the x Replace 1 to 3 times.

[0049] In other embodiments, the present disclosure provides a compound of formula (I) as described above, wherein the compound of formula (I) is a compound of formula (I-ii):

[0050]

[0051] in,

[0052] Indicates cis-trans, include

[0053] X 1 Selected from CH 2 , NH or S;

[0054] R 1 Selected from -C 1～8 Alkyl, -C 0～4 Alkylene-NHC 0～4 Alkyl, -C 0～4 Alkylene-C 3～8 Cycloalkyl, -C 0～4 Alkylene-3 to 8-membered heterocyclic group, -C 0～4 Alkylene-9-12 membered heterocyclic group; said R 1 The alkyl, heterocyclic, cycloalkyl and amino groups in thex Replace 1 to 3 times;

[0055] R 2 Selected from hydrogen, -C 1～6 Alkyl, -C 0～3 Alkylene-C 3～6 Cycloalkyl, -C 0～3 Alkylene-3- to 6-membered heterocyclic group, aryl group and 5- to 6-membered heteroaryl group; the R 2 The alkyl, heterocyclic, cycloalkyl, aryl and heteroaryl groups in the x Replace 1 to 3 times;

[0056] R 3 are independently selected from halogen, cyano, oxo, C 1～3 Alkyl and C 1～3 Haloalkyl;

[0057] R 4 are independently selected from hydrogen, C 1～3 Alkyl, C 1～3 haloalkyl and cyclopropyl;

[0058] n is 0, 1, 2 or 3;

[0059] m is 0, 1 or 2;

[0060] R x are independently selected from halogen, cyano, hydroxyl, amine, C 1～3 Alkyl, C 1～3 Alkoxy and C 3～6 Cycloalkyl; said R x The alkyl, alkoxy and cycloalkyl groups in the above-mentioned groups may be optionally substituted by halogen for 1 to 3 times.

[0061] In some preferred embodiments, R 1 Selected from -C 1～8 Alkyl, -C 0～4 Alkylene-NHC 0～4 Alkyl, -C 0～4 Alkylene-C 3～8 Cycloalkyl, -C 0～4 Alkylene-3 to 8-membered heterocyclic group; the R 1 The alkyl, heterocyclic, cycloalkyl and amino groups in the x Replace 1 to 3 times.

[0062] In other embodiments, the present disclosure provides the compound of formula (Ii), wherein the compound of formula (I) is a compound of formula (Ii-1), formula (Ii-2) or formula (Ii-3):

[0063]

[0064] The remaining definitions are the same as those in formula (Ii).

[0065] In other embodiments, the present disclosure provides a compound of formula (I-ii), wherein the compound of formula (I) is a compound of formula (I-ii-1) or formula (I-ii-2):

[0066]

[0067] The remaining definitions are the same as those in formula (I-ii).

[0068] In some preferred embodiments, R 1 Independently selected from

[0069]

[0070] -CH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 、-CH 2 CH 2 NHCH 3 、-CH 2 CH 2 NH 2 、-CH 2 NHCH 3 、-CH 2 CH 2 NHCH 2 CH 3 、-CH 2 NHCH 2 CH 3 、-CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHCH 3 ; said R 1 The alkyl, heterocyclic, cycloalkyl and amino groups in thex Replace 1 to 3 times.

[0071] In some preferred embodiments, R 1 Independently selected from

[0072] -CH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 CH 3 、-CH 2 CH 2 NHCH 3 、-CH 2 CH 2 NH 2 、-CH 2 NHCH 3 、-CH 2 CH 2 NHCH 2 CH 3 、-CH 2 NHCH 2 CH 3 、-CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NHCH 3 ; said R 1 The alkyl, heterocyclic, cycloalkyl and amino groups in the x Replace 1 to 3 times.

[0073] In some preferred embodiments, R 2 Independently selected from -H, -CH 3 、-CH 2 CH 3 、-CH 2 CH(CH 3 ) 2 、-CH(CH 3 ) 2 , The R 2 The alkyl and heterocyclic groups in the group may be optionally substituted 1 to 3 times by halogen.

[0074] In some preferred embodiments, R 3 Independently selected from -F, -Cl, -Br, =O, -CN, -CH3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 Cl, CCl 3 , -CHCl 2 、-CH 2 CH 2 Cl, -CH 2 CCl 3 、-CH 2 F, -CF 3 , -CHF 2 、-CH 2 CH 2 F, -CH 2 CF 3 .

[0075] In some preferred embodiments, R 4 Independently selected from -H, -F, -Cl, -Br, -CH 3 、-CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 F, -CF 3 , -CHF 2 、-CH 2 CF 3 .

[0076] In some preferred embodiments, X 1 Selected from NH or S.

[0077] In some preferred embodiments, R 1 Independently selected from -CH 2 CH 2 NHCH 3 .

[0078] In some preferred embodiments, R 2 Independently selected from -H, -CH 3 、-CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 CH(CH 3 ) 2 ,

[0079] In some preferred embodiments, R 3 Independently selected from -F, -Cl, -CH 3 .

[0080] In some preferred embodiments, R 4 Independently selected from -H, -CH 3 .

[0081] The present disclosure encompasses compounds resulting from any combination of the various embodiments.

[0082] In some embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein the compound is selected from:

[0083]

[0084]

[0085]

[0086] Pharmaceutical compositions and uses

[0087] The compounds of formula (I) disclosed in the present invention, including the compounds of formula (Ii), formula (I-ii), formula (Ii-1), formula (Ii-2), formula (Ii-3), formula (I-ii-1), formula (I-ii-2), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs thereof are inhibitors of SMARCA2 and can inhibit SMARCA2 activity. Therefore, the compounds of the present invention can be used to prevent or treat diseases, disorders or disorders mediated by SMARCA2.

[0088] On the other hand, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) described in the present disclosure, including a compound of formula (Ii), formula (I-ii), formula (Ii-1), formula (Ii-2), formula (Ii-3), formula (I-ii-1), formula (I-ii-2), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier.

[0089] In some embodiments, the pharmaceutical compositions described herein may further comprise one or more additional therapeutically active agents.

[0090] In another aspect, the present disclosure provides a drug combination, which includes a compound of formula (I) described in the present disclosure, including a compound of formula (Ii), formula (I-ii), formula (Ii-1), formula (Ii-2), formula (Ii-3), formula (I-ii-1), formula (I-ii-2), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, and another therapeutically active agent.

[0091] In another aspect, the present disclosure provides a compound of formula (I) described in the present disclosure, including a compound of formula (Ii), formula (I-ii), formula (Ii-1), formula (Ii-2), formula (Ii-3), formula (I-ii-1), formula (I-ii-2), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition according to the present disclosure, which is used as a drug, including a SMARCA2 inhibitor.

[0092] In another aspect, the present disclosure provides compounds of formula (I) described in the present disclosure, including compounds of formula (Ii), formula (I-ii), formula (Ii-1), formula (Ii-2), formula (Ii-3), formula (I-ii-1), formula (I-ii-2), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs thereof in the preparation of drugs, including SMARCA2 inhibitors.

[0093] In one aspect, the present disclosure provides a method for preventing or treating a SMARCA2-mediated disease, disorder or condition in an individual, wherein the method comprises: administering to the individual a therapeutically effective amount of a compound of formula (I) described in the present disclosure, including a compound of formula (Ii), formula (I-ii), formula (Ii-1), formula (Ii-2), formula (Ii-3), formula (I-ii-1), formula (I-ii-2), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof; or administering to the individual a therapeutically effective amount of a pharmaceutical composition described in the present disclosure.

[0094] In another aspect, the present disclosure provides the compound of formula (I), including the compound of formula (Ii), formula (I-ii), formula (Ii-1), formula (Ii-2), formula (Ii-3), formula (I-ii-1), formula (I-ii-2), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs thereof, or the use of the pharmaceutical composition in the preparation of a medicament for preventing or treating a SMARCA2-mediated disease, disorder or condition in an individual.

[0095] In some embodiments, the disease, disorder or condition is a tumor (eg, cancer), including solid tumors and hematological tumors.

[0096] In some embodiments, the tumor or cancer is selected from non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal-gastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, hematological cancer, non-Hodgkin lymphoma, small cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, central nervous system cancer, thymic tumor, adrenocortical carcinoma, appendix cancer, small intestine cancer or penile cancer.

[0097] In the present disclosure, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with a therapeutic agent and is suitable, within the scope of sound medical judgment, for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0098] As used herein, unless otherwise indicated, the terms "treat," ...

[0099] As used herein, "individual" includes humans or non-human animals. Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals. "Non-human animals" in the present disclosure include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0100] Technical Effects

[0101] The compounds disclosed herein are inhibitors of SMARCA2 and can therefore be used to prevent or treat diseases, disorders or disorders mediated by SMARCA2. The compounds disclosed herein have improved pharmacokinetic properties (e.g., improved bioavailability, improved metabolic stability, suitable half-life and duration of action), improved safety (lower toxicity (e.g., reduced cardiotoxicity) and / or less side effects), less prone to drug resistance and other more excellent properties. DETAILED DESCRIPTION

[0102] definition

[0103] Unless otherwise defined below, the meanings of all technical terms and scientific terms used herein are intended to be the same as those generally understood by those skilled in the art. Reference to the technology used herein is intended to refer to the technology generally understood in the art, including those changes in technology or replacement of equivalent technology that are obvious to those skilled in the art. Although it is believed that the following terms are well understood by those skilled in the art, the following definitions are still set forth to better explain the present invention.

[0104] The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps (i.e., these terms also encompass the terms "consisting essentially of" and "consisting of").

[0105] As used herein, the term "alkane" means a straight-chain or branched saturated aliphatic hydrocarbon.

[0106] As used herein, the term "alkyl" means a linear or branched monovalent saturated aliphatic hydrocarbon, which can be viewed as a group derived from an alkane by losing one hydrogen atom. In some embodiments, the alkyl group has 1 to 12, such as 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms. For example, as used herein, the term "C 1-8 "Alkyl" refers to a straight or branched chain group of 1 to 8 carbon atoms, including "C 1-6 Alkyl", "C 2-6 Alkyl", "C 2-5 Alkyl", "C 1-4 Alkyl" and "C 1-2 Alkyl". "C 1-6 Examples of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. The alkyl is optionally substituted with 1 or more (such as 1 to 3) suitable substituents such as halogen (in this case, the group is referred to as "haloalkyl", for example CF 3 , C 2 F5 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 Cl or -CH 2 CH 2 CF 3 The term “C 1-4 The term "alkyl" refers to an alkyl group having 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

[0107] As used herein, the term "alkylene" refers to a linear or branched divalent saturated aliphatic hydrocarbon. In some embodiments, the alkylene group has 1 to 12 carbon atoms, preferably 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, such as methylene, ethylene, propylene or butylene.

[0108] As used herein, the terms "cycloalkyl", "hydrocarbon ring" and "cycloalkylene" refer to saturated (i.e., "cycloalkyl" and "cycloalkylene") or partially unsaturated (i.e., having one or more double bonds (i.e., "cycloalkenyl" and "cycloalkenylene") and / or triple bonds in the ring) monocyclic or polycyclic fused hydrocarbon rings having, for example, 3-10 (suitably 3-8, more suitably 3-7, 3-6, 4-6 or 5-6) ring carbon atoms. The ring includes, but is not limited to, cyclopropyl (ring), cyclobutyl (ring), cyclopentyl (ring), cyclohexyl (ring), cycloheptyl (ring), cyclooctyl (ring), cyclononyl (ring), cyclobutenyl (ring), cyclopentenyl (ring), cyclohexenyl (ring), cycloheptenyl (ring), cyclooctenyl (ring), cyclononenyl (ring), etc.

[0109] As used herein, the term "fused" means that two or more ring structures share two adjacent atoms with each other.

[0110] As used herein, the terms "cycloalkyl" and "cycloalkylene" refer to a saturated monocyclic or polycyclic (such as bicyclic) fused hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring such as ). The cycloalkyl and cycloalkylene groups have 3 to 10 carbon atoms, suitably 3-8, for example 3-7, 3-6, 4-6 or 5-6. The cycloalkyl and cycloalkylene groups are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g. methyl or halogen), for example methyl-substituted cyclopropyl.

[0111] As used herein, the terms "cycloalkenyl" and "cycloalkenylene" refer to monocyclic or polycyclic (such as bicyclic) fused hydrocarbon rings (e.g., monocyclic, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or bicyclic) having one or more double bonds in the ring. The cycloalkenyl and "cycloalkenylene" have 3 to 10 carbon atoms, suitably 3-8, such as 3-7, 3-6, 4-6 or 5-6. The cycloalkenyl and cycloalkenylene are optionally substituted with 1 or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopentenyl.

[0112] As used herein, the terms "heterocyclyl", "heterocycle" and "heterocyclylene" refer to a saturated (i.e., "heterocycloalkyl" and "heterocycloalkylene") or partially unsaturated (e.g., having one or more double bonds within the ring (i.e., "heterocycloalkenyl" and "heterocycloalkenylene")) monovalent monocyclic or bicyclic fused ring structure having 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms in the ring and 1 or more (e.g., 1, 2, 3 or 4) selected from O, S, S(=O), S(=O) 2 and NR' containing heteroatoms, wherein R' is a hydrogen atom or C 1-6 Alkyl or halo-C 1-6 The heterocyclic group may be attached to the rest of the molecule via any of the carbon atoms or the nitrogen atom (if present). In particular, a 3-10 membered heterocyclic group is a group having 3-10 (e.g. 3-8, 3-7, 3-6, 4-6 or 5-6) carbon atoms and heteroatoms in the ring. The heterocyclic group is optionally substituted by 1 or more (e.g. 1 to 3) suitable substituents (e.g. halogen, OH, NH 2 , oxo (=O), C 1-6 Alkyl, C 1-6 Examples include, but are not limited to, oxirane, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, oxazolidine, thiazolidinyl, pyrazolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, hexahydropyrimidinyl, triazine, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, azocanyl, dihydropyrrolyl, dihydroimidazolyl, azooctenyl.

[0113] As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. 6-14"Aryl" means an aromatic group containing 6 to 14 (e.g. 6 to 12) carbon atoms, such as phenyl or naphthyl. The aryl group is optionally substituted by 1 or more (e.g. 1 to 3) suitable substituents (e.g. halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.) substituted.

[0114] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system having 5 to 14 ring atoms, such as 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, specifically having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and independently selected from N, O, S and S(O). 2 1, 2, 3, 4 or 5 identical or different heteroatoms. One or more ring carbon atoms in the heteroaryl group may be replaced by C(O). The heteroaryl group may be benzo-fused. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridone, pyrimidinyl, pyrimidone, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furanyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, benzisothiazolyl, imidazopyridinyl, quinolyl, indolyl, pyrrolopyridazinyl, benzo The heteroaryl group may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

[0115] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0116] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that the normal valence of the designated atom in the present context is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form stable compounds.

[0117] If a group is described as "optionally substituted by" or "optionally substituted," the group may be: (1) unsubstituted or (2) substituted. If a carbon of a group is described as optionally substituted by one or more of the listed substituents, then one or more hydrogens on that carbon (to the extent of any hydrogens present) may be replaced, individually and / or together, with independently selected optional substituents. If a nitrogen of a group is described as optionally substituted by one or more of the listed substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced by an independently selected optional substituent. If a substituent is described as "independently selected from" a group, then each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0118] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0119] When a bond to a substituent is shown as passing through a bond connecting two atoms in a ring (a "floating bond"), such a substituent may be bonded to any ring-forming atom in the substitutable ring, unless otherwise indicated. Where an available ring member is shown to carry a substitutable hydrogen atom, the substitutable hydrogen atom is substantially substituted (i.e., not present) when the floating bond is bonded to the available ring member.

[0120] The compounds provided in the present disclosure and their pharmaceutically acceptable salts may exist in chiral forms, i.e., S configuration or R configuration. The compounds provided in the present disclosure and their pharmaceutically acceptable salts may exist in achiral forms. When the structure of the compounds described in the present disclosure is exemplified in one of the configurations, it also means that the structure of another configuration or achiral form is disclosed.

[0121] The compounds described in the present disclosure include stereoisomers of the compounds. The stereoisomers described in the present disclosure refer to when there is an asymmetric carbon atom in the compound of formula I or formula II, enantiomers will be produced; when there is a carbon-carbon double bond or a cyclic structure in the compound, cis-trans isomers will be produced; when there is a ketone or oxime in the compound, tautomers will be produced. In some embodiments, the stereoisomers described in the present disclosure include, but are not limited to: enantiomers, diastereomers, racemic isomers, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof.

[0122] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present disclosure.

[0123] The present invention also includes all pharmaceutically acceptable isotope-labeled compounds, which are identical to the compounds of the present invention, except that one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (D, 2 H), tritium (T, 3 H)); isotopes of carbon (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (e.g. 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); isotopes of oxygen (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (e.g. 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically-labeled compounds of the invention (e.g., those incorporating a radioactive isotope) are useful in drug and / or substrate tissue distribution studies (e.g., assays). 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because of their ease of incorporation and ease of detection. 11 C. 18 F. 15 O and 13N) substitution can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotope-labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations by using appropriate isotope-labeled reagents instead of the non-labeled reagents previously used. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D 2 O, acetone-d 6 or DMSO-d 6 In some embodiments, the isotopically labeled compounds of the present invention are deuterated.

[0124] The term "stereoisomer" means an isomer formed due to at least one asymmetric center, which has the same chemical composition but different spatial arrangements of atoms or groups. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, it can produce a racemic mixture, a single enantiomer, a diastereomeric mixture, and a single diastereomer. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures (commonly referred to as tautomers) of two or more structures in rapid equilibrium in different forms. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of the present application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0125] "Diastereomers" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical methods such as electrophoresis and chromatography.

[0126] "Enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0127] The term "chiral" refers to molecules that have the property of non-superimposability of mirror image pairs, whereas the term "achiral" refers to molecules that are superimposable on their mirror image pairs.

[0128] The compounds of the invention may be prepared in racemic form, or individual enantiomers may be prepared by enantioselective synthesis or by resolution.

[0129] As used herein, the term "cis-trans isomers" or "geometric isomers" is caused by the inability to rotate freely around double bonds or single bonds of ring-forming carbon atoms. The compounds provided herein include all cis, trans, cis (syn), anti (anti), entgegen (E) and zusammen (Z) isomers and their corresponding mixtures.

[0130] In this article, solid lines (-), solid wedges Virtual wedge Depicting chemical bonds of the compounds of the invention. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown are present. When present in a racemic mixture, the solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the invention are intended to exist in the form of stereoisomers, which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereoisomer pairs).

[0131] It should also be understood that certain compounds of the present invention may exist in free form for treatment, or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs, which, after being administered to a patient in need thereof, can directly or indirectly provide a compound of the present invention or a metabolite or residue thereof. Therefore, when referring to "compounds of the present invention" herein, the above-mentioned various derivative forms of the compounds are also intended to be covered.

[0132] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0133] When the number of a linking group is 0, such as -(CRR) 0 -, indicating that the connecting group is a single bond.

[0134] When the number of a substituent is 0, it means that the substituent does not exist, such as -A-(R)0 Indicates that the structure is actually -A.

[0135] When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A.

[0136] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0137] When a substituent has a bond that crosses two or more atoms in a ring, the substituent may be bonded to any atom in the ring, e.g. Indicates that the substituent R can be substituted at any position on pyridazine or 1H-pyrrole. When the listed substituent does not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom thereof. For example, pyridyl as a substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

[0138] When the listed linking group does not indicate its linking direction, its linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of the reading order from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0139] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds to become a group with the corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy line As used herein, a wavy line Represents the point of attachment of a substituent to another group.

[0140] The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients making up the formulation and / or the mammal to be treated therewith.

[0141] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

[0142] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate / carbonate, bisulfate / sulfate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrobromide / bromide, hydroiodide / iodide, maleate, malonate, methylsulfate, naphthoate (naphthylate), nicotinate, nitrate, orotate, oxalate, palmitate and other similar salts.

[0143] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, choline, diethylamine, lysine, magnesium, meglumine, potassium and other similar salts.

[0144] For a review of suitable salts see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

[0145] As used herein, the term "ester" means an ester derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form). The compounds of the present invention themselves may also be esters.

[0146] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.

[0147] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol. The amount of polar solvents, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0148] Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc. of the administered compound. Thus, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by contacting the compounds of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0149] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may have less pharmacological activity or no pharmacological activity themselves, and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Usually such prodrugs will be functional group derivatives of the compounds, which are easily converted into the desired therapeutically active compounds in vivo. For additional information on the use of prodrugs, see "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (EBR ° C he ed., American Pharmaceutical Association). The prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moiety" (e.g., "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).

[0150] The present invention also encompasses compounds of the present invention containing protecting groups. In any process of preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive groups or reactive groups on any related molecules, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P. ​​GMWuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Using methods known in the art, the protecting group can be removed at an appropriate subsequent stage. The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxyl protecting group" or "sulfhydryl protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (B°C); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fm°C); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions of the hydroxy group. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

[0151] The compounds provided by the present disclosure can be prepared by a variety of synthetic methods known to those skilled in the art, including the examples listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples below.

[0152] The compounds described in the present disclosure are named according to the chemical structural formula. If the compound name and the chemical structural formula representing the same compound do not match, the chemical structural formula shall prevail.

[0153] Example

[0154] The embodiments of the present invention will be described in detail below in conjunction with the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If no specific conditions are specified in the examples, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be obtained commercially.

[0155] The structure of the compounds disclosed herein can be confirmed by conventional methods known to those skilled in the art. If the disclosure relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD) can be used, wherein the cultured single crystal is used to collect diffraction intensity data using a Bruker D8 venture diffractometer, the light source is CuKα radiation, and the scanning mode is: After collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0156] The present disclosure uses the following abbreviations: aq represents water; HATU represents O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphonium salt; eq represents equivalent; DCM represents dichloromethane; PE represents petroleum ether; DMSO represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; Cbz represents benzyloxycarbonyl, which is an amine protecting group; BOC represents tert-butyloxycarbonyl, which is an amine protecting group; rt represents room temperature; O / N represents overnight; THF represents tetrahydrofuran; B℃ 2 O stands for di-tert-butyl dicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; iPrOH stands for 2-propanol; mp stands for melting point; Prep-HPLC stands for preparative high performance liquid chromatography; TLC stands for thin layer chromatography; AIBN stands for azobisisobutyronitrile; NBS stands for N-bromosuccinimide; Xantphos stands for 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; Pd 2 (dBa) 3 stands for tris(dibenzylideneacetone)dipalladium; EA stands for ethyl acetate; Py stands for pyridine; dppf stands for 1,1'-bis(diphenylphosphino)ferrocene; LiAlH 4 Stands for lithium aluminum hydride; PPh 3 stands for triphenylphosphine; Pd(dppf)Cl 2 represents [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride; DIAD represents diisopropyl azodicarboxylate; Dioxane represents dioxane; IBX represents 2-iodoacylbenzoic acid; DCM represents dichloromethane; and MTBE represents methyl tert-butyl ether.

[0157] Compounds are named according to the conventional nomenclature in the art or using The software names were used, and commercially available compounds were named using the supplier's catalog names.

[0158] The present disclosure 1 H NMR spectra were measured using a Bruker instrument (400 MHz), and chemical shifts were expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0159] The mass spectrum of the present disclosure is measured by LC / MS instrument, and the ionization method can be ESI or APCI.

[0160] Example 1: Synthesis of C001 and C002

[0161]

[0162] Step 1: Compound 1a (500 mg, 3.26 mmol) was dissolved in DCM (20 mL) at room temperature, and compound AlCl 3 (2.46 g, 16.33 mmol), reaction solution 25 ℃ The mixture was stirred at 25 °C for 0.5 hours, acetyl chloride (1.27 g, 16.33 mmol) was added to the reaction solution, and the reaction solution was stirred at 25 °C for 3 days. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was cooled to 0 °C, MeOH (30 mL) was added dropwise to the reaction solution to quench the reaction, and then the mixture was spin-dried. The spin-dried mixture was dissolved in THF (50 mL), and Et 3 N (3.29g, 32.6mmol), DMAP (397mg, 3.26mmol), B℃ 2 O (7.1 g, 32.6 mmol), the reaction solution was stirred at 25°C for 3 hours, water (30 mL) was added and extracted with DCM (30 mL*3), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product. It was purified by silica gel chromatography (petroleum ether: ethyl acetate = 0-50%) to obtain compound 1c (330 mg, yield: 34%).

[0163] Step 2: Compound 1c (330 mg, 1.11 mmol) was dissolved in Dioxane / H 2O (10 / 1) (10 mL), compound 1d (306.36 mg, 2.22 mmol), X-phos Pd G3 (84.65 mg, 0.1 mmol), CS 2 CO 3 (723.72 mg, 2.22 mmol), the reaction solution was stirred at 95 ° C under nitrogen protection for 12 hours. LCMS showed that the reactants were completely converted and the product was detected. Vacuum concentration gave the crude product. Purification by silica gel chromatography (MeOH: DCM = 10%) gave compound 1e (158 mg, yield: 55.8%). LCMS (ESI) m / z: [M+H] + =253.9.

[0164] Step 3: Compound 1e (158 mg, 0.62 mmol) was dissolved in MeOH (5 mL) at room temperature, and compound 1f (401.76 mg, 1.86 mmol) and HOAc (37.2 mg, 0.62 mmol) were added, and the reaction solution was heated under reflux and stirred for 12 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo to obtain a crude product, which was purified by silica gel chromatography (petroleum ether: ethyl acetate = 0-50%) to obtain 90 mg of crude product, and prepared by HPLC. Freeze drying gave compounds Peak 1 of 1g (18 mg, yield: 6.4%) and Peak 2 of 1g (20 mg, yield: 7.1% mmol). LCMS (ESI) m / z: [M+H] + =452.2.

[0165] Step 4: Compound Peak 1 of 1g (18mg, 0.04mmol) was dissolved in DCM (2mL), 4M HCl / Dioxane (0.1mL) was added, and the mixture was stirred at room temperature for 3 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo, the solid was slurried with ether (2mL), the solid was filtered to obtain a solid, and the solid was freeze-dried. Compound C001 (11.85mg, yield: 75%) was obtained. Compound Peak 2 of 1g (20mg, 0.044mmol) was dissolved in DCM (2mL), 4M HCl / Dioxane (0.1mL) was added, and the mixture was stirred at room temperature for 3 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo, the solid was slurried with ether (2mL), the solid was filtered to obtain a solid, and the solid was freeze-dried. Compound C002 (18.8mg, yield: 90.9%) was obtained.

[0166] C001&C002:LCMS(ESI)m / z:[M+H] + =352.2. 1H NMR(400MHz,MeOD)δ9.09(s,1H),8.83(s,1H),7.66–7.62(m,1H),7.51(t,J=7.9Hz,1H),7.13(t,J=7.3Hz,2H),4.54–4.4 6(m,1H),3.26–3.21(m,2H),3.15-3.13(m,2H),2.47(s,3H),2.27–2.19(m,2H),2.06-2.05(m,2H); LCMS(ESI)m / z:[M+H] + =352.2. 1 H NMR(400MHz,MeOD)δ9.06(s,1H),8.73(s,1H),7.70–7.64(m,1H),7.48(t,J=7.0Hz,1H),7.10(d,J=8.6Hz,2H) ,4.60-4.58(m,1H),3.40–3.34(m,2H),3.27-3.21(m,2H),2.41(s,3H),2.29–2.21(m,2H),2.18–2.11(m,2H).

[0167] Example 2: Synthesis of C003 and C004

[0168]

[0169] Step 1: Compound 3a (10.0 g, 48.3 mmol) and compound 3b (22.67 g, 62.79 mmol) were dissolved in Dioxane (100 mL) at room temperature, and Pd(PPh 3 ) 4 (5.58 g, 4.83 mmol), the reaction solution was stirred at 85 ° C for 12 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was filtered and concentrated in vacuo to obtain a crude product. It was purified by silica gel chromatography (petroleum ether: ethyl acetate = 50%) to obtain compound 3c (3 g, yield: 31.1%). LCMS (ESI) m / z: [M+H] + =200.1.

[0170] Step 2: Compound 3c (3 g, 15 mmol) was dissolved in Dioxane / H 2 O (10 / 1) (30 mL), compound 3d (4.14 g, 30 mmol), X-phos Pd G3 (1.26 g, 1.5 mmol), Cs 2 CO 3(9.78 g, 30 mmol), the reaction solution was stirred at 95 ° C under nitrogen protection for 12 hours. LCMS showed that the reactants were completely converted and the product was detected. Vacuum concentration gave the crude product. Purification by silica gel chromatography (petroleum ether: ethyl acetate = 0-30%) gave compound 3e (1.2 g, yield: 30.7%). LCMS (ESI) m / z: [M+H] + =258.1.

[0171] Step 3: Compound 3e (1.2 g, 4.6 mmol) was dissolved in Dioxane (20 mL) at room temperature, and 4 M HCl in Dioxane (1 mL) was added. The reaction solution was stirred at room temperature for 4 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo, then dissolved in ethyl acetate (20 mL), and saturated NaHCO was added. 3 (10mL) and then extracted with ethyl acetate (20mL*3), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product. Purification by silica gel chromatography (petroleum ether: ethyl acetate = 50%) gave compound 3f (320 mg, yield: 8.7%). LCMS (ESI) m / z: [M+H] + =229.9.

[0172] Step 4: Compound 3f (158 mg, 0.62 mmol) was dissolved in MeOH (5 mL) at room temperature, and compound 3g (401.76 mg, 1.86 mmol) and HOAc (37.2 mg, 0.62 mmol) were added, and the reaction solution was heated under reflux and stirred for 12 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo to obtain a crude product, which was purified by silica gel chromatography (petroleum ether: ethyl acetate = 30%-50%) to obtain 150 mg of crude product, and prepared by HPLC. Freeze drying gave compounds Peak1 of 3h (26 mg, 0.06 mmol) and Peak2 of 3h (36 mg, yield: 13.2%). LCMS (ESI) m / z: [M+H] + =428.1.

[0173] Step 5: Compound Peak 1 of 3h (26 mg, 0.06 mmol) was dissolved in DCM (2 mL), 4M HCl / Dioxane (0.1 mL) was added, and stirred at room temperature for 3 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo, the solid was slurried with ether (2 mL), filtered to obtain a solid, and freeze-dried. Compound C003 (20.82 mg, yield: 95%) was obtained. LCMS (ESI) m / z: [M+H] +=327.99. Compound Peak2 of3h (36 mg, 0.084 mmol) was dissolved in DCM (2 mL), 4M HCl / Dioxane (0.1 mL) was added, and stirred at room temperature for 3 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo, the solid was slurried with ether (2 mL), filtered to obtain a solid, and freeze-dried. Compound C004 (30.02 mg, yield: 97.6%) was obtained. C003 & C004: LCMS (ESI) m / z: [M+H] + =327.98. 1 H NMR (400MHz, CD 3 OD)δ8.67(s,1H),7.70(dd,J=8.0,1.6Hz,1H),7.43–7.35(m,1H),7.03-7.00(m,2H),4.85-4.77( m,1H),3.47-3.3(m,2H),3.27–3.21(m,2H),2.46(s,3H),2.31–2.23(m,2H),2.15–2.06(m,2H).; 1 H NMR (400MHz, CD 3 OD)δ8.67(s,1H),7.70(dd,J=8.0,1.7Hz,1H),7.43–7.36(m,1H),7.03-7.00(m,2H),4.80–4.76(m, 1H),3.39-3.30(m,2H),3.28-3.22(m,2H),2.49-2.43(m,3H),2.33-2.22(m,2H),2.12-2.05(m,2H).

[0174] Example 3: Synthesis of C005

[0175]

[0176] Step 1: Compound 5a (1700 mg, 9.1 mmol) was dissolved in THF (20 mL) at room temperature, and (0.5 N) compound 5b (109 mL, 54.5 mmol) was added at -78 °C. After the addition, the reaction solution was stirred at 25 °C for 2 hours, and saturated NH 4 The mixture was quenched with Cl, extracted with EA, and the organic phase was dried and concentrated to obtain compound 5c (2000 mg, 8.44 mmol, yield: 93%). 1 HNMR (400MHz, CD 3 OD) δ4.49(s,1H),2.68(s,1H),1.33(s,9H),1.23(s,3H),1.21(s,3H).

[0177] Step 2: Compound 5c (2000 mg, 8.44 mmol) and compound 5d (1415.6 mg, 8.44 mmol) were dissolved in Toluene (50 mL) at room temperature. ℃ The mixture was stirred for 16 hours. LCMS showed that the reactants were completely converted and the product was detected. The crude product was obtained by vacuum concentration. It was purified by silica gel chromatography (PE:EA=8:2) to obtain compound 5e (1000 mg, 2.83 mmol, yield: 30%). LCMS (ESI) m / z: [M+H] + =336.2.

[0178] Step 3: Compound 5e (1000 mg, 2.83 mmol) was dissolved in ACN (30 mL) at room temperature, and IBX (2498.6 mg, 8.9 mmol) was added. The reaction solution was heated under reflux and stirred for 4 hours. The product was detected by LCMS. The reaction solution was filtered and the filtrate was concentrated in vacuo to obtain a crude product, which was purified by silica gel chromatography (PE:EA=3:1) to obtain compound 5f (750 mg, 2.13 mmol, 71.7% yield). LCMS (ESI) m / z: [M+H] + =334.2.

[0179] Step 4: Dissolve compound 5f (750 mg, 2.13 mmol) in 4M HCl / Dioxane (10 mL) and stir at room temperature for 3 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo to obtain crude compound 5g (680 mg, yield: 100%) which was used directly in the next step. Dissolve compound 5g (680 mg, 2.6 mmol) in ACN (10 mL), add DIEA (1822 mg, 7.8 mmol) and add 75% HCl / Dioxane (10 mL). ℃ The mixture was stirred for 2 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo to obtain a crude product, which was purified by silica gel chromatography (PE:EA=3:2) to obtain compound 5h (150 mg, 0.72 mmol, yield: 25.6%). LCMS (ESI) m / z: [M+H] + =198.2.

[0180] Step 5: Compound 5h (150 mg, 0.76 mmol) was dissolved in Dioxane / H2O (8 / 1) (12.5 mL) at room temperature, and compound 5i (209.4 mg, 1.5 mmol), X-phos Pd G3 (128.5 mg, 0.15 mmol), cesium carbonate (741.9 mg, 2.3 mmol) were added. The reaction mixture was stirred for 95 min. ℃The mixture was stirred for 16 hours under nitrogen protection. LCMS showed that the reactants were completely converted and the product was detected. The crude product was obtained by vacuum concentration. It was purified by silica gel chromatography (PE:EA=1:1) to obtain compound 5j (200 mg, 0.7 mmol, yield: 92.9%). LCMS (ESI) m / z: [M+H] + =256.2.

[0181] Step 6: Compound 5j (200 mg, 0.78 mmol) was dissolved in MeOH (10 mL) at room temperature, and compound 5k (340.5 mg, 1.6 mmol) and HOAc (47 mg, 0.78 mmol) were added, and the reaction solution was heated to reflux and stirred for 16 hours. The product was detected by LCMS. The reaction solution was concentrated in vacuo to obtain a crude compound 5l (200 mg, yield: 53.8%), which was directly used in the next step. Compound 5l (200 mg, 0.42 mmol) was dissolved in 4M HCl / Dioxane (10 mL) and stirred at room temperature for 3 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo to obtain a crude product. The product was purified by prep-HPLC (Column: Gemini, MeCN-H 2 O (0.1% FA)) to obtain compound C005 (111 mg, yield: 71.4%). LCMS (ESI) m / z: [M+H] + =354.2. 1 HNMR (400MHz, CD 3 OD)δ8.77(s,1H),7.78–7.62(m,1H),7.45–7.29(m,1H),7.00(m,2H),4.69(m,1H ),3.42(m,2H),3.31–3.24(m,2H),2.37–2.29(m,2H),2.18(m,2H),1.60(s,6H).

[0182] Example 4: Synthesis of C006

[0183]

[0184] Step 1: Dissolve compound 6a (25 g, 0.12 mol) in toluene (250 mL) at room temperature, add trimethylacetylene silicon (12.95 g, 0.13 mol), CuI (2.28 g, 0.01 mol), Pd(dppf)Cl 2 (2.59 g, 0.0035 mol) and triethylamine (29.12 g, 0.30 mol). ℃The mixture was stirred for 16 hours. LCMS showed that the reactants were completely converted and the product was detected. The mixture was concentrated in vacuo and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 0-10%) to give compound 6b (23 g, yield: 76.4%).

[0185] Step 2: At 0 ℃ Potassium tert-butoxide (16.90 g, 150.6 mmol) was added in batches to a mixed solution of compound 6b (20 g, 88.6 mmol) and dimethylamine hydrochloride (7.22 g, 88.6 mmol) in DMF (200 mL). After the addition was complete, the reaction solution was heated to 120°C. ℃ Stir for 2 hours. LCMS showed that the reactants were completely converted and the product was detected. Concentrated in vacuo, the crude product was purified by silica gel chromatography (methanol: dichloromethane = 0-2%) to give compound 6c (8 g, yield: 32.9%). LCMS (ESI) m / z: [M+H] + =154.30.

[0186] Step 3: At 0 ℃ Compound 6c (500 mg, 3.26 mmol) was dissolved in DCM (15 mL) and compound AlCl was added. 3 (2170.72 mg, 16.28 mmol), compound propionyl chloride (1506.24 mg, 16.28 mmol) was added dropwise to the mixture, slowly warmed to room temperature and stirred for 16 hours. LCMS showed that the reactants were completely converted and the product was detected. It was quenched with MeOH under ice-water bath conditions, concentrated in vacuo, and the crude product was purified by silica gel chromatography (methanol: dichloromethane = 0-10%) to obtain compound 6d (660 mg, yield: 87.7%). LCMS (ESI) m / z: [M+H] + =201.00.

[0187] Step 4: Dissolve compound 6d (600 mg, 2.86 mmol) in DCM (15 mL) and add compound B. 2 O (1874 mg, 8.59 mmol) and DMAP (341.01 mg, 2.86 mmol), the mixture was stirred at room temperature for 2 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was poured into water (20 mL), then extracted with ethyl acetate (20 mL*3), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (methanol: dichloromethane = 0-10%) to obtain compound 6e (200 mg, yield: 22.4%). LCMS (ESI) m / z: [M+H] + =310.05.

[0188] Step 5: Dissolve compound 6e (200 mg, 0.64 mmol) in 1,4-dioxane / H 2 O=4:1 (5 mL), compound 6f (177.54 mg, 1.29 mmol), Cs 2 CO 3 (419.4 mg, 1.29 mmol) and XPhos Pd G3 (54.48 mg, 0.06 mmol) were mixed at 80 ℃ Stirring was continued for 2 hours under the conditions. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was poured into water (20 mL), then extracted with ethyl acetate (20 mL*3), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (methanol: dichloromethane = 0-10%) to obtain compound 6g (50 mg, yield: 29.7%). LCMS (ESI) m / z: [M+H] + =268.25.

[0189] Step 6: Compound 6g (50 mg, 0.19 mmol) was dissolved in MeOH (2 mL), and compound 6h (81.31 mg, 0.37 mmol) and AcOH (2.25 mg, 0.04 mmol) were added, and the mixture was stirred at 80 ° C for 16 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo, and the crude product was purified by silica gel chromatography (methanol: dichloromethane = 0-10%) to obtain compound 6i (70 mg, yield: 78.9%). LCMS (ESI) m / z: [M+H] + =466.20.

[0190] Step 7: Compound 6i (70 mg, 0.15 mmol) was dissolved in DCM (2 mL) at room temperature, HCl (4 M indioxane (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. LCMS showed that the reactants were completely converted and the product was detected. Concentrated in vacuo and separated by HPLC to give compound C006 (28 mg, yield: 53.3%). LCMS (ESI) m / z: [M+H] + =366.20. 1HNMR(400MHz,CD3OD)δ8.98(s,1H),8.50(s,1H),7.74(dd,J=8.0,1.4Hz,1H),7.49–7.30(m,1H),7.21–6.89(m,2H),4.67–4.51(m,1H),3.37(ddd ,J=12.8,8.9,3.9Hz,2H),3.28–3.21(m,2H),2.89(q,J=7.6Hz,2H),2.26 (ddd,J=12.6,8.0,3.7Hz,2H),2.21–2.11(m,2H),1.28(t,J=7.6Hz,3H).

[0191] Example 5: Synthesis of C007

[0192]

[0193] Step 1: Dissolve N B℃-N-methylaminoethanol (2 g, 11.4 mmol) in THF (20 mL) at room temperature, add N-hydroxyphthalimide (2.05 g, 12.5 mmol), triphenylphosphine (3.59 g, 13.6 mmol), add DIAD (2.77 g, 13.6 mmol) dropwise at 0°C, and warm to room temperature after the addition is complete. The reaction solution is stirred at 25°C for 16 hours. LCMS shows that the reactants are completely converted and the product is detected. Concentrate in vacuo, wash the crude product with methyl tert-butyl ether, filter, and collect the filtrate to obtain compound 7a (4.2 g, yield: 92.1%). LCMS (ESI) m / z: [M+H] + =321.10.

[0194] Step 2: Compound 7a (4.0 g, 12.5 mmol) was dissolved in EtOH (40 mL) at room temperature, and compound N was added. 2 H 4 ·H 2 O (0.67 g, 13.7 mmol), the reaction solution was stirred at 25 ° C for 16 hours. LCMS showed that the reactants were completely converted and the product was detected. The crude product was concentrated in vacuo, washed with methyl tert-butyl ether, filtered, and the filtrate was collected to obtain compound 7b (2.2 g, yield: 83.2%). LCMS (ESI) m / z: [M+H] + =192.40.

[0195] Step 3: Compound 7c (130 mg, 0.51 mmol) was dissolved in MeOH (2 mL), compound 7b (196.34 mg, 1.03 mmol) and AcOH (61.65 mg, 1.03 mmol) were added, and the mixture was heated to 80 °C and stirred for 16 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was poured into water (20 mL), then extracted with ethyl acetate (20 mL*3), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (methanol: dichloromethane = 0-2%) to obtain compound 7d (110 mg, yield: 45.1%). LCMS (ESI) m / z: [M+H] + =426.35.

[0196] Step 4: Compound 7d (90 mg, 0.21 mmol) was dissolved in DCM (2 mL) at room temperature, dioxane hydrochloride (1 mL, 4 M) was added, and the mixture was stirred at room temperature for 2 hours. LCMS showed that the reactants were completely converted and the product was detected. Concentrated in vacuo and separated by HPLC to obtain C007 (22 mg, yield: 28.6%). LCMS (ESI) m / z: [M+H] + =326.20. 1 H NMR (400MHz, CD 3 OD)δ9.00(s,1H),8.59(s,1H),7.74(dd,J=8.0,1.4Hz,1H),7.53–7.32(m,1H),7.07(d d,J=7.8,5.6Hz,2H),4.65–4.44(m,2H),3.68–3.36(m,2H),2.79(s,3H),2.41(s,3H).

[0197] Example 6: Synthesis of C008 and C009

[0198]

[0199] Step 1: Compound 8a (180 mg, 0.71 mmol) was dissolved in MeOH (5 mL) at room temperature, and compound 8b (489.9 mg, 2.13 mmol) and HOAc (127.8 mg, 2.13 mmol) were added, and the reaction solution was heated under reflux and stirred for 12 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo to obtain a crude product, which was purified by silica gel chromatography (petroleum ether: ethyl acetate = 0-50%) to obtain 90 mg of crude product, and prepared by HPLC. Freeze drying gave compounds Peak 1 of 8c (9.5 mg, yield: 2.8%) and Peak 2 of 8c (40 mg, yield: 12.1%). LCMS (ESI) m / z: [M+H] + =466.2.

[0200] Step 2: Compound Peak 1 of 8c (9.5 mg, 0.02 mmol) was dissolved in DCM (2 mL), 4M HCl / Dioxane (0.1 mL) was added, and stirred at room temperature for 3 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo, the solid was slurried with ether (2 mL), filtered to obtain a solid, and freeze-dried. Compound C008 (5.85 mg, yield: 80%) was obtained. LCMS (ESI) m / z: [M+H] + =366.2. Compound Peak2 of8c (40 mg, 0.086 mmol) was dissolved in DCM (2 mL), 4M HCl / Dioxane (0.1 mL) was added, and stirred at room temperature for 3 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo, the solid was slurried with ether (2 mL), filtered to obtain a solid, and freeze-dried. Compound C009 (39.71 mg, yield: 100%) was obtained. C008 & C009: 1 H NMR (400MHz, CD 3 OD)δ9.10(s,1H),8.85(s,1H),7.65(dd,J=8.0,1.6Hz,1H),7.56–7.49(m,1H),7.18–7.11(m,2H),4.13(d,J=6.5Hz,2H),3.35(d,J =12.7Hz,2H),2.95-2.88(m,2H),2.45(s,3H),2.20–2.09(m,1H),1.93(d,J=13.8Hz,2H),1.53–1.41(m,2H).;LCMS(ESI)m / z:[M+H] + =366.2. 1 H NMR (400MHz, CD 3OD)δ9.06(s,1H),8.69(s,1H),7.67(d,J=7.7Hz,1H),7.49-7.45(m,1H),7.13-7.09(m,2H),4.20(d,J=6.2Hz,2H),3.43 (d,J=12.8Hz,2H),3.05-2.98(m,2H),2.36(s,3H),2.18-2.17(m,1H),2.08-2.04(d,J=13.6Hz,2H),1.68–1.52(m,2H).

[0201] Example 7: Synthesis of C010 and C011

[0202]

[0203] Step 1: Compound 10a (1000 mg, 6.5 mmol) was dissolved in DCM (20 mL) at room temperature, anhydrous aluminum chloride (4.34 g, 32.6 mmol) was added, the reaction solution was stirred at 25 ° C for 0.5 hours, isobutyryl chloride (3.47 g, 32.6 mmol) was added to the reaction solution, and the reaction solution was stirred at 25 ° C for 16 hours. The product was detected by LCMS. The reaction solution was cooled to 0 ° C, MeOH (30 mL) was added dropwise to the reaction solution to quench the reaction, the reaction solution was spin-dried and dissolved in DMF. Purification by reverse column (H2O: ACN = 10: 3.5) gave compound 10b (500 mg, 2.12 mmol, yield: 32.62%). LCMS (ESI) m / z: [M+H] + =224.2.

[0204] Step 2: Compound 10b (500 mg, 2.12 mmol) was dissolved in Dioxane / H 2 O (8 / 1) (12.5 mL), compound 10c (308.34 mg, 2.24 mmol), X-phos Pd G3 (378.45 mg, 0.44 mmol), cesium carbonate (2185.1 mg, 6.7 mmol), the reaction solution 95 ℃ The mixture was stirred for 16 hours under nitrogen protection. LCMS showed that the reactants were completely converted and the product was detected. The crude product was obtained by vacuum concentration. It was purified by silica gel chromatography (ethyl acetate: methanol = 10: 1) to obtain compound 10d (450 mg, yield: 71.7%). LCMS (ESI) m / z: [M+H] + =282.2.

[0205] Step 3: Compound 10d (400 mg, 1.52 mmol) was dissolved in MeOH (10 mL) at room temperature, and compound 10e (617.9 mg, 2.84 mmol) and HOAc (85.4 mg, 1.42 mmol) were added, and the reaction solution was heated to reflux and stirred for 16 hours. The product was detected by LCMS. The reaction solution was concentrated in vacuo to obtain a crude compound 10f (400 mg, yield: 49.3%), which was directly used in the next step. Compound 10f (400 mg, 0.17 mmol) was dissolved in 4M hydrochloric acid dioxane solution (10 mL) and stirred at room temperature for 3 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo to obtain a crude product. The product was purified by prep-HPLC (Column: Gemini, MeCN-H 2 O (0.1% FA)) to obtain compound C010 (65.5 mg, yield: 9.4%) and compound C011 (67.8 mg, yield: 10%).

[0206] C010&C011:LCMS(ESI)m / z:[M+H] + =380.2. 1 H NMR (400MHz, CD 3 OD)δ8.97(s,1H),8.52(s,1H),7.74(m,1H),7.43–7.36(m,1H),7.08–7.02(m,2H),4.59–4.50(m,1H),3.62–3.52(m,1H), 3.39–3.33(m,2H),3.28–3.22(m,2H),2.29–2.23(m,2H),2.20–2.12(m,2H),1.44(d,J=6.8Hz,6H).;LCMS(ESI)m / z:[M+H] + =380.2. 1 H NMR(400MHz,MeOD)δ8.70(s,1H),8.61(s,1H),7.67(m,1H),7.49–7.42(m,1H),7.12–7.07(m,2H),4.56–4.4 8(m,1H),3.21–3.11(m,2H),3.14–3.08(m,4H),2.21–2.11(m,2H),1.98–1.93(m,2H),1.24(d,J=6.8Hz,6H).

[0207] Example 8: Synthesis of C012 and C013

[0208]

[0209] Step 1: Compound 12a (500 mg, 3.3 mmol) was dissolved in DCM (10 mL) at room temperature, anhydrous aluminum chloride (1.08 g, 8.14 mmol) was added, the reaction solution was stirred at 25 ° C for 0.5 hours, isovaleryl chloride (1.96 g, 8.14 mmol) was added to the reaction solution, and the reaction solution was stirred at 25 ° C for 3 days. The product was detected by LCMS. The reaction solution was cooled to 0 ° C, MeOH (30 mL) was added dropwise to the reaction solution to quench the reaction, 7M NH3 / MeOH was added to adjust the pH of the system to weak alkalinity, and then the mixture was spin-dried. 20 mL of tetrahydrofuran was added to dissolve, di-tert-butyl dicarbonate (852.7 mg, 3.91 mmol) and triethylamine (988.4 mg, 9.77 mmol) were added under a nitrogen atmosphere, and stirred at room temperature for 2 hours. LCMS showed that most of the reactants were converted and the product was detected. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (100 mL × 3), washed with saturated brine (100 mL × 3), and dried over anhydrous sodium sulfate. The filtrate was filtered, dried under vacuum, and concentrated to obtain a crude product. Purification by silica gel chromatography (petroleum ether: ethyl acetate = 10: 1) gave compound 12b (300 mg, yield: 27%). LCMS (ESI) m / z: [M+H] + =338.

[0210] Step 2: Compound 12b (300 mg, 0.89 mmol) was dissolved in Dioxane / H 2 O(5 / 1) (10mL), 2-hydroxyphenylboronic acid (147.6mg, 1.07mmol), X-phos Pd G3 (76.2mg, 0.09mmol), cesium carbonate (724.9mg, 2.22mmol) were added, and the reaction solution was stirred at 95°C under nitrogen protection for 12 hours. LCMS showed that the reactants were completely converted and the product was detected. Vacuum concentration gave a crude product. Purification by Pre-HPLC (MeCN:TFA0.1%=40%) gave compound 12c (40mg, yield: 15.7%). LCMS (ESI) m / z: [M+H] + =296.

[0211] Step 3: Compound 12c (40 mg, 0.14 mmol) was dissolved in MeOH (2 mL) at room temperature, and compound 12d (35.3 mg, 0.16 mmol) and HOAc (8.13 mg, 0.13 mmol) were added. The reaction solution was heated under reflux and stirred for 12 hours. The product was detected by LCMS. The reaction solution was concentrated in vacuo to obtain a crude product, which was purified by prep-TLC (petroleum ether: ethyl acetate = 1:1) to obtain compound 12e (50 mg, yield: 64.3%). LCMS (ESI) m / zS: [M+H] +=494.1.

[0212] Step 4: Compound 12e (50 mg, 0.09 mmol) was dissolved in DCM (2 mL), 4 M dioxane hydrochloride (2 mL) was added, and stirred at room temperature for 3 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo to obtain a crude product. The crude product was purified by prep-HPLC (Column: Gemini, ACN-H 2 O (0.1% FA)) to obtain compound C012 (31.16 mg, yield: 80%) and compound C013 (7.56 mg, yield: 20%). C012 & C013: LCMS (ESI) m / z: [M+H] + =394. 1 H NMR (400MHz, CD 3 OD)δ9.00(s,1H),8.47(s,1H),7.76(dd,J=8.1,1.5Hz,1H),7.44–7.34(m,1H),7.06–7.03(m,2H),4.66–4.54(m,1H),3.40–3.32(m ,2H),3.28–3.24(m,2H),2.81(d,J=7.5Hz,2H),2.31–2.22(m,2H),2.20–2.12(m,3H),1.05(d,J=6.7Hz,6H).;LCMS(ESI)m / z:[M+H] + =394. 1 H NMR (400MHz, CD 3 OD)δ8.72(s,1H),8.66(s,1H),7.78–7.69(m,1H),7.44–7.40(m,1H),7.09–7.06(m,2H),4.58–4.48(m,1H),3.16–3 .07(m,4H),2.68(d,J=7.3Hz,2H),2.26–2.12(m,2H),2.04–1.96(m,2H),1.90–1.81(m,1H),0.96(d,J=6.6Hz,6H).

[0213] Example 9: Synthesis of C014 and C015

[0214]

[0215] Step 1: Compound 14a (500 mg, 3.26 mmol) was dissolved in DCM (10 mL) at room temperature, anhydrous aluminum chloride (2.16 g, 16.3 mmol) was added, the reaction solution was stirred at 25°C for 0.5 hours, cyclopentylcarbonyl chloride (2.16 g, 16.3 mmol) was added to the reaction solution, and the reaction solution was stirred at 25°C for 3 days. The product was detected by LCMS. The reaction solution was cooled to 0°C, MeOH (30 mL) was added dropwise to the reaction solution to quench the reaction, and 7M NH 3 / MeOH was added to adjust the pH of the system to weak alkalinity, and then spun dry. 20 mL of tetrahydrofuran was added to dissolve, di-tert-butyl dicarbonate (1.06 g, 4.88 mmol) and triethylamine (988.4 mg, 9.77 mmol) were added under a nitrogen atmosphere, and stirred at room temperature for 2 hours. LCMS showed that most of the reactants were converted and the product was detected. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (100 mL × 3), washed with saturated brine (100 mL × 3), and dried over anhydrous sodium sulfate. The filtrate was filtered, vacuum dried, and concentrated to obtain a crude product. Compound 14b (400 mg, yield: 35%) was obtained by purification by silica gel chromatography (petroleum ether: ethyl acetate = 10: 1). LCMS (ESI) m / z: [MB℃+H] + =250.3.

[0216] Step 2: Compound 14b (400 mg, 1.14 mmol) was dissolved in Dioxane / H 2 O(5 / 1) (10mL), 2-hydroxyphenylboronic acid (235.9mg, 1.71mmol), X-phos Pd G3 (96.5mg, 0.11mmol), cesium carbonate (928.8mg, 2.85mmol) were added, and the reaction solution was stirred at 95°C under nitrogen protection for 12 hours. LCMS showed that the reactants were completely converted and the product was detected. The crude product was concentrated in vacuo. Purification by Pre-HPLC (MeCN:TFA0.1%=40%) gave compound 14c (130mg, yield: 36.8%). LCMS (ESI) m / z: [M+H] + =308.1.

[0217] Step 3: Compound 14c (130 mg, 0.42 mmol) was dissolved in MeOH (5 mL) at room temperature, and compound 14d (183.8 mg, 0.85 mmol) and HOAc (25.4 mg, 0.42 mmol) were added. The reaction solution was heated under reflux and stirred for 12 hours. The product was detected by LCMS. The reaction solution was concentrated in vacuo to obtain a crude product, which was purified by prep-TLC (petroleum ether: ethyl acetate = 1:1) to obtain compound 14e (100 mg, yield: 40.5%). LCMS (ESI) m / z: [M+H] + =506.3.

[0218] Step 4: Compound 14e (100 mg, 0.17 mmol) was dissolved in DCM (2 mL), 4 M HCl / Dioxane (2 mL) was added, and stirred at room temperature for 3 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo to obtain a crude product. The crude product was purified by prep-HPLC (Column: Gemini, ACN-H 2 O (0.1% FA)) to obtain compounds C014 (10.16 mg, yield: 14.7%) and C015 (15.03 mg, yield: 21.8%).

[0219] C014&C015:LCMS(ESI)m / z:[M+H] + =406.1. 1 H NMR (400MHz, CD 3 OD)δ8.89(s,1H),8.54(s,1H),7.82(dd,J=7.9,1.4Hz,1H),7.38–7.25(m,1H),7.07–6.90(m,2H),3.60–3.48(m,1H),3.37 –3.33(m,1H),3.28–3.22(m,2H),2.34–2.24(m,2H),2.19–3.08(m,4H),2.08–1.83(m,5H),1.82–1.63(m,2H).;LCMS:[M+H] + =406.1. 1H NMR (400MHz, MeOD) δ8.52(d,J=7.4Hz,1H),8.27(s,1H),7.90(d,J=7.3Hz,1H),7.31(t,J=7.7Hz,1H),6.99(t,J=7.2Hz,2 H),4.56–4.46(m,1H),3.37–3.35(m,1H),3.04(t,J=5.9Hz,4H),2.18–2.10(m,2H),2.02–1.89(m,4H),1.87–1.61(m,6H).

[0220] Example 10: Synthesis of C016 and C017

[0221]

[0222] Step 1: Compound 16a (1 g, 6.5 mmol) was dissolved in DCM (50 mL) at room temperature, anhydrous aluminum chloride (4.93 g, 32.67 mmol) was added, the reaction solution was stirred at 25 ° C for 0.5 hours, cyclohexylcarbonyl chloride (4.77 g, 32.67 mmol) was added to the reaction solution, and the reaction solution was stirred at 25 ° C for 3 days. LCMS detected the product. The reaction solution was cooled to 0 ° C, MeOH (30 mL) was added dropwise to the reaction solution to quench the reaction, and then spin-dried. Purification by reverse phase (0.1% TFA / ACN = 2-50%) gave compound 16b (250 mg, yield: 14.6%). LCMS (ESI) m / z: [M+H] + =263.9

[0223] Step 2: Compound 16b (250 mg, 0.95 mmol) was dissolved in Dioxane / H2O (10 / 1) (10 mL) at room temperature, and 2-hydroxyphenylboronic acid (262.2 mg, 1.9 mmol), X-phos Pd G3 (84.65 mg, 0.1 mmol) and CS 2 CO 3 (723.72 mg, 2.22 mmol), the reaction solution was stirred at 95 ° C under nitrogen protection for 12 hours. LCMS showed that the reactants were completely converted and the product was detected. Vacuum concentration gave the crude product. Purification by silica gel chromatography (MeOH: DCM = 10%) gave compound 16c (180 mg, yield: 58.9%). LCMS (ESI) m / z: [M+H] + =322.0.

[0224] Step 3: Compound 16c (180 mg, 0.56 mmol) was dissolved in MeOH (5 mL) at room temperature, and compound 16d (362.88 mg, 1.68 mmol) and HOAc (100.8 mg, 1.68 mmol) were added. The reaction solution was heated under reflux and stirred for 12 hours. The product was detected by LCMS. The reaction solution was concentrated in vacuo to obtain a crude product, which was purified by silica gel chromatography (petroleum ether: ethyl acetate = 0-50%) to obtain a crude compound 16e (160 mg, yield: 41.2%). LCMS (ESI) m / z: [M+H] + =520.3.

[0225] Step 4: Compound 16e (160 mg, 0.308 mmol) was dissolved in DCM (2 mL), 4M HCl / Dioxane (0.1 mL) was added, and stirred at room temperature for 3 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo and freeze-dried. The crude product was purified by prep-HPLC (Column: Gemini, ACN-H 2 O (0.1% FA)) to obtain compounds C016 (54.02 mg, yield: 39%) and C017 (61.81 mg, yield: 45.4%).

[0226] C016&C017:LCMS(ESI)m / z:[M+H] + =420.1. 1 H NMR (400MHz, CD 3 OD)δ8.87(s,1H),8.52(s,1H),8.26(s,1H),7.82(d,J=6.7Hz,1H),7.30(t,J=7.0Hz,1H),7.01-6.96(m,2H),4.58(s,1H),3.38 (s,1H),3.24–3.20(m,2H),2.31–2.22(m,2H),2.19-2.03(m,4H),1.85-1.81(m,6H),1.57–1.26(m,4H).;LCMS(ESI)m / z:[M+H] + =420.1. 1 H NMR (400MHz, CD 3OD)δ8.46(s,1H),8.25(s,1H),7.93–7.86(m,1H),7.31(t,J=7.7Hz,1H),7.04–6.95(m,2H),4.51-4. 50(m,1H),3.33(s,1H),3.04-3.01(m,4H),2.89-2.81(m,1H),2.10-1.96(m,7H),1.46-1.41(m,4H).

[0227] Example 11: Synthesis of C018

[0228]

[0229] Step 1: Compound 18a (800 mg, 6.01 mmol) was dissolved in EtOH (10 mL) at room temperature, and compound 18b (1.2 g, 9.02 mmol) and K were added. 2 CO 3 (1.66 g, 12.02 mmol), the reaction solution was stirred at 25 ° C for 12 hours. LCMS detected the product. The reaction solution was concentrated in vacuo to obtain a crude product. It was purified by silica gel chromatography (ethyl acetate: petroleum ether = 30%) to obtain compound 18c (600 mg, yield: 47.4%). LCMS (ESI) m / z: [M+H] + =210.93.

[0230] Step 2: Compound 18c (600 mg, 2.85 mmol) was dissolved in DCM (10 mL) at room temperature, and 4M HClDioxane (1 mL) was added. The reaction solution was stirred at 25°C for 12 hours. LCMS showed that the reactants were completely converted and the product was detected. Concentration in vacuo gave compound 18d (450 mg, yield: 100%). LCMS (ESI) m / z: [M+H] + =110.95.

[0231] Step 3: Compound 18d (100 mg, 0.68 mmol) and compound 18e (172.04 mg, 0.68 mmol) were dissolved in EtOH / 4M HCl Dioxane (3 mL) at room temperature, and the reaction solution was stirred at 90°C for 2 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo to obtain a crude product. The crude product was purified by prep-HPLC (Column: Gemini, ACN-H 2 O (0.1% FA)) to obtain compound C018 (24.08 mg, yield: 10.3%). LCMS (ESI) m / z: [M+H] + =345.9. 1H NMR (400MHz, DMSO) δ8.96(s,1H),8.69(s,1H),8.55(d,J=6.2Hz,2H),7.97(d,J=6.9Hz,1H),7.36-7.31(m,3H),7.06-7.02(m,2H),2.55(s,3H).

[0232] Example 12 Preparation of Compound C028

[0233]

[0234] Step 1

[0235] The compound tert-butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate (300 mg, 1.24 mmol) was dissolved in THF (10 mL) at room temperature, and N-hydroxyphthalimide (223 mg, 1.37 mmol), triphenylphosphine (423 mg, 1.61 mmol) and DIAD (326 mg, 1.61 mmol) were added. The reaction liquid was stirred at room temperature for 16 hours under nitrogen. TLC showed that the reactants were completely converted and new spots were detected. The reaction solution was concentrated in vacuo to obtain a crude product. It was purified by silica gel chromatography (petroleum ether: ethyl acetate = 0-22%) to obtain compound 28a (451 mg, yield: 93.88%).

[0236] Step 2

[0237] Compound 28a (451 mg, 1.17 mmol) was dissolved in ethanol (5 mL) at room temperature, hydrazine hydrate (1290 mg, 20.58 mmol, 80%) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated in vacuo to obtain a crude product. It was then dissolved in methyl tert-butyl ether (20 mL) and slurried for half an hour, filtered, and concentrated in vacuo to obtain a crude compound 28b (299 mg).

[0238] Step 3

[0239] Compound 28b (230 mg, 1.00 mmol) was dissolved in methanol (20 mL) at room temperature, and compound intermediate 1c (299 mg, 1.17 mmol) and acetic acid (60 mg, 1.0 mmol) were added, and the reaction solution was stirred at 80 ° C for 16 hours under nitrogen. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo to obtain a crude product. Purification by silica gel chromatography (petroleum ether: ethyl acetate = 0-32%) gave compound 28c (193 mg).

[0240] LCMS(ESI)m / z:[M+H] + =468.3.

[0241] Step 4

[0242] Compound 28c (87 mg, 0.19 mmol) was dissolved in dioxane hydrochloride (3 mL, 4 M) at room temperature, and the reaction solution was stirred at room temperature for 1 hour. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo to obtain compound C028 (68 mg). LCMS (ESI) m / z: [M+H] + =368.2.

[0243] Example 13: Preparation of Compound C029

[0244]

[0245] Step 1

[0246] The compound 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1 g, 4.69 mmol) was dissolved in THF (10 mL) at room temperature, and N-hydroxyphthalimide (0.84 g, 5.16 mmol), triphenylphosphine (1.60 g, 6.10 mmol) and DIAD (1.23 g, 6.10 mmol) were added. The reaction liquid was stirred at room temperature for 16 hours under nitrogen. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo to obtain a crude product. It was purified by silica gel chromatography (petroleum ether: ethyl acetate = 0-27%) to obtain compound 29a (1.6 g, yield: 95.21%). LCMS (ESI) m / z: [M+Na] + =381.1.

[0247] Step 2

[0248] Compound 29a (1.6 g, 4.46 mmol, purity 100%) was dissolved in ethanol (50 mL) at room temperature, hydrazine hydrate (0.28 g, 4.46 mmol) was added, and the reaction solution was stirred at 80°C for 2 hours. The reaction solution was filtered and concentrated in vacuo to obtain a crude product. Then, methyl tert-butyl ether (30 mL) was used for slurrying for 1 hour, filtered, and concentrated in vacuo to obtain a crude compound 29b (1 g).

[0249] Step 3

[0250] Compound 29b (300 mg, 1.31 mmol) was dissolved in methanol (5 mL) at room temperature, and compound 3f (600 mg, 2.63 mmol) and acetic acid (78.67 mg, 1.31 mmol) were added, and the reaction solution was stirred at 80 ° C for 16 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was poured into water (50 mL), then extracted with dichloromethane (30 mL * 2), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product. Purification by silica gel chromatography (petroleum ether: ethyl acetate = 0-30%) gave compound 29d (243 mg, yield: 42.25%).

[0251] LCMS(ESI)m / z:[M+H] + =440.3.

[0252] Step 4

[0253] Compound 29d (246 mg, 0.56 mmol) was dissolved in dioxane hydrochloride (3 mL, 4 M) at room temperature, and the reaction solution was stirred at room temperature for 1 hour. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo to obtain compound C029 (190 mg,). LCMS (ESI) m / z: [M+H] + =340.2.

[0254] Example 14: Preparation of Compound C030

[0255]

[0256] Step 1

[0257] The compound 9-hydroxy-3-aza-spiro [5.5] undecane-3-carboxylic acid tert-butyl ester (300 mg, 1.11 mmol) was dissolved in THF (5 mL) at room temperature, N-hydroxyphthalimide (199 mg, 1.22 mmol), triphenylphosphine (378 mg, 1.44 mmol) and DIAD (292 mg, 1.44 mmol) were added, and the reaction liquid was stirred at room temperature for 16 hours under nitrogen. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo to obtain a crude product. Purification by silica gel chromatography (petroleum ether: ethyl acetate = 0-27%) gave compound 30a (410 mg, yield: 88.82%).

[0258] LCMS(ESI)m / z:[M+Na] + =437.2.

[0259] Step 2

[0260] Compound 30a (410 mg, 0.99 mmol) was dissolved in ethanol (5 mL) at room temperature, hydrazine hydrate (0.31 g, 4.95 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo to obtain a crude product. Then, methyl tert-butyl ether (10 mL) was used for slurrying for 1 hour. Filtered and concentrated in vacuo to obtain a crude compound 30b (280 mg).

[0261] Step 3

[0262] Compound 30b (300 mg, 1.31 mmol) was dissolved in methanol (5 mL) at room temperature, intermediate 1c (600 mg, 2.63 mmol) and acetic acid (79 mg, 1.31 mmol) were added, and the reaction solution was stirred at 80 ° C for 16 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was poured into water (50 mL), then extracted with dichloromethane (30 mL * 2), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product. Purification by silica gel chromatography (petroleum ether: ethyl acetate = 0-30%) gave compound 30c (243 mg, yield: 42.25%).

[0263] LCMS(ESI)m / z:[M+H] + =440.3.

[0264] Step 4

[0265] Compound 30c (400 mg, 0.81 mmol) was dissolved in dioxane hydrochloride (4 mL, 4 M) at room temperature, and the reaction solution was stirred at room temperature for 1 hour. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo to obtain compound C030 (319 mg). LCMS (ESI) m / z: [M+H] + =396.3.

[0266] Example 15: Preparation of Compound C031

[0267]

[0268] Step 1

[0269] The compound 7-BOC-7-azaspiro [3.5] nonane-2-methanol (500 mg, 1.96 mmol) was dissolved in THF (10 mL) at room temperature, N-hydroxyphthalimide (384 mg, 2.35 mmol), triphenylphosphine (668 mg, 2.55 mmol) and DIAD (515 mg, 2.55 mmol) were added, and the reaction liquid was stirred at room temperature for 16 hours under nitrogen. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo to obtain a crude product. Purification by silica gel chromatography (petroleum ether: ethyl acetate = 0-18%) gave compound 31a (701 mg, yield: 89.40%).

[0270] LCMS(ESI)m / z:[M+Na] + =423.5.

[0271] Step 2

[0272] Compound 31a (701 mg, 1.75 mmol) was dissolved in ethanol (10 mL) at room temperature, hydrazine hydrate (515 mg, 8.23 ​​mmol, 80%) was added, and the reaction solution was stirred at 80 ° C for 2 hours under nitrogen. The reaction solution was filtered and concentrated in vacuo to obtain a crude product. Then, methyl tert-butyl ether (30 mL) was used for slurrying for half an hour, filtered, and concentrated in vacuo to obtain a crude compound 31b (473 mg).

[0273] Step 3

[0274] Compound 31b (150 mg, 0.65 mmol) was dissolved in methanol (10 mL) at room temperature, and compound 31c (236 mg, 0.87 mmol) and acetic acid (78 mg, 1.30 mmol) were added, and the reaction solution was stirred at 80 ° C for 5 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo to obtain a crude product. Purification by silica gel chromatography (petroleum ether: ethyl acetate = 0-29%-33%) gave compound 31d (376 mg).

[0275] LCMS(ESI)m / z:[M+H] + =382.3.

[0276] Step 4

[0277] Compound 31d (152 mg, 0.32 mmol) was dissolved in dioxane hydrochloride (4 mL, 4 M) at room temperature, and the reaction solution was stirred at room temperature for 1 hour. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo to obtain compound C031 (120 mg). LCMS (ESI) m / z: [M+H] + =382.2

[0278] Example 16: Preparation of Compound C032

[0279]

[0280] Step 1

[0281] Dissolve diphenylphosphonylhydroxylamine (200 mg, 0.86 mmol) in tetrahydrofuran (20 mL) at room temperature, add N-Boc-4-hydroxypiperidine (173 mg, 0.86 mmol), add sodium tert-butoxide (165 mg, 1.72 mmol) at 0°C, raise the temperature to 25°C and react for 12 hours. TLC detection shows that the raw material disappears, add 10 mL of water, stir at room temperature for 2 hours, LCMS shows that the reaction is complete, add water (10 mL) after the reaction is completed, extract with ethyl acetate (10 mL x 3), combine the organic phases and wash with saturated brine (2*20 mL); take the organic layer, wash with Na 2 SO 4 Dry, filter and rotary evaporate to obtain compound 32a (100.5 mg, yield: 50.2%).

[0282] LCMS(ESI)m / z:[M+H] + =232.3.

[0283] Step 2

[0284] 3f (100 mg, 0.43 mmol) was dissolved in methanol (5 mL) at room temperature, and compound 32a (100.5 mg, 0.43 mmol) and compound glacial acetic acid (51.1 mg, 0.86 mmol) were added. The temperature was raised to 75 °C for 12 hours. LCMS showed that the reaction was complete. After the reaction was completed, water (15 mL) was added, and ethyl acetate (10 mL x 3) was extracted. The organic phases were combined and washed with saturated brine (2*20 mL). The organic layer was taken and washed with Na 2 SO 4 The residue was dried, filtered and rotary evaporated; the crude product was analyzed by Pre-TLC (petroleum ether:ethyl acetate=1:1) to obtain compound 32b (50.2 mg, yield: 26.2%).

[0285] LCMS(ESI)m / z:[M+H] + =445.2.

[0286] Step 3

[0287] Compound 32b (50 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL) and methanol (2 mL) at room temperature, HCl / dioxane (0.3 mL) was added, and the reaction solution was stirred at 25°C for 2 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated under vacuum to obtain compound C032 (35 mg, yield: 92.4%).

[0288] LCMS(ESI)m / z:[M+H] + =345.3.

[0289] Example 17: Preparation of Compound C033

[0290]

[0291] Step 1

[0292] N-hydroxyphthalimide (1.0 g, 6.13 mmol) was dissolved in THF (20 mL) at 0 ° C, 5-hydroxyhexahydrocyclopenta [C] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (1.39 g, 6.13 mmol) and triphenylphosphine (2.41 g, 9.2 mmol) were added, DIAD (1.86 g, 9.2 mmol) was added to the reaction solution at 0 ° C, and stirred at 25 ° C for 12 hours. LCMS showed that the reactants were completely converted and the product was detected. After the reaction was completed, water (30 mL) was added, and ethyl acetate (30 mL x3) was extracted, the organic phases were combined and washed with saturated brine (2*50 mL); the organic layer was taken and washed with Na 2 SO 4 Dry, filter and rotavap; purify by silica gel chromatography (petroleum ether: ethyl acetate = 0-38%) to obtain compound 33a (1.26 g, yield: 55.3%). LCMS (ESI) m / z: [M+H] + =372.2.

[0293] Step 2

[0294] Compound 33a (1.26 g, 3.38 mmol) was dissolved in ethanol (20 mL) at room temperature, 80% hydrazine hydrate (0.5 mL) was added, and the reaction solution was stirred at 25°C for 2 hours. LCMS showed that the reactants were completely converted. The crude product was filtered, and the filter cake was washed with methyl tert-butyl ether (20 mL). The filtrate was concentrated under vacuum to obtain a crude product, which was slurried with methyl tert-butyl ether (20 mL) to obtain compound 33b (0.71 g).

[0295] Step 3

[0296] 33b (250 mg, 1.09 mmol) was dissolved in methanol (10 mL) at room temperature, AcOH (0.05 mL) was added, the reaction solution was stirred at 25°C for 10 minutes, compound 113b (527.5 mg, 2.18 mmol) was added, the temperature was raised to 75°C and the reaction was carried out for 12 hours. LCMS showed that the reaction was complete, and a large amount of solid was precipitated after cooling to room temperature. The filter cake was washed with methanol to obtain compound 33c (190.0 mg, yield: 38.5%). LCMS (ESI) m / z: [M+H] + =453.3.

[0297] Step 4

[0298] Compound 33c (100.0 mg, 0.22 mmol) was dissolved in dichloromethane (2 mL) and methanol (2 mL) at room temperature, and dioxane hydrochloride (0.5 mL, 4 M) was added, and the reaction solution was stirred at 25°C for 2 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated under vacuum to obtain compound C033 (66.0 mg, yield: 84.2%). LCMS (ESI) m / z: [M+H] + =353.3.

[0299] Example 18 Preparation of Compound C034

[0300]

[0301] Step 1

[0302] N-hydroxyphthalimide (150 mg, 0.92 mmol), triphenylphosphine (310 mg, 1.2 mmol), N-Boc-4-piperidinol (200 mg, 0.92 mmol) were dissolved in anhydrous THF (10 mL) at room temperature. After nitrogen replacement three times, DIAD (242 mg, 1.2 mmol) was slowly added under ice bath. The temperature was slowly raised from ice bath to room temperature and reacted overnight. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was then quenched, extracted with dichloromethane three times, the organic phase was collected, dried and concentrated, and then purified by chromatography column. Purification with EA:PE = 50% gave 34a (125 mg, yield 40%). LCMS (ESI) m / z: [M+H] + =360.2.

[0303] Step 2

[0304] 34a (125 mg, 0.36 mmol) was dissolved in ethanol (5 mL) at room temperature, and 0.5 mL (1 M) of hydrazine hydrate was added. After reacting at room temperature for 30 min, a solid was generated. The solid was filtered, the filtrate was spin-dried, and methyl tert-butyl ether was added to make a pulp. After filtering, the filtrate was collected and spin-dried for use. No purification was required in this step to obtain 34b (78 mg, 0.36 mmol). LCMS (ESI) m / z: [M+H] + =230.3.

[0305] Step 3

[0306] 34b (78 mg, 0.36 mmol), 3f (74 mg, 0.35 mmol), acetic acid (10 mg, 0.1 mmol) were dissolved in methanol (5 mL) at room temperature and heated under reflux at 60 degrees Celsius for 16 h. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was then quenched, extracted three times with dichloromethane, and the organic phase was collected, dried and concentrated, and then purified by chromatography, methanol: dichloromethane = 10%, to obtain 34c (64 mg, yield 45%). LCMS (ESI) m / z: [M+H] + =441.2.

[0307] Step 4

[0308] The reactant 34c (64 mg, 0.14 mmol) was added to the reaction bottle, followed by 1 mL (4 M) of dioxane hydrochloride solution, and stirred at room temperature for 1 h. The reaction was complete when detected by LCMS. The reaction solution was directly spin-dried and then freed with saturated sodium bicarbonate to obtain C034. LCMS (ESI) m / z: [M+H] + =341.2.

[0309] Example 19: Preparation of Compound C035

[0310]

[0311] / Step 1

[0312] N-hydroxyphthalimide (2.0 g, 12.26 mmol) was dissolved in THF (20 mL) at 0 ° C, 2-hydroxy-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester (3.55 g, 14.71 mmol) and triphenylphosphine (4.82 g, 18.39 mmol) were added, DIAD (3.72 mg, 18.39 mmol) was added to the reaction solution at 0 ° C, and stirred at 25 ° C for 12 hours under nitrogen protection. LCMS showed that the reactants were completely converted and the product was detected. After the reaction was completed, water (30 mL) was added, and ethyl acetate (30 mL x3) was extracted, the organic phases were combined and washed with saturated brine (2*50 mL); the organic layer was taken and washed with anhydrous Na2 SO 4 The residue was dried, filtered and evaporated by rotary evaporation; the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 0%-35%) to give compound 35a (1.83 g, yield: 37.3%).

[0313] LCMS(ESI)m / z:[M+H] + =386.4.

[0314] Step 2

[0315] Compound 35a (1.83 g, 4.66 mmol) was dissolved in ethanol (20 mL) at room temperature, 80% hydrazine hydrate (0.5 mL) was added, and the reaction solution was stirred at 25°C for 2 hours. LCMS showed that the reactants were completely converted. The mixture was filtered, the filter cake was washed with methyl tert-butyl ether (20 mL), and the filtrate was concentrated under vacuum to obtain a crude product, which was slurried with methyl tert-butyl ether (20 mL) to obtain compound 35b (1.2 g).

[0316] Step 3

[0317] 3f (500 mg, 2.18 mmol) was dissolved in methanol (10 mL) at room temperature, and compound AcOH (0.1 mL) was added. The reaction solution was stirred at 25°C for 10 minutes, and compound 35b (838 mg, 3.27 mmol) was added. The temperature was raised to 75°C for 12 hours. LCMS showed that the reaction was completed. The solution was cooled to room temperature, and a large amount of solid precipitated. The solution was filtered and the filter cake was washed with methanol to obtain compound 35c (560 mg).

[0318] LCMS(ESI)m / z:[M+H] + =467.3.

[0319] Step 4

[0320] Compound 35c (560 mg, 1.2 mmol) was dissolved in dichloromethane (6 mL) and methanol (6 mL) at room temperature, and dioxane hydrochloride (2 mL) was added, and the reaction solution was stirred at 25°C for 2 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated under vacuum to obtain compound C035 (350 mg).

[0321] LCMS(ESI)m / z:[M+H] + =367.4.

[0322] Example 20: Preparation of Compound C036

[0323]

[0324] Step 1

[0325] Compound 6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester (500mg, 2.34mmol) was dissolved in tetrahydrofuran (10mL) under an ice bath, N-hydroxyphthalimide (420mg, 2.57mmol), triphenylphosphine (740mg, 2.81mmol) and DIAD (570mg, 2.81mmol) were added, and the reaction solution was stirred at room temperature for 16 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo to obtain a crude product. Purification by silica gel chromatography (petroleum ether: ethyl acetate = 0-22%) gave compound 36a (430mg, yield: 51.18%).

[0326] LCMS(ESI)m / z:[M+Na] + =381.2.

[0327] Step 2

[0328] Compound 36a (430 mg, 1.20 mmol) was dissolved in ethanol (10 mL) at room temperature, hydrazine hydrate (75 mg, 1.2 mmol, purity 80%) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtered and concentrated in vacuo to obtain a crude product, which was then slurried with methyl tert-butyl ether (30 mL), filtered, and concentrated in vacuo to obtain a crude compound 36b (270 mg).

[0329] Step 3

[0330] 3f (200 mg, 0.87 mmol) was dissolved in methanol (5 mL) at room temperature, compound 57b (270 mg, 1.18 mmol) and acetic acid (104 mg, 1.74 mmol) were added, and the reaction solution was stirred at 80 ° C for 16 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo to obtain a crude product. It was purified by silica gel chromatography (petroleum ether: ethyl acetate = 0-32%) to obtain compound 36c (383 mg).

[0331] LCMS(ESI)m / z:[M+H] + =440.3.

[0332] Step 4

[0333] Compound 36c (383 mg, 0.87 mmol) was dissolved in dioxane hydrochloride (4 mL, 4 M) at room temperature, and the reaction solution was stirred at room temperature for 16 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo, then dissolved in saturated sodium carbonate solution (30 mL), and then extracted with dichloromethane (30 mL*2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain compound C036 (208 mg, yield 70.33%). LCMS (ESI) m / z: [M+H] + =340.2.

[0334] Example 21: Preparation of Compound C037

[0335]

[0336] Step 1

[0337] The compound N-hydroxyphthalimide (150mg, 0.92mmol) was dissolved in THF (10mL) at room temperature, triphenylphosphine (310mg, 1.2mmol) and 6-(BOC-amino)-1-hexanol (200mg, 0.92mmol) were added under ice bath, nitrogen was replaced three times, DIAD (242mg, 1.2mmol) was slowly added under ice bath, the temperature was slowly warmed from ice bath to room temperature and stirred for 16 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was poured into water (50mL), then extracted with DCM (30mL*2), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product. Compound 37a (105mg, yield: 30%) was purified by silica gel chromatography (petroleum ether: ethyl acetate = 0-50%).

[0338] LCMS(ESI)m / z:[M+H] + =362.1.

[0339] Step 2

[0340] Compound 37a (105 mg, 0.3 mmol) was dissolved in EtOH (5 mL) at room temperature, and hydrazine hydrate (0.5 mL, 80%) was added. After stirring at room temperature for 30 min, a white solid was generated. The white solid was filtered, the filtrate was spin-dried, and methyl tert-butyl ether was added to slurry. After filtering, the filtrate was collected and spin-dried for use. No purification was required in this step to obtain a crude compound 37b (67 mg).

[0341] LCMS(ESI)m / z:[M+H] + =232.2.

[0342] Step 3

[0343] Compound 37b (67 mg, 0.3 mmol) was dissolved in methanol (5 mL) at room temperature, and compound intermediate 1c (69 mg, 0.3 mmol) and AcOH (10 mg, 0.1 mmol) were added. The reaction solution was stirred at 60 ° C for 16 h. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was poured into water (50 mL), then extracted with DCM (30 mL*2), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product. Compound 37c (66 mg, yield: 47%) was obtained by silica gel chromatography (methanol: dichloromethane = 0-10%).

[0344] LCMS(ESI)m / z:[M+H] + =443.2.

[0345] Step 4

[0346] The reactant 37c (66 mg, 0.14 mmol) was dissolved in methanol (1 mL) at room temperature, and a dioxane hydrochloride solution (1 mL, 4 M) was added at room temperature and stirred for 1 h. LCMS showed that the reactant was completely converted and the product was detected. The reaction solution was directly dried to obtain compound C037 (51 mg). LCMS (ESI) m / z: [M+H] + =343.2.

[0347] Example 22: Preparation of Compound C038

[0348]

[0349] Step 1

[0350] The compound 1-N-BOC-4-acetylpiperidine (2g, 8.80mmol) was dissolved in methanol (20mL) at room temperature, sodium borohydride (0.50g, 13.20mmol) was added under ice bath, and the reaction solution was stirred at room temperature for 2 hours. TLC showed that the reactants were completely converted and new spots were detected. The reaction solution was poured into water (30mL), then extracted with dichloromethane (30mL*2), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product. Purification by silica gel chromatography (petroleum ether: ethyl acetate = 0-22%) gave compound 38a (1.96g, yield: 97.14%).

[0351] Step 2

[0352] Compound 38a (1.96 g, 8.55 mmol) was dissolved in THF (50 mL) at room temperature, N-hydroxyphthalimide (1.67 g, 10.26 mmol), triphenylphosphine (2.92 g, 11.12 mmol) and DIAD (2.25 g, 11.12 mmol) were added, and the reaction solution was stirred at room temperature for 16 hours. TLC showed that the reactants were completely converted and new spots were detected. The reaction solution was concentrated in vacuo to obtain a crude product. Purification by silica gel chromatography (petroleum ether: ethyl acetate = 0-21%) gave compound 38b (3.1 g, yield: 96.87%).

[0353] Step 3

[0354] Compound 38b (3 g, 8.01 mmol) was dissolved in ethanol (30 mL) at room temperature, hydrazine hydrate (2.06 g, 32.92 mmol, Purity 80%) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtered and concentrated in vacuo to obtain a crude product. Then, methyl tert-butyl ether (30 mL) was used for slurrying for 30 minutes, filtered, and concentrated in vacuo to obtain a crude compound 38c (1.9 g).

[0355] Step 4

[0356] Compound 38c (300 mg, 1.31 mmol) was dissolved in methanol (5 mL) at room temperature, 104d (640 mg, 2.62 mmol) and acetic acid (0.16 g, 2.62 mmol) were added, and the reaction solution was stirred at 80 ° C for 16 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo to obtain a crude product. It was purified by silica gel chromatography (petroleum ether: ethyl acetate = 0-26%) to obtain compound 38e (577 mg, yield: 96.78%).

[0357] LCMS(ESI)m / z:[M+H] + =456.3.

[0358] Step 5

[0359] Compound 38e (577 mg, 1.27 mmol) was dissolved in dioxane hydrochloride (4 mL, 4 M) at room temperature, and the reaction solution was stirred at room temperature for 1 hour. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo to obtain compound C038 (450 mg).

[0360] LCMS(ESI)m / z:[M+H] + =356.3.

[0361] Example 23: Preparation of Compound C039

[0362]

[0363] Step 1

[0364] C034 (100 mg, 0.28 mmol) was dissolved in DMF (10 mL) at room temperature, and compound tert-butyl 4-(chloromethyl)-4-fluoropiperidin-1-carbonate (77.5 mg, 0.31 mmol) and potassium carbonate (77.3 mg, 0.56 mmol) were added, and the reaction solution was stirred for 2 hours. LCMS showed that the reactants were completely converted and the product was detected. 30 mL of water was added to the reaction solution to quench the reaction, extracted with DCM (30 mL*3), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product. Purified by silica gel chromatography (petroleum ether: ethyl acetate = 0-70%) to obtain compound 39a (120 mg, yield: 77.1%)

[0365] LCMS(ESI)m / z:[M+H] + =557.7.

[0366] Step 2

[0367] Compound 39a (120 mg, 0.22 mmol) was dissolved in HCl / Dioxane solution (10 mL) at room temperature and stirred for 12 hours. LCMS showed that the reactants were completely converted and the product was detected. The crude product was concentrated in vacuo. It was purified by silica gel chromatography (MeOH: DCM = 10%) to give compound C039 (98 mg).

[0368] LCMS(ESI)m / z:[M+H] + =457.6.

[0369] Example 24: Preparation of Compound C040

[0370]

[0371] Step 1

[0372] The compound dichloro-s-tetrazine (2.5 g, 16.56 mmol) was dissolved in toluene (30 mL) at room temperature, and ethyl ethynyl methanol (2.79 g, 33.12 mmol) was added. The reaction liquid was stirred at 110 ° C for 16 hours under nitrogen. The reaction liquid was concentrated in vacuo to obtain a crude product. It was purified by silica gel chromatography (petroleum ether: ethyl acetate = 0-15%) to obtain compound 40a (1.7 g, yield: 49.57%).

[0373] LCMS(ESI)m / z:[M+H] + =207.0.

[0374] Step 2

[0375] Compound 40a (1.7 g, 8.21 mmol) was dissolved in ethyl acetate (20 mL) at room temperature, IBX (4.60 g, 16.42 mmol) was added, and the reaction solution was stirred at 80 ° C for 5 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was filtered and concentrated in vacuo to obtain a crude product. It was purified by silica gel chromatography (petroleum ether: ethyl acetate = 0-12%) to obtain compound 40b (1.516 g, yield: 90.06%).

[0376] LCMS(ESI)m / z:[M+H] + =205.0.

[0377] Step 3

[0378] Compound 40b (1.516 g, 7.39 mmol) was dissolved in acetonitrile (10 mL) at room temperature, 2,4-dimethoxybenzylamine (1.48 g, 8.87 mmol) and DIPEA (1.91 g, 14.78 mmol) were added, and the reaction solution was stirred at 70 ° C for 4 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated, then dissolved in ethyl acetate (30 mL) and poured into water (50 mL), then extracted with ethyl acetate (30 mL * 2), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product. Purification by silica gel chromatography (petroleum ether: ethyl acetate = 0-27%) gave compound 40c (1.635 g, yield: 65.86%).

[0379] LCMS(ESI)m / z:[M+H] + =336.1.

[0380] Step 4

[0381] Compound 40c (1.635 g, 4.87 mmol) was dissolved in trifluoroacetic acid (10 mL) and dichloromethane (5 mL) at room temperature, and the reaction solution was stirred at room temperature for 48 hours. TLC showed that the reactants were completely converted and new spots were detected. The reaction solution was poured into water (50 mL), then extracted with DCM (30 mL*2), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product. Purification by silica gel chromatography (methanol: dichloromethane = 0-4%) gave compound 40d (0.85 g, yield: 94.05%).

[0382] Step 5

[0383] Compound 40d (0.85 g, 4.58 mmol) was dissolved in 1,4-Dioxane (20 mL) and Water (2 mL) at room temperature, 2-hydroxyphenylboronic acid (0.95 g, 6.87 mmol), cesium carbonate (2.98 g, 9.16 mmol) and XPhos G3 (0.19 g, 0.23 mmol) were added, and the reaction solution was stirred at 95 ° C for 16 hours under nitrogen. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was poured into water (50 mL), then extracted with ethyl acetate (30 mL * 2), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product. Purification by silica gel chromatography (petroleum ether: ethyl acetate = 0-38%) gave compound 40e (421 mg, yield: 37.79%).

[0384] LCMS(ESI)m / z:[M+H] + =244.1.

[0385] Step 6

[0386] Compound 40e (R0, 150 mg, 0.62 mmol) was dissolved in methanol (5 mL) at room temperature, intermediate 2b (286 mg, 1.24 mmol) and acetic acid (37.23 mg, 0.62 mmol) were added, and the reaction solution was stirred at 80 ° C for 16 hours under nitrogen. LCMS showed that most of the reactants were converted and the product was detected. The reaction solution was concentrated in vacuo to obtain a crude product. Purification by silica gel chromatography (petroleum ether: ethyl acetate = 0-23% ~ methanol: dichloromethane = 0-3%) gave compound 40f (280 mg, yield: 99.68%).

[0387] LCMS(ESI)m / z:[M+H] + =456.3.

[0388] Step 7

[0389] Compound 40f (280 mg, 0.61 mmol) was dissolved in dioxane hydrochloride (3 mL, 4 M) at room temperature, and the reaction solution was stirred at room temperature for 1 hour. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated in vacuo to obtain compound C040 (200 mg). LCMS (ESI) m / z: [M+H] + =356.2.

[0390] Example 25: Preparation of Compound C041

[0391]

[0392] Step 1

[0393] N-hydroxyphthalimide (1.0 g, 6.13 mmol) was dissolved in THF (20 mL) at 0 ° C, 4-hydroxycyclohexanecarboxylic acid methyl ester (968.5 mg, 6.13 mmol) and triphenylphosphine (2.41 g, 9.2 mmol) were added, DIAD (1.86 g, 9.2 mmol) was added to the reaction solution at 0 ° C, and stirred at 25 ° C for 12 hours. LCMS showed that the reactants were completely converted and the product was detected. After the reaction was completed, water (30 mL) was added, and ethyl acetate (30 mL x3) was extracted, the organic phases were combined and washed with saturated brine (2*50 mL); the organic layer was taken and washed with Na 2 SO 4 The reaction mixture was dried, filtered and rotary evaporated; the crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate=0-38%) to give compound 41a (1.26 g, yield: 68.3%).

[0394] LCMS (ESI) m / z: [M+H]+=303.31.

[0395] Step 2

[0396] Compound 41a (1.26 g, 4.15 mmol) was dissolved in ethanol (20 mL) at room temperature, 80% hydrazine hydrate (0.5 mL) was added, and the reaction solution was stirred at 25°C for 2 hours. LCMS showed that the reactants were completely converted. The mixture was filtered, the filter cake was washed with MTBE (20 mL), and the filtrate was concentrated under vacuum to obtain a crude product, which was slurried with MTBE (20 mL) to obtain compound 41b (0.71 g).

[0397] Step 3

[0398] Compound 3f (500 mg, 2.18 mmol) was dissolved in methanol (10 mL) at room temperature, and compound AcOH (0.1 mL) was added. The reaction solution was stirred at 25°C for 10 minutes, and compound 41b (565.2 mg, 3.27 mmol) was added. The temperature was raised to 75°C for 12 hours. LCMS showed that the reaction was completed. The solution was cooled to room temperature, and a large amount of solid precipitated. The solid was filtered and the filter cake was washed with methanol to obtain compound 41c (360 mg, yield: 43%).

[0399] LCMS(ESI)m / z:[M+H] + =384.4.

[0400] Step 4

[0401] Compound 41c (160 mg, 0.41 mmol) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL) and water (2 mL) at room temperature, and lithium hydroxide (80 mg, 2.0 mmol) was added. The reaction solution was stirred at 25°C for 12 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was added with 10 mL of water, 1N hydrochloric acid to adjust the pH to between 2-3, ethyl acetate (3*20 mL), the organic layers were combined and washed with saturated saline solution (3*20 mL), and the organic layers were combined with Na 2 SO 4 The solution was dried, filtered and concentrated under reduced pressure by rotary evaporation to obtain compound C041 (98 mg, yield: 64.6%).

[0402] LCMS(ESI)m / z:[M+H] + =370.1.

[0403] Example 26: Preparation of Compound C042

[0404]

[0405] Step 1

[0406] 3f (200 mg, 0.87 mmol) was dissolved in methanol (10 mL) at room temperature, 4-((aminooxy)methyl)cyclohexane-1-carboxylic acid methyl ester (196.3 mg, 1.05 mmol) and acetic acid (2 mL) were added, and the reaction solution was stirred at 60 ° C for 2 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was poured into water (50 mL), then extracted with dichloromethane (20 mL*2), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product. Purification by silica gel chromatography (methanol: dichloromethane = 0-12%) gave compound 42a (180 mg, yield: 51.78%)

[0407] LCMS(ESI)m / z:[M+H] + =399.5.

[0408] Step 2

[0409] Compound 42a (180 mg, 0.45 mmol) was dissolved in tetrahydrofuran: water = 4:1 (10 mL) system at room temperature, and lithium hydroxide (43.4 mg, 1.81 mmol) was added, and the reaction solution was stirred at room temperature for 1 hour. LCMS showed that the reactants were completely converted and the product was detected. 2N hydrochloric acid solution was added to adjust the pH to 4, the reaction solution was poured into water (50 mL), and then extracted with dichloromethane (20 mL*2), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain C042 (170 mg)

[0410] LCMS(ESI)m / z:[M+H] + =385.4.

[0411] Example 27: Preparation of Compound C043

[0412]

[0413] Step 1

[0414] Compound 43a (100 mg, 0.34 mmol) was dissolved in methanol (5 mL) at room temperature, and compound AcOH (0.1 mL) was added. The reaction solution was stirred at 25°C for 10 minutes, and compound 35b (130 mg, 0.51 mmol) was added. The temperature was raised to 75°C for 12 hours. LCMS showed that the reaction was completed. The solution was cooled to room temperature, and a large amount of solid precipitated. The solution was filtered and the filter cake was washed with methanol to obtain compound 43b (60 mg, yield: 33.1%).

[0415] LCMS(ESI)m / z:[M+H] + =533.2.

[0416] Step 2

[0417] Compound 43b (60 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL) and methanol (2 mL) at room temperature, HCl / dioxane (0.3 mL) was added, and the reaction solution was stirred at 25°C for 2 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated under vacuum to obtain compound C043 (45 mg, yield: 92.4%).

[0418] LCMS(ESI)m / z:[M+H] + =433.5.

[0419] Example 28 Preparation of Compound C044

[0420]

[0421] Step 1

[0422] Compound 44a (100 mg, 0.34 mmol) was dissolved in methanol (5 mL) at room temperature, and compound AcOH (0.1 mL) was added. The reaction solution was stirred at 25°C for 10 minutes, and compound 35b (130 mg, 0.51 mmol) was added. The temperature was raised to 75°C for 12 hours. LCMS showed that the reaction was completed. The solution was cooled to room temperature, and a large amount of solid precipitated. The solution was filtered and the filter cake was washed with methanol to obtain compound 44b (60 mg, yield: 33.1%).

[0423] LCMS(ESI)m / z:[M+H]+ =533.2.

[0424] Step 2

[0425] Compound 44b (60 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL) and methanol (2 mL) at room temperature, HCl / dioxane (0.3 mL) was added, and the reaction solution was stirred at 25°C for 2 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated under vacuum to obtain compound C044 (45 mg, yield: 92.4%).

[0426] LCMS(ESI)m / z:[M+H] + =433.5.

[0427] Embodiment 29

[0428]

[0429] Step 1

[0430] Compound 45a (150 mg, 0.62 mmol) was dissolved in methanol (5 mL) at room temperature, and AcOH (0.05 mL) was added. The reaction solution was stirred at 25°C for 10 minutes, and compound 33b (302 mg, 1.23 mmol) was added. The temperature was raised to 75°C for 12 hours. LCMS showed that the reaction was completed. The solution was cooled to room temperature, and solid precipitated. The solid was filtered and the filter cake was washed with methanol to obtain compound 45b (76.0 mg, yield: 26.3%).

[0431] LCMS(ESI)m / z:[M+H] + =467.2.

[0432] Step 2

[0433] Compound 45b (76.0 mg, 0.16 mmol) was dissolved in dichloromethane (2 mL) and methanol (2 mL) at room temperature, and dioxane hydrochloride (0.5 mL, 4 M) was added, and the reaction solution was stirred at 25°C for 2 hours. LCMS showed that the reactants were completely converted and the product was detected. The reaction solution was concentrated under vacuum to obtain compound C045 (52.0 mg, yield: 86.2%).

[0434] LCMS(ESI)m / z:[M+H] + =367.4.

[0435] Experimental example

[0436] Experimental Example 1: SMARCA2 activity test experiment

[0437] The HTRF method was used to test the inhibitory effect of compounds on SMARCA2 activity. SMARCA2 (ACTIVE MOTIF, Cat#81539) and H3 (GenScript, Cat#NJP23893) solutions were prepared in the reaction buffer (Epigeneous Binding Domain diluent buffer), and GST-Tb (Perkin Elmer, Cat#61GSTXLA) and SA-XL665 (Perkin Elmer, Cat#610SAXLB) mixed solutions were prepared in the reaction buffer (Epigeneous Binding Domain Detection buffer). The final concentrations of SMARCA2 and H3 in the reaction mixture were 10 nM and 50 nM, respectively.

[0438] Determination method:

[0439] 1. 0.1 μL of compound in 100% DMSO was delivered into a 384-well plate by acoustic liquid delivery technology (Echo 550; nanoliter range).

[0440] 2. Transfer 2.5 μL of SMARCA2 solution to a 384-well reaction plate and centrifuge at 1000 rpm for 1 minute.

[0441] 3. Transfer 2.5 μL of H3 solution to a 384 reaction plate and centrifuge at 1000 rpm for 1 minute, then incubate at 25°C for 15 minutes.

[0442] 4. Transfer 5 μL of GST-Tb&SA-XL665 mixed solution to a 384 reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 60 minutes.

[0443] 5. Read the HTRF signal (665 / 620) with BMG. Obtain IC50 values ​​and nonlinear regression curve fitting using GraphPad Prism software.

[0444] Experimental results:

[0445]

[0446]

[0447] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. Compounds of formula (I): or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, in: Dashed lines indicate the presence or absence of a bond; Indicates cis-trans, include X1 is selected from CH2, NH, O or S; R1 is selected from -C 1～8 Alkyl, -C 0～4 Alkylene-NHC 0～4 Alkyl, -C 0～4 Alkylene-C 3～8 Cycloalkyl, -C 0～4 Alkylene-3 to 8-membered heterocyclic group, -C 0～4 Alkylene-9-12 membered heterocyclic group; the alkyl, heterocyclic group, cycloalkyl and amino group in R1 may be optionally replaced by R x Replace 1 to 3 times; R2 is selected from hydrogen, -C 1～6 Alkyl, -C 0～3 Alkylene-C 3～6 Cycloalkyl, -C 0～3 Alkylene-3- to 6-membered heterocyclic group, aryl group and 5- to 6-membered heteroaryl group; the alkyl, heterocyclic group, cycloalkyl, aryl and heteroaryl group in R2 may be optionally replaced by R x Replace 1 to 3 times; R3 is independently selected from halogen, cyano, oxo, hydroxyl, C 1～3 Alkyl, C 1～3 Alkoxy and C 1～3 Haloalkyl; R4 is independently selected from hydrogen, C 1～6 Alkyl, C 1～6 Haloalkyl, C 3～6 Cycloalkyl, 3-6 membered heterocyclic group, aryl and 5-6 membered heteroaryl; the alkyl, heterocyclic group, cycloalkyl, aryl and heteroaryl in R4 may be optionally replaced by R x Replace 1 to 3 times; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; R x are independently selected from halogen, cyano, oxo, hydroxyl, amine, C 1～3 Alkyl, C 1～3 Alkoxy, -(C=O)OC 1～3 Alkyl and C 3～6 Cycloalkyl; said R x The alkyl, alkoxy and cycloalkyl groups in the above-mentioned groups may be optionally substituted by halogen for 1 to 3 times.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, characterized in that: The R1 is selected from -C 1～8 Alkyl, -C 0～4 Alkylene-NHC 0～4 Alkyl, -C 0～4 Alkylene-C 3～8 Cycloalkyl, -C 0～4 Alkylene-3 to 8-membered heterocyclic group; the alkyl, heterocyclic group, cycloalkyl and amino group in R1 may be optionally replaced by R x Replace 1 to 3 times.

3. The compound according to claim 1 or 2, wherein the compound has a structure as shown in formula (Ii): or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, in, represents a single bond or a double bond; Dashed lines indicate the presence or absence of a bond; Indicates cis-trans, include X1 is selected from CH2, NH or S; R1 is selected from -C 1～8 Alkyl, -C 0～4 Alkylene-NHC 0～4 Alkyl, -C 0～4 Alkylene-C 3～8 Cycloalkyl, -C 0～4 Alkylene-3 to 8-membered heterocyclic group, -C 0～4 Alkylene-9-12 membered heterocyclic group; the alkyl, heterocyclic group, cycloalkyl and amino group in R1 may be optionally replaced by R x Replace 1 to 3 times; Preferably, R1 is selected from -C 1～8 Alkyl, -C 0～4 Alkylene-NHC 0～4 Alkyl, -C 0～4 Alkylene-C 3～8 Cycloalkyl, -C 0～4 Alkylene-3 to 8-membered heterocyclic group; the alkyl, heterocyclic group, cycloalkyl and amino group in R1 may be optionally replaced by R x Replace 1 to 3 times; R2 is selected from hydrogen, -C 1～6 Alkyl, -C 0～3 Alkylene-C 3～6 Cycloalkyl, -C 0～3 Alkylene-3 to 6-membered heterocyclic group; the alkyl, heterocyclic group and cycloalkyl in R2 may be optionally replaced by R x Replace 1 to 3 times; R3 is independently selected from halogen, cyano, oxo, C 1～3 Alkyl and C 1～3 Haloalkyl; R4 is independently selected from hydrogen, C 1～3 Alkyl, C 1～3 haloalkyl and cyclopropyl; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; R x are independently selected from halogen, cyano, hydroxyl, amine, C 1～3 Alkyl, C 1～3 Alkoxy and C 3～6 Cycloalkyl; said R x The alkyl, alkoxy and cycloalkyl groups in the above-mentioned groups may be optionally substituted by halogen for 1 to 3 times.

4. The compound according to claim 1 or 2, wherein the compound has a structure as shown in formula (I-ii): in, Indicates cis-trans, include X1 is selected from CH2, NH or S; R1 is selected from -C 1～8 Alkyl, -C 0～4 Alkylene-NHC 0～4 Alkyl, -C 0～4 Alkylene-C 3～8 Cycloalkyl, -C 0～4 Alkylene-3 to 8-membered heterocyclic group, -C 0～4 Alkylene-9-12 membered heterocyclic group; the alkyl, heterocyclic group, cycloalkyl and amino group in R1 may be optionally replaced by R x Replace 1 to 3 times; Preferably, R1 is selected from -C 1～8 Alkyl, -C 0～4 Alkylene-NHC 0～4 Alkyl, -C 0～4 Alkylene-C 3～8 Cycloalkyl, -C 0～4 Alkylene-3 to 8-membered heterocyclic group; the alkyl, heterocyclic group, cycloalkyl and amino group in R1 may be optionally replaced by R x Replace 1 to 3 times; R2 is selected from hydrogen, -C 1～6 Alkyl, -C 0～3 Alkylene-C 3～6 Cycloalkyl, -C 0～3 Alkylene-3- to 6-membered heterocyclic group, aryl group and 5- to 6-membered heteroaryl group; the alkyl, heterocyclic group, cycloalkyl, aryl and heteroaryl group in R2 may be optionally replaced by R x Replace 1 to 3 times; R3 is independently selected from halogen, cyano, oxo, C 1～3 Alkyl and C 1～3 Haloalkyl; R4 is independently selected from hydrogen, C 1～3 Alkyl, C 1～3 haloalkyl and cyclopropyl; n is 0, 1, 2 or 3; m is 0, 1 or 2; R x are independently selected from halogen, cyano, hydroxyl, amine, C 1～3 Alkyl, C 1～3 Alkoxy and C 3～6 Cycloalkyl; said R x The alkyl, alkoxy and cycloalkyl groups in the above-mentioned groups may be optionally substituted by halogen for 1 to 3 times.

5. The compound according to claim 3, wherein the compound has a structure as shown in formula (Ii-1), formula (Ii-2) or formula (Ii-3): The remaining definitions are the same as those in formula (Ii).

6. The compound according to claim 4, wherein the compound has a structure as shown in formula (I-ii-1) or formula (I-ii-3): The remaining definitions are the same as those in formula (I-ii).

7. The compound according to claim 1 or 2, wherein R1 is independently selected from -CH2CH2CH3, -CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH2CH3, -CH2CH2NHCH3, -CH2CH2NH2, -CH2NHCH3, -CH2CH2NHCH2CH3, -CH2NHCH2CH3, -CH2CH2CH2NH2, -CH2CH2CH2NHCH3; the alkyl, heterocyclic, cycloalkyl and amine groups in R1 may be optionally replaced by R x Substituted 1 to 3 times; preferably R1 is selected from -CH2CH2CH3, -CH2CH2CH2CH3, -CH2CH2NHCH3, -CH2CH2NH2, -CH2NHCH3, -CH2CH2NHCH2CH3, -CH2NHCH2CH3, -CH2CH2CH2NH2, -CH2CH2CH2NHCH3; the alkyl, heterocyclic, cycloalkyl and amine groups in R1 may be optionally replaced by R x Replace 1 to 3 times; and / or, R2 is independently selected from -H, -CH3, -CH2CH3, -CH2CH(CH3)2, -CH(CH3)2, The alkyl and heterocyclic groups in R2 may be optionally substituted 1 to 3 times by halogen; and / or, R3 is independently selected from -F, -Cl, -Br, =O, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2Cl, CCl3, -CHCl2, -CH2CH2Cl, -CH2CCl3, -CH2F, -CF3, -CHF2, -CH2CH2F, -CH2CF3; and / or, R4 is independently selected from -H, -F, -Cl, -Br, -CH3, -CH2CH3, -CH(CH3)2, -CH2F, -CF3, -CHF2, -CH2CF3; and / or, X1 is selected from NH or S.

8. The compound according to claim 1 or 2, wherein R1 is independently selected from -CH2CH2NHCH3; and / or, R2 is independently selected from -H, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, and / or, R3 is independently selected from -F, -Cl, -CH3; and / or, R4 is independently selected from -H, -CH3; And / or, X is NH.

9. The compound according to claim 1, which is or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof.

10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

11. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof in the preparation of a SMARCA2 inhibitor-related drug; and / or use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating and / or preventing a SMARCA2-mediated disease or condition and related diseases or conditions.

12. A method for preventing and / or treating a SMARCA2-mediated disease or condition and related diseases or conditions in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

13. The use according to claim 11 or the method according to claim 12, wherein the SMARCA2-mediated disease or condition and related diseases or conditions are cancers or tumors, and the cancers or tumors are selected from non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophageal-gastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, hematological cancer, non-Hodgkin's lymphoma, small cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumors, uterine sarcoma, gastrointestinal stromal tumors, central nervous system cancer, thymic tumors, adrenocortical carcinoma, appendix cancer, small intestine cancer or penile cancer.

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