Spiro compound as KRAS mutant inhibitor

Abstract

Provided in the present invention is a compound of formula (X), or an isotopic variant, a tautomer or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as a KRAS mutant inhibitor. Further provided in the present invention are a pharmaceutical composition containing the compound, or the isotopic variant, the tautomer or the stereoisomer thereof, or the pharmaceutically acceptable salt thereof, and the use thereof in the treatment of cancers.

Description

Spirocyclic compounds as inhibitors of KRAS mutants Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to KRAS mutant inhibitors. Background Art

[0002] The human RAS gene family includes three types of RAS genes, KRAS, NRAS, and HRAS, encoding four different RAS proteins (KRAS-4A, KRAS-4B, NRAS, and HRAS). RAS proteins belong to the GTPase protein family. When bound to GDP, they are inactive, but when bound to GTP, they are active, which can lead to the activation of downstream signaling pathways such as RAF-MAPK and PI3K-Akt, resulting in cell anti-apoptosis and proliferation (Cell, 2017; 170(1): 17-33; Cell, 2020; 183(4): 850-859; Nat Rev Drug Discov, 2020; 19(8): 533-552.). Activating mutations of RAS genes are the most common oncogenic driver genes in human cancers, among which KRAS is the most common oncogenic activating mutation. For example, the mutation rate of KRAS in pancreatic cancer is 86-96%, in colorectal cancer is 40-54%, and in lung cancer is 27-39% (PNAS, 2019; 116(32): 15823-15829; Pathol Res Pract, 2009; 205, 858–862; Nature, 2012; 491, 399–405; Nature, 2014; 511, 543–550).

[0003] Oncogenic driver mutations can occur at multiple sites in the KRAS gene. The most common mutations occur at the G12 site, including G12C, G12D, G12V, etc. These mutations can reduce the GTPase activity of the KRAS protein, thereby causing the KRAS protein to be active for a long time, leading to malignant transformation of cells and the occurrence of cancer (Cell, 2017; 170(1): 17-33; Nat Rev Drug Discov, 2020; 19(8): 533-552). The types of KRAS mutations that frequently occur vary in different cancer types. For example, approximately 13% of lung cancer patients have G12C mutations (N Engl Med J, 2021; 384(25): 2382-2393); in pancreatic cancer, 33.8% of patients have G12D mutations and 40% of patients have G12V mutations, but only 1.7% of patients have G12C mutations; in colorectal cancer, approximately 10-12% of patients have G12D mutations, while the incidence of G12C mutations is less than 3% (Nat Rev Cancer 2018; 18(12): 767-777).

[0004] Unlike ATP-dependent protein kinases (proteins with micromolar affinity for ATP), KRAS proteins have picomolar affinity for GDP / GTP, making it difficult for compound molecules to effectively compete with GDP / GTP to inhibit the KRAS signaling pathway. This has seriously hindered the development of KRAS inhibitors (Cell, 2017; 170(1): 17-33; Cell, 2020; 183(4): 850-859; Nat Rev Drug Discov, 2020; 19(8): 533-552.). In recent years, non-GDP / GTP-competing "allosteric" binding cavities have been discovered on the KRAS protein that can effectively bind to small molecules. These findings have greatly promoted the development of targeted drugs targeting KRAS mutation-driven tumors. Currently, MRTX-849 (Adagrasib) and AMG510 (Sotorasib), which target KRAS G12C, have demonstrated excellent efficacy in clinical studies (N Engl J Med. 2020; 383(13):1207-1217; Cancer Discov. 2020; 10(1):54-71), and AMG510 and MRTX-849 have been successfully approved by the FDA for marketing. Compared with the development of KRAS G12C drugs, the development of drugs targeting KRAS G12D, G13D, G12V, G12R and other mutations is still in the early stages, and not many molecules have entered the clinic. Therefore, the development of pan-KRAS mutation inhibitors is of great significance. Summary of the Invention

[0005] In one aspect, the present invention provides a compound of formula (X), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0006] in,

[0007] Z is selected from O, S, SO2, CH2CH2, CH2 or NH;

[0008] Z1, Z2, Z3 are each independently selected from O, S or CH2;

[0009] X1 is selected from CH or N;

[0010] Y is selected from CR y or N;

[0011] R y Selected from H, halogen, CN, OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy or C 1-6 alkoxy;

[0012] R is selected from 5-12 membered heterocyclic group,

[0013] R1 is selected from H, halogen, CN, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl;

[0014] R2 is selected from 3-14 membered heterocyclic groups; said R2 is independently substituted by 1-3 R x replace;

[0015] R x Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy, -(CH2) p CN, NH2, OH, -O(CH2) p OR a 、-O(CH2) p N(R a )(R a '),-N(R a )-(CH2) p OR a 、-O(CH2) p -R a、-C(O)R a 、-C(O)OR a 、-(CH2) p -OR a 、-SR a 、-S(O)2-R a 、-(CH2) p -C(O)OR a 、-(CH2) p -OC(O)N(R a )(R a '),-N(R a )-C(O)OR a 、-N(R a )-S(O)2R a '、-N(R a )-S(O)R a 'or-OC(O)N(R a )(R a ');

[0016] R3 is selected from -NR m R n 、-SR m OR m ;

[0017] R m Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -LC(O)R a 、-LC(O)OR a 、-(CH2) p -OR a 、-S(O)2-R a , -L-5-12 membered heteroaryl, -L-phenyl or -L-5-6 membered heterocyclic group; the R m Optionally substituted with 1-6 halogens, NH2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, CN, -L-OR a 、-L-SR a 、-LN(R a )(R a '), -NH-(CH2) p -C(O)OR a 、C 3-6further substituted by cycloalkyl, 4-6 membered heterocyclyl or 5-12 membered heteroaryl;

[0018] R n Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -LC(O)R a 、-LC(O)OR a 、-(CH2) p -OR a or -S(O)2-R a ; the R n Optionally halogen, -OR a 、-SR a 、C 3-6 further substituted by cycloalkyl, 4-6 membered heterocyclyl or 5-12 membered heteroaryl;

[0019] When R m When selected from -L-5-12 membered heteroaryl, the 5-12 membered heteroaryl may be further substituted by 1-3 R p replace;

[0020] R p Selected from halogen, NH2, OH, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, CN, -L-OR a 、-L-SR a 、-LN(R a )(R a '), -NH-(CH2) p -C(O)OR a 、C 3-6 Cycloalkyl, 4-6 membered heterocyclyl or 5-12 membered heteroaryl;

[0021] L is selected from a bond, C 1-6 Alkylene or C 1-6 L can be optionally replaced by D, halogen, OH, C 1-6 Alkoxy or C 3-6 cycloalkyl substitution;

[0022] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group, C 3-6Cycloalkyl or 5-6 membered heteroaryl;

[0023] R a 'Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group or C 3-6 Cycloalkyl;

[0024] p is independently selected from 0, 1, 2, 3, 4 or 5.

[0025] In another aspect, the present invention provides a compound of the following formula (X), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0026] in,

[0027] Z is selected from O, S, SO2, CH2CH2, CH2 or NH;

[0028] Z1, Z2, Z3 are each independently selected from O, S or CH2;

[0029] X1 is selected from CH or N;

[0030] Y is selected from CR y or N;

[0031] R y Selected from H, halogen, CN, OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy or C 1-6 alkoxy;

[0032] R is selected from 5-12 membered heterocyclic group,

[0033] R1 is selected from H, halogen, CN, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl;

[0034] R2 is selected from 3-14 membered heterocyclic groups; said R2 is independently substituted by 1-3 R x replace;

[0035] R x Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6Alkoxy, -(CH2) p CN, NH2, OH, -O(CH2) p OR a 、-O(CH2) p N(R a )(R a '),-N(R a )-(CH2) p OR a 、-O(CH2) p -R a 、-C(O)R a 、-C(O)OR a 、-(CH2) p -OR a 、-SR a 、-S(O)2-R a 、-(CH2) p -C(O)OR a 、-(CH2) p -OC(O)N(R a )(R a '),-N(R a )-S(O)2R a '、-N(R a )-S(O)R a '、-OC(O)N(R a )(R a ');

[0036] R3 is selected from -NR m R n 、-SR m OR m ;

[0037] R m Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -LC(O)R a 、-LC(O)OR a 、-(CH2) p -OR a 、-S(O)2-R a , -L-5-12 membered heteroaryl, -L-phenyl, -L-5-6 membered heterocyclic group; the R m Optionally substituted with 1-6 halogens, NH2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C1-6 Haloalkoxy, CN, -L-OR a 、-L-SR a 、-LN(R a )(R a '), -NH-(CH2) p -C(O)OR a 、C 3-6 further substituted by cycloalkyl, 4-6 membered heterocyclyl or 5-12 membered heteroaryl;

[0038] R n Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -LC(O)R a 、-LC(O)OR a 、-(CH2) p -OR a or -S(O)2-R a ; the R n Optionally halogen, -OR a 、-SR a 、C 3-6 further substituted by cycloalkyl, 4-6 membered heterocyclyl or 5-12 membered heteroaryl;

[0039] When R m When selected from -L-5-12 membered heteroaryl, the 5-12 membered heteroaryl may be further substituted by 1-3 R p replace;

[0040] R p Selected from halogen, NH2, OH, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, CN, -L-OR a 、-L-SR a 、-LN(R a )(R a '), -NH-(CH2) p -C(O)OR a 、C 3-6 Cycloalkyl, 4-6 membered heterocyclyl or 5-12 membered heteroaryl;

[0041] L is selected from a bond, C 1-6 Alkylene or C 1-6 L may be optionally replaced by halogen, OH or C 1-6Alkoxy substitution;

[0042] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group, C 3-6 Cycloalkyl or 5-6 membered heteroaryl;

[0043] R a 'Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group or C 3-6 Cycloalkyl;

[0044] p is independently selected from 0, 1, 2, 3, 4 or 5.

[0045] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, and optionally a pharmaceutically acceptable excipient.

[0046] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, and further comprising another therapeutic agent.

[0047] In another aspect, the present invention provides use of a compound of the present invention in the preparation of a medicament for treating and / or preventing a disease mediated by a KRAS mutant.

[0048] In another aspect, the present invention provides a method for treating and / or preventing a KRAS mutant-mediated disease in a subject, comprising administering to the subject a compound or composition of the present invention.

[0049] In another aspect, the present invention provides a compound of the present invention or a composition of the present invention for use in treating and / or preventing a disease mediated by a KRAS mutant.

[0050] In a specific embodiment, the diseases treated by the present invention include cancers selected from the group consisting of acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelioma, hemangioma), appendix cancer, benign monoclonal gamma disease, bile duct cancer, bladder cancer, brain cancer (e.g., meningioma, glioma, e.g., astrocytoma, oligodendroglioma, medulloblastoma), bronchogenic carcinoma, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, large intestinal adenocarcinoma), epithelial cancer, ependymoma, endothelial sarcoma (e.g., Kaposi's sarcoma), cerebrospinal fluid (e.g., glioma ...cerebrospinal fluid (e.g., glioma, astrocytoma, oligodendroglioma, medulloblastoma), cerebrospinal fluid (e.g., glioma, astrocytoma, oligodendroglioma, sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's gland carcinoma), Ewing's sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), hypereosinophilia, gallbladder cancer, stomach cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma), oral cancer (e.g., oral squamous cell carcinoma), laryngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic cancer (e.g., leukemia, such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), Acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoma Plasma cell lymphoma, hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell non-Hodgkin lymphoma, such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (such as cutaneous T-cell lymphoma (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); mixtures of one or more of the above leukemias / lymphomas;Multiple myeloma (MM), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immune cell amyloidosis, kidney cancer (e.g., Wilms tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma, malignant hepatocellular carcinoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g., true Polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myeloid metaplasia (AMM), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES), neuroblastoma, neurofibromas (such as neurofibromatosis type 1 or type 2, schwannomatosis), neuroendocrine cancers (such as gastroenteropancreatic neuroendocrine tumors (GEP-NET), carcinoid tumors), osteosarcoma, ovarian cancer (such as cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, and penile cancer.

[0051] Other objects and advantages of the present invention will be apparent to those skilled in the art from the following detailed description, examples and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] FIG1 shows a schematic diagram of the inhibition mechanism of KRAS on state by a reaction inhibitor.

[0053] FIG2 shows the principle diagram of the inhibition of KRAS off state by SOS1 catalytic reaction inhibitors.

[0054] definition

[0055] Chemical definition

[0056] Definitions of specific functional groups and chemical terms are described in more detail below.

[0057] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-6 "Alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6、C 4-5 and C 5-6 alkyl.

[0058] “C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-5 Alkyl, C 1-4 Alkyl and C 1-2 Alkyl groups are preferred. 1-6 Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term “C 1-6 "Alkyl" also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0059] “C 2-6 "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl is preferred. 2-6 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. The term "C 2-6 "Alkenyl" also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). An alkenyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0060] “C 2-6 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 Alkynyl is preferred. 2-6Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), and the like. The term "C 2- "Alkynyl" also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0061] “C 1-6 "Alkylene" refers to the removal of C 1-6 In some embodiments, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3 Alkylene is preferred. Unsubstituted alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylenes, for example, alkylenes substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0062] “C 2-6 "Alkenylene" refers to the removal of C 2-6 In some embodiments, C 2-4Alkenylene is particularly preferred. Exemplary unsubstituted alkenylene groups include, but are not limited to, vinylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene groups, for example, alkenylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylene (-C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like.

[0063] “C 2-6 "Alkynylidene" refers to the removal of C 2-6 In some embodiments, C 2-4 Alkyne is particularly preferred. Exemplary alkynyl includes, but is not limited to, ethynyl (-C≡C-), substituted or unsubstituted propynyl (-C≡CCH2-), and the like.

[0064] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0065] Therefore, “C 1-6 "Haloalkyl" refers to the above-mentioned "C 1-6 Alkyl", which is substituted by one or more halogen groups. In some embodiments, C 1-4 Halogenated alkyl is particularly preferred, more preferably C 1-2 Haloalkyl. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. A haloalkyl group may be substituted at any available point of attachment, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Accordingly, "C 1-6 "Haloalkylene" and "C 1-5 "Haloalkylene" refers to the removal of C 1-6 Haloalkyl and C 1-5 The other hydrogen of the haloalkyl group is replaced to form a divalent group, and the group may be substituted or unsubstituted.

[0066] “C 1-6 "Alkoxy" refers to an -OR group, wherein R is a C1-6 Alkyl. C 1-4 Alkoxy groups are preferred.

[0067] “C 1-6 "Haloalkoxy" refers to "C 1-6 Alkoxy", which is substituted by one or more halogen groups. In some embodiments, C 1-4 Halogenated alkoxyalkyl is particularly preferred, more preferably C 1-2 Halogenated alkoxyalkyl.

[0068] “C 3-10 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 4-10 Cycloalkyl, C 5-10 Cycloalkyl, C 4-7 Cycloalkyl, C 3-7 Cycloalkyl, C 3-6 Cycloalkyl, C 3-5 Cycloalkyl and C 3-4 Cycloalkyl is particularly preferred, more preferably C 5-6 Cycloalkyl. Cycloalkyl also includes a ring system in which the above-mentioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such a case, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyls include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), and the like. The cycloalkyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0069] "3-14 membered heterocyclyl" refers to a group of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. In some embodiments, 5-14 membered heterocyclyl is preferred, which is a 5-14 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 5-12 membered heterocyclyl is preferred, which is a 5-12 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 4-10 membered heterocyclyl is preferred, which is a 4-10 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; in some embodiments, 5-10 membered heterocyclyl is preferred, which is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 5-8 membered heterocyclyl is preferred, which is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms system; in some embodiments, a 3-7 membered heterocyclyl is preferably a 3-7 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; a 3-6 membered heterocyclyl is preferably a 3-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 4-7 membered heterocyclyl is preferably a 4-7 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 4-6 membered heterocyclyl is preferably a 4-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 5-6 membered heterocyclyl is more preferably a 5-6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; a 3-5 membered heterocyclyl is more preferably a 3-5 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes a ring system in which the above-mentioned heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or a ring system in which the above-mentioned heterocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such a case, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyls containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiorenyl. Exemplary 4-membered heterocyclyls containing one heteroatom include, but are not limited to, azetidinyl, oxetane, and thiidine. Exemplary 5-membered heterocyclyls containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolane, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl.Exemplary 6-membered heterocyclyls containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyls containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyls containing three heteroatoms include, but are not limited to, hexahydrotriazinyl. Exemplary 7-membered heterocyclyls containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thienyl. Exemplary 5-membered heterocyclyls fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyls) include, but are not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrobenzopyranyl, tetrahydropyranopyridinyl, and the like. The heterocyclyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0070] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 Aryl also includes ring systems in which an aryl ring as described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Aryl groups can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0071] "5-14 membered heteroaryl" refers to a group of a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-mentioned heteroaryl rings are fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-12 membered heteroaryl is preferred, which is a 5-12 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5-10 membered heteroaryls are preferred, which are 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5-10 membered heteroaryls are preferred, which are 6-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5-9 membered heteroaryls are preferred, which are 5-9 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryls are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azacycloheptatrienyl, oxacycloheptatrienyl, and thiacycloheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanyl, and purinyl.Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. The heteroaryl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0072] "Cycloalkylene", "heterocyclylene", "arylene" or "heteroarylene" is a divalent group formed by removing another hydrogen from the above-defined "cycloalkyl", "heterocyclyl", "aryl" or "heteroaryl", and may be substituted or unsubstituted. For example, "C 5-7 "Cycloalkylene" refers to the removal of C 5-7 The "5-8 membered heterocyclylene" refers to a divalent group formed by removing another hydrogen atom of a 5-8 membered heterocyclyl. The "C 6-10 "Arylene" refers to the removal of C 6-10 The "5- to 6-membered heteroarylene group" refers to a divalent group formed by removing another hydrogen atom of a 5- to 6-membered heteroaryl group.

[0073] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like are defined herein as optionally substituted groups.

[0074] Exemplary substituents on carbon atoms include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa 、-ON(R bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2, -CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NRbb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(Rcc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa )2、-B(OR cc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0075] Or the two geminal hydrogen atoms on the carbon atom are replaced by groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa 、=NNR bb C(=O)OR aa 、=NNR bb S(=O)2R aa 、=NR bb or = NOR cc replace;

[0076] R aa Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R aa The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0077] R bb Each of the following is independently selected from: hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc)2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bb The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0078] R cc Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R cc The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0079] R dd Each of the is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee 、-ON(R ff )2、-N(R ff )2,、-N(R ff )3 + X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=O)N(R ff )2、-C(=NR ff )OR ee 、-OC(=NRff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee 、-SO2N(R ff )2, -SO2R ee 、-SO2OR ee 、-OSO2R ee 、-S(=O)R ee 、-Si(R ee )3、-OSi(R ee )3、-C(=S)N(R ff )2, -C(=O)SR ee 、-C(=S)SR ee 、-SC(=S)SR ee 、-P(=O)2R ee 、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may combine to form =O or =S;

[0080] R ee Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0081] R ff Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ff The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R gggroup substitution;

[0082] R gg Each of the independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - 、-NH(C 1-6 Alkyl)2 + X - 、-NH2(C 1-6 alkyl) + X - 、-NH3 + X - 、-N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1- 6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2、C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1- 6 alkyl) 2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, C3-C7 heterocyclic, C5-C 10 heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; wherein X - For the counter ion.

[0083] Exemplary substituents on nitrogen atoms include, but are not limited to, hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR bb )R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2Rcc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R attached to the nitrogen atom cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substituted, and wherein R aa 、R bb 、R cc and R dd As mentioned above.

[0084] Other definitions

[0085] As used herein, the term "pharmaceutically acceptable salt" refers to those carboxylate salts, amino acid addition salts of the compounds of the present invention that are suitable for use in contact with patient tissues within the scope of sound medical judgment, do not produce undue toxicity, irritation, allergic response, etc., are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the present invention.

[0086] "Subjects" to be administered include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0087] "Disease," "disorder," and "condition" are used interchangeably herein.

[0088] Generally, an "effective amount" of a compound is an amount sufficient to elicit the desired biological response. As will be appreciated by those skilled in the art, the effective amount of a compound of the invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. An effective amount includes both a therapeutically effective amount and a prophylactically effective amount.

[0089] "Combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and other therapeutic agents. For example, a compound of the invention can be administered simultaneously or sequentially with the other therapeutic agents in separate unit dosage forms, or can be administered simultaneously with the other therapeutic agents in a single unit dosage form. DETAILED DESCRIPTION

[0090] In one embodiment, the present invention provides a compound of formula (X), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0091] in,

[0092] Z is selected from O, S, SO2, CH2CH2, CH2 or NH;

[0093] Z1, Z2, Z3 are each independently selected from O, S or CH2;

[0094] X1 is selected from CH or N;

[0095] Y is selected from CR y or N;

[0096] R y Selected from H, halogen, CN, OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy or C 1-6 alkoxy;

[0097] R is selected from 5-12 membered heterocyclic group,

[0098] R1 is selected from H, halogen, CN, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl;

[0099] R2 is selected from 3-14 membered heterocyclic groups; said R2 is independently substituted by 1-3 R x replace;

[0100] R x Selected from H, C 1-6 Alkyl, deuterated C1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy, -(CH2) p CN, NH2, OH, -O(CH2) p OR a 、-O(CH2) p N(R a )(R a '),-N(R a )-(CH2) p OR a 、-O(CH2) p -R a 、-C(O)R a 、-C(O)OR a 、-(CH2) p -OR a 、-SR a 、-S(O)2-R a 、-(CH2) p -C(O)OR a 、-(CH2) p -OC(O)N(R a )(R a '),-N(R a )-S(O)2R a '、-N(R a )-S(O)R a '、-OC(O)N(R a )(R a ');

[0101] R3 is selected from -NR m R n 、-SR m OR m ;

[0102] R m Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -LC(O)R a 、-LC(O)OR a 、-(CH2) p -OR a 、-S(O)2-R a , -L-5-12 membered heteroaryl, -L-phenyl, -L-5-6 membered heterocyclic group; the R m Optionally substituted with 1-6 halogens, NH2, C1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, CN, -L-OR a 、-L-SR a 、-LN(R a )(R a '), -NH-(CH2) p -C(O)OR a 、C 3-6 further substituted by cycloalkyl, 4-6 membered heterocyclyl or 5-12 membered heteroaryl;

[0103] R n Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -LC(O)R a 、-LC(O)OR a 、-(CH2) p -OR a or -S(O)2-R a ; the R n Optionally halogen, -OR a 、-SR a 、C 3-6 further substituted by cycloalkyl, 4-6 membered heterocyclyl or 5-12 membered heteroaryl;

[0104] When R m When selected from -L-5-12 membered heteroaryl, the 5-12 membered heteroaryl may be further substituted by 1-3 R p replace;

[0105] R p Selected from halogen, NH2, OH, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, CN, -L-OR a 、-L-SR a 、-LN(R a )(R a '), -NH-(CH2) p -C(O)OR a 、C 3-6 Cycloalkyl, 4-6 membered heterocyclyl or 5-12 membered heteroaryl;

[0106] L is selected from a bond, C 1-6 Alkylene or C 1-6 L may be optionally replaced by halogen, OH or C 1-6 Alkoxy substitution;

[0107] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group, C 3-6 Cycloalkyl or 5-6 membered heteroaryl;

[0108] R a 'Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group or C 3-6 Cycloalkyl;

[0109] p is independently selected from 0, 1, 2, 3, 4 or 5.

[0110] In another more specific embodiment, the present invention provides a compound of formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0111] in,

[0112] Z is selected from O, S, SO2, CH2CH2, CH2 or NH;

[0113] X1 is selected from CH or N;

[0114] Y is selected from CR y or N;

[0115] R y Selected from H, halogen, CN, OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy or C 1-6 alkoxy;

[0116] R is selected from 5-12 membered heterocyclic group,

[0117] R1 is selected from H, halogen, CN, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl;

[0118] R2 is selected from 3-14 membered heterocyclic groups; said R2 is independently substituted by 1-3 R x replace;

[0119] R x Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy, -(CH2) p CN, NH2, OH, -O(CH2) p OR a 、-O(CH2) p N(R a )(R a '),-N(R a )-(CH2) p OR a 、-O(CH2) p -R a 、-C(O)R a 、-C(O)OR a 、-(CH2) p -OR a 、-SR a 、-S(O)2-R a 、-(CH2) p -C(O)OR a 、-(CH2) p -OC(O)N(R a )(R a '),-N(R a )-S(O)2R a '、-N(R a )-S(O)R a '、-OC(O)N(R a )(R a ');

[0120] R m Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -LC(O)R a 、-LC(O)OR a 、-(CH2) p -OR a 、-S(O)2-R a , -L-5-12 membered heteroaryl, -L-phenyl, -L-5-6 membered heterocyclic group; the R mOptionally substituted with 1-6 halogens, NH2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, CN, -L-OR a 、-L-SR a 、-LN(R a )(R a '), -NH-(CH2) p -C(O)OR a 、C 3-6 further substituted by cycloalkyl, 4-6 membered heterocyclyl or 5-12 membered heteroaryl;

[0121] R n Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -LC(O)R a 、-LC(O)OR a 、-(CH2) p -OR a or -S(O)2-R a ; the R n Optionally halogen, -OR a 、-SR a 、C 3-6 further substituted by cycloalkyl, 4-6 membered heterocyclyl or 5-12 membered heteroaryl;

[0122] When R m When selected from -L-5-12 membered heteroaryl, the 5-12 membered heteroaryl may be further substituted by 1-3 R p replace;

[0123] R p Selected from halogen, NH2, OH, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, CN, -L-OR a 、-L-SR a 、-LN(R a )(R a '), -NH-(CH2) p -C(O)OR a 、C 3-6Cycloalkyl, 4-6 membered heterocyclyl or 5-12 membered heteroaryl;

[0124] L is selected from a bond, C 1-6 Alkylene or C 1-6 L may be optionally replaced by halogen, OH or C 1-6 Alkoxy substitution;

[0125] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group, C 3-6 Cycloalkyl or 5-6 membered heteroaryl;

[0126] R a 'Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group or C 3-6 Cycloalkyl;

[0127] p is independently selected from 0, 1, 2, 3, 4 or 5.

[0128] In another more specific embodiment, the present invention provides a compound of formula (II), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0129] in,

[0130] Y is selected from CH, CCN, CF, CBr, CCl, CCF3, COCF3, COCH3, CCH3 or N;

[0131] R1 is selected from H, halogen, CN, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl;

[0132] R2 is selected from 3-14 membered heterocyclic groups; said R2 is independently substituted by 1-3 R x replace;

[0133] R x Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy, -(CH2) p CN, NH2, OH, -O(CH2)p OR a 、-O(CH2) p N(R a )(R a '),-N(R a )-(CH2) p OR a 、-O(CH2) p -R a 、-C(O)R a 、-C(O)OR a 、-(CH2) p -OR a 、-SR a 、-S(O)2-R a 、-(CH2) p -C(O)OR a 、-(CH2) p -OC(O)N(R a )(R a '),-N(R a )-S(O)2R a '、-N(R a )-S(O)R a '、-OC(O)N(R a )(R a ');

[0134] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group, C 3-6 Cycloalkyl or 5-6 membered heteroaryl;

[0135] R a 'Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group or C 3-6 Cycloalkyl;

[0136] p is independently selected from 0, 1, 2, 3, 4 or 5;

[0137] R3 is selected from The methyl hydrogen atom in the R3 substituent can be replaced by a deuterium atom.

[0138] In another more specific embodiment, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0139] in,

[0140] Y is selected from CH, CCN, CF, CBr, CCl, CCF3, COCF3, COCH3, CCH3 or N;

[0141] R1 is selected from H, halogen, CN, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl;

[0142] R2 is selected from

[0143] In another more specific embodiment, the present invention provides a compound of formula (III), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0144] in,

[0145] Z is selected from O, S, or CH2;

[0146] Y is selected from CH, CCN, CF, CBr, CCl, CCF3, COCF3, COCF2H, COCH3, CCH3 or N;

[0147] X1, X2, X3, X4, X5 are independently selected from CH, CR p or N;

[0148] R1 is selected from H, halogen, CN, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl;

[0149] R2 is selected from 5-14 membered heterocyclic groups; said R2 is independently substituted by 1-3 R x replace;

[0150] R x Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy, -(CH2) pCN, NH2, OH, -O(CH2) p OR a 、-O(CH2) p N(R a )(R a '),-N(R a )-(CH2) p OR a 、-O(CH2) p -R a 、-C(O)R a 、-C(O)OR a 、-(CH2) p -OR a 、-SR a 、-S(O)2-R a 、-(CH2) p -C(O)OR a 、-(CH2) p -OC(O)N(R a )(R a '),-N(R a )-S(O)2R a '、-N(R a )-S(O)R a '、-OC(O)N(R a )(R a ');

[0151] R m1 Selected from H, C 1-5 Alkyl, deuterated C 1-5 Alkyl or C 1-5 alkyl halide;

[0152] R m2 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or CN;

[0153] R n Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -LC(O)R a 、-LC(O)OR a 、-(CH2) p -OR a or -S(O)2-R a ;

[0154] Rp Selected from halogen, NH2, OH, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, CN, -L-OR a 、-L-SR a 、-LN(R a )(R a '), -NH-(CH2) p -C(O)OR a 、C 3-6 Cycloalkyl, 4-6 membered heterocyclyl or 5-12 membered heteroaryl;

[0155] L is selected from a bond, C 1-6 Alkylene or C 1-6 L may be optionally replaced by halogen, OH or C 1-6 Alkoxy substitution;

[0156] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group, C 3-6 Cycloalkyl or 5-6 membered heteroaryl;

[0157] R a 'Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group or C 3-6 Cycloalkyl;

[0158] p is independently selected from 0, 1, 2, 3, 4 or 5.

[0159] In another more specific embodiment, the present invention provides a compound of the following formula (III-1), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0160] in,

[0161] Y is selected from CH, CCN, CF, CBr, CCl, CCF3, COCF3, COCF2H, COCH3, CCH3 or N; X1, X2, X3 are independently selected from CH, CR p or N;

[0162] R1 is selected from H, halogen, CN, C 1-6 Alkyl, deuterated C1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl;

[0163] R2 is selected from 5-14 membered heterocyclic groups; said R2 is independently substituted by 1-3 R x replace;

[0164] R x1 Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Haloalkyl, -(CH2) p CN, -C(O)R a 、-C(O)OR a 、-(CH2) p -OR a 、-S(O)2-R a 、-(CH2) p -C(O)OR a or -(CH2) p -OC(O)N(R a )(R a ');

[0165] R x2 Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy, -(CH2) p CN, NH2, OH, -O(CH2) p OR a 、-O(CH2) p N(R a )(R a '),-N(R a )-(CH2) p OR a 、-O(CH2) p -R a 、-C(O)R a 、-C(O)OR a 、-(CH2) p -OR a 、-SR a 、-S(O)2-R a 、-(CH2) p -C(O)OR a 、-(CH2) p-OC(O)N(R a )(R a '),-N(R a )-S(O)2R a '、-N(R a )-S(O)R a '、-OC(O)N(R a )(R a ');

[0166] R m1 Selected from H, C 1-5 Alkyl, deuterated C 1-5 Alkyl or C 1-5 alkyl halide;

[0167] R m2 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or CN;

[0168] R n Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -LC(O)R a 、-LC(O)OR a 、-(CH2) p -OR a or -S(O)2-R a ;

[0169] R p Selected from halogen, NH2, OH, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, CN, -L-OR a 、-L-SR a 、-LN(R a )(R a '), -NH-(CH2) p -C(O)OR a 、C 3-6 Cycloalkyl, 4-6 membered heterocyclyl or 5-12 membered heteroaryl;

[0170] L is selected from a bond, C 1-6 Alkylene or C 1-6L may be optionally replaced by halogen, OH or C 1-6 Alkoxy substitution;

[0171] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group, C 3-6 Cycloalkyl or 5-6 membered heteroaryl;

[0172] R a 'Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group or C 3-6 Cycloalkyl;

[0173] p is independently selected from 0, 1, 2, 3, 4 or 5.

[0174] In another more specific embodiment, the present invention provides a compound of formula (IV), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0175] in,

[0176] Z is selected from O, S or CH2;

[0177] Y is selected from CH, CCN, CF, CBr, CCl, CCF3, COCF3, COCF2H, COCH3, CCH3 or N;

[0178] R1 is selected from H, F, CN, methyl, ethyl, deuterated methyl, trifluoromethyl, CH2F, CHF2 or cyclopropyl;

[0179] R x1 is selected from H, methyl, ethyl, deuterated methyl, trifluoroethyl, trifluoromethyl, difluoroethyl, -(CH2)2CN, -C(O)Me, -C(O)OMe, -(CH2)2-OH, -S(O)2-Me, -(CH2)2-C(O)OMe or -(CH2)2-OC(O)N(Me)2;

[0180] R x2 Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy, -(CH2) pCN, NH2, OH, -O(CH2) p OR a 、-O(CH2) p N(R a )(R a '),-N(R a )-(CH2) p OR a 、-O(CH2) p -R a 、-C(O)R a 、-C(O)OR a 、-(CH2) p -OR a 、-SR a 、-S(O)2-R a 、-(CH2) p -C(O)OR a 、-(CH2) p -OC(O)N(R a )(R a '),-N(R a )-S(O)2R a '、-N(R a )-S(O)R a '、-OC(O)N(R a )(R a ');

[0181] R m2 is selected from H, F, Cl, Br, I, OH, methyl, deuterated methyl, vinyl, propynyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, cyclopropyl, pyrrolidinyl, morpholinyl or CN;

[0182] R n is selected from H, methyl, deuterated methyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, -CH2-C(O)Me, -CH2-C(O)OMe, -(CH2)2-OMe or -S(O)2-Me;

[0183] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group, C 3-6 Cycloalkyl or 5-6 membered heteroaryl;

[0184] R a 'Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6Halogenated alkyl, 4-6 membered heterocyclic group or C 3-6 Cycloalkyl;

[0185] p is independently selected from 0, 1, 2, 3, 4 or 5.

[0186] In another more specific embodiment, the present invention provides the following compound, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which has the structure of formula (IV-1):

[0187] in,

[0188] Z is selected from O, S or CH2;

[0189] Y is selected from CH, CCN, C-halogen, CC 1-6 Alkyl or C 1-6 alkyl halide;

[0190] R1 is selected from C 1-6 Alkyl, deuterated C 1-6 Alkyl or C 1-6 alkyl halide;

[0191] R x1 Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl or C 1-6 alkyl halide;

[0192] R x2 Selected from H, C 1-6 Alkyl, halogen, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy, NH2, OH, -N(R a )-C(O)OR a 、-N(R a )-S(O)2R a 'or-N(R a )-S(O)R a ';

[0193] R m2 Selected from halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0194] R n Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl or C 1-6 alkyl halide;

[0195] R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl or C 1-6 alkyl halide;

[0196] R a 'Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0197] In another more specific embodiment, the present invention provides the following compound, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which has the structure of formula (IV-1):

[0198] in,

[0199] Z is selected from O, S or CH2;

[0200] Y is selected from CH, CCN, CF, CBr, CCl, CCF3 or CCH3;

[0201] R1 is selected from methyl, ethyl, deuterated methyl, trifluoromethyl, CH2F or CHF2;

[0202] R x1 is selected from H, methyl, ethyl, deuterated methyl, trifluoroethyl, trifluoromethyl or difluoroethyl;

[0203] R x2 Selected from H, C 1-6 Alkyl, F, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy, NH2, OH, -N(R a )-C(O)OR a 、-N(R a )-S(O)2R a 'or-N(R a )-S(O)R a ';

[0204] R m2 is selected from F, Cl, Br, methyl, deuterated methyl, trifluoromethyl, difluoromethyl, trifluoromethoxy or difluoromethoxy;

[0205] R n is selected from H, methyl, deuterated methyl, trifluoromethyl, difluoroethyl or trifluoroethyl;

[0206] R a Selected from H, C1-6 Alkyl, deuterated C 1-6 Alkyl or C 1-6 alkyl halide;

[0207] R a 'Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0208] In another more specific embodiment, the present invention relates to the following compound or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0209] In another more specific embodiment, the present invention relates to the following compound or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0210] The compounds of the present invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and / or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0211] The compounds of the present invention may also exist as tautomers. For compounds that exist in different tautomeric forms, a compound is not limited to any specific tautomer, but is intended to encompass all tautomeric forms.

[0212] The present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (A) except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl. Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes of other atoms, their prodrugs and pharmaceutically acceptable salts of the compounds or prodrugs are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those in which radioactive isotopes (e.g. 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. 2 H, because greater metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, and thus may be preferred in some cases. Isotopically labeled compounds of formula (A) of the present invention and prodrugs thereof can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when carrying out the processes disclosed in the following schemes and / or the Examples and Preparations.

[0213] Pharmaceutical compositions and kits

[0214] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present invention.

[0215] Pharmaceutically acceptable excipients used in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0216] The present invention also includes kits (e.g., pharmaceutical packaging). The kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compound of the invention and other therapeutic agents. In some embodiments, the kit provided may also optionally include a third container containing a pharmaceutical excipient for diluting or suspending the compound of the invention and / or other therapeutic agents. In some embodiments, the compound of the invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0217] Drug administration

[0218] Pharmaceutical compositions provided by the invention can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration by implant or other modes of administration. For example, parenteral administration used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration, intrathecal administration, intralesional administration, and intracranial injection or infusion technology.

[0219] Typically, an effective amount of the compounds provided herein is administered. The amount of compound actually administered can be determined by a physician based on the relevant circumstances, including the condition being treated, the route of administration selected, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0220] When used to prevent the conditions described herein, the compounds provided herein are administered to a subject at risk of developing the condition, typically based on the advice and under the supervision of a physician, at dosage levels as described above. Subjects at risk of developing a particular condition typically include those with a family history of the condition, or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0221] The pharmaceutical compositions provided herein can also be administered long-term ("chronic administration"). Long-term administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or administration can continue indefinitely, e.g., for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of the compound in the blood over an extended period of time, e.g., within the therapeutic window.

[0222] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by injection, for example, in order to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient by the body, for example, an intramuscular or subcutaneous bolus dose slowly releases the active ingredient, and the bolus (for example, by IV intravenous drip) delivered directly to the vein can be delivered more quickly so that the concentration of the active ingredient in the blood is rapidly increased to an effective level. In other embodiments, the pharmaceutical composition can be given in a continuous infusion form, for example, by IV intravenous drip, so as to provide a steady-state concentration of the active ingredient in the subject's body. In addition, in other embodiments, the pharmaceutical composition of the bolus dose can be first given, and then continuous infusion.

[0223] Oral compositions can be in the form of bulk liquid solutions or suspensions or bulk powders. However, more generally, in order to facilitate accurate dosing, the compositions are provided in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined amount of active substance suitable for producing the desired therapeutic effect and a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions. In such compositions, the compound is typically a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients and processing aids useful for forming the desired dosage form.

[0224] For oral dosage, a representative regimen is one to five oral doses per day, particularly two to four oral doses, typically three oral doses. Using these dosage administration modes, each dose provides about 0.01 to about 20 mg / kg of the compound of the invention, with preferred doses each providing about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg.

[0225] To provide blood levels similar to, or lower than, those obtained with an injectable dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.

[0226] From about 1 to about 120 hours, and particularly from 24 to 96 hours, the injected dose level is in the range of about 0.1 mg / kg / hour to at least 10 mg / kg / hour. To achieve adequate steady-state levels, a preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered. For a 40 to 80 kg human patient, the maximum total dose may not exceed about 2 g / day.

[0227] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous carrier and buffers, suspending and dispersing agents, colorants, flavorings, etc. Solid forms may include, for example, any of the following components, or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor.

[0228] Injectable compositions are typically based on sterile saline or phosphate buffered saline for injection, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.

[0229] Typically, transdermal compositions are formulated as topical ointments or creams containing the active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream together with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include other components that enhance the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided by the present invention.

[0230] The compounds of the present invention may also be administered by transdermal devices.Thus, transdermal administration may be achieved using patches of the reservoir or porous membrane type, or various solid matrices.

[0231] The above components for oral administration, injection or topical administration are representative only. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0232] The compounds of the invention can also be administered in sustained release form or from a sustained release delivery system. Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0233] The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins consisting of 6, 7, and 8 α-1,4-linked glucose units, respectively, which optionally include one or more substituents on the linked sugar portion, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US5,376,645. In some embodiments, the formulation includes hexapropyl-β-cyclodextrin (e.g., in water, 10-50%).

[0234] Example

[0235] The reagents used in the present invention are commercial reagents purchased directly or synthesized using common methods well known in the art.

[0236] Notes on commonly used abbreviations:

[0237] Example 1: Preparation of intermediates

[0238] Preparation of intermediates a1 and a33

[0239] Step 1: At 10°C, under nitrogen, starting material a1-1 (20.0 g, 117.5 mmol) and starting material allyl acetate a1-2 (15.3 g, 152.7 mmol) were dissolved in 51 mL of a mixture of toluene and water (v / v, 50 / 1). Tetramethylguanidine (27.1 g, 235.0 mmol) was added, and the mixture was stirred at 10°C for 30 minutes. The catalyst, allylpalladium chloride dimer (30 mg, 0.08 mmol), and the ligand (SS)-DACH-Phenyl Trost (130 mg, 0.19 mmol) were added to the reaction mixture. The reaction was continued at this temperature for 12 hours, after which the reaction was terminated. The mixture was added with 250 mL of saturated aqueous ammonium chloride, extracted with MTBE, dried over anhydrous sodium sulfate, and concentrated to afford compound a1-3 (16.6 g) in a 67% yield.

[0240] Step 2: Under nitrogen at 10°C, the intermediate a1-3 from the previous step (16.2 g, 77.0 mmol) was dissolved in 65 mL of ethylene glycol. TMSCl (20.9 g, 192.6 mmol) was added dropwise, and the mixture was reacted at 10°C for 12 hours. Aqueous NaOH (65 mL, 2N) was added to the reaction solution, which was extracted with MTBE, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 9 / 1) to afford a1-4 (16.0 g) as a yellow oil in an 82% yield.

[0241] Step 3: Dissolve the intermediate a1-4 (16.0 g, 62.9 mmol) in 25 mL of anhydrous tetrahydrofuran in an ice bath under nitrogen. Add 9-BBN (0.5 M in THF) (121 mL, 75.5 mmol) dropwise. The mixture is reacted in an ice bath for 1 hour. Methyl chloroacetate a1-5 (8.9 g, 81.78 mmol) is added to the reaction solution. The temperature is lowered to -45°C, and LiHMDS (1 M, 207 mL) is added dropwise. After completion of the addition, the mixture is reacted at room temperature for 12 hours. Aqueous NaOH (40 mL, 2N) and 50 mL of ethanol are added to the reaction solution. The temperature is raised to 70°C and the reaction is continued for 8 hours to terminate the reaction. 400 mL of ice water was added to the reaction solution, extracted with MTBE, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 3 / 1) to obtain a yellow oil a1 (12.3 g). Yield: 87%. LCMS ESI-MS m / z: 225 [M+H] + .

[0242] Referring to the synthetic route of intermediate a1, similar raw materials / compounds were used to synthesize the following intermediates.

[0243] Preparation of intermediates a2-a3, a11

[0244] Step 1: In an ice bath, under nitrogen, intermediate a1 (1.9 g, 8.44 mmol) and starting material ethyl 2-chloropyrimidine-4-carboxylate a2-1 (1.05 g, 5.63 mmol) were dissolved in 10 mL of anhydrous dichloromethane. EtOMgBr2 (2M in THF) (4.9 g, 19.1 mmol) and DIEA (2.2 g, 16.9 mmol) were added dropwise. The mixture was reacted at room temperature for 72 hours, after which the reaction was stopped. Dilute hydrochloric acid (20 mL, 1 M) was added to the reaction solution, which was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 10 / 1) to afford a2-2 (932 mg) as a yellow oil in a 45% yield. LCMS ESI-MS m / z: 365 [M+H] + .

[0245] Step 2: Dissolve the intermediate a2-2 (930 mg, 2.55 mmol) and NH2OH.HCl (220 mg, 3.14 mmol) in 19 mL of anhydrous pyridine. The mixture is reacted at room temperature for 48 hours, after which the reaction is stopped. Dilute hydrochloric acid (20 mL, 1 M) is added to the reaction solution, which is then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product is separated by column chromatography (PE / EA, 10 / 1) to afford a2-3 and a2-4 (765 mg) as yellow oils in a 79% yield. LCMS ESI-MS m / z: 380 [M+H] + .

[0246] Step 3: Dissolve the intermediate mixture from the previous step (765 mg, 2.01 mmol) in 8 mL of tetrahydrofuran and add dilute hydrochloric acid (4 M, 8 mL). The mixture is allowed to react at room temperature for 12 hours, after which the reaction is stopped. Add 40 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography (PE / EA, 10 / 1) to afford a2 (228 mg), a yellow solid, in a 36% yield. LCMS ESI-MS m / z: 318 [M+H] + .

[0247] Referring to the synthetic route of intermediate a2, similar raw materials / compounds (such as intermediate d) were used to synthesize the following intermediates.

[0248] Preparation of intermediate a4

[0249] Step 1: In an ice bath, under nitrogen, raw material a4-1 (5.0 g, 38.74 mmol), N,O-dimethylhydroxylamine hydrochloride b3-1 (4.2 g, 42.6 mmol), and DIEA (15.0 g, 116 mmol) were dissolved in 100 mL of anhydrous dichloromethane. HOBT (5.2 g, 38.74 mmol) and EDCI (11.1 g, 58.11 mmol) were added. The mixture was reacted at room temperature for 2 hours, and then the reaction was stopped. 100 mL of ice water was added to the reaction solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 3 / 1) to obtain a4-2 (3.2 g) as a white solid in a 48% yield. LCMS ESI-MS m / z: 173 [M+H] + .

[0250] Step 2: Dissolve the intermediate a4-2 (3.2 g, 18.59 mmol) and Boc2O (8.1 g, 37.18 mmol) in 64 mL of anhydrous acetonitrile in an ice bath. Add DMAP (0.45 g, 3.72 mmol). Warm the mixture to 80°C and react for 3 hours, then stop the reaction. Add 100 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography (PE / EA, 3 / 1) to obtain a4-3 (3.5 g) as a yellow oil in a 69% yield. LCMS ESI-MS m / z: 273 [M+H] + .

[0251] Step 3: Dissolve the intermediate a4-3 (3.5 g, 12.86 mmol) in 70 mL of anhydrous tetrahydrofuran in an ice bath. Add a 1 M solution of MeMgBr (64.3 mL) in tetrahydrofuran dropwise. Incubate the mixture in an ice bath for 3 hours, then stop the reaction. Add 100 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography (PE / EA, 9 / 1) to afford a4-4 (2.1 g) as a yellow oil in a 72% yield. LCMS ESI-MS m / z: 228 [M+H] + .

[0252] Step 4: In an ice bath, under nitrogen, intermediate a4-4 (2.1 g, 9.24 mmol) and MeNH2 (2M in THF) (1.7 g, 18.5 mmol) from the previous step were dissolved in 42 mL of methanol. Titanium(IV) ethoxide (5.2 g, 18.48 mmol) was added and the reaction was heated to 80°C for 13 hours. NaBH4 (0.7 g, 18.48 mmol) was added to the reaction solution and the reaction was continued at room temperature for 1 hour to terminate the reaction. 50 mL of saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse phase column chromatography (C18 column; CH3CN / H2O (0.1% ammonia), 4 / 1) to afford intermediate a4 (1.5 g) in a 67% yield. LCMS ESI-MS m / z: 243 [M+H] + .

[0253] Preparation of intermediates a5-a10

[0254] Step 1: Under nitrogen at -78°C, dissolve raw material a5-1 (5.0 g, 23.44 mmol) in 75 mL of anhydrous THF. Add LDA (3.0 g, 28.10 mmol) and stir for 20 minutes. Then add TMSCl (3.2 g, 29.27 mmol) dropwise. Warm to -20°C and allow to react for 4 hours before stopping the reaction. Add 500 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. Dissolve the mixture in 100 mL of acetonitrile, add 1-chloromethyl-4-fluoro-1,4-diazobicyclo-2.2.2-octane bis(tetrafluoroborate) selectfluor (7.5 g, 23.45 mmol), and allow to react at room temperature for 12 hours before stopping the reaction. Add 50 mL of saturated aqueous NaHCO₃ solution to the reaction solution, extract with ether, dry over anhydrous sodium sulfate, and concentrate. The crude product was separated by flash column chromatography (PE / EA, 6 / 1) to give a white solid a5-2 (1.1 g), yield: 20%, LCMS ESI-MS m / z: 232 [M+H] + .

[0255] Step 2: Under nitrogen at -30°C, borane dimethyl sulfide complex BH3-Me2S (6.2 mL, 6.18 mmol) was dissolved in a 1.5 mL solution of R-2-Me-CBS-oxazaborolidine (1 M, 1.4 mL) in tetrahydrofuran. After stirring for 1 hour, a 4 mL solution of intermediate a5-2 (1.1 g, 4.76 mmol) in tetrahydrofuran was added dropwise. The mixture was heated to 0°C and allowed to react for 2 hours to terminate the reaction. 5 mL of glacial ethanol was added to the reaction solution, which was stirred for 30 minutes. Then, 20 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 5 / 1) to afford a5-3 (1.07 g) as a white solid in a 96% yield. LCMS ESI-MS m / z: 234 [M+H] + .

[0256] Step 3: Dissolve the intermediate a5-3 (980 mg, 4.20 mmol) in 20 mL of a 4M solution of hydrogen chloride in 1,4-dioxane in an ice bath. Allow to react at room temperature for 2 hours, then stop the reaction. Add ammonia to the reaction solution to adjust the pH to approximately 10. Extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain a5-4 (500 mg) as a yellow solid in a 90% yield. LCMS ESI-MS m / z: 134 [M+H] + .

[0257] Step 4: In an ice bath, under nitrogen protection, the intermediate a5-4 (500 mg, 3.76 mmol) from the previous step was dissolved in 5 mL of methanol. NaBH3CN (283.1 mg, 4.51 mmol) and aqueous formaldehyde (564 mg, 7.51 mmol, 40%) were added. The reaction was allowed to react at room temperature for 2 hours, and then the reaction was stopped. Aqueous ammonia was added to the reaction solution to adjust the pH to around 12. After stirring for 30 minutes, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (DCM / MeOH, 5 / 1) to obtain a5 (100 mg) as a colorless oil in an 18% yield. LCMS ESI-MS m / z: 148 [M+H] + .

[0258] Referring to the synthetic route of intermediate a5, similar raw materials / compounds were used to synthesize the following intermediates.

[0259] Preparation of intermediate a12

[0260] Step 1: Dissolve the starting material a12-1 (4.5 g, 32.8 mmol) in 45 mL of dichloromethane. Add oxalyl chloride (4.2 g, 32.8 mmol). Heat the mixture to 50°C for 13 hours, then terminate the reaction. Evaporate the solvent under reduced pressure to obtain a12-2 (6.2 g) as a crude oil.

[0261] Step 2: Dissolve the intermediate a12-2 (6.2 g, 38.1 mmol) from the previous step in 31 mL of toluene, add phenol (3.6 g, 38.0 mmol), and react at room temperature for 24 hours. Stop the reaction and remove the solvent under reduced pressure. Add 50 mL of ice water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash column chromatography (PE / EA, 4 / 1) to obtain a12-3 (2.0 g) as a white solid. The two-step yield is 24%. LCMS ESI-MS m / z: 258 [M+H] + .

[0262] Step 3: Dissolve the intermediate a12-3 (2.0 g, 7.78 mmol) and K2CO3 (1.1 g, 7.78 mmol) from the previous step in 21 mL of acetonitrile, add intermediate a27 (1.9 g, 7.78 mmol), and react at room temperature for 1 hour. Add K2CO3 (1.1 g, 7.78 mmol), raise the temperature to 60°C, and continue the reaction for 2 hours. Stop the reaction and remove the solvent under reduced pressure. Add dilute hydrochloric acid to the reaction solution to adjust the pH to approximately 2, and remove the solvent under reduced pressure. The crude product is separated by flash reverse column chromatography (column: C18; CH3CN / H2O, 1 / 1) to obtain a12-4 (1.8 g) as a white solid in a yield of 73%. LCMS ESI-MS m / z: 317 [M+H] + .

[0263] Step 4: Dissolve intermediate a12-4 (1.8 g, 5.69 mmol) and intermediate a12-5 (1.7 g, 11.38 mmol) in 9 mL of phosphorus oxychloride in an ice bath. Heat the mixture to 90°C and react for 2 hours to stop the reaction. Add 50 mL of ice water to the reaction solution, extract with ethyl acetate, and evaporate the solvent under reduced pressure. The crude product is separated by flash column chromatography (PE / EA, 3 / 1) to obtain a12-6 (1.2 g) as a white solid in a 60% yield. LCMS ESI-MS m / z: 353 [M+H] + .

[0264] Step 5: In an ice bath, under nitrogen protection, the intermediate a12-6 (1.2 g, 3.4 mmol) and ethylene glycol (12 mL) from the previous step were dissolved in 6 mL of dichloromethane. TMSCl (1.1 g, 10.2 mmol) was added dropwise. After completion of the addition, the mixture was reacted at room temperature for 1 hour to stop the reaction. The solvent was evaporated under reduced pressure, 30 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE / EA, 10 / 1) to obtain intermediate a12 (600 mg) with a yield of 44%. LCMS ESI-MS m / z: 397 [M+H] + .

[0265] Preparation of intermediates a13-a19, a21-a23, and a29

[0266] Procedure: Dissolve the starting material a13-1 (5.0 g, 22.5 mmol) and cyclopropylamino (1.5 g, 27.0 mmol) in 100 mL of dichloromethane. Add acetic acid (5.4 g, 90.0 mmol) and sodium triacetoxyborohydride (5.4 g, 90.0 mmol). The mixture is reacted at room temperature for 1 hour, and then the reaction is stopped. Add 50 mL of ice water to the reaction solution, adjust the pH to approximately 8 with aqueous ammonia, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse-phase column chromatography (column: C18; CH3CN / H2O, 4 / 1) to obtain an oily product a13 (2.0 g) in a 34% yield. LCMS ESI-MS m / z: 264 [M+H] + .

[0267] Referring to the synthetic route of intermediate a13, similar raw materials / compounds were used to synthesize the following intermediates.

[0268] Preparation of intermediate a20

[0269] Step 1: Dissolve the starting materials (2S)-1-aminopropyl-2-ol a20-1 (1.1 g, 11.7 mmol) and triethylamine (3.0 g, 29.3 mmol) in 24 mL of anhydrous acetonitrile in an ice bath under nitrogen. Add the intermediate a20-2 (2.5 g, 13.2 mmol) dropwise, and allow the mixture to react at room temperature for 1 hour. Add Boc2O (3.2 g, 14.7 mmol) and triethylamine (1.5 g, 14.7 mmol) to the reaction mixture, continue the reaction for 1 hour, and then terminate the reaction. The solvent was evaporated under reduced pressure, and 100 mL of ice water was added to the mixture. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse column chromatography (chromatographic column: C18; CH3CN / H2O, 1 / 1) to obtain an oil a20-3 (3.0 g) in a yield of 73%. LCMS ESI-MS m / z: 282 [M+H] + .

[0270] Step 2: Dissolve the intermediate a20-3 (200 mg, 0.71 mmol) from the previous step in 5 mL of a 4M solution of hydrogen chloride in 1,4-dioxane. The mixture is reacted at room temperature for 1 hour to precipitate a solid. Filter, wash with ethyl acetate, and dry to obtain the hydrochloride salt of a20 (180 mg) as a white solid. LCMS ESI-MS m / z: 182 [M+H] + .

[0271] Preparation of intermediate a24

[0272] Step 1: In an ice bath, under nitrogen, the starting material (2S)-1-aminopropyl-2-ol a20-1 (2.0 g, 26.6 mmol) and triethylamine (8.1 g, 79.9 mmol) were dissolved in 44 mL of anhydrous acetonitrile. Tert-butyldimethylsilyl chloride (TBSCl) (5.2 g, 34.6 mmol) and DMAP (0.33 g, 2.66 mmol) were added dropwise. The mixture was reacted at room temperature for 2 hours, after which the reaction was stopped. The solvent was evaporated under reduced pressure, and the mixture was added with 100 mL of ice water. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE / EtOAc, 3 / 1) to afford a24-1 (3.0 g) as an oil in a 60% yield. LCMS ESI-MS m / z: 190 [M+H] + .

[0273] Step 2: Dissolve the intermediate a24-1 (510 mg, 2.7 mmol) and the starting material a13-1 (500 mg, 2.25 mmol) in 10 mL of dichloromethane. Add acetic acid (540 mg, 9.0 mmol) and sodium triacetoxyborohydride (1.43 g, 6.75 mmol). The mixture is reacted at room temperature for 12 hours, and then the reaction is stopped. Add 50 mL of ice water to the reaction solution, adjust the pH to approximately 8 with saturated sodium bicarbonate aqueous solution, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse phase column chromatography (column: C18; CH3CN / H2O (10 mmol / L NH4HCO3), 10 / 1) to obtain an oil a24 (300 mg) in a 34% yield. LCMS ESI-MS m / z: 396 [M+H] + .

[0274] Preparation of intermediate a25

[0275] Step 1: Under nitrogen at -78°C, raw material a25-1 (8.5 g, 43.1 mmol) was dissolved in 170 mL of anhydrous tetrahydrofuran. nBuLi (34.5 mL, 86.2 mmol, 2.5 M) was added dropwise. After stirring for 1 hour, anhydrous DMF (4.7 g, 64.7 mmol) was added to the mixture. The mixture was allowed to react for another 2 hours before stopping the reaction. The reaction mixture was quenched by adding 100 mL of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE / EtOAc, 4 / 1) to afford a25-2 (6.0 g) as a white solid in a 62% yield. LCMS ESI-MS m / z: 226 [M+H] + .

[0276] Step 2: Dissolve the intermediate a25-2 (3.2 g, 14.2 mmol) and the starting material methylamine hydrochloride (2.9 g, 42.6 mmol) in 64 mL of dichloromethane. Add acetic acid (3.4 g, 56.8 mmol) and sodium triacetoxyborohydride (9.0 g, 42.6 mmol). The mixture is reacted at room temperature for 2 hours, and then the reaction is stopped. Add 50 mL of ice water to the reaction solution, adjust the pH to approximately 8 with saturated sodium bicarbonate solution, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse phase column chromatography (column: C18; CH3CN / H2O (10 mmol / LNH4HCO3), 7 / 3) to obtain an oil a25 (2.3 g) in a 67% yield. LCMS ESI-MS m / z: 241 [M+H] + .

[0277] Preparation of intermediates a26 and a34

[0278] Step 1: Dissolve intermediate a1 (50.0 g, 222.9 mmol) in 500 mL of anhydrous tetrahydrofuran under nitrogen in an ice bath. Add LiHMDS (1 M in THF) (245 mL) dropwise. Stir under ice bath for 1 hour. Add ethyl oxalate (39.1 g, 267.5 mmol) dropwise to the reaction mixture, warm to room temperature, and react for 2 hours to obtain a mixture. Dissolve acetyl chloride (39.3 g, 501.6 mmol) in 200 mL of ethanol and stir under ice bath for 1 hour to prepare reaction solution S1. Add reaction solution S1 and NH2OH.HCl (16.2 g, 234.1 mmol) to the mixture, heat to 65°C, and continue the reaction for 12 hours. Stop the reaction, and remove the solvent under reduced pressure. Add 500 mL of ice water to the reaction mixture, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The mixture was redissolved in 100 mL of 1,4-dioxane, and the pH was adjusted to approximately 2 with dilute hydrochloric acid (1 M). The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to afford a26-1 (21.5 g) as a white solid. LCMS ESI-MS m / z: 278 [M+H] + .

[0279] Step 2: Dissolve the intermediate a26-1 (21.5 g, 77.5 mmol) and aqueous ammonia (129 mL) in 44 mL of ethanol. The mixture is reacted at room temperature for 12 hours, and the reaction is stopped. Add 200 mL of water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain a26-2 (18.0 g) as a yellow solid. LCMS ESI-MS m / z: 249 [M+H] + .

[0280] Step 3: Dissolve the intermediate mixture a26-2 (18.0 g, 72.5 mmol) and pyridine (13.7 g, 174 mmol) in 72 mL of acetonitrile. Add TFAA (18.2 g, 87.0 mmol) dropwise. The mixture is allowed to react at room temperature for 0.5 hours, then the reaction is stopped. Add 400 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain a26 (15.0 g) as a yellow oil. The total yield for the three steps is 29%. LCMS ESI-MS m / z: 231 [M+H] + .

[0281] Referring to the synthetic route of intermediate a26, similar raw materials / compounds were used to synthesize the following intermediates.

[0282] Preparation of intermediates a27-a28, a30-a32, a35, and a38

[0283] Step 1: Dissolve intermediate a26 (15.0 g, 65.1 mmol) and MeONa (2.93 g, 16.3 mmol) in 40 mL of anhydrous methanol in an ice bath under nitrogen protection and react at room temperature for 2 hours. Add NH4Cl (3.8 g, 71.65 mmol) to the reaction solution, raise the temperature to 30°C, and continue the reaction for 12 hours. The reaction is stopped and the solvent is evaporated under reduced pressure. Add 500 mL of ice water to the reaction solution, adjust the pH to approximately 8 with saturated sodium bicarbonate aqueous solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain a white solid a27 (14.0 g) in an 87% yield. LCMS ESI-MS m / z: 248 [M+H] + .

[0284] Step 2: Dissolve intermediate 27 (4.0 g, 16.2 mmol) and starting material a28-1 (8.65 g, 48.6 mmol) in 44 mL of DMF. Add DBU (7.39 g, 48.5 mmol). The mixture is heated to 90°C and reacted for 12 hours, after which the reaction is stopped. Add 200 mL of water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse-phase column chromatography (column: C18; CH3CN / H2O = 1 / 1) to afford a28-2 (3.3 g) as a white solid in a 61% yield. LCMS ESI-MS m / z: 334 [M+H] + .

[0285] Step 3: Dissolve the intermediate a28-2 (3.0 g, 9.0 mmol) and POCl3 (9.0 mL) in 18 mL of N,N-diethylaniline. The mixture is heated to 80°C and reacted for 12 hours, after which the reaction is stopped. Add 100 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography (PE / EA, 4 / 1) to afford a28 (1.6 g) as a white solid in a 48% yield. LCMS ESI-MS m / z: 370 [M+H] + .

[0286] Referring to the synthetic route of intermediate a28, similar raw materials / compounds (such as intermediates a34, a37, etc.) were used to synthesize the following intermediates.

[0287] Preparation of intermediate a36

[0288] Step 1: Under nitrogen, raw material a36-1 (18.0 g, 103.3 mmol) and raw material 3-bromopropene a36-2 (25 g, 206.65 mmol) were dissolved in 180 mL of acetonitrile. K2CO3 (42.8 g, 400 mmol) was added, and the mixture was reacted at 60°C for 24 hours, after which the reaction was stopped. 250 mL of saturated aqueous ammonium chloride was added to the mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to afford compound a36-3 (21 g) in a 95% yield.

[0289] Step 2: Under nitrogen at 10°C, the intermediate a36-3 (21 g, 98 mmol) from the previous step was dissolved in 84 mL of dichloromethane. TMSCl (26.6 g, 245 mmol) and ethylene glycol (84 mL) were added dropwise, and the mixture was reacted at 20°C for 24 hours. 250 mL of ice water was added to the reaction solution, which was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 10 / 1) to afford a36-4 (14 g) as a white solid in a 55% yield.

[0290] Step 3: Dissolve the intermediate a36-4 (14.0 g, 54.19 mmol) in 50 mL of anhydrous tetrahydrofuran (THF) under an ice bath and nitrogen. Add 9-BBN (0.5 M in THF) (131 mL, 65 mmol) dropwise. The mixture is reacted on ice for 1 hour. Methyl chloroacetate a1-5 (7.7 g, 70.45 mmol) is added to the reaction solution. The temperature is lowered to -45°C, and LiHMDS (1 M, 178 mL) is added dropwise. After completion of the addition, the mixture is reacted at room temperature for 18 hours. Aqueous NaOH (54 mL, 2 N) and 42 mL of ethanol are added to the reaction solution. The temperature is raised to 70°C and the reaction is continued for 14 hours to terminate the reaction. 400 mL of ice water was added to the reaction mixture, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 3 / 1) to obtain a yellow oil a36 (10 g) in a 76% yield. LCMS ESI-MS m / z: 243 [M+H] + .

[0291] Preparation of intermediate a37

[0292] Step 1: Dissolve intermediate a36 (10.0 g, 41.26 mmol) in 50 mL of anhydrous tetrahydrofuran under nitrogen in an ice bath. Add LiHMDS (1 M in THF) (42 mL) dropwise. Stir under ice bath for 30 minutes. Add ethyl oxalate (7.24 g, 49.52 mmol) dropwise to the reaction mixture, warm to room temperature, and react for 2 hours to obtain a mixture. Dissolve acetyl chloride (7.29 g, 92.85 mmol) in 40 mL of ethanol and stir under ice bath for 1 hour to prepare reaction solution S2. Add reaction solution S2 and NH2OH.HCl (3.0 g, 43.33 mmol) to the mixture, warm to 65°C, and continue the reaction for 12 hours. Stop the reaction and remove the solvent under reduced pressure. Add 500 mL of ice water to the reaction mixture, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain an oily product a37-1 (4.0 g). LCMS ESI-MS m / z:340[M+H] + .

[0293] Step 2: Dissolve the intermediate a37-1 (4.0 g, 11.78 mmol) and aqueous ammonia (21 mL) in 20 mL of ethanol. The mixture is reacted at room temperature for 12 hours, then the reaction is stopped. Add 80 mL of water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain a37-2 (1.7 g) as a yellow solid in a 47% yield. LCMS ESI-MS m / z: 311 [M+H] + .

[0294] Step 3: Dissolve the intermediate mixture a37-2 (1.7 g, 5.48 mmol) and pyridine (1.1 g, 13.15 mmol) in 7 mL of acetonitrile. Add TFAA (1.4 g, 6.57 mmol) dropwise. The mixture is allowed to react at room temperature for 0.5 hours, after which the reaction is stopped. Add 40 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to afford a37 (1.0 g) as a yellow oil in a 63% yield. LCMS ESI-MS m / z: 293 [M+H] + .

[0295] Preparation of intermediate b1-b2

[0296] Step 1: Dissolve raw material b1-1 (24.0 g, 97.9 mmol) and triethylamine (14.9 g, 147 mmol) in 240 mL of anhydrous dichloromethane in an ice bath under nitrogen. Add methylsulfonyl chloride (16.8 g, 147 mmol) dropwise. The mixture is allowed to react at room temperature for 3 hours, then the reaction is stopped. Add 100 mL of ice water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography (PE / EA, 10 / 1) to obtain b1-2 (30 g) as a yellow oil in a 95% yield.

[0297] Step 2: Dissolve the intermediate b1-2 (30 g, 92.8 mmol) and potassium thioacetate (16.0 g, 139 mmol) in 200 mL of anhydrous DMF. The mixture is heated to 50°C and reacted for 10 hours, after which the reaction is terminated. Add 500 mL of ice water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography (PE / EA, 10 / 1) to afford b1-3 (26 g) as a yellow oil in a 92% yield. LCMS ESI-MS m / z: 304 [M+H] + .

[0298] Step 3: Dissolve the intermediate b1-3 (23.0 g, 75.8 mmol) from the previous step in 390 mL of methanol, add a 1 M aqueous solution of NaOH (83.3 mL) and dimethyl sulfate (11.5 g, 91.0 mmol), and allow the mixture to react at room temperature for 1 hour, after which the reaction is stopped. A 1 M aqueous solution of NaOH (166 mL) is added to the reaction solution, and after stirring for 30 minutes, the solvent is evaporated under reduced pressure. Dilute hydrochloric acid is added to adjust the pH to approximately 3, and the product is extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product is separated by column chromatography (PE / EA, 5 / 1) to afford b1 (18 g) as a colorless oil in a 91% yield. LCMS ESI-MS m / z: 262 [M+H] + .

[0299] Referring to the synthetic route of intermediate b1, similar raw materials / compounds were used to synthesize the following intermediates.

[0300] Preparation of intermediates b3-b15, b22-b35

[0301] Step 1: In an ice bath, under nitrogen, intermediate b2 (5.5 g, 21.5 mmol), N,O-dimethylhydroxylamine hydrochloride b3-1 (1.4 g, 23.1 mmol), and DIEA (8.2 g, 63.1 mmol) were dissolved in 110 mL of anhydrous dichloromethane. HOBT (2.8 g, 21.5 mmol) and EDCI (6.1 g, 31.6 mmol) were added. The mixture was reacted at room temperature for 2 hours, and then the reaction was stopped. 100 mL of ice water was added to the reaction solution, which was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 1 / 1) to obtain b3-2 (4.3 g), a yellow solid, in a 67% yield. LCMS ESI-MS m / z: 305 [M+H] + .

[0302] Step 2: Dissolve the intermediate b3-2 (4.3 g, 14.1 mmol) in 86 mL of anhydrous tetrahydrofuran in an ice bath. Add a 1 M solution of MeMgBr (21.2 mL) in tetrahydrofuran dropwise. Incubate the mixture in an ice bath for 3 hours, then stop the reaction. Add 100 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography (PE / EA, 1 / 1) to obtain b3-3 (3.1 g) as a yellow oil in an 85% yield. LCMS ESI-MS m / z: 260 [M+H] + .

[0303] Step 3: Under nitrogen at -15°C, dissolve borane dimethyl sulfide complex BH3-Me2S (7.5 mL, 15.04 mmol) in a tetrahydrofuran solution (1.5 mL) of R-2-Me-CBS-oxazaborolidine (1 M, 2.31 mL). After stirring for 1 hour, a tetrahydrofuran solution (10 mL) of intermediate b3-3 (3.0 g, 11.6 mmol) from the previous step was added dropwise. The mixture was warmed to room temperature and reacted for 2 hours to terminate the reaction. 50 mL of icy methanol was added to the reaction solution, which was stirred for 30 minutes. Then, 100 mL of ice water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 2 / 1) to obtain b3-4 (2.5 g) as a colorless oil in an 83% yield. LCMS ESI-MS m / z: 262 [M+H] + .

[0304] Step 4: Dissolve the intermediate b3-4 (2.5 g, 9.6 mmol) in 13 mL of anhydrous tetrahydrofuran under nitrogen in an ice bath. Add a solution of LiAlH4 (19.1 mL, 19.13 mmol) in tetrahydrofuran (5 mL). Heat to 55°C and react for 2 hours to stop the reaction. Add 50 mL of saturated aqueous ammonium chloride to the reaction solution, stir for 30 minutes, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to obtain a colorless oil b3 (450 mg) in a 27% yield. LCMS ESI-MS m / z: 176 [M+H] + .

[0305] Referring to the synthetic route of intermediate b3, similar raw materials / compounds were used to synthesize the following intermediates.

[0306] Preparation of intermediate b16-b17

[0307] Step 1: Dissolve borane dimethyl sulfide complex BH3-Me2S (180 mL, 2M) and 2-methylbut-2-ene (40 mL) in 320 mL of tetrahydrofuran under nitrogen in an ice bath. After stirring for 2 hours, a solution of starting material b16-1 (40.0 g, 165.8 mmol) in tetrahydrofuran (10 mL) was added dropwise. The mixture was warmed to room temperature and reacted for 12 hours. The reaction mixture was cooled to -10°C, and 90 mL of glacial ethanol and a 3M aqueous NaOH solution (80 mL) were added dropwise. H2O2 (30%, 80 mL) was added dropwise. After stirring for 3 hours, the solvent was evaporated under reduced pressure. 1000 mL of ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 1 / 1) to obtain b16-2 (28 g) as a yellow oil in a 65% yield. LCMS ESI-MS m / z:260[M+H] + .

[0308] Step 2: Dissolve the intermediate b16-2 (28 g, 108 mmol) and tert-butyldimethylsilyl chloride (TBSCl) (40.7 g, 270 mmol) in 280 mL of DMF. Add imidazole (36.7 g, 539.9 mmol) and allow to react at room temperature for 2 hours, then stop the reaction. Add 1000 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography (PE / EA, 10 / 1) to obtain b16-3 (40 g) as a yellow oil in a 99% yield. LCMS ESI-MS m / z: 374 [M+H] + .

[0309] Step 3: Dissolve the intermediate b16-3 (40 g, 107.1 mmol) and LiOH (10.2 g, 428.3 mmol) in 800 mL of a mixture of tetrahydrofuran and water (v / v, 4 / 1). React at room temperature for 2 hours, stop the reaction, and remove the solvent under reduced pressure. Add 100 mL of ice water to the reaction solution, adjust the pH to approximately 5 with dilute hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain b16-4 (28 g) as a yellow oil in a 73% yield. LCMS ESI-MS m / z: 360 [M+H] + .

[0310] Step 4: In an ice bath, under nitrogen, the intermediate b16-4 (28 g, 77.9 mmol), N,O-dimethylhydroxylamine hydrochloride b3-1 (8.3 g, 85.7 mmol), and DIEA (30.2 g, 233.6 mmol) were dissolved in 560 mL of anhydrous dichloromethane. HOBT (10.5 g, 77.9 mmol) and EDCI (18.1 g, 116.8 mmol) were added. The mixture was reacted at room temperature for 2 hours, and the reaction was stopped. 500 mL of ice water was added to the reaction solution, which was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 3 / 1) to obtain b16-5 (24 g) as a yellow oil in a 77% yield. LCMS ESI-MS m / z: 403 [M+H] + .

[0311] Step 5: Dissolve the intermediate b16-5 (24 g, 59.6 mmol) from the previous step in 480 mL of anhydrous tetrahydrofuran in an ice bath. Add a solution of MeMgBr (1 M, 89.7 mL) in tetrahydrofuran dropwise. Incubate the mixture in an ice bath for 3 hours, then stop the reaction. Add 500 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography (PE / EA, 5 / 1) to afford b16-6 (18 g) as a yellow oil in an 84% yield. LCMS ESI-MS m / z: 358 [M+H] + .

[0312] Step 6: Under nitrogen at -25°C, borane dimethyl sulfide complex BH3-Me2S (33.3 mL, 2 M) was dissolved in a tetrahydrofuran solution (9 mL) of R-2-Me-CBS-oxazaborolidine (1 M, 10.6 mL toluene solution). After stirring for 1 hour, a tetrahydrofuran solution (54 mL) of intermediate b16-6 from the previous step (18.0 g, 50.3 mmol) was added dropwise. The mixture was warmed to room temperature and reacted for 2 hours to terminate the reaction. 100 mL of icy methanol was added to the reaction solution, which was stirred for 30 minutes. Then, 500 mL of ice water was added to the reaction solution, and the solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 5 / 1) to obtain b16-7 (15.6 g) as a yellow oil in an 86% yield. LCMS ESI-MS m / z: 360 [M+H] + .

[0313] Step 7: Dissolve the intermediate b16-7 (5.0 g, 13.9 mmol) from the previous step in 25 mL of anhydrous tetrahydrofuran under nitrogen in an ice bath. Add 50 mL of a 1 M solution of LiAlH4 in tetrahydrofuran and heat to 55°C for 2 hours to terminate the reaction. Add 150 mL of saturated aqueous ammonium chloride to the reaction solution, stir for 30 minutes, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to obtain b16 (2.4 g) as a brown oil in a 63% yield. LCMS ESI-MS m / z: 274 [M+H] + .

[0314] Referring to the synthetic route of intermediate b16, similar raw materials / compounds were used to synthesize the following intermediates.

[0315] Preparation of intermediate b18-b19

[0316] Procedure: Dissolve intermediate b8 (330 mg, 2.47 mmol) and potassium carbonate (684 mg, 4.96 mmol) in 12 mL of acetonitrile in an ice bath under nitrogen. Add 1-fluoro-2-iodoethane (472 mg, 2.71 mmol) dropwise. Allow to react at room temperature for 12 hours. Add 40 mL of ice water to the reaction mixture, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by column chromatography (PE / EA, 1 / 1) to afford b18 (230 mg) as a yellow oil in a 52% yield. LCMS ESI-MS m / z: 180 [M+H] + .

[0317] Referring to the synthetic route of intermediate b18, similar raw materials / compounds were used to synthesize the following intermediates.

[0318] Preparation of intermediates b20-b21

[0319] Procedure: Dissolve raw materials b20-1 (450 mg, 2.47 mmol) and b20-2 (357 mg, 4.95 mmol) in 5 mL of methanol in an ice bath under nitrogen. Slowly add NaBH3CN (187 mg, 2.97 mmol) and react at room temperature for 2 hours. Add 40 mL of ice water to the reaction mixture, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to obtain b20 (350 mg) as a yellow oil in a 70% yield. LCMS ESI-MS m / z: 202 [M+H] + .

[0320] Referring to the synthetic route of intermediate b20, similar raw materials / compounds were used to synthesize the following intermediates.

[0321] Preparation of intermediate b36

[0322] Step 1: Under nitrogen at -30°C, intermediate b35 (5.0 g, 18.42 mmol) and DMAP (6.7 g, 55.27 mmol) were dissolved in 100 mL of anhydrous dichloromethane. Tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) (5.8 g, 22.11 mmol) was added, and the mixture was reacted at 0°C for 3 hours, after which the reaction was stopped. 100 mL of ice water was added to the reaction solution, which was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 10 / 1) to afford b36-1 (6.0 g) as a yellow oil in an 84% yield. LCMS ESI-MS m / z: 386 [M+H] + .

[0323] Step 2: Under nitrogen, intermediate b36-1 (6.0 g, 15.55 mmol) and Rh(PPh3)4Cl2 (4.3 g, 4.66 mmol) were dissolved in 60 mL of a 9 / 1 v / v mixture of ethanol and water. Triethylenediamine TEDA (1.0 g, 9.33 mmol) was added, and the mixture was reacted at 140°C for 24 hours, after which the reaction was stopped. The reaction mixture was added with 100 mL of ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 5 / 1) to afford b36-2 (2.1 g) as a yellow oil in a 39% yield. LCMS ESI-MS m / z: 346 [M+H] + .、

[0324] Step 3: Under nitrogen at 0°C, intermediate b36-2 (2.1 g, 6.07 mmol) and 3-hydroxypyridine b36-3 (870 mg, 9.11 mmol) were dissolved in 42 mL of tetrahydrofuran. PPh3 (2.4 g, 9.11 mmol) and DIAD (1.8 g, 9.11 mmol) were slowly added. The mixture was allowed to warm to room temperature and allowed to react for 4 hours, after which the reaction was stopped. 50 mL of icy methanol was added to the reaction solution, which was stirred for 30 minutes. Then, 100 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (C18 column; CH3CN / H2O (0.1% formic acid), 2 / 1) to afford b36-4 (1.7 g) as a brown oil in a 66% yield. LCMS ESI-MS m / z: 423 [M+H] + .

[0325] Step 4: Under nitrogen at 0°C, the intermediate b36-4 (1.7 g, 4.02 mmol) from the previous step was dissolved in 34 mL of tetrahydrofuran. TBAF (1 M, 12.1 mL) was slowly added and the mixture was allowed to react on ice for 24 hours, after which the reaction was stopped. 50 mL of saturated aqueous ammonium chloride was added to the reaction solution, which was stirred for 30 minutes. Then, 100 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (C18 column; CH3CN / H2O (0.1% trifluoroacetic acid), 1 / 1) to afford b36-5 (1.1 g) as a brown oil in an 89% yield. LCMS ESI-MS m / z: 309 [M+H] + .

[0326] Step 5: Dissolve the intermediate b36-5 (500 mg, 1.62 mmol) from the previous step in 3 mL of anhydrous tetrahydrofuran under nitrogen in an ice bath. Add a solution of LiAlH4 (3.3 mL, 3.3 mmol) in tetrahydrofuran and heat to 55°C for 4 hours to terminate the reaction. Add 50 mL of saturated aqueous ammonium chloride to the reaction solution, stir for 30 minutes, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to obtain b36 (290 mg) as a brown oil in an 80% yield. LCMS ESI-MS m / z: 223 [M+H] + .

[0327] Synthesis of intermediate c1

[0328] Step 1: In an ice bath, raw material c1-1 (4.0 g, 19.32 mmol) and DIEA (10.0 g, 77.29 mmol) were dissolved in 80 mL of acetonitrile. Intermediate a1 (4.8 g, 21.26 mmol) and Et2OMgBr2 (15.0 g, 57.97 mmol) were slowly added dropwise to the system. After completion, the temperature was raised to 80°C and the reaction was allowed to proceed for 48 hours, after which the reaction was stopped. 300 mL of ice water was added to the system, and the pH was adjusted to approximately 5 with dilute hydrochloric acid. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 10 / 1) to obtain c1 (3.0 g) as a yellow oil in a yield of 39%. LCMS ESI-MS m / z: 399 [M+H] + .

[0329] Synthesis of intermediate c9

[0330] Step 1: Under nitrogen, raw materials c9-1 (10.0 g, 48 mmol) and raw material c9-2 (26.0 g, 72 mmol) were dissolved in 100 mL of DMF. Catalyst Pd(dppf)Cl2 (5.0 g, 7.2 mmol) was added, and the mixture was heated to 100°C for 12 hours before stopping the reaction. 1000 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. The mixture was dissolved in 100 mL of tetrahydrofuran, and 15 mL of concentrated hydrochloric acid (6 M) was added. The reaction was allowed to react at room temperature for 1 hour before stopping the reaction. Saturated aqueous sodium bicarbonate was slowly added to the reaction solution, and the pH was adjusted to approximately 8. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE / EA, 2 / 1) to obtain intermediate c9-3 (7.0 g) in an 85% yield. LCMS ESI-MS m / z:172[M+H] + .

[0331] Step 2: Dissolve the intermediate c9-3 (7.0 g, 40.8 mmol) and the raw material Boc2O (13.4 g, 61.2 mmol) in 140 mL of dichloromethane, add TEA (12.4 g, 122 mmol) and DMAP (2.5 g, 20.4 mmol), react at room temperature for 3 hours, and stop the reaction. Add 100 mL of ice water to the reaction solution, extract with dichloromethane, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The crude product was separated by flash column chromatography (PE / EA, 2 / 1) to obtain intermediate c9-4 (5.0 g) with a yield of 33%. LCMS ESI-MS m / z: 372 [M+H] + .

[0332] Step 3: Under nitrogen protection, the intermediate c9-4 (5.0 g, 13.5 mmol) and Pin2B2 (5.1 g, 20.17 mmol) from the previous step were dissolved in 100 mL of 1,4-dioxane, KOAc (2.6 g, 26.9 mmol) and catalyst Pd(dppf)Cl2 (1.0 g, 1.35 mmol) were added, and the temperature was raised to 95°C for 3 hours to stop the reaction. 500 mL of ice water was added to the reaction solution, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain intermediate c9-5 (crude). LCMS ESI-MS m / z: 338 [M+H] + .

[0333] Step 4: Dissolve the intermediate c9-5 from the previous step in 60 mL of acetonitrile and add Mg(ClO4)2 (0.40 g, 1.78 mmol). After stirring for 5 minutes, heat to 50°C and react for 1 hour. Stop the reaction. Add 10 mL of ice water to the reaction solution, extract with dichloromethane, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse column chromatography (chromatographic column: C18; CH3CN / H2O (10 mmol / LNH4HCO3), 7 / 10) to obtain intermediate c9 (800 mg) in a yield of 38%. LCMS ESI-MS m / z: 238 [M+H] + .

[0334] Synthesis of intermediates C10-C11, C18-C19, C22-C27

[0335] Step 1: Dissolve raw material c10-1 (14 g, 78.6 mmol) in 700 mL of dichloromethane, add NBS (13.9 g, 78.6 mmol), and react at room temperature for 16 hours, then stop the reaction. Add 50 mL of ice water and 50 mL of saturated sodium thiosulfate aqueous solution to the reaction solution, extract with dichloromethane, wash with saturated brine, concentrate under reduced pressure, and separate by flash column chromatography (PE / EA, 1 / 1) to obtain intermediate c10-2 (7.38 g) in a 37% yield. LCMS ESI-MS m / z: 257 [M+H] + .

[0336] Step 2: Under nitrogen, intermediate c10-2 (7.3 g, 28.7 mmol) and starting material c9-2 (11.4 g, 31.58 mmol) from the previous step were dissolved in 73 mL of 1,4-dioxane. Catalyst Pd(PPh3)4 (3.3 g, 2.87 mmol) was added, and the mixture was heated to 100°C for 16 hours before stopping the reaction. 100 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. The mixture was dissolved in 73 mL of tetrahydrofuran, and 15 mL of concentrated hydrochloric acid was added. The reaction was allowed to react at room temperature for 2 hours before stopping the reaction. Saturated aqueous sodium bicarbonate was slowly added to the reaction solution, and the pH was adjusted to approximately 8. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE / EA, 1 / 1) to obtain intermediate c10-3 (5.0 g) in an 80% yield. LCMS ESI-MS m / z:221[M+H] + .

[0337] Step 3: Dissolve the intermediate c10-3 (5.0 g, 22.8 mmol) and the raw material Boc2O (9.9 g, 45.6 mmol) in 200 mL of dichloromethane, add DIEA (5.8 g, 45.6 mmol) and DMAP (1.3 g, 11.4 mmol), react at room temperature for 2 hours, and then stop the reaction. Add 100 mL of ice water to the reaction solution, extract with dichloromethane, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse column chromatography (chromatographic column: C18; CH3CN / H2O (10 mmol / L NH4HCO3), 1 / 4) to obtain intermediate c10 (3.34 g) with a yield of 46%. LCMS ESI-MS m / z: 321 [M+H] + .

[0338] Referring to the synthetic route of intermediate c10, similar raw materials / compounds were used to synthesize the following key intermediates.

[0339] Synthesis of intermediates C12-C17, C20-C21

[0340] Step 1: Dissolve the raw material c12-1 (3.0 g, 20.8 mmol) and oxalyl chloride (COCl) 2 (3.9 g, 31.2 mmol) in 15 mL of dichloromethane under an ice bath. Slowly add DMF (5 drops) to the system. After the addition is complete, react at room temperature for 2 hours. Stop the reaction and remove the solvent under reduced pressure. Dissolve the mixture in 5 mL of dichloromethane to prepare reagent S1. Dissolve the raw material (R)-3-fluoro-tetrahydropyrrole hydrochloride c12-2 (2.8 g, 22.9 mmol) and TEA (6.3 g, 62.4 mmol) in 10 mL of anhydrous dichloromethane. Add reagent S1 dropwise. After the addition is complete, react at room temperature for 3 hours and stop the reaction. 30 mL of ice water was added to the reaction mixture, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 1 / 2) to obtain a yellow oil c12-3 (3.5 g) in a yield of 78%. LCMS ESI-MS m / z: 216 [M+H] + .

[0341] Step 2: Dissolve the intermediate c12-3 (3.0 g, 13.9 mmol) from the previous step in 20 mL of anhydrous tetrahydrofuran under nitrogen in an ice bath. Add LiAlH4 (1.3 g, 34.84 mmol) and stir for 2 hours under ice bath to stop the reaction. Pour the reaction solution into 100 mL of ice water, extract with ethyl acetate, wash with saturated brine, and concentrate. The crude product is separated by column chromatography (100% EtOAc) to obtain compound c12 (1.3 g) as an oil in a yield of 54%. LCMS ESI-MS m / z: 174 [M+H] + .

[0342] Referring to the synthetic route of intermediate c12, similar raw materials / compounds were used to synthesize the following intermediates.

[0343] Synthesis of intermediate C28

[0344] Step 1: Dissolve raw materials c28-1 (3.5 g, 13.67 mmol) and Cs2CO3 (6.69 g, 20.5 mmol) in 100 mL of acetonitrile. Add PMBNH2 (1.88 g, 13.67 mmol) and heat to 80°C for 16 hours, then stop the reaction. Add 500 mL of ice-cold dichloromethane to the reaction solution, wash with saturated brine, concentrate under reduced pressure, and separate by flash column chromatography (PE / EA, 1 / 1) to obtain intermediate c28-2 (2.7 g) in a 55% yield. LCMS ESI-MS m / z: 359 [M+H] + .

[0345] Step 2: Dissolve the intermediate c28-2 (2.6 g, 7.26 mmol) from the previous step in 50 mL of dichloromethane and add TFA (10 mL). Allow to react at room temperature for 12 hours to stop the reaction. Add 500 mL of ice water to the reaction solution, adjust the pH to approximately 8 with saturated sodium bicarbonate solution, extract with dichloromethane, wash with saturated brine, concentrate under reduced pressure, and separate by flash column chromatography (PE / EA, 1 / 4) to obtain intermediate c28-3 (1.4 g) in an 81% yield. LCMS ESI-MS m / z: 238 [M+H] + .

[0346] Step 3: Under nitrogen, intermediate c28-3 (1.3 g, 5.49 mmol) and starting material c9-2 (2.18 g, 6.03 mmol) from the previous step were dissolved in 23 mL of 1,4-dioxane. Catalyst Pd(PPh3)4 (635 mg, 0.55 mmol) was added, and the mixture was heated to 100°C for 16 hours before stopping the reaction. 100 mL of ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. The mixture was dissolved in 33 mL of tetrahydrofuran, and 8 mL of concentrated hydrochloric acid was added. The reaction was allowed to react at room temperature for 2 hours before stopping the reaction. Saturated aqueous sodium bicarbonate was slowly added to the reaction solution, and the pH was adjusted to approximately 8. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE / EA, 1 / 1) to obtain intermediate c28 (540 mg) in a yield of 49%. LCMS ESI-MS m / z:203[M+H] + .

[0347] Synthesis of intermediates d1-d9, d16-d18

[0348] Step 1: Under nitrogen, intermediate c1 (631 mg, 1.58 mmol), DIEA (1.1 g, 7.90 mmol), and intermediate b3 (332 mg, 1.90 mmol) were dissolved in 13 mL of acetonitrile. The mixture was heated to 60°C for 12 hours, after which the reaction was stopped. 100 mL of ice water was added to the reaction solution, which was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 10 / 1) to afford d1-1 (470 mg) as a pale yellow solid in a 55% yield. LCMS ESI-MS m / z: 538 [M+H] + .

[0349] Step 2: Dissolve the intermediate d1-1 (470 mg, 0.87 mmol) and formic acid (61 mg, 1.31 mmol) in 2 mL of 1,4-dioxane in an ice bath. Add 50 mL of a 50% aqueous solution of NH2OH dropwise. The mixture is allowed to react at room temperature for 13 hours, after which the reaction is stopped. Add 10 mL of ice water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to afford d1-2 (390 mg) as a yellow solid in an 81% yield. LCMS ESI-MS m / z: 553 [M+H] + .

[0350] Step 3: Under nitrogen, the intermediate d1-2 (390 mg, 0.70 mmol) from the previous step was dissolved in 2 mL of 1,4-dioxane. Dilute hydrochloric acid (3.9 mL, 4 M) was added dropwise. After completion of the addition, the mixture was heated to 40°C and allowed to react for 12 hours, after which the reaction was stopped. 50 mL of ice water was added to the reaction solution, and the pH was adjusted to approximately 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (DCM / MeOH, 10 / 1) to afford d1 (290 mg) as a white solid in an 83% yield. LCMS ESI-MS m / z: 491 [M+H] + .

[0351] Referring to the synthetic route of intermediate d1, similar raw materials / compounds were used to synthesize the following intermediates.

[0352] Synthesis of intermediates d10-d15, d19-d20

[0353] Step 1: Under nitrogen, intermediate c1 (955 mg, 5.51 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran. LiHMDS (1 M in THF) (7.5 mL, 7.51 mmol) was added dropwise and stirred at room temperature for 30 minutes. Intermediate c12 (2.0 g, 5.01 mmol) was added to the reaction solution, and the mixture was heated to 60°C for 1 hour, after which the reaction was stopped. 100 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 4 / 1) to obtain d10-1 (1.1 g) as a pale yellow solid in a 39% yield. LCMS ESI-MS m / z: 536 [M+H] + .

[0354] Step 2: Dissolve the intermediate d10-1 (956 mg, 1.78 mmol) and formic acid (123 mg, 2.68 mmol) in 4 mL of 1,4-dioxane in an ice bath. Add 50 mL of a 50% aqueous solution of NH2OH dropwise. The mixture is allowed to react at room temperature for 2 hours, after which the reaction is stopped. Add 50 mL of ice water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate to afford d10-2 (950 mg) as a yellow solid in a 97% yield. LCMS ESI-MS m / z: 551 [M+H] + .

[0355] Step 3: Under nitrogen, the intermediate d10-2 (950 mg, 1.72 mmol) from the previous step was dissolved in 5 mL of 1,4-dioxane. Dilute hydrochloric acid (9.5 mL, 4 M) was added dropwise. After completion of the addition, the mixture was heated to 40°C and allowed to react for 12 hours, after which the reaction was stopped. The reaction mixture was added with 60 mL of ice water and the pH was adjusted to approximately 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (DCM / MeOH, 10 / 1) to afford d10 (615 mg) as a yellow solid in a 73% yield. LCMS ESI-MS m / z: 489 [M+H] + .

[0356] Referring to the synthetic route of intermediate d10, similar raw materials / compounds were used to synthesize the following intermediates.

[0357] Synthesis of intermediates d21-d22, d43-d45, d47, d55-d56

[0358] Procedure: Dissolve intermediate d7 (7.75 g, 17.5 mmol) and ethylene glycol (73 mL) in 37 mL of dichloromethane in an ice bath under nitrogen protection. Add TMSCl (5.7 g, 52.86 mmol) dropwise. After completion of the dropwise addition, react at room temperature for 3 hours to stop the reaction. The solvent was evaporated under reduced pressure, and 30 mL of ice water was added to the reaction solution. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse column chromatography (chromatographic column: C18; CH3CN / H2O, 1 / 1) to obtain intermediate d21 (6.6 g) in a yield of 77%. LCMS ESI-MS m / z: 489 [M+H] + .

[0359] Referring to the synthetic route of intermediate d21, similar raw materials / compounds (such as intermediates a3, a30-a32, a28, a35, a38, etc.) were used to synthesize the following intermediates.

[0360] Synthesis of intermediates d23-d42, d46, d48-d54

[0361] Step 1: In an ice bath, under nitrogen, raw material d23-1 (2.5 g, 10.58 mmol) and MeNH2 (2M in THF) (10 mL) were dissolved in 50 mL of tetrahydrofuran. Titanium(IV) ethoxide (1.2 g, 5.29 mmol) was added and allowed to react at room temperature for 13 hours. NaBH4 (2.0 g, 52.91 mmol) and 50 mL of ethanol were added to the reaction solution, and the reaction was continued for 12 hours before stopping. 50 mL of saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (C18 column; CH3CN / H2O (0.1% ammonia), 5 / 1) to afford intermediate d23 (800 mg) in a 30% yield. LCMS ESI-MS m / z: 252 [M+H] + .

[0362] Referring to the synthetic route of intermediate d23, similar raw materials / compounds (such as intermediates c9-c11, c18-c24) were used to synthesize the following intermediates.

[0363] Synthesis of intermediates e1-e8

[0364] Procedure: Under nitrogen, intermediate d18 (800 mg, 1.75 mmol), ammonium acetate (216 mg, 2.80 mmol), and elemental S (90 mg, 2.8 mmol) were dissolved in 16 mL of ethanol and the mixture was heated to 60°C for 1 hour. Malononitrile (191 mg, 2.88 mmol) was added to the reaction solution, and the temperature was raised to 65°C for 1 hour to stop the reaction. 50 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (column: C18; CH3CN / H2O, 9 / 1) to obtain e1 (700 mg) as a white solid in a 74% yield. LCMS ESI-MS m / z: 537 [M+H] + .

[0365] Referring to the synthetic route of intermediate e1, similar raw materials / compounds (such as d1-d20) were used to synthesize the following intermediates.

[0366] Synthesis of intermediates e9-e28

[0367] Procedure: Under nitrogen, intermediate d22 (310 mg, 0.78 mmol) and DIEA (506 mg, 3.91 mmol) were dissolved in 7 mL of DMSO. Intermediate d24 (393 mg, 1.56 mmol) was added, and the mixture was allowed to react at room temperature for 18 hours. 50 mL of ice water was added to the reaction solution, which was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (C18; CH3CN / H2O (0.1% trifluoroacetic acid), 9 / 1) to afford e9 (200 mg) as a white solid in a 42% yield. LCMS ESI-MS m / z: 611 [M+H] + .

[0368] Referring to the synthetic route of intermediate e9, similar raw materials / compounds (such as d23-d47, etc.) were used to synthesize the following intermediates.

[0369] Example 2: Synthesis of target molecules P1, H1-H11, H19, H35, H98

[0370] Step 1: Under nitrogen, intermediate d1 (390 mg, 0.79 mmol), ammonium acetate (98 mg, 1.27 mmol), and elemental S (41 mg, 1.27 mmol) were dissolved in 4 mL of ethanol. The mixture was heated to 60°C for 1 hour. Malononitrile (87 mg, 1.31 mmol) was added to the reaction solution, and the temperature was raised to 80°C for 1 hour to stop the reaction. 50 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (column: C18; CH3CN / H2O, 3 / 2) to obtain a pale yellow solid P1-2 (250 mg) in a yield of 55%. LCMS ESI-MS m / z: 571 [M+H] + .

[0371] Step 2: Dissolve compound P1-2 (85 mg, 0.15 mmol) and starting material P1-1 (95 mg, 0.45 mmol) in 1 mL of DMSO in an ice bath. Add DIEA (96 mg, 0.74 mmol). The mixture is heated to 90°C and allowed to react for 3 hours, after which the reaction is stopped. Add 10 mL of ice water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by preparative HPLC (XSelect CSH Prep C18 OBD Column; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min, retention time: 9.459 min) to afford P1-3 (11 mg) as a white solid in a 10% yield. LCMS ESI-MS m / z: 747 [M+H] + .

[0372] Step 3: Under nitrogen, compound P1-3 (11 mg, 0.02 mmol) from the previous step was dissolved in 0.5 mL of dichloromethane. A solution of hydrogen chloride in 1,4-dioxane (0.2 mL, 4 M) was added dropwise. The mixture was allowed to react at room temperature for 2 hours, after which the reaction was stopped. The reaction solution was adjusted to a pH of approximately 8 by adding saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative HPLC (column: Xbridge Prep phenyl OBD Colum; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 25 mL / min, retention time: 11.4 min) to afford P1 (4.8 mg) as a white solid in a 50% yield. LCMS ESI-MS m / z: 647 [M+H] + .

[0373] 1 H NMR (400MHz, DMSO-d6) δ6.94 (s, 2H), 6.04 (s, 1H), 5.29 (p, J = 6.1Hz, 1H), 3.26 ( s,1H),3.16(p,J=8.0Hz,1H),2.99(dd,J=16.6,4.9Hz,1H),2.80(t,J=5.1Hz,2 H),2.74(dt,J=8.8,5.9Hz,1H),2.36(s,3H),2.13(q,J=7.8,6.3Hz,2H),2.08( d,J=4.1Hz,3H),2.03–1.66(m,10H),1.21(d,J=6.2Hz,3H),0.54–0.40(m,3H).

[0374] Referring to the synthetic route of target molecule P1, similar raw materials / intermediates (such as intermediates a5-a17, a20, d1-d17, e1-e8) were used to synthesize the following target molecules.

[0375] Example 3: Synthesis of target molecules H12, H14-H18, H34

[0376] Step 1: Dissolve intermediate compound P1-2 (40 mg, 0.07 mmol) and starting material H12-1 (28 mg, 0.21 mmol) in 1 mL of DMSO in an ice bath. Add DIEA (96 mg, 0.74 mmol). Warm the mixture to 90°C and react for 13 hours, then stop the reaction. Add 10 mL of ice water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. A yellow oil, H12-2 (41 mg), is obtained in a 77% yield. LCMS ESI-MS m / z: 666 [M+H] + .

[0377] Step 2: Under nitrogen, compound H12-2 (34 mg, 0.05 mmol) from the previous step was dissolved in 1.5 mL of chloroform. Trifluoroacetic acid (0.4 mL) and water (0.4 mL) were added dropwise. The mixture was heated to 50°C and allowed to react for 2 hours to terminate the reaction. The reaction mixture was adjusted to pH 8 by adding saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative HPLC (column: Xbridge Prep phenyl OBD Colum, 30 x 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH₄HCO₃), mobile phase B: acetonitrile; flow rate: 60 mL / min, retention time: 10.9 min) to afford the target molecule H12 (12.1 mg) in a 38% yield. LCMS ESI-MS m / z: 622 [M+H] + .

[0378] 1H NMR (300MHz, DMSO-d6, ppm) δ6.95(s,2H),5.94(s,1H),5.30(p,J=6.2Hz,1H),4.49(s,2H),3.27(dd,J=8.9,6.4Hz,1H),3.15(p,J=8.2Hz,1H ),3.02(s,4H),2.74(dt,J=9.1,5.9Hz,1H),2.54(d,J=8.4Hz,3H),2.35(s,3H),2.19–2.02(m,8H),2.02–1.64(m,9H),1.21(d,J=6.4Hz,3H).

[0379] Referring to the synthetic route of the target molecule H12, similar raw materials / intermediates (such as intermediates e1, e7-e8, etc.) were used to synthesize the following target molecules.

[0380] Example 4: Synthesis of target molecule H13

[0381] Step 1: Dissolve intermediate a13 (598 mg, 2.28 mmol) and intermediate a32 (400 mg, 1.14 mmol) in 9 mL of acetonitrile in an ice bath. Add DIEA (734 mg, 5.57 mmol). Heat the mixture to 90°C and react for 13 hours, then stop the reaction. Add 30 mL of ice water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse-phase column chromatography (column: C18; CH3CN / H2O, 9 / 1) to obtain compound H13-1 (151 mg) in a yield of 23%. LCMS ESI-MS m / z: 579 [M+H] + .

[0382] Step 2: Under nitrogen, compound H13-1 (130 mg, 0.22 mmol) and intermediate b9 (44 mg, 0.33 mmol) were dissolved in 3 mL of DMF. Potassium carbonate (47 mg, 0.33 mmol) and CuI (0.43 mg, 0.002 mmol) were added. The mixture was heated to 110°C and reacted for 13 hours, after which the reaction was stopped. 30 mL of ice water was added to the reaction solution, which was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (column: C18; CH3CN / H2O, 9 / 1) to obtain compound H13-2 (31 mg) in a yield of 23%. LCMS ESI-MS m / z: 572 [M+H] + .

[0383] Step 3: Under nitrogen, compound H13-2 (30 mg, 0.052 mmol), ammonium acetate (6.5 mg, 0.083 mmol), and elemental S (4 mg, 0.13 mmol) were dissolved in 1 mL of ethanol. The mixture was heated to 60°C for 0.5 hours. Malononitrile (5.7 mg, 0.086 mmol) was added to the reaction solution, and the temperature was raised to 80°C for 2 hours to terminate the reaction. The reaction solution was added with 5 mL of ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative HPLC (column: XBridge Shield RP18 OBD Column 30*150 mm, 5 μm; mobile phase A: H2O (0.1% formic acid); mobile phase B: CH3CN; flow rate: 60 mL / min; retention time: 7.5 min) to obtain the target molecule, the formate salt H13 (2.0 mg), in a yield of 5%. LCMS ESI-MS m / z:652[M+H] + .

[0384] 1 H NMR (300MHz, DMSO-d6) δ8.43 (s, 2H), 7.83 (s, 1H), 7.09 (d, J = 7.4Hz, 1H), 6. 94(s,1H),6.53–6.44(m,1H),6.24(s,1H),5.85(s,1H),5.38–5.29(m,1H), 4.72–4.58(m,2H),2.96(s,2H),2.66(s,3H),2.37(s,4H),2.19(d,J=8.7Hz ,2H),2.03–1.52(m,12H),1.25(d,J=5.8Hz,3H),0.94(s,2H),0.73(s,2H).

[0385] Example 5: Synthesis of target molecules H20-H30, H36, H47, H112-H115

[0386] Step 1: In an ice bath, under nitrogen, intermediate a32 (6.2 g, 17.6 mmol) and ethylene glycol (73 mL) were dissolved in 37 mL of dichloromethane. TMSCl (5.7 g, 52.86 mmol) was added dropwise. The mixture was allowed to react at room temperature for 3 hours, after which the reaction was stopped. The solvent was evaporated under reduced pressure, and 30 mL of ice water was added to the reaction solution. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (column: C18; CH3CN / H2O, 1 / 1) to obtain compound d22 (5.5 g) in a yield of 79%. LCMS ESI-MS m / z: 396 [M+H] + .

[0387] Step 2: Dissolve intermediate a15 (359 mg, 1.51 mmol) and compound d22 (500 mg, 1.26 mmol) in 10 mL of acetonitrile in an ice bath. Add DIEA (800 mg, 6.34 mmol). Warm the mixture to 50°C and react for 1 hour, then stop the reaction. Add 50 mL of ice water to the reaction solution, extract with dichloromethane, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse-phase column chromatography (column: C18; CH3CN / H2O, 9 / 1) to obtain compound H20-2 (401 mg) in a 53% yield. LCMS ESI-MS m / z: 597 [M+H] + .

[0388] Step 3: In an ice bath, under nitrogen protection, intermediate b9 (43 mg, 0.33 mmol) and NaH (21 mg, 0.87 mmol) were dissolved in 2 mL of anhydrous tetrahydrofuran and stirred for 30 minutes. Compound H20-2 (130 mg, 0.22 mmol) from the previous step was added, and the mixture was warmed to room temperature for 13 hours to stop the reaction. 30 mL of ice water was added to the reaction solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse column chromatography (chromatographic column: C18; CH3CN / H2O, 4 / 1) to obtain compound H20-3 (81 mg), yield: 53%, LCMS ESI-MS m / z: 690 [M+H] + .

[0389] Step 4: In an ice bath, under nitrogen protection, compound H20-3 (80 mg, 0.12 mmol) from the previous step was dissolved in 3 mL of a 4M solution of hydrogen chloride in 1,4-dioxane. The mixture was reacted at room temperature for 13 hours, and the reaction was stopped. Saturated aqueous sodium bicarbonate was added to the reaction solution to adjust the pH to approximately 8. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain compound H20-4 (20 mg). Yield: 32%. LCMS ESI-MS m / z: 546 [M+H] + .

[0390] Step 3: Under nitrogen, compound H20-4 (20 mg, 0.04 mmol), ammonium acetate (7.6 mg, 0.1 mmol), and elemental S (1.3 mg, 0.04 mmol) were dissolved in 1 mL of ethanol. The mixture was heated to 60°C for 0.5 hours. Malononitrile (5.7 mg, 0.086 mmol) was added to the reaction solution, and the temperature was raised to 80°C for 1 hour to terminate the reaction. The reaction solution was added with 5 mL of ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative HPLC (column: Xbridge Prep phenyl OBD Colum, 30 x 150 mm, 5 μm; mobile phase A: H2O (10 mmol / L NH4HCO3); mobile phase B: MeOH; flow rate: 60 mL / min; retention time: 10.5 min) to obtain the target molecule H20 (6.0 mg) in a yield of 26%. LCMS ESI-MS m / z:626[M+H] + .

[0391] 1 H NMR (300MHz, DMSO-d6) δ7.85(dd,J=4.9,1.8Hz,1H),7.17(s,1H),6.95(s,2H),6.50(dd,J=7.3,4.9Hz,1H),5.90(d,J=18.3Hz,3H),5.29(q ,J=6.1Hz,1H),4.61(d,J=14.1Hz,2H),3.09–2.87(m,5H),2.62–2.54(m,2H),2.34(s,3H),2.22–2.13(m,1H),1.97(q,J=14.4Hz,3H),1.86 -1.58(m,10H),1.22(t,J=6.6Hz,3H).

[0392] Referring to the synthetic route of the target molecule H20, similar raw materials / intermediates (such as intermediates a5-a10, a13-a19, a21-a35, b1-b31, etc.) were used to synthesize the following target molecules.

[0393] Example 6: Synthesis of target molecule H31

[0394] Step 1: Dissolve intermediate a24 (113 mg, 0.29 mmol) and NaH (46 mg, 1.16 mmol, 60%) in 3 mL of DMF in an ice bath and stir for 1 hour. Intermediate d21 (140 mg, 0.29 mmol) was added to the reaction mixture, and the mixture was warmed to room temperature and reacted for 12 hours before stopping the reaction. 50 mL of ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (C18 column; CH3CN / H2O (0.1% HCOOH), 2 / 1) to obtain compound H31-1 (71 mg) in a 33% yield. LCMS ESI-MS m / z: 734 [M+H] + .

[0395] Step 2: In an ice bath, under nitrogen protection, compound H31-1 (70 mg, 0.095 mmol) from the previous step was dissolved in 2 mL of a 4M solution of hydrogen chloride in 1,4-dioxane. The mixture was reacted at room temperature for 13 hours, and the reaction was stopped. Saturated aqueous sodium bicarbonate was added to the reaction solution to adjust the pH to approximately 8. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse column chromatography (column: C18; CH3CN / H2O (0.1% HCOOH), 2 / 3) to obtain compound H31-2 (16 mg), yield: 28%, LCMS ESI-MS m / z: 590 [M+H] + .

[0396] Step 3: Under nitrogen, compound H31-2 (16 mg, 0.027 mmol), ammonium acetate (3.4 mg, 0.043 mmol), and elemental S (1.4 mg, 0.04 mmol) were dissolved in 1 mL of ethanol. The mixture was heated to 60°C for 0.5 hours. Malononitrile (5.7 mg, 0.086 mmol) was added to the reaction solution, and the temperature was raised to 80°C for 1 hour to terminate the reaction. 5 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative HPLC (column: Xselect CSH Prep C18 OBD Colum, 19*250 mm, 5 μm; mobile phase A: H2O (0.1% HCOOH); mobile phase B: MeOH; flow rate: 20 mL / min; retention time: 11.0 min) to obtain the target molecule H31 (4.1 mg) in a yield of 23%. LCMS ESI-MS m / z:670[M+H] + .

[0397] 1H NMR(300MHz,DMSO-d6)δ8.26(s,1H),7.84(d,J=3.9Hz,1H),7.07(s,1H),6.94(s,2H ),6.47-6.51(m,1H),5.88(s,3H),5.29-5.20(m,1H),4.64-4.45(m,2H),3.99(d,J=3 .0Hz,2H),3.35-3.22(m,1H),2.95(d,J=6.9Hz,1H),2.73-2.50(s,3H),2.35(s,3H), 2.23-2.18(m,1H),1.98-1.66(m,14H),1.20(d,J=6.0Hz,3H),1.09(d,J=6.0Hz,3H).

[0398] Example 7: Synthesis of target molecules H32-H33, H37-H46, H48-H70, H89-H94, H108

[0399] Step 1: Dissolve intermediate b9 (64 mg, 0.49 mmol) and NaH (32 mg, 1.31 mmol, 60%) in 4 mL of THF in an ice bath and stir for 1 hour. Add intermediate e9 (200 mg, 0.33 mmol) to the reaction mixture, warm the mixture to 70°C, and react for 4 hours to stop the reaction. Add 50 mL of ice water to the reaction mixture, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product was separated by flash reverse-phase column chromatography (C18 column; CH3CN / H2O (0.1% trifluoroacetic acid), 4 / 1) to obtain compound H32-1 (201 mg) in an 87% yield. LCMS ESI-MS m / z: 704 [M+H] + .

[0400] Step 2: In an ice bath, under nitrogen protection, compound H32-1 (200 mg, 0.28 mmol) from the previous step was dissolved in 8 mL of a 6M solution of hydrogen chloride in 1,4-dioxane. The mixture was reacted at room temperature for 13 hours, and the reaction was stopped. Saturated aqueous sodium bicarbonate was added to the reaction solution to adjust the pH to approximately 8. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain compound H32-2 (150 mg, crude product). LCMS ESI-MS m / z: 560 [M+H] + .

[0401] Step 3: Under nitrogen, compound H32-2 (150 mg, 0.27 mmol), ammonium acetate (33 mg, 0.43 mmol), and elemental S (14 mg, 0.43 mmol) were dissolved in 3 mL of ethanol. The mixture was heated to 60°C for 0.5 hours. Malononitrile (29 mg, 0.44 mmol) was added to the reaction solution, and the temperature was raised to 80°C for 1 hour to stop the reaction. 30 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain crude product H32 (150 mg). The crude product H32 was separated by preparative HPLC chromatography (column: Xselect CSH Prep C18 OBD Colum, 30*150 mm, 5 μm; mobile phase A: H2O (0.1% HCOOH); mobile phase B: MeOH; flow rate: 60 mL / min) to obtain the target molecules H32a (12.1 mg, formate salt, retention time: 8.88 min, yield: 7%) and H32b (27 mg, formate salt, retention time: 10.17 min, yield: 15%). LCMS ESI-MS m / z: 640 [M+H] + .

[0402] H32a: 1 H NMR (400MHz, DMSO-d6, HCOOH) δ7.89 (dd, J=4.9, 1.8Hz, 1H), 7.57 (d, J=7.4Hz, 1H), 6.97 (s, 2 H),6.64–6.53(m,1H),6.03(s,1H),5.90(d,J=1.9Hz,1H),5.75(s,2H),5.30(q,J=6.3Hz,1H ),3.11–2.92(m,2H),2.77–2.60(m,5H),2.61–2.53(m,2H),2.40(dd,J=6.2,2.8Hz,3H),2.2 9(d,J=15.1Hz,1H),2.05–1.63(m,12H),1.46(d,J=6.8Hz,3H),1.24(dd,J=6.3,1.7Hz,3H).

[0403] H32b: 1H NMR(400MHz,DMSO-d6,free base)δ7.89(dd,J=4.9,1.8Hz,1H),7.57(d,J=7.4Hz,1H),6.97(s,2H),6.64–6.53(m, 1H),6.03(s,1H),5.90(d,J=1.9Hz,1H),5.75(s,2H),5.30(q,J=6.3Hz,1H),3.11–2.9 2(m,2H),2.77–2.60(m,5H),2.61–2.53(m,2H),2.40(dd,J=6.2,2.8Hz,3H),2.29(d,J =15.1Hz,1H),2.05–1.63(m,12H),1.46(d,J=6.8Hz,3H),1.24(dd,J=6.3,1.7Hz,3H).

[0404] Referring to the synthetic route of the target molecule H20, similar raw materials / intermediates (such as intermediates a4-a10, d23-d54, b1-b30, c10-c25, e9-e28, etc.) were used to synthesize the following target molecules.

[0405] # = Presumed configuration

[0406] Example 8: Synthesis of target molecule H71

[0407] Step 1: Dissolve intermediate b16 (537 mg, 1.96 mmol) and NaH (209 mg, 5.24 mmol, 60%) in 14 mL of THF in an ice bath and stir for 1 hour. Intermediate e9 (800 mg, 1.31 mmol) was added to the reaction mixture, and the mixture was heated to 50°C for 2 hours before stopping the reaction. Add 50 mL of ice water to the reaction mixture, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product was separated by flash reverse-phase column chromatography (C18 column; CH3CN / H2O (0.1% trifluoroacetic acid), 7 / 10) to obtain compound H71-1 (600 mg) in a 62% yield. LCMS ESI-MS m / z: 734 [M+H] + .

[0408] Step 2: Dissolve compound H71-1 (320 mg, 0.44 mmol) and TEA (177 mg, 1.76 mmol) in 4 mL of THF in an ice bath under nitrogen. Add 4-nitrophenyl chloroformate (264 mg, 1.32 mmol), and allow the mixture to react for 1 hour in an ice bath. Add morpholine (114 mg, 1.32 mmol) dropwise to the reaction mixture, continue the reaction at room temperature for 1 hour, and then stop the reaction. Add 50 mL of ice water to the reaction mixture, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product was separated by preparative HPLC (column: Torus Diol OBD, 3 x 25 cm, 5 μm; flowability A: CO2; flowability B: CH3CN / MeOH, 4 / 1; flow rate: 75 mL / min, retention time: 6.73 min) to obtain compound H71-2 (80 mg) in a yield of 22%. LCMS ESI-MS m / z:847[M+H] + .

[0409] Step 3: Dissolve the compound H71-2 (80 mg, 0.094 mmol) in 2 mL of 1,4-dioxane in an ice bath under nitrogen. Add dilute hydrochloric acid (2 mL, 4 M). Incubate the mixture in an ice bath for 1 hour and continue at room temperature for 12 hours before stopping the reaction. Add 50 mL of ice water to the reaction solution, adjust the pH to approximately 8 with saturated sodium bicarbonate solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain compound H71-3 (60 mg) in a 90% yield. LCMS ESI-MS m / z: 703 [M+H] + .

[0410] Step 4: Under nitrogen, compound H71-3 (60 mg, 0.085 mmol), ammonium acetate (11 mg, 0.14 mmol), and elemental S (4.4 mg, 0.14 mmol) were dissolved in 2 mL of ethanol. The mixture was heated to 60°C for 0.5 h. Malononitrile (9.3 mg, 0.14 mmol) was added to the reaction solution, and the temperature was raised to 80°C for 1 h to terminate the reaction. 30 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain crude product H71. Crude H71 was separated by preparative HPLC (column: Xselect CSH Prep C18 OBD Colum, 30*150 mm, 5 μm; mobile phase A: H2O (10 mmol / L NH4HCO3 + 0.05% NH3.H2O); mobile phase B: CH3CN; flow rate: 60 mL / min) to afford the target molecule H71 (7.6 mg, retention time: 7.25 min, yield: 11%). LCMS ESI-MS m / z: 783 [M+H] + .

[0411] 1 H NMR(400MHz,CD3OD)δ7.84(s,1H),7.68(d,J=6.0,1H),6.70–6.67(m,1H),6.29(s,1H),5.8 9(s,1H),5.11–5.03(m,1H),4.34–4.29(m,2H),3.59(d,J=23.3Hz,4H),3.43(d,J=14.5Hz,4 H),3.20(dd,J=16.7,4.9Hz,1H),3.05–2.88(m,2H),2.69(d,J=3.7Hz,4H),2.64–2.52(m,4H ),2.44–2.31(m,4H),2.18–1.93(m,9H),1.54(dd,J=6.9,4.6Hz,3H),1.22(d,J=6.4Hz,3H).

[0412] Example 9: Synthesis of target molecules H72-H75

[0413] Step 1: Dissolve intermediate a12 (170 mg, 0.43 mmol) and DIEA (280 mg, 2.14 mmol) in 2 mL of THF in an ice bath and stir for 1 hour. Add intermediate d23 (161 mg, 0.64 mmol) to the reaction mixture, and allow the mixture to react on ice for 1 hour before stopping the reaction. Add 50 mL of ice water to the reaction mixture, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product was separated by flash reverse-phase column chromatography (C18 column; CH3CN / H2O (0.1% formic acid), 7 / 10) to afford compound H72-1 (150 mg) in a 57% yield. LCMS ESI-MS m / z: 612 [M+H] + .

[0414] Step 2: Dissolve intermediate b8 (54 mg, 0.37 mmol) and NaH (40 mg, 0.98 mmol, 60%) in 2 mL of THF in an ice bath and stir for 1 hour. Add compound H72-1 (150 mg, 0.25 mmol) to the reaction solution and react at room temperature for 1 hour to stop the reaction. Add 50 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain crude compound H72-2 (200 mg). LCMS ESI-MS m / z: 723 [M+H] + .

[0415] Step 3: In an ice bath, under nitrogen, compound H72-2 (200 mg, 0.28 mmol) from the previous step was dissolved in 2 mL of 1,4-dioxane. Dilute hydrochloric acid (2 mL, 4 M) was added, and the mixture was reacted in an ice bath for 1 hour. The reaction continued at room temperature for 12 hours, after which the reaction was stopped. 50 mL of ice water was added to the reaction solution, and the pH was adjusted to approximately 8 with saturated sodium bicarbonate aqueous solution. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (column: C18; CH3CN / H2O (0.1% formic acid), 1 / 1) to afford compound H72-3 (90 mg), with a two-step yield of 62%. LCMS ESI-MS m / z: 579 [M+H] + .

[0416] Step 4: Under nitrogen, compound H72-3 (90 mg, 0.16 mmol), ammonium acetate (19 mg, 0.25 mmol), and elemental S (8 mg, 0.25 mmol) were dissolved in 2 mL of ethanol. The mixture was heated to 60°C for 0.5 hours. Malononitrile (17 mg, 0.26 mmol) was added to the reaction solution, and the temperature was raised to 80°C for 1 hour to stop the reaction. 30 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain crude product H72. The crude product H72 was separated by preparative HPLC (column: Xselect XBridge Prep Shield RP18 OBD Column, 30*150 mm, 5 μm; mobile phase A: H2O (0.1% HCOOH); mobile phase B: CH3CN; flow rate: 60 mL / min) to obtain the target molecule H72 (63.2 mg, retention time: 10.0 min, yield: 62%). LCMS ESI-MS m / z: 659 [M+H] + .

[0417] 1 H NMR(300MHz, DMSO-d6)δ8.07–8.00(m,2H),7.34(d,J=2.2Hz,1H),7.17–6.92(m,3H),5.97–5.87(m,1H),5.76-5.41(m,2H),3.84(s,1H),3 .65-3.55(m,5H),3.18–2.93(m,7H),2.62(d,J=6.4Hz,3H),2.25-1.98(m,4H),1.96(d,J=14.1Hz,4H),1.60(t,J=6.0Hz,3H),1.42(m,3H).

[0418] Referring to the synthetic route of the target molecule H72, similar raw materials / intermediates (such as intermediates C12-C17, C20-C21, D23-D54) were used to synthesize the following target molecules.

[0419] Example 10: Synthesis of target molecules H76-H88, H99-H102, H106-H107, H109-H110, H124-H126

[0420] Step 1: Dissolve intermediate d22 (300 mg, 0.75 mmol) and DIEA (978 mg, 7.57 mmol) in 6 mL of DMSO in an ice bath and stir for 1 hour. Add intermediate d38 (245 mg, 0.90 mmol) to the reaction mixture, and incubate the mixture at 50°C for 12 hours before stopping the reaction. Add 50 mL of ice water to the reaction mixture, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product was separated by flash reverse-phase column chromatography (C18 column; CH3CN / H2O (0.1% formic acid), 4 / 1) to afford compound H76-1 (380 mg) in an 80% yield. LCMS ESI-MS m / z: 629 [M+H] + .

[0421] Step 2: Dissolve intermediate b9 (62 mg, 0.47 mmol) and NaH (102 mg, 2.54 mmol, 60%) in 4 mL THF in an ice bath and stir for 1 hour. Add compound H76-1 (200 mg, 0.31 mmol) to the reaction solution, heat to 50°C and react for 5 hours to stop the reaction. Add 50 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain crude compound H76-2 (290 mg). LCMS ESI-MS m / z: 722 [M+H] + .

[0422] Step 3: In an ice bath, under nitrogen, compound H76-2 (290 mg, 0.4 mmol) from the previous step was dissolved in 4 mL of 1,4-dioxane. Dilute hydrochloric acid (4 mL, 4 M) was added, and the mixture was reacted in an ice bath for 1 hour. The reaction was continued at room temperature for 2 hours before stopping the reaction. 50 mL of ice water was added to the reaction solution, and the pH was adjusted to approximately 8 with saturated sodium bicarbonate aqueous solution. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (column: C18; CH3CN / H2O (0.1% formic acid), 1 / 1) to obtain compound H76-3 (100 mg), with a two-step yield of 53%. LCMS ESI-MS m / z: 578 [M+H] + .

[0423] Step 4: Under nitrogen protection, the compound H76-3 (100 mg, 0.17 mmol), ammonium acetate (21 mg, 0.27 mmol) and elemental S (8 mg, 0.25 mmol) from the previous step were dissolved in 2 mL of ethanol, and the mixture was reacted at 60°C for 0.5 hours. Malononitrile (17 mg, 0.26 mmol) was added to the reaction solution, and the temperature was raised to 80°C for 1 hour to stop the reaction. 30 mL of ice water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain crude product H76. The crude product H76 was separated by HPLC preparative chromatography (chromatographic column: Xselect XBridge Prep Shield RP18 OBD Column, 30*150 mm, 5 μm; mobile phase A: H2O (10 mmol / L NH4HCO3 + 0.05% NH3 . H2O); mobile phase B: CH3CN; flow rate: 60 mL / min;) to obtain the target molecule H76a # (10.2 mg, retention time: 7.03 min, yield: 9%) and target molecule H76b # (11.6 mg, yield: 10%). LCMS ESI-MS m / z: 658 [M+H] + .

[0424] H76a,HCOOH salts: 1 H NMR (300MHz, DMSO-d6) δ7.89(d,J=2.8Hz,1H),7.58(d,J=9.4Hz,1H),6.97(s,2H),5.93(s,2H),5.75(s,2H),5.32(q,J=6.3Hz,1H),3.02(s, 2H),2.68(d,J=13.0Hz,5H),2.55(s,2H),2.42(s,3H),2.35–2.23(m,1H),2.10–1.61(m,12H),1.48(d,J=6.8Hz,3H),1.25(d,J=6.2Hz,3H).

[0425] H76b,HCOOH salts: 1H NMR (300MHz, DMSO-d6) δ7.89(d,J=2.8Hz,1H),7.58(d,J=9.4Hz,1H),6.97(s,2H),5.93(s,2H),5.75(s,2H),5.32(q,J=6.3Hz,1H),3.02(s, 2H),2.68(d,J=13.0Hz,5H),2.55(s,2H),2.42(s,3H),2.35–2.23(m,1H),2.10–1.61(m,12H),1.48(d,J=6.8Hz,3H),1.25(d,J=6.2Hz,3H).

[0426] Referring to the synthetic route of the target molecule H76, similar raw materials / intermediates (such as intermediates a5-a10, b2-b36, c10-c27, d21-d22, d43-d54, e9-e28, etc.) were used to synthesize the following target molecules.

[0427] # = Presumed configuration

[0428] Example 11: Synthesis of target molecules H95-H97

[0429] Step 1: In an ice bath, the raw material H95-1 (43 mg, 0.38 mmol) and DIEA (108 mg, 0.84 mmol) were dissolved in 2 mL of acetonitrile and stirred for 10 minutes. The intermediate e9 (115 mg, 0.19 mmol) was added to the reaction solution, and the mixture was reacted at room temperature for 14 hours, after which the reaction was stopped. 50 mL of ice water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse column chromatography (chromatographic column: C18; CH3CN / H2O (10 mmol / L HCOOH), 2 / 1) to obtain compound H95-2 (81 mg), yield: 62%, LCMS ESI-MS m / z: 689 [M+H] + .

[0430] Step 2: In an ice bath, under nitrogen protection, compound H95-2 (117 mg, 0.17 mmol) from the previous step was dissolved in 3 mL of a 4M solution of hydrogen chloride in 1,4-dioxane. The mixture was reacted at room temperature for 1 hour, and the reaction was stopped. Saturated sodium bicarbonate aqueous solution was added to the reaction solution to adjust the pH to about 10, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain compound H95-3 (92 mg, crude product). LCMS ESI-MS m / z: 545 [M+H] + .

[0431] Step 3: Under nitrogen, compound H95-3 (92 mg, 0.17 mmol), ammonium acetate (21 mg, 0.27 mmol), and elemental S (8.7 mg, 0.27 mmol) were dissolved in 1 mL of ethanol. The mixture was heated to 60°C for 0.5 hours. Malononitrile (18.4 mg, 0.28 mmol) was added to the reaction solution, and the temperature was raised to 80°C for 1 hour to stop the reaction. 30 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain crude product H95 (110 mg). The crude product H95 was separated by preparative HPLC (column: Xselect CSH Prep Phenyl-Hexyl Column, 19 x 250 mm, 5 μm; mobile phase A: H2O (0.05% TFA); mobile phase B: MeOH; flow rate: 20 mL / min) to afford the target molecules H95a (20.9 mg, retention time: 15.7 min, yield: 20%) and H95b (11.6 mg, retention time: 17.7 min, yield: 11%). LCMS ESI-MS m / z: 625 [M+H] + .

[0432] H95a: 1 H NMR(300MHz,DMSO-d6)δ8.53(s,2H),8.16(m,1H),7.96(m,1H),7.48–6.66( m,3H),6.02(t,J=7.0Hz,1H),5.59(s,1H),4.12(d,J=7.1Hz,2H),3.79-3.6 6(s,2H),3.45(s,1H),3.22(s,1H),2.94(s,6H),2.75(s,4H),2.45(s,2H), 2.33(s,1H),2.22(s,1H),1.99(s,4H),1.94(d,J=11.2Hz,4H),1.85(s,3H).

[0433] H95b: 1H NMR (400MHz, DMSO-d6) δ8.51 (s, 2H), 8.15 (d, J = 7.4Hz, 1H), 7.95 (m, 1H), 6.98–6.9 0(m,3H),5.98(d,J=7.1Hz,1H),5.59(s,1H),4.06–3.98(m,1H),3.90(s,2H),3.48( s,2H),3.01(d,J=16.4Hz,1H),2.87(s,6H),2.77–2.65(m,4H),2.54(s,2H),2.44(s ,1H),2.22(s,1H),2.03–1.92(m,4H),1.84(d,J=9.5Hz,4H),1.51(d,J=6.9Hz,3H).

[0434] Referring to the synthetic route of the target molecule H95, similar raw materials / intermediates were used to synthesize the following target molecules.

[0435] # = Presumed configuration

[0436] Example 12: Synthesis of target molecules H103-H105, H123

[0437] Step 1: Dissolve intermediate b27 (357 mg, 1.38 mmol) and NaH (147 mg, 3.68 mmol, 60%) in 10 mL of THF in an ice bath and stir for 1 hour. Add intermediate e13 (562 mg, 0.92 mmol) to the reaction solution, warm the mixture to 50°C, and react for 24 hours before stopping the reaction. Add 50 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash column chromatography (DCM / MeOH, 20 / 1) to obtain compound H103-1 (260 mg) in a 33% yield. LCMS ESI-MS m / z: 835 [M+H] + .

[0438] Step 2: Dissolve the compound H103-1 (200 mg, 0.24 mmol) from the previous step in 3 mL of tetrahydrofuran, and add TBAF (1.77 mL, 1 M) dropwise. The mixture is allowed to react at room temperature for 2 hours, after which the reaction is stopped. Add 10 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse-phase column chromatography (column: C18; CH3CN / H2O (0.1% HCOOH), 4 / 1) to afford compound H103-2 (102 mg), yield: 56%. LCMS ESI-MS m / z: 721 [M+H] + .

[0439] Step 3: Dissolve compound H103-2 (100 mg, 0.14 mmol) and NaH (22.2 mg, 0.56 mmol, 60%) in 2 mL of anhydrous DMF. Add compound H103-3 (86.7 mg, 0.42 mmol) dropwise. The mixture is heated to 50°C and reacted for 12 hours, after which the reaction is stopped. Add 20 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product is separated by flash reverse-phase column chromatography (column: C18; CH3CN / H2O (0.1% HCOOH), 1 / 1) to obtain compound H103-4 (45 mg) in a yield of 38%. LCMS ESI-MS m / z: 849 [M+H] + .

[0440] Step 4: In an ice bath, under nitrogen protection, compound H103-4 (45 mg, 0.053 mmol) from the previous step was dissolved in 1 mL of a 4M solution of hydrogen chloride in 1,4-dioxane. The mixture was reacted at room temperature for 12 hours, and the reaction was stopped. Saturated aqueous sodium bicarbonate was added to the reaction solution to adjust the pH to approximately 10. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to afford compound H103-5 (13 mg). Yield: 40%. LCMS ESI-MS m / z: 621 [M+H] + .

[0441] Step 5: Under nitrogen, compound H103-5 (13 mg, 0.021 mmol), ammonium acetate (2.6 mg, 0.034 mmol), and elemental S (1.1 mg, 0.034 mmol) were dissolved in 0.5 mL of ethanol. The mixture was heated to 60°C for 0.5 h. Malononitrile (2.3 mg, 0.035 mmol) was added to the reaction solution, and the temperature was raised to 80°C for 4 h to terminate the reaction. 5 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product (11 mg). The crude product was separated by preparative HPLC (column: XSelect CSH Prep C18 OBD Column, 30*150 mm, 5 μm; mobile phase A: H2O (0.1% HCOOH); mobile phase B: CH3CN; flow rate: 60 mL / min) to afford the target molecules H103a (3.2 mg, retention time: 9.03 min, yield: 21%) and H103b (1.3 mg, retention time: 10.32 min, yield: 9%). LCMS ESI-MS m / z: 701 [M+H] + .

[0442] H103a: 1H NMR (400 MHz, DMSO-d 6, HCOOH salt)δ8.28(d,J=24.0Hz,2H),6.98(s,2H),6.80(s,2H),5.99–5.94(m,2 H),5.31(s,1H),3.99(s,2H),3.40–3.39(m,2H),3.31(s,2H),3.18(s,1H ),3.05–2.93(m,3H),2.89–2.83(m,1H),2.72(s,4H),2.41(s,2H),2.32( s,1H),2.08–1.77(m,10H),1.50(d,J=5.6Hz,3H),1.23(d,J=6.0Hz,3H).

[0443] H103b: 1 H NMR (400MHz, DMSO-d6) δ8.30 (d, J = 11.6Hz, 2H), 6.97 (s, 2H), 6.79 (s, 2H), 6. 08–5.89(m,2H),5.36–5.27(m,1H),4.57(s,1H),3.96(s,1H),3.46(s,2H),3 .28–3.24(m,2H),3.18–3.08(m,1H),2.78–2.61(m,6H),2.34(s,3H),2.23–2 .19(m,1H),2.09–1.75(m,11H),1.52(d,J=7.1Hz,3H),1.22(d,J=6.1Hz,3H).

[0444] Referring to the synthetic route of the target molecule H103, similar raw materials / intermediates (such as intermediates a5-a10, b2-b31, c10-c27, d21-d22, d43-d45, e9-e28) were used to synthesize the following target molecules.

[0445] # = Presumed configuration

[0446] Example 13: Synthesis of target molecule H111

[0447] Step 1: Under nitrogen at -50°C, compound H54a (11 mg, 0.02 mmol) was dissolved in 0.5 mL of anhydrous DCM. BBr (20 mg, 0.1 mmol) was added, and the mixture was slowly warmed to 20°C for 3 hours, after which the reaction was stopped. 5 mL of ice water was added to the reaction solution, which was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative HPLC (column: YMC-Actus Triart C18 ExRS30*150 mm, 5 μm; mobile phase A: H2O (0.1% HCOOH); mobile phase B: CH3CN; flow rate: 60 mL / min) to afford compound H111 (1.0 mg), yield: 7% for both steps. LCMS ESI-MS m / z: 674 [M+H] + .

[0448] 1 H NMR(300MHz, DMSO-d6)δ8.79(s,1H),7.52(d,J=2.7Hz,1H),7.09(s,1H),6.95(s,2H),5.91(s,2H),5.33–5.29(m,2H),5.06–4.98(m,3H),3.48–3 .41(m,1H),3.15–3.02(m,1H),2.92–2.89(m,1H),2.73–2.64(m,5H),2. 42(s,3H),2.14–1.77(m,11H),1.43(d,J=6.8Hz,3H),1.31–1.13(m,3H).

[0449] Example 14: Synthesis of target molecules H116-H117

[0450] Step 1: Dissolve intermediate d55 (170 mg, 0.41 mmol) and DIEA (265 mg, 2.05 mmol) in 4 mL of DMSO in an ice bath and stir for 1 hour. Intermediate d38 (166 mg, 0.63 mmol) was added to the reaction mixture, and the mixture was allowed to react at 50°C for 12 hours before stopping the reaction. 30 mL of ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (C18 column; CH3CN / H2O (0.1% formic acid), 5 / 1) to obtain compound H116-1 (200 mg) in a 75% yield. LCMS ESI-MS m / z: 647 [M+H] + .

[0451] Step 2: Dissolve intermediate b9 (60 mg, 0.46 mmol) and NaH (59 mg, 2.47 mmol, 60%) in 2 mL of THF in an ice bath and stir for 30 minutes. Add compound H116-1 (200 mg, 0.31 mmol) from the previous step to the reaction solution, raise the temperature to 50°C, and react for 6 hours to stop the reaction. Add 50 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. Obtain crude compound H116-2 (350 mg). LCMS ESI-MS m / z: 740 [M+H] + .

[0452] Step 3: In an ice bath, under nitrogen protection, compound H116-2 (200 mg, 0.33 mmol) from the previous step was dissolved in 2 mL of dichloromethane. Trifluoroacetic acid (4 mL) was added, and the mixture was allowed to react at room temperature for 48 hours, after which the reaction was stopped. 50 mL of ice water was added to the reaction solution, and the pH was adjusted to approximately 8 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (column: C18; CH3CN / H2O (0.1% formic acid), 1 / 1) to obtain compound H116-3 (110 mg) in a yield of 56%. LCMS ESI-MS m / z: 596 [M+H] + .

[0453] Step 4: Under nitrogen, compound H116-3 (110 mg, 0.18 mmol), ammonium acetate (27 mg, 0.35 mmol), and elemental S (11.2 mg, 0.35 mmol) were dissolved in 2 mL of ethanol. The mixture was heated to 60°C for 0.5 h. Malononitrile (23.8 mg, 0.36 mmol) was added to the reaction solution, and the temperature was raised to 80°C for 1 h to terminate the reaction. 30 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to yield crude product H116 (130 mg). Crude H116 was separated by preparative HPLC (Xselect CSH Prep Column, 30 x 150 mm, 5 μm; mobile phase A: H2O (0.1% formic acid); mobile phase B: CH3CN; flow rate: 60 mL / min) to afford the target molecules H116a and H116b (10.2 mg, retention time: 9.41 min, yield: 9%), and target molecules H116c and H116d (11.6 mg, retention time: 10.45 min, yield: 10%). LCMS ESI-MS m / z: 676 [M+H] + .

[0454] H116a and H116b were separated by chiral SFC (column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; mobile phase A: n-hexane (2 M NH3-MeOH), mobile phase B: EtOH / DCM = 1 / 1; flow rate: 20 mL / min) to obtain the target molecule H116a. # (8.198 min, 13.9 mg, yield: 9%) and H116b # (14.377 min, 10.0 mg, yield: 7%).

[0455] H116c and H116d were separated by chiral SFC (column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; mobile phase A: n-hexane (0.1% DIEA), mobile phase B: EtOH / DCM = 1 / 1; flow rate: 1 mL / min) to obtain the target molecule H116c. # (8.198 min, 10.3 mg, yield: 7%) and H116d # (14.377 min, 10.6 mg, yield: 7%)

[0456] H116a: 1 H NMR(300MHz, DMSO-d6)7.91(d,J=2.9Hz,1H),7.66–7.53(m,1H),7.07(s,2H),6.11(s,2H),5.71(s ,2H),5.27(dd,J=9.2,6.0Hz,1H),3.91(d,J=16.2Hz,1H),3.71(s,1H),3.63–3.50(m,1H),3.44(d ,J=16.2Hz,1H),3.24–2.90(m,7H),2.73(s,4H),2.45(s,1H),2.26(dd,J=11.4,5.1Hz,1H),2.08( dt,J=13.1,6.6Hz,1H),1.88(ddd,J=22.7,12.9,6.9Hz,5H),1.44(dd,J=26.7,6.4Hz,6H).H116b: 1HNMR(300MHz,DMSO-d6)7.91(d,J=2.9Hz,1H),7.66–7.53(m,1H),7.07(s,2H),6.11(s,2H),5.71(s,2H),5.27(dd,J=9.2,6.0Hz,1H),3.91(d,J=16.2Hz,1H),3.71(s,1H),3.63–3.50(m,1H),3.44(d,J=16.2Hz,1H),3.24–2.90(m,7H),2.73(s,4H),2.45(s,1H),2.26(dd,J=11.4,5.1Hz,1H),2.08(dt,J=13.1,6.6Hz,1H),1.88(ddd,J=22.7,12.9,6.9Hz,5H),1.44(dd,J=26.7,6.4Hz,6H).

[0457] H116c: 1 H NMR(300MHz,DMSO-d6)7.91(d,J=2.9Hz,1H),7.66–7.53(m,1H),7.07(s,2H),6.11(s,2H),5.71(s,2H),5.27(dd,J=9.2,6.0Hz,1H),3.91(d,J=16.2Hz,1H),3.71(s,1H),3.63–3.50(m,1H),3.44(d,J=16.2Hz,1H),3.24–2.90(m,7H),2.73(s,4H),2.45(s,1H),2.26(dd,J=11.4,5.1Hz,1H),2.08(dt,J=13.1,6.6Hz,1H),1.88(ddd,J=22.7,12.9,6.9Hz,5H),1.44(dd,J=26.7,6.4Hz,6H).

[0458] H116d: 1H NMR(300MHz, DMSO-d6)7.91(d,J=2.9Hz,1H),7.66–7.53(m,1H),7.07(s,2H),6.11(s,2H),5.71(s,2H) ,5.27(dd,J=9.2,6.0Hz,1H),3.91(d,J=16.2Hz,1H),3.71(s,1H),3.63–3.50(m,1H),3.44(d,J=16.2Hz ,1H),3.24–2.90(m,7H),2.73(s,4H),2.45(s,1H),2.26(dd,J=11.4,5.1Hz,1H),2.08(dt,J=13.1,6.6Hz,1H),1.88(ddd,J=22.7,12.9,6.9Hz,5H),1.44(dd,J=26.7,6.4Hz,6H).(The configurations of the four isomers are inferred, not determined by single crystal)

[0459] Following the synthetic route of the target molecule H116, similar raw materials / intermediates (such as intermediates a5-a10, b2-b31, c10-c27, d21-d22, d43-d45, e9-e28) were used to synthesize the following target molecules.

[0460] # = Presumed configuration

[0461] Example 15: Synthesis of target molecules H118-H119

[0462] Step 1: Dissolve intermediate a11 (500 mg, 1.25 mmol) and DIEA (486 mg, 3.75 mmol) in 10 mL of DMSO in an ice bath and stir for 1 hour. Intermediate d38 (337 mg, 1.25 mmol) was added to the reaction mixture, and the mixture was allowed to react at 50°C for 12 hours before stopping the reaction. Add 50 mL of ice water to the reaction mixture, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product was separated by flash reverse-phase column chromatography (C18 column; CH3CN / H2O (0.1% trifluoroacetic acid), 9 / 1) to afford compound H118-1 (370 mg) in a 47% yield. LCMS ESI-MS m / z: 632 [M+H] + .

[0463] Step 2: Dissolve the compound H118-1 (370 mg, 0.58 mmol) and HCOOH (40 mg, 0.87 mmol) from the previous step in 2 mL of 1,4-dioxane in an ice bath. Stir for 5 minutes, then add NH2OH (58 mg, 50% aqueous solution) to the reaction mixture. Warm the mixture to 30°C and allow to react for 48 hours to terminate the reaction. Add 50 mL of ice water to the reaction mixture, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. Dissolve the crude compound in 2 mL of 1,4-dioxane solution, add dilute hydrochloric acid (4 M, 4.0 mL) dropwise, and react at room temperature for 5 hours to terminate the reaction. Add 20 mL of saturated sodium bicarbonate aqueous solution to the reaction mixture, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product was separated by flash reverse phase column chromatography (chromatographic column: C18; CH3CN / H2O (0.1% trifluoroacetic acid), 3 / 2) to obtain compound H118-2 (180 mg), yield: 63%, LCMS ESI-MS m / z: 485 [M+H] + .

[0464] Step 3: Dissolve intermediate b8 (82 mg, 0.55 mmol) and NaH (119 mg, 2.97 mmol, 60%) in 4 mL of THF in an ice bath and stir for 1 hour. Add compound H118-2 (180 mg, 0.37 mmol) to the reaction solution, heat to 50°C and react for 5 hours to stop the reaction. Add 50 mL of ice water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain crude compound H118-3 (60 mg). LCMS ESI-MS m / z: 596 [M+H] + .

[0465] Step 4: Under nitrogen, compound H118-3 (60 mg, 0.10 mmol), ammonium acetate (12.4 mg, 0.16 mmol), and elemental S (5.1 mg, 0.16 mmol) were dissolved in 1.5 mL of ethanol. The mixture was heated to 60°C for 0.5 hours. Malononitrile (11 mg, 0.16 mmol) was added to the reaction solution, and the temperature was raised to 80°C for 2 hours to terminate the reaction. 10 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain crude product H118. Crude product H118 was separated by preparative HPLC (column: XSelect CSH Prep C18 OBD Column, 30*150 mm, 5 μm; mobile phase A: H2O (0.1% trifluoroacetic acid); mobile phase B: CH3CN; flow rate: 60 mL / min) to obtain the target molecule H118a. # (4.8 mg, retention time: 8.87 min, yield: 7%) and target molecule H118b# (3.2 mg, retention time: 10.58 min, yield: 5%). LCMS ESI-MS m / z: 676 [M+H] + .

[0466] H118a: 1 H NMR (300MHz, DMSO-d6) δ7.89(d,J=2.8Hz,1H),7.55(s,1H),6.91(s,2H),6.67(s,1H),5.96(s,1H),5.71(s,2H),5.32–5.04(m,2H),3.51–3.36(m, 1H),3.25(s,1H),2.94(s,1H),2.79(s,3H),2.61(d,J=23.7Hz,3H),2.42 (s,3H),2.15–1.65(m,11H),1.48(d,J=6.7Hz,3H),1.23(d,J=6.3Hz,3H).

[0467] H118b: 1 H NMR (300MHz, DMSO-d6) δ7.89(d,J=2.8Hz,1H),7.55(s,1H),6.91(s,2H),6.67(s,1H),5.96(s,1H),5.71(s,2H),5.32–5.04(m,2H),3.51–3.36(m, 1H),3.25(s,1H),2.94(s,1H),2.79(s,3H),2.61(d,J=23.7Hz,3H),2.42 (s,3H),2.15–1.65(m,11H),1.48(d,J=6.7Hz,3H),1.23(d,J=6.3Hz,3H).

[0468] Following the synthetic route of the target molecule H118, similar raw materials / intermediates (such as intermediates b2-b31) were used to synthesize the following target molecules.

[0469] # = Presumed configuration

[0470] Example 16: Synthesis of target molecules H120-H122

[0471] Step 1: Dissolve intermediate b34 (620 mg, 2.47 mmol) and NaH (660 mg, 16.52 mmol, 60%) in 26 mL of THF in an ice bath. Stir for 1 hour. Add compound H76-1 (1.3 g, 2.06 mmol) to the reaction mixture, warm to 50°C, and react for 5 hours before stopping the reaction. Add 100 mL of ice water to the reaction mixture, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate. The crude product was separated by flash reverse-phase column chromatography (C18 column; CH3CN / H2O (0.1% trifluoroacetic acid), 2 / 1) to afford compound H120-1 (1.2 g) in a 69% yield. LCMS ESI-MS m / z: 841 [M+H] + .

[0472] Step 2: Compound H120-1 (240 mg, 0.28 mmol) and Pd / C (91 mg, 10% wt) were dissolved in 5 mL of isopropanol. 1,1,2-trichloroethane (76 mg, 0.57 mmol) was added. The mixture was reacted under hydrogen (10 atm) for 24 hours. The reaction was terminated, filtered, and the filtrate concentrated. The crude product was separated by flash reverse-phase column chromatography (C18 column; CH3CN / H2O (0.1% trifluoroacetic acid), 1 / 1) to afford compound H120-2 (170 mg) in a 79% yield. LCMS ESI-MS m / z: 751 [M+H] + .

[0473] Step 3: In an ice bath, under nitrogen protection, compound H120-2 (170 mg, 0.22 mmol) and TEA (69 mg, 0.67 mmol) were dissolved in 4 mL of dichloromethane. Methanesulfonyl chloride (31 mg, 0.27 mmol) was added, and the mixture was reacted at room temperature for 2 hours, after which the reaction was stopped. 50 mL of ice water was added to the reaction solution, which was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to obtain compound H120-3 (200 mg). LCMS ESI-MS m / z: 829 [M+H] + .

[0474] Step 4: In an ice bath, under nitrogen, compound H120-3 (200 mg, crude) from the previous step was dissolved in 4 mL of 1,4-dioxane. Dilute hydrochloric acid (4 mL, 4 M) was added, and the mixture was reacted in an ice bath for 1 hour. The reaction was continued at room temperature for 2 hours before stopping the reaction. 50 mL of ice water was added to the reaction solution, and the pH was adjusted to approximately 8 with saturated sodium bicarbonate aqueous solution. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash reverse-phase column chromatography (C18 column; CH3CN / H2O (0.1% formic acid), 1 / 1) to obtain compound H120-4 (100 mg), with a two-step yield of 66%. LCMS ESI-MS m / z: 685 [M+H] + .

[0475] Step 5: Under nitrogen, compound H120-4 (100 mg, 0.15 mmol), ammonium acetate (21 mg, 0.27 mmol), and elemental S (8 mg, 0.25 mmol) were dissolved in 2 mL of ethanol. The mixture was heated to 60°C for 0.5 hours. Malononitrile (17 mg, 0.26 mmol) was added to the reaction solution, and the temperature was raised to 80°C for 1 hour to terminate the reaction. 30 mL of ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain crude H120. Crude H120 was separated by preparative HPLC (Column: Xselect CSH Prep C18 OBD Colum, 19*250 mm, 5 μm; Mobile phase A: H2O (0.05% trifluoroacetic acid); Mobile phase B: MeOH; Flow rate: 20 mL / min) to obtain the target molecule H120a. # (12.4 mg, retention time: 8.3 min, yield: 11%) and target molecule H120b # (17.5 mg, retention time: 11.3 min, yield: 15%). LCMS ESI-MS m / z: 765 [M+H] + .

[0476] H120a: 1H NMR(300MHz,DMSO-d6,ppm)δ7.88(s,1H),7.57(d,J=9.5Hz,1H),6.97(s,2H),6.05–5.90(m,2H),5.74(s,2H),5.35–5.32(m,1H),4.25–4.21(m ,1H),3.06–3.02(m,2H),2.89(s,3H),2.81–2.51(m,10H),2.38–2.33(m ,4H),2.08–1.72(m,10H),1.47(d,J=6.8Hz,3H),1.25(d,J=6.3Hz,3H).

[0477] H120b: 1 H NMR(300MHz,DMSO-d6,ppm)δ7.87(s,1H),7.57(d,J=9.5Hz,1H),6.97(s,2H),6.05–5.90(m,2H),5.76(s,2H),5.38–5.32(m,1H),4.26–4.18(m ,1H),3.08–2.99(m,2H),2.89(s,3H),2.79–2.53(m,10H),2.37–2.27(m ,4H),2.08–1.72(m,10H),1.47(d,J=6.8Hz,3H),1.25(d,J=6.3Hz,3H).

[0478] Following the synthetic route of the target molecule H120, similar raw materials / intermediates were used to synthesize the following target molecules.

[0479] # = Presumed configuration

[0480] Example 17: Compounds for KRAS G12D Mediated p-ERK inhibition test (directly reflects the cellular level inhibitory effect of the test compound)

[0481] AGS cells cultured in F-12K medium (Gibco, Cat. No. 30-2004) containing 10% fetal bovine serum and 1% penicillin-streptomycin were seeded onto 384-well microplates and incubated overnight at 37°C in 5% carbon dioxide. 200 nL of various compound concentrations (1000 nM starting concentration, 4-fold dilution) were added to each well and incubated at 37°C for 3 hours. The cells were then fixed in 8% fixative (Solarbio, Cat. No. P1112) and washed once with phosphate-buffered saline (PBS). After washing, blocking solution (LI-COR, Cat. No. 927-40000) was added to each well and blocked for 1 hour at room temperature. After removing the blocking solution, phospho-p44 / 42 MAPK (T202 / Y204) Rabbit mAb (CST, Cat. No. 4370S) and GAPDH (D4C6R) Mouse mAb (CST, Cat. No. 97166S) antibody working solutions were added to each well and incubated overnight at 4°C. The microplate was washed three times with PBS containing 0.1% Tween-80 (PBST), and IRDye 800CW Goat anti-Rabbit IgG (H+L) (LI-COR, Cat. No. 926-32211) and IRDye 680RD Goat anti-Mouse IgG (H+L) (LI-COR, Cat. No. 926-68070) antibody working solutions were added, and the microplate was incubated at room temperature in the dark. After washing the microplate three times with PBST, the microplate was centrifuged at 1000 rpm for 1 minute, and the plate was scanned and read using an Odyssey CLx (LI-COR) instrument to record the signal value.

[0482] IC 50 The calculation formula

[0483] Calculate compound IC using nonlinear regression equation 50 Value: Y = lower platform signal + (upper platform signal - lower platform signal) / (1 + 10^((LogIC 50 -X)*Hill slope); X=logarithm of compound concentration.

[0484] Table 17.1 Target molecules for AGS (KRAS G12D ) cells pERK inhibition effect

[0485] Referring to WO2023099608, compound II-17 (reference A1 herein) was synthesized, and the structure is as follows:

[0486] Referring to WO2023099624, a compound (referenced herein as A2) was synthesized, and the structure is as follows:

[0487] ND = not tested; # = proposed configuration

[0488] After testing, the molecule of the present invention has an effect on KRAS G12D Mutated tumor cells have a good inhibitory effect and are expected to be able to inhibit KRAS G12D to achieve better tumor suppression effects.

[0489] After testing, most of the molecules of the present invention are effective for KRAS G12D The mutant cell inhibitory activity is significantly better than the control molecule A1, and the activity of molecules such as H32a, H48a, H49a, H76a, H77a, H80a, H109a, H116a is increased by more than 50-100 times.

[0490] After testing, some molecules of the present invention have the effect of KRAS G12D The mutant cell inhibitory activity was significantly better than the control molecule A2, and the activity of molecules such as H76a and H116a was increased by more than 10 times.

[0491] Example 18: Compounds for KRAS G12V Mediated p-ERK inhibition test (directly reflects the cellular level inhibitory effect of the test compound)

[0492] SW480 cells cultured in DMEM (Gibco, Cat. No. 11995065) containing 10% fetal bovine serum and 1% penicillin-streptomycin were seeded onto 384-well microplates and incubated overnight at 37°C in 5% carbon dioxide. 200 nL of various compound concentrations (1000 nM starting concentration, 4-fold dilution) were added to each well and incubated at 37°C for 3 hours. The cells were then fixed in 8% fixative (Solarbio, Cat. No. P1112) and washed once with phosphate-buffered saline (PBS). After washing, blocking solution (LI-COR, Cat. No. 927-40000) was added to each well and blocked for 1 hour at room temperature. After removing the blocking solution, phospho-p44 / 42 MAPK (T202 / Y204) Rabbit mAb (CST, Cat. No. 4370S) and GAPDH (D4C6R) Mouse mAb (CST, Cat. No. 97166S) antibody working solutions were added to each well and incubated overnight at 4°C. The microplate was washed three times with PBS containing 0.1% Tween-80 (PBST), and IRDye 800CW Goat anti-Rabbit IgG (H+L) (LI-COR, Cat. No. 926-32211) and IRDye 680RD Goat anti-Mouse IgG (H+L) (LI-COR, Cat. No. 926-68070) antibody working solutions were added, and the microplate was incubated at room temperature in the dark. After washing the microplate three times with PBST, the microplate was centrifuged at 1000 rpm for 1 minute, and the plate was scanned and read using an Odyssey CLx (LI-COR) instrument to record the signal value.

[0493] IC 50 The calculation formula

[0494] Calculate compound IC using nonlinear regression equation 50 Value: Y = lower platform signal + (upper platform signal - lower platform signal) / (1 + 10^((LogIC 50 -X)*Hill slope); X=logarithm of compound concentration.

[0495] Table 18.1 Target molecules for SW480 (KRAS G12v ) cells pERK inhibition effect ND = not tested; # = proposed configuration;

[0496] After testing, the molecule of the present invention has an effect on KRAS G12V Mutated tumor cells have a good inhibitory effect and are expected to be able to inhibit KRAS G12V to achieve better tumor suppression effects.

[0497] Example 19: Compounds for KRAS G12V Second cell activity inhibition test of p-ERK mediated by mitochondria (directly reflects the cellular level inhibitory effect of the test compound)

[0498] SW620 cells cultured in DMEM (Gibco, Cat. No. 11995065) supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin were seeded onto 384-well microplates and incubated overnight at 37°C in 5% carbon dioxide. 200 nL of various compound concentrations (1000 nM starting concentration, 4-fold dilution) were added to each well and incubated at 37°C for 3 hours. The cells were then fixed in 8% fixative (Solarbio, Cat. No. P1112) and washed once with phosphate-buffered saline (PBS). After washing, blocking solution (LI-COR, Cat. No. 927-40000) was added to each well and blocked for 1 hour at room temperature. After removing the blocking solution, phospho-p44 / 42 MAPK (T202 / Y204) Rabbit mAb (CST, Cat. No. 4370S) and GAPDH (D4C6R) Mouse mAb (CST, Cat. No. 97166S) antibody working solutions were added to each well and incubated overnight at 4°C. The microplate was washed three times with PBS containing 0.1% Tween-80 (PBST), and IRDye 800CW Goat anti-Rabbit IgG (H+L) (LI-COR, Cat. No. 926-32211) and IRDye 680RD Goat anti-Mouse IgG (H+L) (LI-COR, Cat. No. 926-68070) antibody working solutions were added, and the microplate was incubated at room temperature in the dark. After washing the microplate three times with PBST, the microplate was centrifuged at 1000 rpm for 1 minute, and the plate was scanned and read using an Odyssey CLx (LI-COR) instrument to record the signal value.

[0499] IC 50 The calculation formula

[0500] Calculate compound IC using nonlinear regression equation 50 Value: Y = lower platform signal + (upper platform signal - lower platform signal) / (1 + 10^((LogIC 50 -X)*Hill slope); X=logarithm of compound concentration.

[0501] Table 19.1 Target molecules for SW620 (KRAS G12v ) cells pERK inhibition effect # = proposed configuration;

[0502] After testing, the molecule of the present invention has an effect on KRAS G12V Mutated tumor cells have a good inhibitory effect and are expected to be able to inhibit KRAS G12V to achieve better tumor suppression effects.

[0503] After testing, most of the molecules of the present invention are effective for KRAS G12v The mutant cell inhibitory activity is significantly better than the control molecule A1, and the activity of molecules such as H32a, H48a, H49a, H76a, H77a, H80a, H109a, H116a is increased by more than 10 times to 50 times.

[0504] Example 20: Inhibitory activity of compounds against GTP-KRAS (inhibitory effect of reaction inhibitors on KRAS on-state)

[0505] The test compound was diluted in a 4-fold concentration gradient, and 0.1 μL of different concentrations of the test compound was transferred to each well of a 384-well microplate using ECHO (Labcyte). 5 μL of diluted Tag2-KRAS G12D>P or Tag2-KRAS G12V>P was added to each well, and the plates were centrifuged at 1000 RPM for 1 minute. Then, 5 μL of diluted Tag1-cRAF was added to each well, and the plates were centrifuged at 1000 RPM for 1 minute and incubated at 25°C for 15 minutes. 10 μL of a mixture of anti-Tag1-Tb3 and anti-Tag2-XL665 was added to each well, and the plates were centrifuged at 1000 RPM for 1 minute and incubated at 4°C for 3 hours. The plates were read using Envision at 665 / 615 nm and the signal values ​​were recorded.

[0506] Reagent sources: KRAS-G12D-related detection reagents were all derived from the commercially available kit KRAS-G12D / cRAF BINDING ASSAY KITS (Cisbio, Cat. No. 63ADK000CB21PEG); GST-cRAF was prepared by Beijing Kanglong Chemical (Cat. No. 20190718), MAb Anti GST-Tb cryptate was purchased from Cisbio (Cat. No. 61GSTTLA), and other key reagents were derived from the commercially available kit KRAS-WT / SOS1 BINDING ASSAY KITS (Cisbio, Cat. No. 63ADK000CB15PEH).

[0507] Analyze the calculation results according to the following formula:

[0508] Relative ratio (RR) = (Ratio 665 / 615 -Ratio背景 )

[0509] Inhibition percentage = [1-(RR 化合物 -RR 阳性对照孔 Average) / (RR 阴性对照孔 Mean-RR 阳性对照孔 Average value)]×100

[0510] IC 50 Calculation: Y = lower platform signal + (upper platform signal - lower platform signal) / (1 + 10^(LogIC 50 =X)×Hill slope). X: logarithmic value of compound concentration; Y: percentage of inhibition.

[0511] Table 20.1: Compounds' inhibitory effects on the activation state of KRASG12D or G12V mutations

[0512] This result indicates that the molecule of the present invention has an excellent inhibitory effect on the KRAS G12D or G12V mutation activation on state.

[0513] Example 21: Inhibitory activity of compounds against GDP-KRAS (SOS1 catalytic reaction inhibitors against KRAS off-state inhibition)

[0514] Cisbio detection kits: KRAS-G12D / SOS1 BINDING ASSAY KITS and KRAS-G12V / SOS1 BINDING ASSAY KITS

[0515] Test compounds were serially diluted fourfold, and 0.1 μL of each concentration was transferred to each well of a 384-well microplate using an ECHO reader (Labcyte). 5 μL of diluted Tag2-KRAS G12D & GDP or Tag2-KRAS G12V & GDP was added to each well and centrifuged at 1000 rpm for 1 minute. 5 μL of the specified concentration of Tag1-SOS1 was added to the assay plate and centrifuged at 1000 rpm for 1 minute. The plates were incubated at 25°C for 15 minutes. 10 μL of a mixture of anti-Tag1-Tb3 and anti-Tag2-XL665 was added to each well, centrifuged at 1000 rpm for 1 minute, and incubated at 4°C for 3 hours. The plate was read using an Envision reader at 665 / 615 nm, and the signal was recorded.

[0516] Analyze the calculation results according to the following formula:

[0517] Relative ratio (RR) = (Ratio 665 / 615 -Ratio背景 )

[0518] Inhibition percentage = [1-(RR 化合物 -RR 阳性对照孔 Average) / (RR 阴性对照孔 Mean-RR 阳性对照孔 Average value)]×100

[0519] IC 50 Calculation: Y = lower platform signal + (upper platform signal - lower platform signal) / (1 + 10^(LogIC 50 =X)×Hill slope). X: logarithmic value of compound concentration; Y: percentage of inhibition.

[0520] Table 21.1: Effects of compounds on off-state inhibitory exchange of KRASG12D or G12V mutations

[0521] This result indicates that the molecule of the present invention has an excellent inhibitory effect on the KRAS G12D or G12V mutation off state.

[0522] ND = Not Tested

[0523] Example 22: Antiproliferative Effects of Compounds on KRAS Mutant Cell Lines

[0524] Basic Information:

[0525] The 3D anti-proliferative effects of the compound on the KRAS G12D mutant pancreatic cancer HPAC cell line are as follows:

[0526] Cell culture: HPAC pancreatic cancer cells were cultured in T75 flasks in RPMI 1640 medium containing 10% fetal bovine serum and 1% penicillin / streptomycin.

[0527] Cell culture: SW620 colorectal cancer cells were cultured in T75 flasks in RPMI 1640 medium containing 10% fetal bovine serum and 1% penicillin / streptomycin.

[0528] Test process: 200 nL of the diluted test compound (1000 nM, 4-fold dilution) was added to a 384-well low-adsorption cell culture plate using a nanoliter pipetting system. After the cells were plated, the culture plate was placed in a 37°C, 5% CO2 constant temperature incubator under 3D conditions. After the test compound and cells were incubated for 5 days, the test compound was added to each well. 3D reagent, using Envision multifunctional microplate reader (Perkin Elmer, catalog number Envision 2104) to read the luminescence value. The light signal is proportional to the amount of ATP in the system, and the ATP content directly represents the number of viable cells in the system. Finally, the IC value of the compound was obtained using the nonlinear fitting formula using XLFIT software. 50 (half inhibitory concentration).

[0529] Inhibition rate (%) = 100 × (negative control average value - compound reading) / (negative control average value - positive control average value)

[0530] Negative control: DMSO. Positive control: culture medium.

[0531] Table 22.1: Antiproliferative effects of compounds on HPAC cells with KRASG12D mutation at half effective concentration

[0532] Table 22.2: Antiproliferative effects of compounds on KRASG12V mutant SW620 cells at half effective concentration

[0533] After testing, the molecule of the present invention has an effect on KRAS G12V Mutations and KRAS G12D Mutated tumor cells have good anti-proliferative effects.

[0534] Example 23: Liver microsome stability test of the compound

[0535] The compounds of the present invention were subjected to a liver microsome stability test. The test compounds were co-incubated with liver microsomes of different species with or without the addition of NADPH. The final concentration of the test compound in the test system was 1 μM, the final concentration of NADPH was 1 mM, and the final concentration of liver microsomes was 0.5 mg / mL. The concentration of the compound in the incubation supernatant at different time points within 15, 30, 45, and 60 minutes was measured and the pharmacokinetic parameters (such as clearance Cl) were calculated. int ).

[0536] The remaining percentage of the test compound was plotted against the reaction time, T 1 / 2 =0.693 / k, as the half-life of the compound.

[0537] Table 23.1: Results of the compound stability test on human liver microsomes in vitro

[0538] Some molecules of the present invention have good metabolic stability.

[0539] Unexpected discovery: Compared with pyridazine substitution (such as H49a) or pyrazine substitution (such as H40a), pyridine substituents (such as H76a, H77a) or pyrimidine substituents (such as H48a) significantly improved human metabolic stability.

[0540] Unexpected discovery: The same substituent, but different substituent positions (such as H77a vs. H78a), significantly affects the metabolic stability of the human body.

[0541] Example 24: Pharmacokinetic evaluation experiment in mice

[0542] CD1 female mice were used as test animals and the drug was administered orally / intravenously (oral dosage was 10 mg / kg (or 20 mg / kg), intravenous dosage was 2 mg / kg (or 4 mg / kg)).

[0543] Experimental protocol: Oral administration (vehicle: 0.5% hydroxyethyl cellulose + 5% HPβCD) was performed in three mice per group, and intravenous administration (vehicle: 5% DMSO + 95% (20% HPβCD)) was performed in three mice per group. Oral administration: Plasma samples were collected before (0 h) and after (0.25, 0.5, 1, 2, 4, 8, and 24 h) administration; intravenous administration: Plasma samples were collected before (0 h) and after (0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h) administration. Plasma concentrations in mice following oral and intravenous administration were determined by LC / MS / MS. Data were calculated using AB Sciex QTRAP 6500 software. The results are as follows:

[0544] Table 24.1: In vivo PK results of the molecules of the present invention in mice

[0545] Table 24.2: In vivo PK results of the molecules of the present invention in mice &=20mg / kg po,4mg / kg iv. &&=10mg / kg po,2mg / kg iv.

[0546] The above results show that the molecule of the present invention has good oral absorption effect.

Claims

1. A compound of formula (X), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in, Z is selected from O, S, SO2, CH2CH2, CH2 or NH; Z1, Z2, Z3 are each independently selected from O, S or CH2; X1 is selected from CH or N; Y is selected from CR y or N; R y Selected from H, halogen, CN, OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy or C 1-6 alkoxy; R is selected from 5-12 membered heterocyclic group, R1 is selected from H, halogen, CN, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; R2 is selected from 3-14 membered heterocyclic groups; said R2 is independently substituted by 1-3 R x replace; R x Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy, -(CH2) p CN, NH2, OH, -O(CH2) p OR a 、-O(CH2) p N(R a )(R a '),-N(R a )-(CH2) p OR a 、-O(CH2) p -R a 、-C(O)R a 、-C(O)OR a 、-(CH2) p -OR a 、-SR a 、-S(O)2-R a 、-(CH2) p -C(O)OR a 、-(CH2) p -OC(O)N(R a )(R a '),-N(R a )-C(O)OR a 、-N(R a )-S(O)2R a '、-N(R a )-S(O)R a 'or-OC(O)N(R a )(R a '); R3 is selected from -NR m R n 、-SR m OR m ; R m Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -LC(O)R a 、-LC(O)OR a 、-(CH2) p -OR a 、-S(O)2-R a , -L-5-12 membered heteroaryl, -L-phenyl or -L-5-6 membered heterocyclic group; the R m Optionally substituted with 1-6 halogens, NH2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, CN, -L-OR a 、-L-SR a 、-LN(R a )(R a '), -NH-(CH2) p -C(O)OR a 、C 3-6 further substituted by cycloalkyl, 4-6 membered heterocyclyl or 5-12 membered heteroaryl; R n Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -LC(O)R a 、-LC(O)OR a 、-(CH2) p -OR a or -S(O)2-R a ; the R n Optionally halogen, -OR a 、-SR a 、C 3-6 further substituted by cycloalkyl, 4-6 membered heterocyclyl or 5-12 membered heteroaryl; When R m When selected from -L-5-12 membered heteroaryl, the 5-12 membered heteroaryl may be further substituted by 1-5 R p replace; R p Selected from halogen, NH2, OH, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, CN, -L-OR a 、-L-SR a 、-LN(R a )(R a '), -NH-(CH2) p -C(O)OR a 、C 3-6 Cycloalkyl, 4-6 membered heterocyclyl or 5-12 membered heteroaryl; L is selected from a bond, C 1-6 Alkylene or C 1-6 L can be optionally replaced by D, halogen, OH, C 1-6 Alkoxy or C 3-6 cycloalkyl substitution; R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group, C 3-6 Cycloalkyl or 5-6 membered heteroaryl; R a 'Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group or C 3-6 Cycloalkyl; p is independently selected from 0, 1, 2, 3, 4 or 5.

2. The compound of claim 1, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (I): in, Z is selected from O, S, SO2, CH2CH2, CH2 or NH; X1 is selected from CH or N; Y is selected from CR y or N; R y Selected from H, halogen, CN, OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy or C 1-6 alkoxy; R is selected from 5-12 membered heterocyclic group, R1 is selected from H, halogen, CN, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; R2 is selected from 3-14 membered heterocyclic groups; said R2 is independently substituted by 1-3 R x replace; R x Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy, -(CH2) p CN, NH2, OH, -O(CH2) p OR a 、-O(CH2) p N(R a )(R a '),-N(R a )-(CH2) p OR a 、-O(CH2) p -R a 、-C(O)R a 、-C(O)OR a 、-(CH2) p -OR a 、-SR a 、-S(O)2-R a 、-(CH2) p -C(O)OR a 、-(CH2) p -OC(O)N(R a )(R a '),-N(R a )-C(O)OR a 、-N(R a )-S(O)2R a '、-N(R a )-S(O)R a 'or-OC(O)N(R a )(R a '); R m Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -LC(O)R a 、-LC(O)OR a 、-(CH2) p -OR a 、-S(O)2-R a , -L-5-12 membered heteroaryl, -L-phenyl, -L-5-6 membered heterocyclic group; the R m Optionally substituted with 1-6 halogens, NH2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, CN, -L-OR a 、-L-SR a 、-LN(R a )(R a '), -NH-(CH2) p -C(O)OR a 、C 3-6 further substituted by cycloalkyl, 4-6 membered heterocyclyl or 5-12 membered heteroaryl; R n Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -LC(O)R a 、-LC(O)OR a 、-(CH2) p -OR a or -S(O)2-R a ; the R n Optionally halogen, -OR a 、-SR a 、C 3-6 further substituted by cycloalkyl, 4-6 membered heterocyclyl or 5-12 membered heteroaryl; When R m When selected from -L-5-12 membered heteroaryl, the 5-12 membered heteroaryl may be further substituted by 1-5 R p replace; R p Selected from halogen, NH2, OH, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, CN, -L-OR a 、-L-SR a 、-LN(R a )(R a '), -NH-(CH2) p -C(O)OR a 、C 3-6 Cycloalkyl, 4-6 membered heterocyclyl or 5-12 membered heteroaryl; L is selected from a bond, C 1-6 Alkylene or C 1-6 L can be optionally replaced by D, halogen, OH, C 1-6 Alkoxy or C 3-6 cycloalkyl substitution; R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group, C 3-6 Cycloalkyl or 5-6 membered heteroaryl; R a 'Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group or C 3-6 Cycloalkyl; p is independently selected from 0, 1, 2, 3, 4 or 5.

3. The compound of claim 1, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (II): in, Y is selected from CH, CCN, CF, CBr, CCl, CCF3, COCF3, COCH3, CCH3 or N; R1 is selected from H, halogen, CN, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; R2 is selected from 3-14 membered heterocyclic groups; said R2 is independently substituted by 1-3 R x replace; R x Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy, -(CH2) p CN, NH2, OH, -O(CH2) p OR a 、-O(CH2) p N(R a )(R a '),-N(R a )-(CH2) p OR a 、-O(CH2) p -R a 、-C(O)R a 、-C(O)OR a 、-(CH2) p -OR a 、-SR a 、-S(O)2-R a 、-(CH2) p -C(O)OR a 、-(CH2) p -OC(O)N(R a )(R a '),-N(R a )-C(O)OR a 、-N(R a )-S(O)2R a '、-N(R a )-S(O)R a 'or-OC(O)N(R a )(R a '); R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group, C 3-6 Cycloalkyl or 5-6 membered heteroaryl; R a 'Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group or C 3-6 Cycloalkyl; p is independently selected from 0, 1, 2, 3, 4 or 5; R3 is selected from The methyl hydrogen atom in the R3 substituent can be replaced by a deuterium atom.

4. The compound of claim 3, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in, Y is selected from CH, CCN, CF, CBr, CCl, CCF3, COCF3, COCH3, CCH3 or N; R1 is selected from H, halogen, CN, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; R2 is selected from 5. The compound of claim 2, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (III): in, Z is selected from O, S or CH2; Y is selected from CH, CCN, CF, CBr, CCl, CCF3, COCF3, COCF2H, COCH3, CCH3 or N; X1, X2, X3, X4, X5 are independently selected from CH, CR p or N; R1 is selected from H, halogen, CN, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; R2 is selected from 5-14 membered heterocyclic groups; said R2 is independently substituted by 1-3 R x replace; R x Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy, -(CH2) p CN, NH2, OH, -O(CH2) p OR a 、-O(CH2) p N(R a )(R a '),-N(R a )-(CH2) p OR a 、-O(CH2) p -R a 、-C(O)R a 、-C(O)OR a 、-(CH2) p -OR a 、-SR a 、-S(O)2-R a 、-(CH2) p -C(O)OR a 、-(CH2) p -OC(O)N(R a )(R a '),-N(R a )-C(O)OR a 、-N(R a )-S(O)2R a '、-N(R a )-S(O)R a 'or-OC(O)N(R a )(R a '); R m1 Selected from H, C 1-5 Alkyl, deuterated C 1-5 Alkyl, C 1-5 Haloalkyl or C 3-6 Cycloalkyl; R m2 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or CN; R n Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -LC(O)R a 、-LC(O)OR a 、-(CH2) p -OR a or -S(O)2-R a ; R p Selected from halogen, NH2, OH, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, CN, -L-OR a 、-L-SR a 、-LN(R a )(R a '), -NH-(CH2) p -C(O)OR a 、C 3-6 Cycloalkyl, 4-6 membered heterocyclyl or 5-12 membered heteroaryl; L is selected from a bond, C 1-6 Alkylene or C 1-6 L can be optionally replaced by D, halogen, OH, C 1-6 Alkoxy or C 3-6 cycloalkyl substitution; R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group, C 3-6 Cycloalkyl or 5-6 membered heteroaryl; R a 'Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group or C 3-6 Cycloalkyl; p is independently selected from 0, 1, 2, 3, 4 or 5.

6. The compound of claim 5, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (III-1): in, Y is selected from CH, CCN, CF, CBr, CCl, CCF3, COCF3, COCF2H, COCH3, CCH3 or N; X1, X2, X3 are independently selected from CH, CR p or N; R1 is selected from H, halogen, CN, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl; R2 is selected from 5-14 membered heterocyclic groups; said R2 is independently substituted by 1-3 R x replace; R x1 Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Haloalkyl, -(CH2) p CN, -C(O)R a 、-C(O)OR a 、-(CH2) p -OR a 、-S(O)2-R a 、-(CH2) p -C(O)OR a or -(CH2) p -OC(O)N(R a )(R a '); R x2 Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy, -(CH2) p CN, NH2, OH, -O(CH2) p OR a 、-O(CH2) p N(R a )(R a '),-N(R a )-(CH2) p OR a 、-O(CH2) p -R a 、-C(O)R a 、-C(O)OR a 、-(CH2) p -OR a 、-SR a 、-S(O)2-R a 、-(CH2) p -C(O)OR a 、-(CH2) p -OC(O)N(R a )(R a '),-N(R a )-C(O)OR a 、-N(R a )-S(O)2R a '、-N(R a )-S(O)R a 'or-OC(O)N(R a )(R a '); R m1 Selected from H, C 1-5 Alkyl, deuterated C 1-5 Alkyl, C 1-5 Haloalkyl or C 3-6 Cycloalkyl; R m2 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl or CN; R n Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -LC(O)R a 、-LC(O)OR a 、-(CH2) p -OR a or -S(O)2-R a ; R p Selected from halogen, NH2, OH, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, CN, -L-OR a 、-L-SR a 、-LN(R a )(R a '), -NH-(CH2) p -C(O)OR a 、C 3-6 Cycloalkyl, 4-6 membered heterocyclyl or 5-12 membered heteroaryl; L is selected from a bond, C 1-6 Alkylene or C 1-6 L can be optionally replaced by D, halogen, OH, C 1-6 Alkoxy or C 3-6 cycloalkyl substitution; R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group, C 3-6 Cycloalkyl or 5-6 membered heteroaryl; R a 'Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group or C 3-6 Cycloalkyl; p is independently selected from 0, 1, 2, 3, 4 or 5.

7. The compound of claim 5, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (IV): in, Z is selected from O, S or CH2; Y is selected from CH, CCN, CF, CBr, CCl, CCF3, COCF3, COCF2H, COCH3, CCH3 or N; R1 is selected from H, F, CN, methyl, ethyl, deuterated methyl, trifluoromethyl, CH2F, CHF2 or cyclopropyl; R x1 is selected from H, methyl, ethyl, deuterated methyl, trifluoroethyl, trifluoromethyl, difluoroethyl, -(CH2)2CN, -C(O)Me, -C(O)OMe, -(CH2)2-OH, -S(O)2-Me, -(CH2)2-C(O)OMe or -(CH2)2-OC(O)N(Me)2; R x2 Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, halogen, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy, -(CH2) p CN, NH2, OH, -O(CH2) p OR a 、-O(CH2) p N(R a )(R a '),-N(R a )-(CH2) p OR a 、-O(CH2) p -R a 、-C(O)R a 、-C(O)OR a 、-(CH2) p -OR a 、-SR a 、-S(O)2-R a 、-(CH2) p -C(O)OR a 、-(CH2) p -OC(O)N(R a )(R a '),-N(R a )-C(O)OR a 、-N(R a )-S(O)2R a '、-N(R a )-S(O)R a 'or-OC(O)N(R a )(R a '); R m2 is selected from H, F, Cl, Br, I, OH, methyl, deuterated methyl, vinyl, propynyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, cyclopropyl, pyrrolidinyl, morpholinyl or CN; R n is selected from H, methyl, deuterated methyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, -CH2-C(O)Me, -CH2-C(O)OMe, -(CH2)2-OMe or -S(O)2-Me; R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group, C 3-6 Cycloalkyl or 5-6 membered heteroaryl; R a 'Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, 4-6 membered heterocyclic group or C 3-6 Cycloalkyl; p is independently selected from 0, 1, 2, 3, 4 or 5.

8. The compound of claim 1, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the structure of formula (IV-1): in, Z is selected from O, S or CH2; Y is selected from CH, CCN, C-halogen, CC 1-6 Alkyl or C 1-6 alkyl halide; R1 is selected from C 1-6 Alkyl, deuterated C 1-6 Alkyl or C 1-6 alkyl halide; R x1 Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl or C 1-6 alkyl halide; R x2 Selected from H, C 1-6 Alkyl, halogen, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy, NH2, OH, -N(R a )-C(O)OR a 、-N(R a )-S(O)2R a 'or-N(R a )-S(O)R a '; R m2 Selected from halogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 haloalkoxy; R n Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl or C 1-6 alkyl halide; R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl or C 1-6 alkyl halide; R a 'Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl or C 1-6 Halogenated alkyl.

9. The compound of claim 8, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in, Z is selected from O, S or CH2; Y is selected from CH, CCN, CF, CBr, CCl, CCF3 or CCH3; R1 is selected from methyl, ethyl, deuterated methyl, trifluoromethyl, CH2F or CHF2; R x1 is selected from H, methyl, ethyl, deuterated methyl, trifluoroethyl, trifluoromethyl or difluoroethyl; R x2 Selected from H, C 1-6 Alkyl, F, deuterated C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkoxy, NH2, OH, -N(R a )-C(O)OR a 、-N(R a )-S(O)2R a 'or-N(R a )-S(O)R a '; R m2 is selected from F, Cl, Br, methyl, deuterated methyl, trifluoromethyl, difluoromethyl, trifluoromethoxy or difluoromethoxy; R n is selected from H, methyl, deuterated methyl, trifluoromethyl, difluoroethyl or trifluoroethyl; R a Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl or C 1-6 alkyl halide; R a 'Selected from H, C 1-6 Alkyl, deuterated C 1-6 Alkyl or C 1-6 Halogenated alkyl.

10. A compound, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

11. A compound, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

12. Use of a compound according to any one of claims 1 to 11 or an enantiomer, diastereomer or isotopic variant thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing a disease mediated by a KRAS mutant.

13. The method of claim 12, wherein the KRAS mutant-mediated disease is cancer, selected from colorectal cancer (e.g., colon cancer, rectal cancer, large intestine adenocarcinoma), lung cancer (e.g., bronchial cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), or pancreatic cancer.

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