A KRAS inhibitor and its use

Abstract

The present invention relates to KRAS G12D Inhibitors and their uses. Specifically, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof, including a pharmaceutical composition thereof, and the use of the above compound or composition in the preparation of a pharmaceutical composition for treating, inhibiting or preventing KRAS G12D Use in medicine for mutation-related diseases.

Description

Technical Field

[0001] The present invention relates to a KRAS inhibitor, or a pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof, and a method for preparing a KRAS inhibitor for treating, inhibiting or preventing KRAS. G12D Use in medicine for mutation-related diseases. Background Art

[0002] The KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) gene belongs to the RAS family and is one of the most commonly mutated genes in human cancers. The protein it encodes is a small GTPase. The KRAS gene participates in the kinase signaling pathway that controls gene transcription, thereby regulating cell growth and differentiation. Within cells, the KRAS protein switches between inactive and active states. When bound to guanine diphosphate (GDP), KRAS is inactive; when bound to guanine triphosphate (GTP), it becomes active and can activate downstream signaling pathways. In most cells, KRAS is inactive. When activated, it can activate downstream signaling pathways including the MAPK signaling pathway, the PI3K signaling pathway, and the Ral-GEF signaling pathway. These signaling pathways play an important role in promoting cell survival, proliferation, and cytokine release, thereby influencing tumor development and progression.

[0003] In human cancers, KRAS gene mutations occur in nearly 90% of pancreatic cancers, about 30% to 40% of colon cancers, about 17% of endometrial cancers, and about 15% to 20% of lung cancers (mostly non-small cell lung cancer, Non-SmallCell Lung Cancer, NSCLC). It also appears in cancer types such as bile duct cancer, cervical cancer, bladder cancer, liver cancer, and breast cancer. In other words, a high proportion of KRAS gene mutations are present in many of the above cancers. Most KRAS missense mutations occur in codon 12, resulting in glycine being changed to other amino acids. Depending on the specific mutations present, G12C, G12D, and G12R are the most common KRAS mutations in patients, such as KRAS G12D and KRAS G12V mutations, both of which are found in approximately 90% of pancreatic cancers, and KRAS G12D It is the most common KRAS mutation in colon cancer. G12C As a cutting-edge target, the mutant protein has attracted a lot of research, but unfortunately, the amino acid residues at the mutation site are difficult to chemically bind, so the KRAS G12DThere are very few reports on inhibitor compounds of KRAS. Although WO2021041671 and WO2021106231 disclose some compounds, the disclosed administration method is intraperitoneal administration (IP). Currently, oral administration (PO) and intravenous injection (IV) are generally used for clinical treatment of patients (see Xiaolun Wang, Shelley Allen et al.; Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D Inhibitor; 2021; E). Therefore, it is necessary to find more types of KRAS inhibitors with higher activity and better therapeutic effects that can be applied clinically. G12D The research on anti-tumor inhibitors is of great significance. Summary of the Invention

[0004] The main technical problem solved by the present invention is to provide a KRAS G12D Inhibitors. The applicant has found that the compound of formula (A) or its pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer has good anti-tumor activity:

[0005]

[0006] Among them, X 2 independently selected from hydrogen, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted acyl (including saturated or unsaturated aliphatic acyl and aromatic acyl), amino acid residue, substituted or unsubstituted oligopeptide (dipeptide, tripeptide, tetrapeptide) residue, phosphoryl, phosphonyl, aminophosphonyl, sulfonyl, thioacyl, substituted or unsubstituted benzyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted mercaptothiocarbonyl, substituted or unsubstituted alkylthio (thiocarbonyl), substituted or unsubstituted ester alkyl, substituted or unsubstituted benzyloxycarbonyl, glycoside group, glycoside group, bile acid substituent;

[0007] A is an organic group containing a cyclic structure, including a monocyclic, bicyclic, condensed, bridged, spirocyclic, heterocyclic, aromatic, aromatic heterocyclic, aliphatic, and combinations thereof, and the cyclic structure contains two or more substituents;

[0008] Group A 1 、A 2 、A 3 and A 4 are independently selected from hydrogen or a short chain hydrocarbon group of C1 to C6, or A 1 、A 2 、A 3and A 4 One or two groups and the piperazine ring to which they are connected together form a bridged ring, a fused ring or a spiro ring.

[0009] In some embodiments, the compound of formula (A) is a compound of formula (B) or a pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof:

[0010]

[0011] Among them, X 2 independently selected from hydrogen, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted acyl (including saturated or unsaturated aliphatic acyl and aromatic acyl), amino acid residue, substituted or unsubstituted oligopeptide (dipeptide, tripeptide, tetrapeptide) residue, phosphoryl, phosphonyl, aminophosphonyl, sulfonyl, thioacyl, substituted or unsubstituted benzyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted mercaptothiocarbonyl, substituted or unsubstituted alkylthio (thiocarbonyl), substituted or unsubstituted ester alkyl, substituted or unsubstituted benzyloxycarbonyl, glycoside group, glycoside group, bile acid substituent;

[0012] A is an organic group containing a cyclic structure, including a monocyclic ring, a bicyclic ring, a condensed ring, a bridged ring, a spirocyclic ring, a heterocyclic ring, an aromatic ring, a heteroaromatic ring, an aliphatic ring, and combinations thereof, and the cyclic structure contains two or more substituent groups.

[0013] In some embodiments, formula (B) may be a compound of formula (I) or a pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof, wherein the compound of formula (I) has excellent anti-tumor activity:

[0014]

[0015] wherein W is selected from oxygen (O), sulfur (S) or nitrogen (NH);

[0016] X 1 and X 2 independently selected from hydrogen, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted acyl (including saturated or unsaturated aliphatic acyl and aromatic acyl), amino acid residue, substituted or unsubstituted oligopeptide (dipeptide, tripeptide, tetrapeptide) residue, phosphoryl, phosphonyl, aminophosphonyl, sulfonyl, thioacyl, substituted or unsubstituted benzyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted mercaptothiocarbonyl, substituted or unsubstituted alkylthio (thiocarbonyl), substituted or unsubstituted ester alkyl, substituted or unsubstituted benzyloxycarbonyl, glycoside group, glycoside group, bile acid substituent;

[0017] In some embodiments, X1 and X 2 Independently selected from substituted or unsubstituted alkyl or heteroalkyl, bile acid substituents;

[0018] X 3 Independently selected from or lone pair electrons; when X 3 When X is a lone pair of electrons, 1 and X 2 are not hydrogen at the same time; and when X 3 for When X 3 The connected N atoms form a quaternary ammonium ion with a positive charge, and form an inner salt with the negative ion in the molecule or form a salt with another acid molecule, the acid molecule includes but is not limited to a hydrohalide, wherein R 6a 、R 6b Any one selected from hydrogen, C1 to C 20 a hydrocarbon group or a cyclic hydrocarbon group (optionally, a lower hydrocarbon group or cyclic hydrocarbon group of C1 to C6),

[0019] Y 1a 、Y 1b independently selected from hydrogen, halogen (F, Cl, or Br), hydroxy, amino, amine, hydroxymethyl, alkoxy, or acyloxy;

[0020] Y 2 independently selected from hydrogen, halogen, hydroxy, amino, amine, hydroxymethyl, alkoxy, acyloxy, or lower hydrocarbon;

[0021] Y 3 、Y 4 are independently selected from H, halogen, halomethyl (monohalomethyl, dihalomethyl, and trihalomethyl), or Y 3 、Y 4 Together with the benzene ring structures to which they are connected, they form a substituted or unsubstituted benzo-fused ring, including but not limited to a naphthalene ring structure.

[0022] The compounds provided herein, or pharmaceutically acceptable salts, esters, hydrates, solvates or stereoisomers thereof, can be used as KRAS G12D Inhibitors for the treatment of KRAS G12D mutation-related diseases and has good therapeutic effects.

[0023] Furthermore, X 1 and X 2 Independently select hydrogen, C1-C 20 Saturated or unsaturated alkoxycarbonyl (optionally, C1-C4 alkoxycarbonyl, specifically, C1, C2, C3, C4), C1-C 20Saturated or unsaturated alkyl acyl (optionally, C1-C6 alkyl acyl, specifically, C1, C2, C3, C4, C5, C6), 6-membered to 15-membered (hetero) arylcarbonyl (e.g., phenylcarbonyl, naphthylcarbonyl, pyridylcarbonyl, etc.), 4-membered to 15-membered (hetero) cycloalkylcarbonyl (e.g., cyclohexylcarbonyl, tetrahydropyranylcarbonyl, etc.), C1-C 20 Alkylthio (optionally, C1-C6 alkylthio, specifically, C1, C2, C3, C4, C5, C6),

[0024] where R 1 Independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, C3-C6 cycloalkyl (specifically, C3, C4, C5, C6), aromatic groups (such as substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, etc.).

[0025] R 2 independently selected from hydrogen, C1 to C 20 A saturated or unsaturated alkyl group (optionally, a lower aliphatic hydrocarbon group of C1 to C6, specifically, C1, C2, C3, C4, C5, C6), an azaalkyl group, an aryl hydrocarbon group, a heterocyclic aromatic hydrocarbon group, a C3-C8 carbocyclic or heterocyclic hydrocarbon group (specifically, C5, C6, C7, C8), a condensed ring, a naphthalene ring, a bridged ring hydrocarbon group or an amino acid residue, wherein the amino acid residue may be natural or non-natural, and H at any position on the amino acid residue may be substituted or unsubstituted.

[0026] In some embodiments, R 2 Selected from Among them, R 2a 、R 2b 、R 2c 、R 2d 、R 2e are independently selected from hydrogen, C1-C6 substituted or unsubstituted alkyl or hydrocarbon groups (specifically, C1, C2, C3, C4, C5, C6). Specifically, R 2a R is selected from hydrogen, methyl, ethyl, propyl, isopropyl, 2-isobutyl, 3-isobutyl, benzyl; 2b 、R 2c Any one selected from hydrogen, C1-C6 substituted or unsubstituted alkyl or hydrocarbon group (specifically, C1, C2, C3, C4, C5, C6); R 2d 、R 2e Any one selected from hydrogen, C1-C6 alkyl (specifically, C1, C2, C3, C4, C5, C6).

[0027] R 3are independently selected from hydrogen, methyl, ethyl or propyl.

[0028] R 4 independently selected from hydrogen, C2 to C 20 (Specifically, it can be C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12 、C 13 、C 14 、C 15 、C 16 、C 17 、C 18 、C 19 、C 20 ) alkyl, isopropyl, isobutyl, aryl hydrocarbon, carbocyclic or heterocyclic hydrocarbon, C2 to C 20 Alkanoyloxy (specifically, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12 、C 13 、C 14 、C 15 、C 16 、C 17 、C 18 、C 19 、C 20 ).

[0029] R 5 The substituents at the 2-position are independently selected from ethyl groups substituted at the 2-position, and the substituents at the 2-position include, but are not limited to, amino, alkoxycarbonyl, alkanoyloxy, and acyloxy groups derived from amino acids.

[0030] R 6a 、R 6b Any one selected from hydrogen or C1 to C 20 The hydrocarbon group or cycloalkyl group (specifically, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12 、C 13 、C 14 、C 15 、C 16 、C 17 、C 18 、C 19 、C 20 ), aryl,

[0031] R 7 are independently selected from lower alkyl or substituted or unsubstituted aryl.

[0032] R 8 Independently selected from substituted or unsubstituted C2 to C 20 a saturated or unsaturated alkanoyl group, a saturated or unsaturated alkoxycarbonyl group;

[0033] R 9 independently selected from lower alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted imidazole-5-methyl, oligoethylene glycol (-[CH2CH2O] n CH3, wherein n is an integer from 0 to 4, specifically, 1, 2, 3, 4), C2 to C 20 Saturated or unsaturated alkanoyl (specifically, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12 、C 13 、C 14 、C 15 、C 16 、C 17 、C 18 、C 19 、C 20 );

[0034] R 10 independently selected from hydrogen, C1-C6 alkoxy (specifically, C1, C2, C3, C4, C5, C6), C2 to C 20 Saturated or unsaturated alkanoyloxy (specifically, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12 、C 13 、C 14 、C 15 、C 16 、C 17 、C 18 、C 19 、C 20 ), substituted or unsubstituted C2 to C 20 Saturated or unsaturated alkanoyl (specifically, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12 、C 13 、C 14 、C 15 、C 16 、C 17 、C 18 、C 19 、C 20 ), saturated or unsaturated alkoxycarbonyl;

[0035] n is an integer from 0 to 4, specifically, can be 1, 2, 3, or 4.

[0036] In some embodiments, X 1 and X 2 Can be

[0037] In some embodiments, X 1 and X 2 may independently be hydrogen,

[0038] In some embodiments, X 1 and X 2 Can be independently

[0039]

[0040]

[0041]

[0042] In some embodiments, X 1 or X 2 are independently hydrogen or where R 1 is methyl, propyl, isopropyl, cyclohexyl, preferably R 1 is methyl; R 2 C1-C 20 Saturated or unsaturated alkyl (specifically, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12 、C 13 、C 14 、C 15 、C 16 、C 17 、C 18 、C 19 、C 20 ), pyridyl, phenyl, naphthyl, etc.; preferably, X 1 is hydrogen, X 2 for In some embodiments, R 2 Selected from Among them, R 2a is selected from hydrogen, methyl, ethyl, propyl, isopropyl, 2-isobutyl, 3-isobutyl, and aromatic groups; R 2b 、R 2c Any one of hydrogen, C1-C6 substituted or unsubstituted alkyl or hydrocarbon groups.

[0043] In some embodiments, X 1 C1-C 20 saturated or unsaturated alkyl acyl, pyridyl, phenyl, naphthyl, and X 2 For hydrogen.

[0044] In some embodiments, X 2 or X 1 for where R 2 C1-C 20 Saturated or unsaturated alkyl (specifically, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12 、C 13 、C 14 、C 15 、C 16 、C 17 、C 18 、C 19 、C 20 ).

[0045] In some embodiments, Y 1a 、Y 1b 、Y 2 Independently selected from hydrogen, or halogen (F, Cl, or Br, especially F).

[0046] In some embodiments, X 3 Selected from or lone pair electrons.

[0047] In some embodiments, Y 3 、Y 4 are independently selected from H, Cl, CF3, or the benzene ring structures to which they are connected together form a substituted or unsubstituted naphthalene ring, for example where R 11 is selected from hydrogen, halogen atoms (especially F), hydroxyl, substituted hydroxyl, and lower alkyl; Y 4 is selected from hydrogen, a halogen atom, a hydroxyl group, a substituted hydroxyl group, and a lower alkyl group.

[0048] Furthermore, the compound is a compound represented by formula (II) and (III):

[0049]

[0050] where R 11 is selected from hydrogen, a halogen atom, a hydroxyl group, a substituted hydroxyl group, and a lower alkyl group; Y 4 is selected from hydrogen, a halogen atom, a hydroxyl group, a substituted hydroxyl group, and a lower alkyl group.

[0051] In some embodiments, W in formula (II) is oxygen, R 11 In some embodiments, W in formula (II) is oxygen, R 11 In some embodiments, W in formula (III) is oxygen, Y 4 In some embodiments, W in formula (III) is NH, Y 4 In some embodiments, W in formula (III) is NH, Y 4 For chlorine.

[0052] Furthermore, Y in any of the above chemical formulas 1b and Y 2 At the same time, it is hydrogen.

[0053] In some embodiments, the compound is a compound represented by formula (IV) to (VII):

[0054]

[0055] In some embodiments, R 9 、R 10 Alkanoyl groups independently selected from C2-C20, specifically, can be C2-C5, C6-C9, C10-C15, C16-C20, preferably, can be C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20.

[0056] In some embodiments, the compound is a derivative based on compound A1, A2, or A3, wherein A1, A2, or A3 is a base compound. The chemical structures of base compounds A1 to A3 are shown in Table 1. The compound can be the compound represented by the corresponding structure, or a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof.

[0057] Table 1

[0058]

[0059] In some embodiments, the compound is a compound as shown in Table 2 and Table 2a below, or a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof:

[0060] Table 2

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077] Table 2a

[0078]

[0079]

[0080]

[0081]

[0082] In some embodiments, the compounds provided herein may be naturally abundant or isotopically substituted compounds, and the isotopes may be 1 H, D, 16 O. 12 C. 18 O. 17 O. 15 N and 13 C, etc.

[0083] The above compounds have good biological activity and can be used to treat KRAS-related G12D In some embodiments, the compounds provided herein can be used as a prodrug to enter the subject's body and decompose into effective biologically active components, thereby playing a role in treating diseases related to KRAS mutations.G12D The role of related diseases.

[0084] The present invention also provides a pharmaceutical composition comprising any of the above-mentioned compounds or pharmaceutically acceptable salts, esters, hydrates, solvates or stereoisomers thereof.

[0085] Furthermore, it also includes at least one pharmaceutically acceptable excipient, carrier or diluent.

[0086] Furthermore, the pharmaceutically acceptable excipients include one or more of a binder, a filler, a disintegrant, a lubricant and a glidant.

[0087] Furthermore, the pharmaceutically acceptable carrier includes one or more of creams, emulsions, gels, liposomes and nanoparticles.

[0088] Furthermore, the composition is suitable for oral administration or injection. That is, the present invention provides a compound or a pharmaceutical composition thereof suitable for oral administration or injection.

[0089] The present application also provides a use of any of the above-described compounds, or pharmaceutically acceptable salts, esters, isomers, hydrates, or compositions thereof, in the preparation of a medicament for treating, inhibiting, or preventing a hyperproliferative disorder. Furthermore, the present invention also provides a method for treating, inhibiting, or preventing a hyperproliferative disorder, comprising administering an effective amount of the above-described compound and / or pharmaceutical composition to a subject, thereby treating the relevant disease.

[0090] In some embodiments, the hyperproliferative disorder is a KRAS G12D Related malignancies or cancers.

[0091] Further, the above-mentioned malignant tumor or cancer is selected from: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, mesothelioma; gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyoma, lymphoma), stomach (carcinoma, lymphoma, leiomyoma), pancreas (ductal adenocarcinoma, insulinoma, glucosamine, gastrinoma, carcinoid tumor, vasodilator peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), Intestine (adenocarcinoma, tubular adenoma, chorioadenoma, hematoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilms tumor (Nephroblastoma), lymphoma, leukemia); bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma); prostate (adenocarcinoma, sarcoma); testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid, lipoma); Liver: liver cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder cancer, ampulla carcinoma, bile duct cancer; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticular Cell sarcoma), multiple myeloma, malignant giant cell tumor, chordal tumor, osteochondroma (osteochondroma), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningiosarcomas, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, epididymal tumors, germ cell tumors (pinealomas), glioblastomas of various forms, oligodendrogliomas, gliomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas); Gynecological: uterus (endometrial carcinoma (serous bladder carcinoma, mucinous bladder carcinoma, unclassified carcinoma), granulosa cell carcinoma Tumors: ovarian (epithelial rhabdomyosarcoma, ulcerative colitis, leukemia, dysplasia, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, uveal sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); Hematology: blood (myeloid leukemias (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Morse's dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, or adrenal neuroblastoma.

[0092] In some embodiments, the malignant tumor is one or more of non-small cell lung cancer, small cell lung cancer, pancreatic cancer, colorectal cancer, bile duct cancer, cervical cancer, bladder cancer, liver cancer, or breast cancer.

[0093] The present application also provides a kit comprising any of the above-mentioned compounds or pharmaceutically acceptable salts, esters, hydrates, solvates or stereoisomers, or any of the above-mentioned compositions, which can be used to prepare a method for treating, inhibiting or preventing KRAS. G12D Drugs for diseases or conditions associated with mutations.

[0094] The compound provided by the present application, or its pharmaceutically acceptable salt, ester, isomer or hydrate, has good KRAS G12D Inhibitory effects can be used to treat, inhibit or prevent KRAS G12D Preparation of a medicament for a disease or condition associated with a mutation. BRIEF DESCRIPTION OF THE DRAWINGS

[0095] In order to better understand the present invention and to more clearly show how it may be implemented, further description will now be given by way of example with reference to the accompanying drawings, which illustrate various aspects and features of embodiments according to the present invention, in which:

[0096] Figure 1 : Drug-time curves of Compound 1, Compound 61 and Compound A1 at equimolar doses when administered orally. Experimental animals: ICR mice.

[0097] Figure 2 : Drug-time curves of Compound 4, Compound 17, Compound 69 and Compound A1 at equimolar doses when administered orally. Experimental animals: ICR mice.

[0098] Figure 3 : Drug-time curves of Compound 32, Compound 39, Compound 52 and Compound A1 at equimolar doses when administered by intravenous injection. Experimental animals: ICR mice.

[0099] Figure 4 : The drug-time curves of Compound 55, Compound 56 and Compound A1 of the present invention at equimolar doses when administered by intravenous injection. Experimental animals: ICR mice.

[0100] Figure 5 : Comparison of the tumor growth inhibition effects of compound 1, compound A1 and blank control in mice after oral administration.

[0101] Figure 6: Comparison of the tumor growth inhibition effects in mice after intraperitoneal administration of compound 52, intravenous administration of compound 52, intraperitoneal administration of control compound A1 and blank control. DETAILED DESCRIPTION

[0102] In order to provide a clear and consistent understanding of the terms used in the specification of the present invention, some definitions are provided below. In addition, unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention belongs.

[0103] When used in conjunction with the term "comprising" in the claims and / or the specification, the use of the word "a" can mean "one", but it is also known in the sense of "one or more", "at least one" and "one or more than one". Similarly, the word "another" can mean at least a second or many.

[0104] As used in this specification and claims, the words "comprising" (and any form of comprising, such as "including" and "comprising"), "having" (and any form of having, "having," "including," and "containing") are inclusive and open-ended and do not exclude additional, unrecited elements or process steps. The terms "about" or "approximately" are used to indicate that the value includes error for the equipment and method employed in determining the value.

[0105] The term "pharmaceutically acceptable" as used herein means that the drugs, medicines, inert ingredients, etc. described by the term are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, incompatibility, instability, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio.

[0106] "Pharmaceutically acceptable stereoisomers" of a compound refer to isomers resulting from different spatial arrangements of atoms in a molecule. Specifically, isomers resulting from the same order of bonding but different spatial arrangements of atoms or groups of atoms in a molecule are called stereoisomers. They are primarily divided into two categories: Stereoisomers caused by factors such as bond length, bond angle, the presence of double bonds or rings within the molecule are called configurational stereoisomers. Generally speaking, configurational stereoisomers cannot or are difficult to convert into each other. Stereoisomers resulting solely from rotation about a single bond are called conformational stereoisomers, sometimes also called rotamers. When rotation is hindered within a rotamer, it becomes a "stereoisomer." For example, in a biphenyl structure, when large and different substituents are present at the α- and α'-positions, the single bond between the two benzene rings cannot rotate freely due to the obstruction between the substituents, resulting in two stereoisomers.

[0107] The term "Kras G12D" refers to a mutant form of the mammalian Kras protein that contains an amino acid substitution of glycine, such as aspartic acid, in codon 12.

[0108] A "pharmaceutically acceptable salt" of a compound refers to a salt of a compound that is pharmaceutically acceptable. The desired salt of the compound (basic, acidic or charged functional group) retains or improves the biological activity and properties of the parent compound as defined herein and is not biologically undesirable. Pharmaceutically acceptable salts can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Typically, such salts are prepared by reacting the compound (free acid or base) with an equistoichiometric amount of the base or acid in water or an organic solvent or in a mixture of the two. Salts can be prepared in situ during the final isolation or purification of the agent, or by reacting a purified compound of the invention in free acid or base form separately with the desired corresponding base or acid and isolating the salt thus formed. The term "pharmaceutically acceptable salt" also includes zwitterionic compounds containing a cationic group covalently bonded to an anionic group, which are referred to as "inner salts."

[0109] The term "ester" as used herein refers to a compound represented by the general formula RCOOR (carboxylic acid ester). These compounds are generally obtained by reacting a carboxylic acid with an alcohol (eliminating a portion of water).

[0110] The term "substituted" or "substituted" means that the parent compound or moiety has at least one substituent group. The term "unsubstituted" or "no substituents" means that the parent compound or moiety has no substituents other than chemical saturation of undefined valencies with hydrogen atoms.

[0111] In some embodiments, when the present invention refers to an alkyl group, an azaalkyl group, an acyl group, a cycloalkyl group, a heterocycloalkyl group, an alkoxy group, an aryloxy group, a heteroalkoxy group, a heteroaryloxy group, an aryl group, a heteroaryl group, an amino acid residue, an oligopeptide (dipeptide, tripeptide, tetrapeptide) residue, a phosphoryl group, a phosphonyl group, an aminophosphonyl group, a sulfonyl group, a thioacyl group, a benzyl group, an alkoxycarbonyl group, an aminocarbonyl group, a mercaptothiocarbonyl group, an alkylthio group, a thiocarbonyl group, a benzyloxycarbonyl group, a glycosidic group, a glycosidic group, it is optionally substituted (e.g., a "substituted" or "unsubstituted" alkyl group, a "substituted" or "unsubstituted" heterocyclyl group, a "substituted" or "unsubstituted" aryl group, or a "substituted" or "unsubstituted" heteroaryl group).

[0112] Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when substituted at more than one position in any given structure, the substituent is the same or different at each position.

[0113] As used herein, a "substituent" or "substituent group" refers to a group selected from halogen (F, Cl, Br or I), hydroxy, thiol, amino, nitro, carbonyl, carboxyl, alkyl, alkoxy, alkylamino, aryl, aryloxy, arylamino, acyl, sulfinyl, sulfonyl, phosphonyl or other organic moieties conventionally used and accepted in organic chemistry.

[0114] The term "hydrocarbyl" refers to a group containing only carbon and hydrogen atoms. Hydrocarbyl groups can be saturated or unsaturated, and include alkyl, alkenyl, and alkynyl groups. Common examples of hydrocarbyl groups include methyl, ethyl, propyl, n-butyl, isobutyl, vinyl, and propynyl.

[0115] Unless otherwise specified with respect to the number of carbon atoms, the "lower" in "lower aliphatic," "lower hydrocarbon," "lower alkyl," "lower alkenyl," and "lower alkynyl" as used herein means that the moiety has at least one (at least two for alkenyl and alkynyl) and equal to or less than 6 carbon atoms.

[0116] The terms "cycloalkyl", "alicyclic", "carbocycle" and equivalent expressions refer to groups containing saturated or partially unsaturated carbocyclic rings in a monocyclic, spirocyclic (sharing one atom) or fused (sharing at least one bond) carbocyclic ring system, wherein the carbocyclic ring system has 3 to 15 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexen-1-yl, cyclohexen-2-yl, cyclohexen-3-cycloheptyl, bicyclo[4,3,0]nonyl, norbornyl, and the like. The term cycloalkyl includes unsubstituted cycloalkyl groups and substituted cycloalkyl groups.

[0117] The terms "aryl" and "aromatic group" used in the present invention refer to an aromatic group having "4n+2" (π) electrons in a conjugated monocyclic or polycyclic ring system (condensed or non-condensed), and having 6 to 14 ring atoms, wherein n is an integer from 1 to 3. The polycyclic ring system includes at least one aromatic ring. The aryl group can be directly connected or connected through a C1-C3 alkyl group (also referred to as an arylalkyl or aralkyl group). Examples of aryl groups include, but are not limited to, phenyl, benzyl, phenethyl, 1-phenylethyl, tolyl, naphthyl, biphenyl, terphenyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, azulenyl, acenaphthenyl, fluorenyl, phenanthrenyl, anthracenyl, etc. The term aryl includes unsubstituted aryl and substituted aryl. Aryl groups are connected through a hydrocarbyl group, also referred to as arylhydrocarbyl.

[0118] As used herein, the term "heterocycle" and equivalent expressions refer to a group containing a saturated or partially unsaturated carbocyclic ring in a monocyclic, spirocyclic (sharing one atom) or fused (sharing at least one bond) carbocyclic ring system, a group having 3 to 15 carbon atoms, including 1 to 6 heteroatoms (e.g., N, O, S, P) or a group containing heteroatoms (e.g., NH, NRx (Rx is alkyl, acyl, aryl, heteroaryl or cycloalkyl), PO2, SO, SO2, etc.). The heterocycloalkyl group can be attached to C or to a heteroatom (e.g., through a nitrogen atom). "Heterocycle" or "heterocyclic" includes heterocycloalkyl and heteroaryl. Examples of heterocycles include, but are not limited to, acridinyl, azcinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, 4αH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, benzothiazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl, 4αH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, benzothiazolyl ... furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, 3H-indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrol phenanyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridinyl, pyrrolyl, pyrrolyl, quinazolinyl, quinolyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, Examples of heterocyclic rings include tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 3,4-triazolyl, and xanthenyl. The term heterocyclic ring includes both unsubstituted and substituted heterocyclic rings. Heterocyclic rings connected by a hydrocarbon group are also referred to as heterocycloalkyl.

[0119] The term "fused ring" or "fused ring" refers to a polycyclic ring system containing fused rings. Typically, a fused ring system comprises 2 or 3 rings, and / or up to 18 ring atoms. As described above, cycloalkyl, aryl, and heterocyclic groups can form a fused ring system. Thus, a fused ring system can be aromatic, partially aromatic, or non-aromatic and can contain heteroatoms. According to this definition, a spirocyclic ring system is not a fused polycyclic ring, but the fused polycyclic ring systems of the present invention can themselves have spirocyclic rings connected thereto by individual ring atoms of the system. Examples of fused ring systems include, but are not limited to, naphthyl (e.g., 2-naphthyl), indenyl, phenanthrenyl, anthracenyl, pyrenyl, benzimidazole, benzothiazole, and the like.

[0120] The term "acyl" used in the present invention refers to the -C(=O)R residue left after dehydroxylation of a molecule of carbonic acid. a The term "acyl" refers to a compound or fragment in which at least one carbon or heteroatom is covalently bonded to a carbon atom on -C=O. The term "amino" or "amino group" as used herein refers to an unsubstituted or substituted group of the general formula -NR b R c Fragment of. R a 、R b and R c Each is independently substituted or unsubstituted hydrogen, hydrocarbon, aryl, cyclic or heterocyclic group, or R b and R c Together with the nitrogen atom to which they are attached, they form a heterocyclic ring. The term "amide" refers to the structure -C(=O)NR b R c The term "amido" refers to a compound or fragment in which at least one carbon or heteroatom is covalently bonded to a carbon atom in an amide group.

[0121] The term "alkanoyloxy" refers to an acyl group with R a The alkyl group has one end of the oxygen atom of the oxy group connected to the carbon atom of the acyl group, and the other end is covalently bonded to at least one carbon or heteroatom in the compound or fragment.

[0122] "Thioacyl" refers to a -C(=S)R a Fragments

[0123] "Aliphatic acyl" refers to an acyl group attached to a carbon atom of an acyl group, i.e., R a Is an aliphatic. "Aroyl" refers to an acyl group connected to the carbon atom of an acyl group, i.e., R a It is an aryl group.

[0124] "Phosphono" or "phosphoryl" refers to the fragment -P(=O)(OR d )R e"Phosphono" refers to a compound or fragment in which at least one carbon or heteroatom is covalently bonded to the phosphorus atom of a phosphono group. d is substituted or unsubstituted hydrogen, hydrocarbon, aryl, cyclic or heterocyclic, etc., "aminophosphonyl" refers to an amino group connected to a phosphonyl group, that is, R e It is an amino group.

[0125] "Sulfonyl" refers to the fragment remaining after dehydroxylation of a molecule of sulfonic acid, and "sulfonyl" refers to a compound or fragment in which at least one carbon or heteroatom is covalently bonded to the sulfur atom of the sulfonyl group.

[0126] The term "carbonyl" refers to a carbon and oxygen atom connected by a double bond -C=OR f Fragment, "carbonyl" is a component of a functional group such as an aldehyde, ketone, or acid. The term "carbonyl" refers to a compound or fragment in which at least one carbon or heteroatom is bound to -C=OR f The carbon atoms on the f is substituted or unsubstituted hydrogen, hydrocarbon, aryl, cyclic or heterocyclic alkyl, etc. The term "alkoxycarbonyl" refers to R f It is an alkoxy group, that is, the oxygen atom of the alkoxy group is connected to the carbon atom of the carbonyl group. The term "aminocarbonyl" refers to R f The term "benzyloxycarbonyl" refers to an amine group in which the nitrogen atom of the amine group is connected to the carbon atom of the carbonyl group.

[0127] The term "thiocarbonyl" refers to a -C(=S)R f The term "thiolthiocarbonyl" refers to R f It is a thiol group, that is, the carbon atom on the thiocarbonyl group is connected to the sulfur atom on the thiol group.

[0128] The term "alkylthio" refers to an alkyl group having a mercapto group attached thereto. Suitable alkylthio groups include those having 1 to about 20 carbon atoms, preferably 1 to about 15 carbon atoms.

[0129] As used herein, the term "alkoxy" or "lower alkoxy" refers to a structure in which an alkyl group is connected to an oxygen atom. Representative alkoxy groups include groups having 1 to about 6 carbon atoms, such as methoxy, ethoxy, propoxy, tert-butoxy, and the like. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, pentyloxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, and the like. The term "alkoxy" includes unsubstituted or substituted alkoxy groups, as well as perhalogenated alkoxy groups.

[0130] The "bile acid substituents" referred to in the present invention refer to bile acids synthesized by hepatocytes, which can be called primary bile acids, including cholic acid, ursodeoxycholic acid, chenodeoxycholic acid, glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, especially chenodeoxycholic acid substitutions and ursodeoxycholic acid substitutions.

[0131] The term "base compound" or "base molecule" used in the present invention refers to a specific compound or drug molecule with biological activity; in addition to being a drug molecule itself, it can also be further modified or derivatized to form a new compound, such as a prodrug compound or a derivative compound.

[0132] The term "ester-forming group" or "ester" as used in the present invention refers to a structure containing an ester functional group -RCOOR' (R' is generally an alkyl group or other non-H group) in the fragment. Wherein, R is, for example, a lower alkyl or aryl group, such as methylene, ethylene, isopropylidene, phenylene, etc., but not limited thereto; R' is, for example, a lower alkyl or aryl group, such as methyl, ethyl, propyl, isopropyl, butyl, phenyl, etc., but not limited thereto. The term "salt-forming portion" as used in the present invention refers to a portion that can form a salt with an acidic group, such as a carboxyl group, such as, but not limited to, sodium, potassium, tetraethylamine, tetrabutylamine, etc.

[0133] A "pharmaceutically acceptable salt" of a compound refers to a salt of a compound that is pharmaceutically acceptable. A desired salt of a compound (basic, acidic, or charged functional group) retains or improves the biological activity and properties of the parent compound as defined herein and is not biologically undesirable. Pharmaceutically acceptable salts may be those described by Berge et al. in "Pharmaceutical Salts," J. Pharm. Sci. 66, 1-19 (1977). Examples include, but are not limited to:

[0134] (1) Salts formed by adding an acid to a basic or positively charged functional group. Inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, aminosulfonic acid, nitric acid, phosphoric acid, carbonates, etc. Organic acids include acetic acid, propionic acid, lactic acid, oxalic acid, glycolic acid, pivalic acid, tert-butylacetic acid, β-hydroxybutyric acid, valeric acid, hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, succinic acid, malic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, cyclohexylamino Sulfonic acid, benzenesulfonic acid, sulfanilic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 3-phenylpropionic acid, laurylsulfonic acid, laurylsulfonic acid, oleic acid, palmitic acid, stearic acid, lauric acid, pamoic acid, pantothenic acid, lactobionic acid, alginic acid, galactaric acid, galacturonic acid, gluconic acid, glucoheptonic acid, glutamic acid, naphthoic acid, hydroxynaphthoic acid, salicylic acid, ascorbic acid, stearic acid, muconic acid, etc.

[0135] (2) When acidic protons are present in the parent compound or are replaced by metal ions, a base may be added to obtain a salt. The metal ions include alkaline metal ions (e.g., lithium, sodium, potassium), alkaline earth metal ions (magnesium, calcium, barium), or other metal ions such as aluminum, zinc, iron, etc. Organic bases include, but are not limited to, N,N'-dibenzylethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, piperazine, chloroprocaine, procaine, choline, lysine, etc.

[0136] Pharmaceutically acceptable salts can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Typically, such salts are prepared by reacting a compound (free acid or base) with an equistoichiometric amount of a base or acid in water, an organic solvent, or a mixture of the two. Salts can be prepared in situ during the final isolation or purification of the pharmaceutical agent, or by reacting a purified compound of the invention in its free acid or base form with the desired corresponding base or acid and isolating the salt thus formed. The term "pharmaceutically acceptable salt" also includes zwitterionic compounds containing a cationic group covalently bonded to an anionic group, which are referred to as "inner salts." The compounds of the invention encompass all acid, salt, base, and other ionic and non-ionic forms. For example, if a compound of the invention is an acid, the salt form of the compound is also encompassed. Similarly, if a compound of the invention is a salt, the acid and / or base forms of the compound are also encompassed.

[0137] As used herein, the term "effective amount" refers to the amount or dosage of a therapeutic agent (e.g., a compound) that provides the desired therapeutic, diagnostic, or prognostic effect in a subject after administration to the subject in a single dose or multiple doses. The attending physician or diagnostician can readily determine the effective amount by known techniques and by observing the results obtained under similar circumstances. In determining the effective amount or dosage of the compound to be administered, many factors are considered, including but not limited to: the weight, age, and general health of the subject; the specific disease involved; the degree of involvement or severity of the disease or condition to be treated; the response of the individual subject; the specific compound to be administered; the mode of administration; the bioavailability characteristics of the administered formulation; the dosage regimen selected; the use of concomitant medications; and other relevant considerations.

[0138] The present invention also provides a pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises: a compound disclosed in the present invention or a pharmaceutically acceptable salt, ester, isomer or hydrate thereof, and a pharmaceutically acceptable excipient, carrier or diluent.

[0139] Specifically, pharmaceutically acceptable excipients include one or more of binders, fillers, disintegrants, lubricants, and glidants. Pharmaceutically acceptable carriers or diluents include one or more of creams, emulsions, gels, liposomes, and nanoparticles.

[0140] A "pharmaceutical composition" refers to a composition comprising a compound as described herein and, depending on the mode of administration and dosage form requirements, at least one component including a pharmaceutically acceptable carrier, diluent, adjuvant, excipient or vehicle, such as a preservative, filler, disintegrant, wetting agent, emulsifier, suspending agent, sweetener, flavoring agent, fragrance, antibacterial agent, antifungal agent, lubricant and dispersant, etc. "Prevention" or "prevention" is used to mean at least reducing the likelihood of acquiring a disease or condition (or susceptibility) to acquire a disease or disorder (i.e., preventing the development of at least one clinical symptom of a disease in a patient who may be exposed to or susceptible to the disease but has not yet experienced or displayed symptoms of the disease).

[0141] In some embodiments, "treating" or "treatment" of any disease or condition refers to alleviation of at least one disease or condition. In certain embodiments, "treating" or "treatment" refers to alleviation of at least one physical parameter, which may or may not be discernible by the patient. In certain embodiments, "treating" or "treatment" refers to inhibiting a disease or condition physically (e.g., stabilization of discernible symptoms) or physiologically (e.g., stabilization of a physical parameter), or both. In certain embodiments, "treating" or "treatment" refers to improving the quality of life or side effects of a disease in a subject in need thereof. A "therapeutically effective amount" refers to the amount of a compound administered to a subject for the treatment or prevention of a disease sufficient to achieve the effect of treating or preventing the disease. The "therapeutically effective amount" will vary depending on the compound; the disease and its severity; the age, weight, etc. of the subject to be treated or prevented from having the disease. As used herein, a "therapeutically effective amount" refers to a compound or composition sufficient to prevent, cure, inhibit, reduce, alleviate or eliminate one or more causes, symptoms or complications of a disease, such as cancer.

[0142] The term "subject" refers to animals including mammals and humans, particularly humans.

[0143] The term "prodrug" or its equivalent refers to an agent that is converted directly or indirectly into an active form in vitro or in vivo (see, for example, RB Silverman, 1992, "The Organic Chemistry of Drug Design and Drug Action," Academic Press, Chap. 8; Bundgaard, Hans; Editor. Neth. (1985), "Design of Prodrugs." 360 pp. Elsevier, Amsterdam; Stella, V.; Borchardt, R.; Hageman, M.; Oliyai, R.; Maag, H.; Tilley, J. (Eds.) (2007), "Prodrugs: Challenges and Rewards, XVIII, 1470 p. Springer). Prodrugs can be used to alter the biodistribution of a particular drug (e.g., so that the agent does not normally enter a protease reaction site) or the pharmacokinetics. A variety of groups have been used to modify compounds to form prodrugs, such as esters, ethers, phosphates, etc. When the prodrug is administered to a subject, the group is cleaved off enzymatically or non-enzymatically, by reduction, oxidation, or hydrolysis, or otherwise releases the active compound. As used herein, "prodrug" includes pharmaceutically acceptable salts or esters, or pharmaceutically acceptable solvates or chelates, as well as any crystalline forms of the above.

[0144] The term "amino acid" generally refers to an organic compound that contains both a carboxylic acid group and an amino group. The term "amino acid" includes both "natural" and "unnatural" amino acids. Additionally, the term amino acid includes O-alkylated amino acids or N-alkylated amino acids, as well as amino acids with nitrogen-, sulfur-, or oxygen-containing side chains (e.g., Lys, Cys, or Ser), wherein the nitrogen, sulfur, or oxygen atom may or may not be acylated or alkylated. Amino acids may be pure L-isomers or D-isomers, or mixtures of L-isomers and D-isomers, including but not limited to racemic mixtures.

[0145] The term "natural amino acid" and equivalent expressions refer to L-amino acids commonly found in naturally occurring proteins. Examples of natural amino acids include, but are not limited to, alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), β-alanine (β-Ala) and gamma-aminobutyric acid (GABA).

[0146] The term "non-natural amino acid" refers to any derivative of a natural amino acid, including D-amino acids, and α- and β-amino acid derivatives. The terms "non-natural amino acid" and "not a natural amino acid" are used interchangeably herein. It should be noted that certain amino acids that can be classified as non-natural amino acids in the present invention (e.g., hydroxyproline) can also be present in certain biological tissues or specific proteins in nature. Amino acids with many different protecting groups suitable for direct application in solid-phase peptide synthesis are commercially available. In addition to the twenty most common natural amino acids, the following exemplary non-natural amino acids and amino acid derivatives can be used according to the present invention (common abbreviations are in brackets): 2-aminoadipic acid (Aad), 3-aminoadipic acid (β-Aad), 2-aminobutyric acid (2-Abu), α, β-dehydro-2-aminobutyric acid (8-AU), 1-aminocyclopropane-1-carboxylic acid (ACPC), aminoisobutyric acid (Aib), 3-aminoisobutyric acid (β-Aib), 2-amino-thiazoline-4- Carboxylic acids, 5-aminopentanoic acid (5-Ava), 6-aminohexanoic acid (6-Ahx), 2-aminoheptanoic acid (Ahe), 8-aminooctanoic acid (8-Aoc), 11-aminoundecanoic acid (11-Aun), 12-aminododecanoic acid (12-Ado), 2-aminobenzoic acid (2-Abz), 3-aminobenzoic acid (3-Abz), 4-aminobenzoic acid (4-Abz), 4-amino-3-hydroxy-6-methylheptanoic acid (statin, Sta), aminooxyacetic acid (Aoa), 2-aminotetralin-2-carboxylic acid (ATC), 4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA), p-aminophenylalanine (4-NH2-Phe), 2-aminopimelanediol (Apm), biphenylalanine (Bip), p-bromophenylalanine (4-Br-Phe), o-chlorophenylalanine (2-Cl-Phe), m-chlorophenylalanine (3-Cl-Phe), p-chlorophenylalanine (4-Cl-Phe), m-chlorotyrosine (3-C l-Tyr), p-benzoylphenylalanine (Bpa), tert-butylglycine (TLG), cyclohexylalanine (Cha), cyclohexylglycine (Chg), desmosine (Des), 2,2-diaminopimelanediol (Dpm), 2,3-diaminopropionic acid (Dpr), 2,4-diaminobutyric acid (Dbu), 3,4-dichlorophenylalanine (3,4-Cl2-Phe), 3,4-difluorophenylalanine (3,4-F2-Phe), 3,5-diiodotyrosine (3,5-I2-Tyr), N-ethylglycine (EtGly), N-ethylasparagine (EtAsn), o-fluorophenylalanine (2-F-Phe), m-fluorophenylalanine (3-F-Phe), p-fluorophenylalanine (4-F-Phe), m-fluorotyrosine (3-F-Tyr), homoserine (Hse), homophenylalanine (Hfe), homotyrosine (Htyr), hydroxylysine (Hyl), isohydroxylysine (aHyl), 5-hydroxytryptophan (5-OH-Trp), 3- or 4-hydroxyproline (3- or 4-Hyp), p-iodophenylalanine-isotrosine (3-I-Tyr), indoline-2-carboxylic acid (Idc), isoiduromicin (Ide), isoleucine (α-Ile), isopenecolic acid (Inp), N-methylisoleucine (M eLys), m-methyltyrosine (3-Me-Tyr), N-methylvaline (MeVal), 1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), p-nitrophenylalanine (4-NO2-Phe), 3-nitrotyrosine (3-NO2-Tyr), norleucine (Nle), norvaline (Nva), ornithine (Orn), o-phosphotyrosine (H2PO3-Tyr), octahydroindole-2-carboxylic acid (Oic), penicillamine (Pen), pentafluorophenylalanine (F5-Phe), phenylglycine (Phg), pipecolic acid (Pip), propargylglycine (Pra), pyroglutamic acid (PGLU), sarcosine (Sar), tetrahydroisoquinoline-3-carboxylic acid (Tic), thiazolidine-4-carboxylic acid (thioproline, Th).

[0147] The term "peptide" or "oligopeptide" refers to a compound formed by dehydration condensation of two or more amino acid molecules linked together by amide bonds. Generally speaking, the number of amino acids constituting a peptide ranges from 2 (dipeptide) to 20 (eicosapeptide).

[0148] The term "residue" refers to the main part of a molecule after a certain group is removed, such as amino acid residues (such as the structure H2NCH2CO-, i.e. glycyl, which is the part after a hydroxyl group is removed from glycine) and peptide residues.

[0149] In other embodiments, the present invention provides a method for treating a KRAS cell with at least one KRAS cell provided by the present invention. G12D Methods of treating and / or preventing immune-related diseases, disorders and conditions, diseases with an inflammatory component, and disorders related thereto by using inhibitory compounds or compositions.

[0150] By inhibiting KRAS G12D Other diseases, disorders and conditions that can be treated or prevented in whole or in part by KRAS activity are also provided by the present invention. G12D Candidate indications for inhibitor compounds and compositions.

[0151] The term "treat" refers to initiating an action (e.g., administering KRAS G12D Inhibitors or pharmaceutical compositions comprising the same) to temporarily or permanently eliminate, alleviate, inhibit, slow down or improve at least one potential cause of the disease, disorder or condition afflicting the subject, or symptoms associated with the disease, disorder or condition afflicting the subject. Thus, treatment includes inhibiting (e.g., preventing or alleviating the development or further development of the disease, disorder or condition or clinical symptoms associated therewith) active disease. Specifically, the term "treatment" as used in this application is used to specifically indicate that a therapeutic comprising a compound or composition according to the present invention is administered to a patient already suffering from an infection. The term "treatment" also relates to administering a compound or composition according to the present invention, optionally together with one or more antibacterial agents, to alleviate or alleviate KRAS G12D Mutations or KRAS G12D One or more symptoms associated with the mutation; or slowing of the KRAS G12D Mutations or KRAS G12D development of one or more symptoms associated with the KRAS mutation; or G12D The severity of the mutation may be related to KRAS G12D The severity of one or more symptoms associated with the mutation; or inhibition of KRAS G12D Clinical manifestations of D mutations; or inhibition of KRAS G12D Manifestations of adverse symptoms of mutations.

[0152] The term "prevent" means to initiate an action (e.g., administering a KRAS G12D Inhibitors or pharmaceutical compositions comprising the same) to temporarily or permanently prevent, inhibit, suppress or reduce the risk of a subject developing a disease, disorder or condition, etc. (as determined by, for example, the absence of clinical symptoms) or to delay the onset of a subject susceptible to a particular disease, disorder or condition. In some cases, the term also refers to slowing the progression of a disease, disorder or condition or inhibiting its development into a harmful or other undesirable state. Specifically, the term "prevention" as used in this application is used to refer to the administration of a compound or composition according to the present invention to prevent KRAS G12D The term “prevention” also encompasses the prevention of diseases caused by KRAS mutations. G12D Patients with KRAS mutations may have G12D Patients at risk of developing a KRAS mutation are administered a compound or composition according to the present invention to prevent the occurrence of at least one KRAS mutation. G12D D mutation.

[0153] As used herein, the term "KRAS G12D D mutation-associated diseases" or "KRAS G12D KRAS D-related disease" or other synonymous expressions refer to KRAS G12D Any disease, disorder or other pathological condition in which KRAS plays a role. G12D The severity of one or more diseases in which D plays a role. Specifically, KRAS G12D The disease associated with the D mutation is a hyperproliferative disease, such as a malignant tumor, preferably lung cancer such as non-small cell lung cancer, pancreatic cancer, bile duct cancer, cervical cancer, bladder cancer, liver cancer or breast cancer.

[0154] In some embodiments, the present invention further provides the KRAS described herein. G12D The use of inhibitor compounds and compositions in combination with one or more additional agents. The one or more additional agents may have KRAS G12D In some embodiments, such agents include radiation (e.g., localized or systemic radiation therapy) and / or other treatment modalities that are not pharmacological in nature. When combined therapy is used, KRAS G12D The inhibitor and one additional agent can be in the form of a single composition or multiple compositions, and the treatment regimen can be administered simultaneously, sequentially, or by some other regimen. For example, in some embodiments, embodiments are provided in which a chemotherapy phase is followed by a radiation phase. Combination therapy can have additive or synergistic effects.

[0155] Pharmaceutical compositions containing active ingredients (e.g., KRAS inhibitors) can be in a form suitable for oral use, such as tablets, capsules, lozenges, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads, or elixirs. Pharmaceutical compositions for oral use can be prepared according to any method known in the art for making pharmaceutical compositions, and such compositions may contain one or more agents, such as sweeteners, flavorings, colorants, and preservatives to provide pharmaceutically acceptable formulations. Tablets, capsules, and the like typically contain the active ingredient mixed with a non-toxic, pharmaceutically acceptable carrier or excipient suitable for making tablets. These carriers or excipients can be, for example, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc.

[0156] In some embodiments, the composition is an injectable formulation. In other embodiments, the composition is formulated for oral administration to a subject.

[0157] In some embodiments, the pharmaceutical composition is contained in a single-use container (e.g., a single-use vial, ampoule, syringe, or autoinjector), while in other embodiments, it is contained in a multiple-use container (e.g., a multiple-use vial).

[0158] The formulation may also include a carrier to protect the composition from rapid degradation or elimination from the body, such as a controlled release formulation, including liposomes, hydrogels, and microencapsulated delivery systems. For example, a time-delay material such as glyceryl monostearate or glyceryl stearate, alone or in combination with a wax, may be used. Any drug delivery device can be used to deliver KRAS G12D Inhibitors, including implants (eg, implantable pumps) and catheter systems, slow infusion pumps and devices, all of which are well known to those skilled in the art.

[0159] Pharmaceutical compositions can also be in the form of sterile injectable aqueous or oily suspensions. The suspensions can be prepared according to known techniques using suitable dispersants or wetting agents and suspending agents mentioned herein. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable diluents, solvents, and dispersion media that can be used include water, Ringer's solution, isotonic sodium chloride solution, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS), ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. In addition, sterile fixed oils are commonly used as solvents or suspending media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids (e.g., oleic acid) can be used to prepare injections. Prolonged absorption of specific injectable formulations can be achieved by including agents that delay absorption (e.g., aluminum monostearate or gelatin).

[0160] The KRAS provided by the present invention G12D Inhibitor compounds and compositions can be administered to a subject in any appropriate manner known in the art. Suitable routes of administration include, but are not limited to, oral; parenteral, such as intramuscular, intravenous, subcutaneous (e.g., injection or implantation), intraperitoneal, intracisternal, intraarticular, intracerebral (intraparenchymal and intraventricular); other routes of administration include nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), oral, and inhalation. Depot injections, typically administered subcutaneously or intramuscularly, can also be used to release the KRAS inhibitors disclosed herein over a limited period of time.

[0161] The present invention also provides a KRAS G12D Kits of inhibitor compounds or compositions. Kits are generally in the form of a physical structure that houses various components and can be used, for example, to implement the methods provided herein. For example, a kit may include one or more KRAS inhibitors disclosed herein. G12D D inhibitor (e.g., provided in a sterile container), which may be in the form of a pharmaceutical composition suitable for administration to a subject. G12D The inhibitor may be provided in a ready-to-use form (e.g., tablets or capsules) or in a form that requires, for example, reconstitution or dilution prior to administration (e.g., powder). G12D When the inhibitor is in a form that needs to be reconstituted or diluted by the user, the kit may also include a KRAS G12D The present invention can be used to prepare a kit comprising a plurality of therapeutic agents, a diluent (e.g., sterile water), a buffer, a pharmaceutically acceptable excipient, and the like, packaged together with the inhibitor or separately. When a combination therapy is employed, the kit can contain several therapeutic agents independently, or they can be combined in the kit. Each component of the kit can be packaged in a separate container, and all of the various containers can be in a single package. The kit of the present invention can be designed to appropriately maintain the conditions required for the components contained therein (e.g., refrigerated or frozen).

[0162] In order to better understand the present invention and to more clearly show how to implement the present invention, features according to embodiments of the present invention are now described by way of example with reference to the accompanying drawings.

[0163] Example

[0164] The present invention will be more readily understood by reference to the following examples, which are provided to illustrate the invention and are not to be construed as limiting the scope of the invention in any way.

[0165] Unless otherwise defined or the context clearly dictates otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. It should be understood that any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. Unless otherwise indicated, the materials and instruments used in this application are all commercially available.

[0166] Preparation example:

[0167] Synthesis of compound 1

[0168]

[0169] A 4M hydrochloric acid solution in dioxane (50 mL) was slowly added to a solution of compound 1-1 (7 g, 12.7 mmol) in methanol (30 mL). The mixture was stirred at room temperature for 2 hours and then dried by evaporation. The crude product was adjusted to pH 8 with aqueous sodium bicarbonate solution, diluted with methanol, filtered, and dried by evaporation. The residue was then dissolved in dichloromethane, filtered, and dried by evaporation to afford crude product 1-2 (6.0 g, 100% yield).

[0170] Crude product 1-2 (3 g, 1 eq, 6.65 mmol) was added to compound 1-3 (4.09 g, 1.2 eq, 7.98 mmol) in dioxane (50 mL). Cesium carbonate (6.5 g, 3 eq, 19.96 mmol) in water (20 mL) was then added, followed by [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (810 mg, 0.15 eq, 1 mmol). The mixture was purged with nitrogen three times, heated to 100°C under a nitrogen atmosphere, and stirred at this temperature for 2 hours. After cooling, the reaction mixture was diluted with water and dichloromethane. The organic phase was separated, washed with water and brine, dried, filtered, and spun down. The residue was purified by column chromatography (MeOH / DCM (0.1% TEA) = 0% to 5%) to afford compound 1-4 (4 g, 75.06% yield).

[0171] A 1M solution of TBAF in tetrahydrofuran (25 mL, 5 eq, 25 mmol) was added to a solution of compound 1-4 (4 g, 1 eq, 5 mmol) in tetrahydrofuran (40 mL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was purified by column chromatography (MeOH / DCM (0.1% TEA) = 0% to 6%) to afford compound 1-5 (1.9 g, 59.02% yield).

[0172] Triethylamine (16.99 g, 1.2 eq, 167.87 mmol) was added to a solution of p-nitrophenol (21.41 g, 1.1 eq, 153.88 mmol) in dichloromethane (96.23 mL), and then compound 1-a (20 g, 1 eq, 139.89 mmol) was slowly added at 0°C. The mixture was warmed to room temperature and stirred for 1 hour, then washed with water, washed with brine, dried over anhydrous sodium sulfate, and filtered and dried. The residue was purified by column chromatography (PE / EA = 0% to 6%) to give compound 1-b (17.5 g, 50.93% yield).

[0173] Compound 1-b (10 g, 1 eq, 40.71 mmol) was dissolved in acetone (100 mL), and sodium iodide (24.41 g, 4 eq, 162.86 mmol) was added. The mixture was purged with nitrogen, heated to 50° C., and stirred at that temperature for 30 hours. The mixture was filtered, and the filtrate was dried by rotary evaporation. The residue was purified by column chromatography (PE / EA = 0% to 3%) to give compound 1-c (8.3 g, 60.48% yield).

[0174] n-Butyric acid (20 g, 1 eq, 227.00 mmol) was dissolved in a mixture of acetonitrile (200 mL) and water (100 mL), and silver oxide (31.56 g, 0.6 eq, 136 mmol) was added. The mixture was reacted in the dark at room temperature for 16 hours and then filtered. The filtrate was dried to yield silver butyrate (11 g, 24.85% yield).

[0175] Silver butyrate (2.53 g, 1.15 eq, 12.96 mmol) was added to a solution of compound 1-c (3.8 g, 1 eq, 11.27 mmol) in toluene (38 mL). The reaction mixture was heated to 50°C and stirred overnight at this temperature. The reaction mixture was cooled to room temperature and filtered, and the filtrate was evaporated to obtain a solid. This solid was purified by column chromatography (PE / EA = 0% to 3%) to obtain compound 1-d (1.59 g, 47.51% yield).

[0176] Compound 1-d (1.58 g, 1.8 eq, 5.3 mmol) was added to a solution of compound 1-5 (1.9 g, 1 eq, 2.95 mmol) in dichloromethane (19 mL), followed by the addition of triethylamine (745.56 mg, 2.5 eq, 7.37 mmol) and DMAP (72.01 mg, 0.2 eq, 0.589 mmol). The mixture was stirred at 40° C. for 1 hour and then spin-dried. The residue was purified by column chromatography (MeOH / DCM = 0% to 3%) to give compound 1-6 (1.56 g, 65.93% yield).

[0177] Compound 1-6 (1.56 g, 1 eq, 1.94 mmol) was dissolved in a mixed solvent of dichloromethane (100 mL) and methanol (0.5 mL), and then a 4 M hydrochloric acid dioxane solution (6 mL) was slowly added. The reaction solution was stirred at room temperature for 15 minutes and then quickly dried at 40 ° C. The residue was dissolved in dichloromethane, the pH was adjusted to alkaline with triethylamine, and then dried. The residue was dissolved in dichloromethane again, washed with water two to three times, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was dried to give a crude product 1. The crude product was purified by column chromatography (MeOH / DCM=0%~5%) to give compound 1 (1.2 g, yield 80.07%). 1H NMR(500MHz,CD3OD)δppm 0.96-1.05(m,3H),1.57(s,3H),1.69(s,2H),1.84-2.13(m,7H),2.18-2.48(m,5 H),3.06-3.18(m,1H),3.38-3.50(m,3H),3.70-3.88(m,2H),4.19-4.34(m,2H), 4.29-4.45(m,2H),4.46-4.56(m,2H),5.33(s,0.5H),5.44(s,0.5H),6.84-6.95 (m,1H),7.24(s,1H),7.32-7.42(m,2H),7.87-7.94(m,1H),9.06(s,1H).m / z(ESI + ):759.3.

[0178] Synthesis of compound 2

[0179] The synthesis method of compound 2 refers to compound 1, using isovaleric acid as the raw material. 1 H NMR (500MHz, CD3OD) δppm9.14(s,1H),7.92(dd,J=9.0,6.0Hz,1H),7.41(d,J=2.5Hz,1H),7.38(t,J=9.0Hz,1 H),7.25(d,J=2.5Hz,1H),6.87(q,J=5.5Hz,1H),5.61(d,J=52Hz,1H),4.82-4.62(m,4H),4.54(s,2H),4.12- 3.72(m,5H),3.56-3.46(m,1H),3.38(d,J=9.2Hz,1H),2.82-2.55(m,3H),2.52-2.44(m,1H),2.43-2.34(m,2 H),2.27-2.16(m,1H),2.14-1.96(m,2H),1.87(d,J=7.9Hz,2H),1.58(d,J=4.3Hz,3H),1.21(s,6H).m / z(ESI + ):759.6.

[0180] Synthesis of compound 3

[0181] The synthesis method of compound 3 refers to compound 1, using acetic acid as the raw material. 1H NMR (500MHz, CD3OD) δppm9.14(s,1H),7.91(dd,J=9.0,6.0Hz,1H),7.41(d,J=2.5Hz,1H),7.37(t, J=9.0Hz,1H),7.25(d,J=2.5Hz,1H),6.87(q,J=5.0Hz,1H),5.61(d,J=51.0Hz,1H),4.84-4.64(m,4 H),4.53(s,2H),4.11-3.71(m,5H),3.57-3.47(m,1H),3.38(d,J=9.1Hz,1H),2.81-2.57(m,2H),2. 52-2.43(m,1H),2.43-2.34(m,2H),2.27-1.98(m,6H),1.86(d,J=8.0Hz,2H),1.57(s,3H).m / z(ESI + ):731.57.

[0182] Synthesis of compound 4

[0183] Compound 3 (50 mg, 0.068 mmol, 1 eq) was dissolved in dichloromethane (5 mL), and isovaleric acid (6.99 mg, 0.068 mmol, 1 eq), DCC (14.12 mg, 0.068 mmol, 1 eq), and DMAP (8.36 mg, 0.068 mmol, 1 eq) were added. The mixture was stirred at room temperature for 1 hour and then dried. The residue was purified by column chromatography (MeOH / DCM = 0% to 3%) to give compound 4 (36.1 mg, 64.3% yield). 1 H NMR(500MHz,CD3OD)δppm 9.08(s,1H),8.13(dd,J=9.0,6.0Hz,1H),7.91(d,J=2.5Hz,1H),7.51(t,J=9.0Hz,1H),7.47(s, 1H),6.86(d,J=5.5Hz,1H),5.38(d,J=53.5Hz,1H),4.82-4.62(m,2H),4.57-4.46(m,2H),4.46-4 .30(m,2H),3.94-3.70(m,2H),3.57-3.38(m,3H),3.16-3.09(m,1H),2.57(d,J=7.0Hz,2H),2.49 -2.18(m,4H),2.13-1.93(m,8H),1.93-1.80(m,2H),1.56(s,3H),1.11(d,J=6.5Hz,6H).m / z(ESI + ):815.5.

[0184] Synthesis of compound 5

[0185] The synthesis method of compound 5 refers to compound 1, using pivalic acid as the raw material. 1 H NMR (500MHz, CD3OD) δppm9.05(s,1H),7.89(dd,J=9.0,5.5Hz,1H),7.38(d,J=2.0Hz,2H),7.35(t ,J=9.0Hz,1H),7.24(s,1H),6.85(q,J=5.0Hz,1H),5.37(d,J=53.5Hz,1H),4.80-4.63(m,2H),4.5 8-4.44(m,2H),4.42-4.28(m,2H),3.93-3.64(m,2H),3.50-3.36(m,2H),3.32-3.26(m,1H),3.16 -3.05(m,1H),2.47-2.15(m,3H),2.13-1.82(m,7H),1.57(s,3H),1.24(d,J=6.5Hz,9H).m / z,(ESI + ):773.3.

[0186] Synthesis of compound 6

[0187] The synthesis method of compound 6 refers to compound 1, using 2-propyl valeric acid as the raw material. 1 H NMR (500 MHz, DMSO-d6) δ ppm 10.19(s,1H),9.04(s,1H),8.00(m,1H),7.62-7.36(m,2H),7.19(s,1H),6 .81(q,J=5.0Hz,1H),5.30(d,J=53.5Hz,1H),4.49(m,4H),4.17-3.95(m,3H ),3.81-3.40(m,2H),3.07(m,3H),2.85(m,1H),2.08(m,3H),1.92-1.76(m, 6H),1.50(m,5H),1.41(m,2H),1.26(m,5H),1.07(m,1H),0.90(m,6H).(ESI + ):815.3.

[0188] Synthesis of compound 7

[0189] The synthesis method of compound 7 refers to compound 4, using pivalic acid and compound 1 as raw materials. 1H NMR(500MHz,CD3OD)δppm 0.93-1.01(m,3H),1.40(s,9H),1.49-1.58(m,3H),1.60-1.72(m,2H),1.80-2.07(m,7H),2.10 -2.40(m,5H),2.99-3.08(m,1H),3.14-3.28(m,3H),3.43-3.52(m,1H),3.73-3.85(m,1H),4.2 1-4.36(m,2H),4.42-4.52(m,2H),4.59-4.75(m,2H),5.26(s,0.5H),5.37(s,0.5H),6.81-6.9 0(m,1H),7.41(s,1H),7.46-7.53(m,1H),7.87(s,1H),8.06-8.13(m,1H),9.04(s,1H).m / z(ESI + ):843.4.

[0190] Synthesis of compound 8

[0191] The synthesis method of compound 8 refers to compound 1, using 3-cyclopentylpropionic acid as the raw material. 1 H NMR(500MHz,CD3OD)δppm 9.06(s,1H),7.89(dd,J=9.0,5.5Hz,1H),7.38(d,J=2.5Hz,1H),7.36(t,J=9.0Hz,1H),7.24(s ,1H),6.88(d,J=5.5Hz,1H),5.37(d,J=54.0Hz,1H),4.80-4.60(m,2H),4.51(s,2H),4.44-4.2 7(m,2H),3.92-3.68(m,2H),3.50-3.37(m,2H),3.17-3.04(m,1H),2.48-2.24(m,4H),2.24-2. 16(m,1H),2.13-2.00(m,4H),2.00-1.76(m,6H),1.74-1.48(m,9H),1.20-1.08(m,2H).m / z(ESI + ):813.3.

[0192] Synthesis of compound 9

[0193] The synthesis method of compound 9 refers to compound 1, using cyclopentyl acetic acid as the raw material. 1H NMR(500MHz,CD3OD)δppm 9.06(s,1H),7.89(dd,J=9.0,5.5Hz,1H),7.42-7.31(m,2H),7.23(s,1H),6.88(d,J =5.0Hz,1H),5.39(d,J=53.5Hz,1H),4.8-4.63(m,2H),4.56-4.46(m,2H),4.45-4.31 (m,2H),3.90-3.70(m,2H),3.51-3.37(m,3H),3.19-3.08(m,1H),2.52-2.18(m,6H), 2.15-1.94(m,5H),1.93-1.81(m,4H),1.76-1.49(m,7H),1.29-1.18(m,2H).m / z(ESI + ):799.3.

[0194] Synthesis of compound 10

[0195] The synthesis method of compound 10 refers to compound 1, using isovaleric acid as the raw material. 1 H NMR(500MHz,CD3OD)δppm 0.94-1.03(m,6H),1.48-1.58(m,3H),1.81-2.06(m,7H),2.06-2.39(m,6H),2.99-3. 08(m,1H),3.20-3.29(m,2H),3.34-3.40(m,1H),3.64-3.84(m,2H),4.21-4.36(m,2H) ,4.43-4.53(m,2H),4.60-4.76(m,3H),5.27(s,0.5H),5.38(s,0.5H),6.82-6.91(m,1 H),7.21(d,J=2.0Hz,1H),7.29-7.39(m,2H),7.83-7.90(m,1H),9.02(s,1H).m / z(ESI + ):773.4.

[0196] Synthesis of compound 11

[0197] The synthesis method of compound 11 refers to compound 1, using n-hexanoic acid as the raw material. 1H NMR(500MHz,CD3OD)δppm 0.84-0.97(m,3H),1.31-1.41(m,4H),1.45-1.58(m,3H),1.58-1.69(m,2H),1.80-2.11(m,7 H),2.13-2.43(m,5H),3.02-3.13(m,1H),3.23-3.29(m,1H),3.34-3.43(m,2H),3.63-3.85(m ,2H),4.25-4.40(m,2H),4.43-4.52(m,2H),4.60-4.75(m,2H),5.29(s,0.5H),5.39(s,0.5H) ,6.82-6.89(m,1H),7.20(s,1H),7.28-7.39(m,2H),7.83-7.91(m,1H),9.02(s,1H).m / z(ESI + ):787.3.

[0198] Synthesis of compound 12

[0199] The synthesis method of compound 12 refers to compound 1, using adamantane acetic acid as the raw material. 1 H NMR(500MHz,CD3OD)δppm 1.53(s,3H),1.66-1.73(m,12H),1.87-2.35(m,15H),3.02(s,1H),3.17-3.36(m,4H),3.70-3.78(m,2H),4.22-4.32(m,2H),4.4 8(s,2H),4.67(s,2H),5.25-5.36(m,1H),6.86(s,1H),7.20(s,1H),7.30-7.35(m,2H),7.84-7.87(m,1H),9.00(s,1H).m / z(ESI + ):866.4.

[0200] Synthesis of compound 13

[0201] The synthesis method of compound 13 refers to compound 1, using 2-methylbutyric acid as the raw material. 1H NMR(500MHz,CD3OD)δppm 0.93(s,3H),1.15(s,3H),1.29(s,1H),1.54-1.67(m,6H),1.86-2.40(m,12H),3.07-3.39(m,2H),3.72-3.78(m,2H),4.26-4.37(m,2H ),4.47(s,2H),4.67(s,2H),5.28-5.39(m,1H),6.86(s,1H),7.20(s,1H),7.31-7.35(m,2H),7.85-7.88(m,1H),9.02(s,1H).m / z(ESI + ):773.3.

[0202] Synthesis of compound 14

[0203] The synthesis method of compound 14 refers to compound 1, using cyclohexylcarboxylic acid as the raw material. 1 H NMR(500MHz,CD3OD)δppm 9.06(s,1H),7.90(dd,J=9.0,5.5Hz,1H),7.42-7.33(m,2H),7.24(s,1H),6.86(q,J=5.0Hz,1H ),5.37(d,J=53.5Hz,1H),4.82-4.60(m,2H),4.57-4.45(m,2H),4.43-4.29(m,2H),3.90-3.67 (m,2H),3.46-3.37(m,2H),3.17-3.06(m,1H),2.50-2.15(m,4H),2.15-1.84(m,9H),1.83-1.7 4(m,2H),1.74-1.62(m,1H),1.61-1.53(m,3H),1.53-1.43(m,2H),1.42-1.24(m,5H).m / z(ESI + ):799.3.

[0204] Synthesis of compound 15

[0205] The synthesis method of compound 15 refers to compound 1, using n-octanoic acid as the raw material. 1H NMR (500 MHz, CD3OD) δ ppm 0.81-0.95(m,3H),1.27-1.36(m,8H),1.49-1.68(m,5H),1.80-2.55(m,12 H),3.12-3.21(m,1H),3.34-3.50(m,3H),3.68-3.87(m,2H),4.32-4.53(m ,4H),4.60-4.78(m,2H),5.34(s,0.5H),5.45(s,0.5H),6.80-6.90(m,1H) ,7.20(s,1H),7.29-7.39(m,2H),7.83-7.91(m,1H),9.04(s,1H).m / z(ESI + ):815.3.

[0206] Synthesis of compound 16

[0207] The synthesis method of compound 16 refers to compound 1, using 2,2-dimethylbutyric acid as the raw material. 1 H NMR (500 MHz, CD3OD) δ ppm 9.05(s,1H),7.94-7.85(m,1H),7.44-7.30(m,2H),7.23(s,1H),6.87-6.88( m,1H),5.31-5.41(m,1H),4.71(s,2H),4.50(m,2H),4.41-4.26(m,2H),3.81( m,2H),3.41(s,1H),3.30(m,2H),3.09(s,1H),2.19-2.39(m,3H),2.13-1.84 (m,7H),1.57-1.62(m,5H),1.31-1.33(m,1H),1.21(s,6H),0.91(s,3H).(ESI + ):787.4.

[0208] Synthesis of compound 17

[0209] The synthesis method of compound 17 refers to compound 1, using 3,3-dimethylbutyric acid as the raw material. 1H NMR(500MHz,CD3OD)δppm 1.06(s,9H),1.54(s,3H),1.86-2.34(m,13H),3.03-3.04(m,1H),3.22-3.38(m,3H),3.75-3.78(m,2H),4.23-4.33(m,2H),4. 48(s,2H),4.70(s,2H),5.26-5.37(m,1H),6.86(s,1H),7.20(s,1H),7.31-7.35(m,2H),7.85-7.88(m,1H),9.01(s,1H).(ESI + ):755.4.

[0210] Synthesis of compound 18

[0211] The synthesis method of compound 18 refers to compound 1, using 2-ethylhexanoic acid as the raw material. 1 H NMR(500MHz,CD3OD)δppm 0.87-1.02(m,6H),1.28-1.31(m,4H),1.47-1.68(m,7H),1.82-2.42(m,11H),2.99- 3.09(m,1H),3.23-3.28(m,1H),3.35-3.47(m,3H),3.68-3.86(m,1H),4.22-4.37(m ,2H),4.42-4.53(m,2H),4.62-4.76(m,2H),5.27(s,0.5H),5.38(s,0.5H),6.82-6. 94(m,1H),7.21(s,1H),7.28-7.39(m,2H),7.82-7.91(m,1H),9.02(s,1H).m / z(ESI + ):815.4.

[0212] Synthesis of compound 19

[0213] The synthesis method of compound 19 refers to compound 1, using propionic acid as the raw material. 1H NMR(500MHz,CD3OD)δppm1.07-1.18(m,3H),1.49-1.59(m,3H),1.80-2.46(m,12H),2 .98-3.09(m,1H),3.21-3.27(m,2H),3.36-3.47(m,3H),3.74-3.87(m,1H),4.19-4.3 7(m,2H),4.42-4.54(m,2H),4.59-4.74(m,1H),5.27(s,0.5H),5.37(s,0.5H),6.81- 6.90(m,1H),7.21(s,1H),7.29-7.40(m,2H),7.82-7.93(m,1H),9.02(s,1H).m / z(ESI + ):745.3.

[0214] Synthesis of compound 20

[0215] The synthesis method of compound 20 refers to compound 1, using 2-butylhexanoic acid as the raw material. 1 H NMR(500MHz,CD3OD)δppm 0.85(s,6H),1.25(s,8H),1.48-1.55(m,7H),1.88-1.90(m,7H),2.12(s,1H),2.20-2.42(m,3H),3.03(s,1H),3.34(s,3H),3.65-3 .74(m,2H),4.26-4.62(m,7H),5.24-5.35(m,1H),6.83(s,1H),7.15(s,1H),7.27-7.29(m,2H),7.80(s,1H),8.97(s,1H).m / z(ESI + ):843.4.

[0216] Synthesis of compound 21

[0217] The synthesis method of compound 21 refers to compound 1, using valeric acid as the raw material. 1H NMR(500MHz,CD3OD)δppm0.95-0.98(t,J=7.5Hz,3H),1.32-1.42(m,3H),1.57-1.64(m, 5H),1.86-1.87(m,2H),2.06-2.19(m,3H),2.39-2.48(m,6H),2.59-2.74(m,2H),3.39- 3.51(m,2H),3.82-4.09(m,5H),4.33(s,2H),4.73-4.78(m,4H),5.56-5.66(m,1H),6.8 8-6.89(m,1H),7.25(s,1H),7.36-7.41(m,2H),7.90-7.93(m,1H),9.14(s,1H).m / z(ESI + ):773.3.

[0218] Synthesis of compound 22

[0219] The synthesis method of compound 22 refers to compound 1, using nicotinic acid as the raw material. 1 H NMR(500MHz,CD3OD)δppm1.71(s,3H),1.87-2.34(m,11H),3.04-3.30(m,3H),3.81(s,2H),4.27-4.32(m,2H),4.50-4.65(m,5H),5.27-5.38 (m,1H),7.14(s,1H),7.20(s,1H),7.33-7.35(m,2H),7.60(s,1H),7.8 6(s,1H),8.44(s,1H),8.78(s,1H),9.02(s,1H),9.16(s,1H).m / z(ESI + ):794.3.

[0220] Synthesis of compound 23

[0221] The synthesis method of compound 23 refers to compound 1, using 1-naphthoic acid as the raw material. 1H NMR(500MHz,CD3OD)δppm 1.73(s,3H),1.82-2.22(m,11H),3.00(s,1H),3.18-3.22(m,3H),3.78-3.80(m,2H),4.22-4.26(m,2H),4.49-4.62(m,4H),5.22- 5.33(m,1H),7.20(m,2H),7.27-7.29(m,2H),7.53-7.55(m,3H),7.82-7.93(m,2H),8.10-8.23(m,2H),8.85-9.00(m,2H).m / z(ESI + ):843.3.

[0222] Synthesis of compound 24

[0223] The synthesis method of compound 24 refers to compound 1, using benzoic acid as the raw material. 1 H NMR(500MHz,CD3OD)δppm 9.04(d,J=15.5Hz,1H),8.08(s,2H),7.89(dd,J=9.0,5.5Hz,1H),7.67(s,1H),7.53(t,J=7.5Hz,2H) ,7.41-7.32(m,2H),7.23(s,1H),7.14(d,J=5.5Hz,1H),5.36(d,J=53.5Hz,1H),4.84-4.61(m,2H),4. 60-4.47(m,2H),4.42-4.25(m,2H),3.93-3.71(m,2H),3.40(d,J=8.5Hz,1H),3.31-3.25(m,1H),3.1 5-3.03(m,1H),2.48-2.14(m,4H),2.13-2.01(m,4H),2.00-1.79(m,3H),1.79-1.65(m,3H).m / z,(ESI + ):793.3.

[0224] Synthesis of compound 25

[0225] The synthesis method of compound 25 refers to compound 1, using 2-butyloctanoic acid as the raw material. 1H NMR(500MHz,CD3OD)δppm 0.94(s,6H),1.33(s,12H),1.57(t,J=14.0Hz,7H),1.90(s,3H),2.03(s,3H),2.13- 2.34(m,3H),2.36-2.38(m,2H),3.06(s,1H),3.24-3.27(m,3H),3.39(m,1H),3.74-3 .82(m,2H),4.24-4.37(m,2H),4.50(s,2H),4.70(s,2H),5.34(d,J=53.5Hz,1H),6. 91(s,1H),7.23(s,1H),7.34-7.35(m,2H),7.86-7.93(m,1H),9.04(s,1H).m / z,(ESI + ):871.4.

[0226] Synthesis of the salt of compound 26

[0227]

[0228] A 4M solution of dioxane hydrochloride (3 mL) was slowly added to a solution of compound 1-3 (1.2 g, 2.34 mmol, 1 eq) in dichloromethane (10 mL). The mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was purified by column chromatography (EA / PE = 0% to 15%) to give compound 26-1 (1.02 g, 93.27% yield).

[0229] Compound 1-1 (1 g, 1.81 mmol, 1 eq) was added to a solution of compound 26-1 (1.02 g, 2.18 mmol, 1.2 eq) in dioxane (25 mL). Cesium carbonate (1.77 g, 5.44 mmol, 1 eq) in water was then added, followed by [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (294.21 mg, 0.36 mmol, 0.2 eq). The mixture was purged with nitrogen three times, heated to 100°C under a nitrogen atmosphere, and stirred at this temperature for 2 hours. After cooling, the reaction mixture was diluted with water and ethyl acetate. The organic phase was separated, washed with water and brine, dried, filtered, and spun down. The residue was purified by column chromatography (MeOH / DCM = 0% to 4%) to afford compound 26-2 (759 mg, 48.8% yield).

[0230] A 1M solution of TBAF in tetrahydrofuran (4.43 mL) was added to a solution of compound 26-2 (759 mg, 0.88 mmol, 1 eq) in tetrahydrofuran (7.6 mL). The reaction mixture was stirred at room temperature for 1.5 hours and then concentrated in vacuo. The residue was purified by column chromatography (MeOH / DCM = 0% to 10%) to give compound 26-3 (639 mg, 100% yield).

[0231] Decanoic acid (7.67 mg, 0.044 mmol, 1 eq) was added to a solution of compound 26-3 (31.2 mg, 0.044 mmol, 1 eq) in dichloromethane (2.99 mL), followed by the addition of DMAP (0.54 mg, 0.004 mmol, 0.1 eq) and DCC (9.19 mg, 0.044 mmol, 1 eq). The reaction mixture was stirred at room temperature for 1.5 hours and then concentrated in vacuo. The residue was purified by column chromatography (MeOH / DCM = 0% to 4%) to give compound 26-4 (29 mg, yield 76.18%).

[0232] Trifluoroacetic acid (1 mL) was added to a solution of compound 26-4 (29 mg, 0.033 mmol, 1 eq) in dichloromethane (1 mL). The reaction solution was stirred at room temperature for 5 minutes and then concentrated in vacuo. The residue was purified by reverse phase preparative chromatography to give the salt of compound 26 (12.2 mg, yield 32.32%). 1 H NMR 500MHz, CD3OD)δppm 9.16(s,1H),8.14(dd,J=9.0,5.5Hz,1H),7.92(s,1H),7.52(t,J=9.0Hz,1H),7.48(s,1H) ,5.61(d,J=51.5Hz,1H),4.75(s,2H),4.31(d,J=10.0Hz,2H),4.15-3.82(m,5H),3.49(dd ,J=18.4,9.0Hz,2H),2.83-2.56(m,4H),2.53-2.43(m,1H),2.43-2.32(m,2H),2.17(dd,J =33.0,9.0Hz,5H),1.84-1.75(m,2H),1.57-1.27(m,14H),0.91(t,J=6.5Hz,3H).m / z,(ESI + ):755.7.

[0233] Synthesis of the salt of compound 27

[0234] The synthesis method of the salt of compound 27 refers to compound 26, using isovaleric acid as the raw material. 1H NMR(500MHz,CD3OD)δppm 1.08(d,J=5.0Hz,7H),2.03-2.47(m,10H),2.55-2.74(m,2H),2.57-2.75(m,2H),3.44-3.50(m,2H),3.85-4.05(m,5H),4.28(d,J=10.0Hz, 2H),4.72-4.74(m,2H),5.53-5.63(m,1H),7.44(s,1H),7.50(d,J=10.0Hz,1H),7.90(s,1H),8.12(q,J=10.0Hz,1H),9.13(s,1H).m / z,(ESI + ):785.5.

[0235] Synthesis of the Salt of Compound 28 The synthesis method of the salt of Compound 28 was similar to that of Compound 26, using pivalic acid as the raw material. 1 H NMR(500MHz,CD3OD)δ9.16(s,1H),8.15(dd,J=9.0,5.5Hz,1H),7.92(d,J=2.0H z,1H),7.53(t,J=9.0Hz,1H),7.44(s,1H),5.61(d,J=51.5Hz,1H),4.81-4.71( m,2H),4.32(s,2H),4.12-3.87(m,5H),3.59-3.44(m,2H),2.87-2.61(m,2H),2 .55-2.44(m,1H),2.43-2.34(m,2H),2.28-2.10(m,5H),1.43(s,9H).m / z,(ESI + ):685.6.

[0236] Synthesis of the salt of compound 29

[0237] The synthesis method of the salt of compound 29 refers to compound 26, using dodecanoic acid as the raw material. 1H NMR(500MHz,CD3OD)δppm 0.53-0.94(m,3H),1.28-1.48(m,16H),1.71-1.82(m,2H),2.01-2.24(m,5H),2.29- 2.50(m,3H),2.56-2.77(m,4H),3.42-3.52(m,2H),3.81-4.07(m,5H),4.23-4.34(m ,2H),4.66-4.77(m,2H),4.86(s,1H),5.53(s,0.5H),5.63(s,0.5H),7.46(s,1H),7 .50(d,J=9.0Hz,1H),7.91(d,J=2.0Hz,1H),8.08-8.17(m,1H),9.13(s,1H).m / z(ESI + ):783.4.

[0238] Synthesis of the salt of compound 30

[0239] The synthesis method of the salt of compound 30 refers to compound 26, using cyclopentylpropionic acid as the raw material. 1 H NMR(500MHz,CD3OD)δppm 9.16(s,1H),8.14(dd,J=9.0,5.5Hz,1H),7.93(d,J=2.2Hz,1H),7.53(t,J=9.0Hz,1H ),7.49(s,1H),5.61(d,J=51.5Hz,1H),4.90(d,J=13.0Hz,1H),4.75(s,2H),4.38-4.2 7(m,2H),4.12-3.87(m,5H),3.55-3.45(m,2H),2.82-2.58(m,4H),2.55-2.32(m,3H) ,2.31-2.07(m,5H),1.99-1.78(m,5H),1.77-1.54(m,4H),1.28-1.17(m,2H).m / z(ESI + ):725.4.

[0240] Synthesis of the Salt of Compound 31 The synthesis method of the salt of Compound 31 was similar to that of Compound 26, using hexadecanoic acid as the raw material. 1H NMR(500MHz,CD3OD)δppm 0.87-0.91(m,3H),1.28-1.50(m,24H),1.72-1.82(m,2H),1.96-2.20(m,6H),2.20- 2.52(m,3H),2.53-2.63(m,1H),2.63-2.72(m,2H),3.43-3.51(m,3H),3.74-4.01(m ,4H),4.15-4.26(m,2H),4.58-4.71(m,2H),4.79-4.85(m,2H),5.49(s,0.5H),5.60 (s,0.5H),7.42-7.56(m,2H),7.91(s,1H),8.07-8.20(m,1H),9.12(s,1H).m / z(ESI + ):839.6.

[0241] Synthesis of the Salt of Compound 32 The synthesis method of the salt of Compound 32 was based on the method of Compound 26, using 2-hexyldecanoic acid as the raw material. 1 H NMR(500MHz,CD3OD)δppm 0.87(t,J=5.0Hz,6H),1.28-1.46(m,22H),1.64-1.66(m,2H),75-1.81(m,2H),2 .10-2.16(m,5H),2.35-2.44(m,3H),2.57-2.75(m,3H),3.45=3.50(m,2H),3.86- 4.02(m,5H),4.27-4.29(m,2H),4.72(s,2H),5.53-5.63(m,1H),7.38(s,1H),7. 51(t,J=10.0Hz,1H),7.87-7.88(m,1H),8.12-8.15(m,1H),9.14(s,1H).m / z(ESI + ):839.5.

[0242] Synthesis of the salt of compound 33

[0243] The synthesis method of the salt of compound 33 refers to compound 26, using isobutyric acid as the raw material. 1H NMR (500 MHz, CD3OD) δ ppm 1.36(s,3H),1.38(s,3H),2.13-2.21(m,5H),2.35-2.50(m,3H),2.60-2.78( m,2H),2.91-2.97(m,1H),3.47-3.53(m,2H),3.90-4.06(m,2H)4.31(s,2H), 4.74-4.75(d,J=5.0Hz,2H),4.88-4.91(m,2H),5.56-5.67(m,1H),7.47(s,1 H),7.51-7.55(m,1H),7.93(s,1H),8.14-8.16(m,1H),9.17(s,1H).m / z(ESI + ):671.3.

[0244] Synthesis of the salt of compound 34

[0245] The synthesis method of the salt of compound 34 refers to compound 26, using ursodeoxycholic acid as the raw material. 1 H NMR(500MHz,CD3OD)δppm 0.73(s,3H),0.97(s,3H),1.04(d,J=5.5Hz,3H),1.14-1.39(m,9H),1.40-1.67(m ,12H),1.77-2.26(m,12H),2.29-2.49(m,3H),2.54-2.79(m,4H),3.41-3.55(m,4H ),3.83-4.08(m,5H),4.23-4.33(m,2H),4.64-4.76(m,2H),5.53(s,0.5H),5.64( s,0.5H),7.42-7.55(m,2H),7.90(s,1H),8.07-8.15(m,1H),9.13(s,1H).m / z(ESI + ):975.5.

[0246] Synthesis of compound 35

[0247] The synthesis method of compound 35 refers to compound 26, using arachidonic acid as the raw material. 1H NMR (500 MHz, CD3OD) δ ppm 0.89-0.92(t,J=7.5Hz,3H),1.31-1.37(m,10H),1.85-1.91(m,2H),2.04-2. 08(m,2H),2.13-2.50(m,10H),2.75-2.91(m,9H),3.48-3.52(m,2H),3.89-4 .08(m,6H),4.31-4.33(m,2H),4.75(s,4H),5.29-5.48(m,8H),5.57-5.67(m ,1H)7.50-7.55(m,2H)7.94(s,1H),8.12-8.15(m,1H),9.16(s,1H).m / z(ESI + ):887.5.

[0248] Synthesis of the salt of compound 36

[0249] The synthesis method of the salt of compound 36 refers to compound 26, using 2-methylbutyric acid as the raw material. 1 H NMR(500MHz,CD3OD)δ1.06(t,J=7.5Hz,3H),1.32(d,J=7.0Hz,3H),1.63-1.75(m,1H),1.81-1.88(m, 1H),2.10-2.18(m,5H),2.31-2.39(m,2H),2.45(s,1H),2.56-2.79(m,3H),3.45-3.51(m,2H),3.85-4 .08(m,5H),4.29(d,J=10.0Hz,2H),4.68-4.76(m,2H),4.86(s,2H),5.53(s,1H),5.64(s,1H),7.43(s ,1H),7.51(t,J=9.0Hz,1H),7.91(d,J=2.0Hz,1H),8.13(dd,J=9.0,5.5Hz,1H),9.14(s,1H).m / z(ESI + ):685.3.

[0250] Synthesis of compound 37

[0251] The synthesis method of compound 37 was based on compound 26, using tetradecanoic acid as the raw material. 1H NMR(500MHz,CD3OD)δ9.16(s,1H),8.13-8.14(m,1H),7.93(s,1H),7.49-7. 55(m,2H),5.56-5.61(m,1H),4.91(m,2H),4.75(s,2H),4.31(s,2H),4.09-3 .86(m,4H),3.48-3.50(d,2H),2.60-2.75(m,4H),2.37-2.47(m,3H),2.07- 2.19(m,5H),1.78-1.79(m,2H),1.31-1.48(m,21H),0.90-0.93(m,3H).(ESI + ):811.5.

[0252] Synthesis of the salt of compound 38

[0253] The synthesis method of the salt of compound 38 refers to compound 26, using 2-propylpentanoic acid as the raw material. 1 H NMR(500MHz,CD3OD)δppm 0.99(t,J=5.0Hz,6H),1.45-1.79(m,8H),2.11-2.76(m,11H),3.48-3.49(m,2H),3.86-4.05(m,5H),4.26-4.29(m,2H),4.72(s,2H) ,4.84-4.93(m,2H),5.54-5.64(m,1H),7.38(s,1H),7.51(t,J=10.0Hz,1H),7.88-7.89(m,1H),8.13-8.16(m,1H),9.13(s,1H).(ESI + ):727.3.

[0254] Synthesis of the salt of compound 39

[0255] The synthesis method of compound 39 refers to compound 26, using nonanoic acid as the raw material. 1H NMR(500MHz,CD3OD)δppm0.91-0.93(m,3H),1.35-1.47(m,12H),1.61-1.64(m,2H),1.76- 1.81(m,2H),2.13-2.23(m,4H),2.29-2.49(m,4H),2.68-2.7(m,2H),3.49-3.50(m,2H),3. 89-4.07(m,4H),4.30-4.32(m,2H),4.75(s,2H),5.56-5.67(m,1H),7.49(s,1H),7.51-7. 55(t,J=18.0Hz,1H),7.91-7.94(d,J=2.0Hz,1H),8.13-8.16(m,1H),9.16(s,1H).m / z(ESI + ):741.3.

[0256] Synthesis of the salt of compound 40

[0257] The synthesis method of the salt of compound 40 refers to compound 26, using oleic acid as the raw material. 1 H NMR(500MHz,CD3OD)δppm 9.16(s,1H),8.15-8.16(m,1H),7.94(s,1H),7.49-7.55(m,2H),5.56-5.66(m, 1H),5.37(s,2H),4.89-4.95(m,1H),4.72-4.78m,2H),4.32(s,2H),3.82-4.06( m,4H),3.48-3.52(m,2H),2.81-2.55(m,4H),2.31-2.47(m,3H),2.01-2.19(m,8 H),1.78-1.81(m,2H),1.63(s,1H),1.31-1.48(m,22H),0.91-0.93(m,3H).(ESI + ):865.4.

[0258] Synthesis of salt of compound 41

[0259] The synthesis method of the salt of compound 41 refers to compound 26, using 2-butyloctanoic acid as the raw material. 1H NMR(500MHz,CD3OD)δppm 0.88-0.96(m,6H),1.29-1.42(m,13H),1.65-1.78(m,4H),2.09-2.15(m, 5H),2.35-2.76(m,5H),3.46-3.48(m,2H),3.86-4.02(m,5H),4.26-4.29 (m,2H),4.72(s,2H),4.85-4.94(m,2H),5.53-5.64(m,1H),7.38(s,1H), 7.51(t,J=10.0Hz,1H),7.88(s,1H),8.13-8.15(m,1H),9.14(s,1H).(ESI + ):783.4.

[0260] Synthesis of the salt of compound 42

[0261] The synthesis method of the salt of compound 42 refers to compound 26, using 2-butylhexanoic acid as the raw material. 1 H NMR(500MHz,CD3OD)δppm 0.95(t,J=5.0Hz,6H),1.39-1.42(s,8H),1.65-1.66(m,2H),1.79(t,J=5.0Hz,2H),2.1 0-2.15(m,5H),2.35-2.45(m,3H),2.57-2.75(m,3H),3.46-3.50(m,2H),3.90-4.04(m, 5H),4.27-4.29(m,2H),4.69-4.75(m,2H),4.85-4.93(m,2H),5.53-5.64(m,1H),7.38( s,1H),7.51(t,J=10.0Hz,1H),7.88-7.89(m,1H),8.13-8.16(m,1H),9.14(s,1H).(ESI + ):755.4.

[0262] Synthesis of the salt of compound 43

[0263] The synthesis method of the salt of compound 43 refers to compound 26, using octanoic acid as the raw material. 1H NMR(500MHz,CD3OD)δppm 0.91(t,J=6.5Hz,3H),1.32-1.48(m,8H),1.71-1.82(m,2H),2.08-2.22(m,5H),2.2 8-2.50(m,3H),2.55-2.78(m,4H),3.46(d,J=8.0Hz,2H),3.86-4.02(m,5H),4.29(s ,2H),4.72(s,2H),4.87(d,J=12.5Hz,2H),5.58(d,J=51.7Hz,1H),7.49(dd,J=20.0 ,11.1Hz,2H),7.91(d,J=2.0Hz,1H),8.12(dd,J=9.0,5.5Hz,1H),9.13(s,1H).(ESI + ):727.4.

[0264] Synthesis of the salt of compound 44

[0265] The synthesis method of the salt of compound 44 was based on the method of compound 26, using adamantane acetic acid as the starting material. 1 H NMR (500 MHz, CD3OD) δ ppm 1.66-1.84(m,15H),2.09-2.15(m,5H),2.34-2.36(m,2H),2.39(s,2H),2.44- 2.45(m,1H),2.59-2.72(m,2H),3.45-3.49(m,2H),3.85-4.04(m,5H),4.26-4 .29(m,2H),4.72(s,2H),4.84-4.93(m,2H),5.53-5.63(m,1H),7.43(s,1H),7 .50(t,J=10.0Hz,1H),7.88-7.89(m,1H),8.12-8.14(m,1H),9.13(s,1H).(ESI + ):777.3.

[0266] Synthesis of the salt of compound 45

[0267] The synthesis method of the salt of compound 45 refers to compound 26, using nicotinic acid as the raw material. 1H NMR(500MHz,CD3OD)δppm 2.10-2.22(m,5H),2.33-2.35(m,2H),2.45-2.47(m,1H),2.56-2.77(m,2H),3.46 -3.51(m,2H),3.85-4.03(m,5H),4.27-4.29(m,2H),4.72-4.75(m,2H),4.87-4.8 8(m,2H),5.54-5.64(m,1H),7.52-7.55(m,1H),7.69(s,1H),7.73-7.76(m,1H),8 .12-8.18(m,2H),8.69-8.70(m,1H),8.89(s,1H),9.15(s,1H),9.38(s,1H).(ESI + ):706.2.

[0268] Synthesis of the salt of compound 46

[0269] The synthesis method of the salt of compound 46 refers to compound 26, using 3,3-dimethylbutyric acid as the raw material. 1 H NMR(500MHz,CD3OD)δppm 9.16(s,1H),8.15-8.18(m,1H),7.94(s,1H),7.54(t,J=8.5Hz,1H),7.46(s,1H),5.56-5.66(m,1H),4.75(m,2H),4.31(d,J=11.0Hz,2H),4 .10-3.88(m,6H),3.49-3.50(m,2H),2.63-2.78(m,2H),2.58(s,2H),2.48(m,1H),2.35-2.41(m,2H),2.28-2.08(m,6H),1.19(s,9H).(ESI + ):699.3.

[0270] Synthesis of the salt of compound 47

[0271] The synthesis method of the salt of compound 47 refers to compound 26, using 1-naphthoic acid as the raw material. 1H NMR (500 MHz, CD3OD) δ ppm 2.10-2.15(m,5H),2.35-2.45(m,3H),2.57-2.75(m,2H),3.49-3.51(m,2H),3 .86-4.02(m,5H),4.27-4.30(m,2H),4.69-4.73(m,2H),4.89-4.93(m,2H),5.5 4-5.64(m,1H),7.53-7.56(m,1H),7.60-7.70(m,4H),8.02(d,J=5.0Hz,1H),8 .14-8.24(m,3H),8.58(d,J=5.0Hz,1H),8.99(d,J=5Hz,1H),9.16(s,1H).(ESI + ):755.3.

[0272] Synthesis of compound 48

[0273]

[0274] Pyridine (109.7 mg, 1.39 mmol, 0.1 eq) was added to a solution of compound 48-1 (1 g, 13.87 mmol, 1 eq) in carbon tetrachloride (10 mL). The mixture was cooled to -20°C to -10°C under nitrogen, and triphosgene (2.36 g, 6.93 mmol, 0.5 eq) was slowly added. The mixture was slowly warmed to room temperature, then heated to 40°C and stirred at this temperature for 1 hour. The reaction mixture was cooled to room temperature and then filtered. The filtrate was spin-dried to give compound 48-2 (1.5 g, 63.24% yield).

[0275] Triethylamine (1.07 g, 10.52 mmol, 1.2 eq) was added to a solution of p-nitrophenol (1.34 g, 9.65 mmol, 1.1 eq) in tetrahydrofuran (20 mL), followed by the addition of compound 48-2 (1.5 g, 8.77 mmol, 1 eq). The reaction mixture was stirred at room temperature for 1.5 hours, followed by the addition of dichloromethane and water. The separated organic phase was washed with water and brine, then dried over anhydrous sodium sulfate and filtered. The filtrate was dried, and the residue was purified by column chromatography (DCM) to yield compound 48-3 (2.2 g, 91.66% yield).

[0276] Compound 48-3 (2.2 g, 8.04 mmol, 1 eq) was dissolved in acetone (20 mL), and sodium iodide (3.01 g, 20.1 mmol, 2.5 eq) was added. The mixture was heated to 50°C and stirred at this temperature for 15 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was dried and the residue was purified by column chromatography (DCM) to obtain compound 48-4 (1.6 g, 60% yield).

[0277] Compound 48-4 (0.5 g, 0.82 mmol, 1 eq) was dissolved in toluene (10 mL), and silver butyrate (240.3 mg, 1.23 mmol, 1.5 eq) was added. The mixture was heated to 50°C and stirred at this temperature for 15 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (DCM) to afford compound 48-5 (120 mg, 44.89% yield).

[0278] Compound 48-5 (60.55 mg, 0.18 mmol, 3 eq) was added to a solution of compound 1-5 (40 mg, 0.062 mmol, 1 eq) in dichloromethane (3 mL), followed by the addition of DMAP (1.52 mg, 0.012 mmol, 0.2 eq) and triethylamine (18.84 mmol, 0.18 mmol, 3 eq). The mixture was heated to 40°C and stirred at this temperature for 1.5 hours. The reaction mixture was cooled and concentrated in vacuo, and the residue was purified by column chromatography (MeOH / DCM = 0% to 4%) to give compound 48-6 (40 mg, 77.59% yield).

[0279] Compound 48-6 (40 mg, 0.048 mmol, 1 eq) was dissolved in dichloromethane (5 mL), and then a 4 M solution of hydrochloric acid in dioxane (0.5 mL) was added. The reaction mixture was stirred at room temperature for 15 minutes and then concentrated in vacuo. The residue was basified with triethylamine and then purified by column chromatography (MeOH / DCM = 0% to 6%) to give compound 48 (16.8 mg, 43.5% yield). 1 H NMR(500MHz,CD3OD)δppm 9.12(s,1H),7.96-7.88(m,1H),7.40(d,J=2.5Hz,1H),7.37(t,J=9.0Hz,1H),7.24(s,1H), 6.83(s,1H),5.58(d,J=50.5Hz,1H),4.75-4.59(m,2H),4.57-4.47(m,2H),4.02-3.76(m,4H ),3.50-3.38(m,4H),2.77-2.51(m,2H),2.49-2.28(m,5H),2.25-1.98(m,3H),1.94-1.80(m ,4H),1.76-1.60(m,2H),1.60-1.45(m,2H),1.42-1.26(m,4H),1.11-0.96(m,6H).m / z,(ESI + ):787.3.

[0280] Synthesis of compound 49

[0281] The synthesis method of compound 49 refers to compound 48, using isobutyraldehyde as the raw material. 11 H NMR(500MHz,CD3OD)δppm 9.04(s,1H),7.89(dd,J=9.0,5.5Hz,1H),7.45-7.31(m,2H),7.23(s,1H),6.65(d,J=4.3Hz ,1H),5.34(d,J=54.0Hz,1H),4.79-4.62(m,2H),4.59-4.46(m,2H),4.38-4.22(m,2H),3.9 2-3.60(m,2H),3.40(d,J=8.0Hz,1H),3.32-3.18(m,3H),3.09-2.98(m,1H),2.48-2.09(m, 4H),2.09-1.99(m,4H),1.98-1.83(m,3H),1.77-1.60(m,2H),1.16-0.96(m,9H).m / z,(ESI + ):787.4.

[0282] Synthesis of compound 50

[0283] The synthesis method of compound 50 refers to compound 48, using isobutyraldehyde as the raw material. 1 H NMR (500 MHz, CD3OD) δ ppm 0.97(t,J=5.0Hz,3H),1.21-1.69(m,6H),1.66-1.72(m,3H),1.80-2.01(m,1 2H),2.13-2.37(m,5H),3.02-3.03(m,1H),3.22-3.38(m,3H),3.78(s,2H),4. 23-4.33(m,2H),4.47(s,2H),4.69(s,2H),5.26-5.37(m,1H),6.61-6.61(m,1 H),7.21(s,1H),7.31-7.35(s,2H),7.85-7.88(m,1H),9.02(s,1H).m / z,(ESI + ):827.4.

[0284] Synthesis of salt of compound 51

[0285]

[0286] DMF (13.3 mg, 0.18 mmol, 0.0008 eq) was added to a solution of compound 51-1 (5.8 g, 22.6 mmol, 1 eq) in thionyl chloride (50 mL). The reaction mixture was heated to 85°C and stirred at this temperature for 3 hours before being cooled to room temperature. The reaction mixture was concentrated to obtain the crude acid chloride.

[0287] Dihydroxyacetone (1.04 g, 11.56 mmol, 1 eq) was dissolved in dichloromethane (30 mL), pyridine (1.87 g, 23.7 mmol, 2.05 eq) was added, and finally the crude acid chloride was slowly added. The reaction solution was stirred at room temperature overnight, and then water and dichloromethane were added. The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (EA / PE = 0% to 25%) to give compound 51-2 (2.32 g, yield 35.41%).

[0288] Compound 51-2 (2.22 g, 3.92 mmol, 1 eq) was dispersed in a mixed solution of tetrahydrofuran (22 mL) and water (15 mL), which was then cooled to 0°C. Sodium borohydride (222 mg, 5.87 mol, 1.5 eq) was then added, and the reaction solution was stirred at 0°C for 2 minutes. The pH was adjusted to 7 with 0.5 N aqueous hydrochloric acid solution while maintaining the internal temperature at 0°C, and then extracted with dichloromethane. The separated organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the obtained residue was purified by column chromatography (EA / PE = 0% to 10%) to give compound 51-3 (1.02 g, yield 45.78%).

[0289] Triethylamine (80 mg, 0.79 mmol, 1.5 eq) was added to a solution of compound 51-3 (300 mg, 0.53 mmol, 1 eq) in dichloromethane (3 mL), followed by DMAP (6.44 mg, 0.05 mmol, 0.1 eq), and finally p-nitrophenyl chloroformate (127 mg, 0.63 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 5 hours, and the solvent was removed in vacuo. The residue was purified by column chromatography (EA / PE = 0% to 10%) to give compound 51-4 (123 mg, 31.78% yield).

[0290] Triethylamine (8.66 mg, 0.085 mmol, 1.5 eq) was added to a solution of compound 26-3 (40 mg, 0.057 mmol, 1 eq) in dichloromethane (4 mL), followed by DMAP (0.7 mg, 0.005 mmol, 0.1 eq), and finally compound 51-4 (50.28 mg, 0.068 mmol, 1.2 eq). The reaction solution was stirred at room temperature for 3 hours and then dried. The residue was purified by column chromatography (MeOH / DCM = 0% to 4%) to give a crude product of compound 51-5 (73 mg, 100% yield).

[0291] Trifluoroacetic acid (3 mL) was added to a solution of compound 51-5 (73 mg, 0.056 mmol, 1 eq) in dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 10 minutes and then concentrated in vacuo. The residue was purified by thin-layer chromatography to give the salt of compound 51 (15.6 mg, yield 16.48%). 1 H NMR(500MHz,CD3OD)δppm 0.87-0.91(m,6H),1.20-1.31(m,48H),1.58-1.66(m,4H),1.96-2.24(m,5H),2. 24-2.51(m,7H),2.51-2.74(m,2H),3.82-4.03(m,5H),4.16-4.46(m,4H),4.49-4 .59(m,2H),4.63-4.75(m,2H),5.21(s,1H),5.51(s,0.5H),5.62(s,0.5H),7.48 -7.55(m,1H),7.58(s,1H),8.02(s,1H),8.11-8.17(m,1H),9.14(s,1H).m / z(ESI + ):1196.0.

[0292] Synthesis of the salt of compound 52

[0293] The synthesis method of the salt of compound 52 refers to compound 51, using nonanoic acid as the raw material. 1H NMR(500MHz,CD3OD)δppm 9.18(s,1H),8.17(dd,J=9.0,5.5Hz,1H),8.06(d,J=2.0Hz,1H),7.61(s,1H),7.56(t,J=9.0Hz,1 H),5.62(d,J=51.5Hz,1H),5.29-5.21(m,1H),4.75(s,2H),4.57(d,J=10.0Hz,2H),4.40-4.28(m ,4H),4.14-3.81(m,5H),3.61-3.45(m,2H),2.84-2.57(m,2H),2.55-2.44(m,1H),2.40(t,J=6.6 Hz,6H),2.32-2.12(m,5H),1.74-1.61(m,4H),1.44-1.18(m,20H),0.87(t,J=6.0Hz,6H).m / z(ESI + ):999.5.

[0294] Synthesis of the salt of compound 53

[0295] The synthesis method of the salt of compound 53 refers to compound 51, using dodecanoic acid as the raw material. 1 H NMR(500MHz,CD3OD)δppm 0.86(t,J=5.0Hz,6H),1.23-1.36(m,32H),1.59-1.62(m,5H),2.08-2.15(m,6H),2 .35-2.43(m,8H),2.54-2.75(m,1H),3.45-3.48(m,2H),3.81-4.03(m,5H),4.27-4 .30(m,4H),4.52-4.55(m,2H),4.69(s,2H),5.21(s,1H),5.52-5.62(m,1H),7.51( t,J=5.0Hz,1H),7.58(s,1H),8.01(s,1H),8.11-8.14(m,1H),9.13(s,1H).m / z(ESI + ):1083.7.

[0296] Synthesis of the salt of compound 54

[0297] The synthesis method of the salt of compound 54 was similar to that of compound 51, using oleic acid as the starting material. 1H NMR(500MHz,CD3OD)δppm 0.89(t,J=5.0Hz,6H),1.21-1.27(m,40H),1.60-1.62(m,5H),1.97-2.16(m,13 H),2.36-2.73(m,10H),3.46-3.47(m,2H),3.86-4.05(m,5H),4.23-4.44(m,4H) ,4.53-55(m,2H),4.72(s,2H),5.20-5.41(m,5H),5.53-5.64(m,1H),7.52(t,J =5.0Hz,1H),7.58(s,1H),8.02(s,1H),8.11-8.14(m,1H),9.14(s,1H).m / z(ESI + ):1248.5.

[0298] Synthesis of the salt of compound 55

[0299] The synthesis method of the salt of compound 55 refers to compound 51, using butyric acid as the raw material. 1 H NMR (500 MHz, CD3OD) δ ppm 0.91-0.95(m,6H),1.61-1.66(m,4H),2.10-2.18(m,5H),2.31-2.73(m,10H ),3.46-3.50(m,2H),3.85-4.06(m,5H),4.24-4.30(m,4H),4.38-4.42(m,1 H),4.51-4.56(m,2H),4.72(s,2H),5.21-5.64(m,2H),7.52(t,J=5.0Hz,1H ),7.57(s,1H),8.01-8.02(m,1H),8.12-8.15(m,1H),9.14(s,1H).m / z(ESI + ):859.4.

[0300] Synthesis of the salt of compound 56

[0301] The synthesis method of the salt of compound 56 refers to compound 51, using decanoic acid as the starting material. 1H NMR (500 MHz, CD3OD) δ ppm 0.84(t,J=5.0Hz,6H),1.24-1.31(m,24H),1.59-1.62(m,4H),2.10-2.76(m,1 4H),3.47-3.48(m,2H),3.86-4.06(m,5H),4.28-4.30(m,4H),4.53-55(m,2H) ,4.72(s,2H),4.86-4.90(m,2H),5.21(s,1H),5.54-5.64(m,1H),7.52(t,J=5 .0Hz,1H),7.58(s,1H),8.02(s,1H),8.12-8.15(m,1H),9.14(s,1H).m / z(ESI + ):1027.5.

[0302] Synthesis of the salt of compound 57

[0303] The synthesis method of the salt of compound 57 was based on the method of compound 51, using undecanoic acid as the starting material. 1 H NMR(500MHz,CD3OD)δppm 0.85(t,J=5.0Hz,6H),1.21-1.29(m,28H),1.59-1.62(m,4H),2.10-2.18(m,6H),2 .35-2.47(m,8H),2.57-2.76(m,2H),3.46-3.48(m,2H),3.86-4.06(m,5H),4.28-4. 29(m,4H),4.52-4.55(m,2H),4.72(s,2H),5.21(s,1H),5.53-5.64(m,1H),7.52(t ,J=10.0Hz,1H),7.58(s,1H),8.02(s,1H),8.12-8.15(m,1H),9.14(s,1H).m / z(ESI + ):1055.5.

[0304] Synthesis of the salt of compound 58

[0305] The synthesis method of the salt of compound 58 refers to compound 51, using tetradecanoic acid as the raw material. 1H NMR(500MHz,CD3OD)δppm 0.88(t,J=7.0Hz,6H),1.21-1.29(m,40H),1.55-1.66(m,4H),2.09-2.16(m,5H),2.28-2. 48(m,7H),2.61-2.66(m,2H),3.47(d,J=9.0Hz,2H),3.84-3.99(m,5H),4.21-4.34(m,4H), 4.50-4.57(m,2H),4.71(s,4H),5.21(s,1H),5.53(s,1H),5.63(s,1H),7.52(t,J=9.0Hz, 1H),7.58(s,1H),8.02(d,J=2.0Hz,1H),8.13(dd,J=9.0,6.0Hz,1H),9.14(s,1H).m / z(ESI + ):1139.7.

[0306] Synthesis of the salt of compound 60

[0307] The synthesis method of the salt of compound 60 refers to compound 51, using tridecanoic acid as the raw material. 1 H NMR(500MHz,CD3OD)δppm 0.87(t,J=5.0Hz,6H),1.21-1.30(m,36H),1.58-1.62(m,4H),2.10-2.16(m,5H),2.35- 2.47(m,7H),2.57-2.76(m,2H),3.47-3.49(m,2H),3.86-4.06(m,5H),4.27-4.29(m,4H) ,4.52-4.55(m,2H),4.72(s,2H),4.85-4.92(m,2H),5.21(s,1H),5.54-5.64(m,1H),7. 52(t,J=10.0Hz,1H),7.58(s,1H),8.02(s,1H),8.12-8.15(m,1H),9.14(s,1H).m / z(ESI + ):1111.7.

[0308] Synthesis of compound 61

[0309]

[0310] 60% sodium hydride (116 mg, 2.9 mmol, 1.2 eq) was added to anhydrous tetrahydrofuran (10 mL) and cooled to 0°C under nitrogen. Compound 61-1 (300 mg, 2.42 mmol, 1 eq) was then added. After the bubbles in the reaction solution disappeared, the mixture was warmed to room temperature and stirred for 30 minutes, then cooled to 0°C. Pivaloyl chloride (320 mg, 2.66 mmol, 1.1 eq) was slowly added dropwise. The reaction solution was stirred at 0°C for 30 minutes, then warmed to room temperature and stirred at room temperature for 2 hours. The reaction was quenched with 10 mL of saturated sodium bicarbonate aqueous solution, followed by addition of water and ethyl acetate. The separated organic phase was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was spin-dried to obtain a residue, which was purified by column chromatography (EA / Hexane = 0% to 40%) to obtain compound 61-2 (381 mg, 75.7% yield).

[0311] Triethylamine (58.31 mg, 0.57 mmol, 1.2 eq) was added to a solution of compound 61-2 (100 mg, 0.48 mmol, 1 eq) in dichloromethane (2 mL), followed by the addition of p-nitrophenyl chloroformate (106.5 mg, 0.53 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for 6 hours and then concentrated. The residue was purified by column chromatography (EA / Hexane = 0% to 10%) to afford compound 61-3 (124 mg, 69.17% yield) as a colorless oil.

[0312] Triethylamine (9.42 mg, 0.093 mmol, 1.5 eq) was added to a solution of compound 1-5 (40 mg, 0.062 mmol, 1 eq) in dichloromethane (4 mL), followed by the addition of DMAP (0.758 mg, 0.006 mmol, 0.1 eq) and compound 61-3 (27.8 mg, 0.074 mmol, 1.2 eq). The reaction solution was heated to 40°C and stirred at this temperature for 3 hours. The reaction solution was cooled and concentrated, and the residue was purified by column chromatography (MeOH / DCM = 0% to 4%) to give a crude product of compound 61-4 (79 mg, 100% yield).

[0313] A 4M solution of dioxane hydrochloride (1 mL) was added to a solution of compound 61-4 (79 mg, 0.089 mmol, 1 eq) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 2 minutes and then concentrated in vacuo. The residue was purified by preparative chromatography to afford compound 61 (20.7 mg, 27.24% yield). 1H NMR(500MHz,CD3OD)δppm 1.35(s,9H),1.79-1.94(m,3H),1.95-2.05(m,4H),2.10-2.37(m,3H),2.97-3.05(m, 1H),3.14-3.29(m,3H),3.34-3.38(m,1H),3.76(s,2H),4.19-4.34(m,2H),4.50(s,2H ),4.66(s,2H),5.19-5.28(m,2.5H),5.36(s,0.5H),7.08(d,J=8.5Hz,2H),7.20(s,1 H),7.28-7.38(m,2H),7.48(d,J=8.5Hz,2H),7.82-7.91(m,1H),9.01(s,1H).m / z(ESI + ):835.4.

[0314] Synthesis of compound 62

[0315] The synthesis method of compound 62 refers to compound 61, using butyryl chloride as the raw material. 1 H NMR(500MHz,CD3OD)δppm 1.03(t,J=5.0Hz,3H),1.73-1.79(m,2H),1.83-1.92(m,4H),1.96-2.00(m,5H),2.12-2.3 6(m,3H),2.56(t,J=10.0Hz,2H),2.99-3.02(m,1H),3.17-3.24(m,3H),3.75(s,2H),4.22- 4.32(m,2H),4.50-4.65(m,4H),5.22(s,2H),5.25-5.36(m,1H),7.11(d,J=10Hz,2H),7.20 (s,1H),7.30-7.35(m,2H),7.47(d,J=5.0Hz,2H),7.84-7.87(m,1H),9.00(s,1H).m / z(ESI + ):821.6.

[0316] Synthesis of compound 63

[0317] The synthesis method of compound 63 refers to compound 61, using acetyl chloride as the raw material. 1H NMR(500MHz,CD3OD)δppm 1.85-2.01(m,8H),2.15-2.23(m,2H),2.27(s,3H),3.02-3.03(m,5H),3.76(s,1H),4.26-4.32(m,1H),4.51-4.59(m,7H),5.22(s,2H) ,5.26-5.37(m,2H),7.12-7.13(d,J=5.0Hz,2H),7.20(s,1H),7.31-7.35(m,2H),7.47-7.48(m,2H),7.86(s,1H),9.01(s,1H).m / z(ESI + ):793.59.

[0318] Synthesis of compound 64

[0319] The synthesis method of compound 64 refers to compound 61, using decanoyl chloride as the starting material. 1 H NMR(500MHz,CD3OD)δppm 0.90(t,J=10.0Hz,3H),1.31-1.42(m,14H),1.69-2.00(m,9H),2.12-2.33(m,3H),2.57(t,J=5.0 Hz,2H),3.01-3.03(m,1H),3.20-3.24(m,2H),3.33(t,J=10.0Hz,1H),3.75(s,2H),4.22-4.32(m ,2H),4.50-4.65(m,4H),5.22(s,2H),5.25-5.36(m,1H),7.10(d,J=5.0Hz,2H),7.20(s,1H),7.3 2(d,J=10.0Hz,1H),7.35(s,1H),7.47(d,J=5.0Hz,2H),7.85(q,J=5Hz,1H),9.00(s,1H).m / z(ESI + ):905.7.

[0320] Synthesis of compound 65

[0321] The synthesis method of compound 65 was based on compound 61, using isovaleryl chloride as the starting material. 1H NMR(500MHz,CD3OD)δppm 1.05(d,J=5.0Hz,7H),1.82(d,J=10.0Hz,2H),2.02(s,2H),2.16-2.21(m,2H),2.32-2.35(m,2H ),2.45(m,J=5.0Hz,2H),2.55-2.74(m,2H),3.44-3.50(m,1H),3.75-4.05(m,5H),4.52(s,2H), 4.62-4.71(m,4H),5.23(s,2H),5.52-5.62(m,1H),7.10(d,J=5.0Hz,2H),7.21(s,1H),7.34(d, J=10.0Hz,1H),7.37(s,1H),7.48(d,J=10.0Hz,2H),7.88(q,J=5.0Hz,1H),9.09(s,1H).m / z(ESI + ):835.7.

[0322] Synthesis of compound 66

[0323] The synthesis method of compound 66 refers to compound 61, using 2-propylpentanoyl chloride as the raw material. 1 H NMR(500MHz,CD3OD)δppm 0.97(t,J=10.0Hz,6H),1.41-1.46(m,4H),1.53-1.58(m,2H),1.68-1.75(m,2H),1.82-1.8 9(m,3H),1.99-2.35(m,7H),2.63(t,J=5.0Hz,1H),3.17-3.36(m,4H),3.75(s,2H),4.22-4. 31(m,2H),4.49-4.64(m,4H),5.22(s,2H),5.25-5.36(m,1H),7.07(d,J=10.0Hz,2H),7.20 (s,1H),7.30-7.34(m,2H),7.48(d,J=10.0Hz,2H),7.83-7.86(m,1H),9.00(s,1H).m / z(ESI + ):877.5.

[0324] Synthesis of compound 67

[0325] The synthesis method of compound 67 was based on compound 61, using valeryl chloride as the starting material. 1H NMR(500MHz,CD3OD)δppm 0.97(t,J=5.0Hz,3H),1.42-1.48(m,2H),1.67-1.70(m,2H),1.83-1.99(m,7H),2.11-2.22 (m,3H),2.58(t,J=5.0Hz,2H),2.99-3.02(m,1H),3.19-3.36(m,4H),3.75(s,2H),4.21-4. 28(m,2H),4.49-4.63(m,4H),5.22(s,2H),5.25-5.35(m,1H),7.10(d,J=10.0Hz,2H),7.20 (s,1H),7.30-7.35(m,2H),7.47(d,J=10.0Hz,2H),7.84-7.86(m,1H),9.00(s,1H).m / z(ESI + ):835.4.

[0326] Synthesis of compound 68

[0327] The synthesis method of compound 68 refers to compound 61, using cyclopentylacetyl chloride as the raw material. 1 H NMR(500MHz,CD3OD)δppm 1.25-1.29(m,2H),1.60-1.70(m,4H),1.82-2.03(m,9H),2.11-2.35(m,4H),2.57(d, J=5.0Hz,2H),2.99-3.02(m,1H),3.20-3.36(m,4H),3.74(s,2H),4.21-4.31(m,2H),4 .49-4.64(m,4H),5.22(s,2H),5.24-5.35(m,1H),7.10(d,J=10.0Hz,2H),7.20(s,1H ),7.30-7.34(m,2H),7.47(d,J=10.0Hz,2H),7.84-7.87(m,1H),8.99(s,1H).m / z(ESI + ):861.5.

[0328] Synthesis of compound 69

[0329] The synthesis method of compound 69 refers to compound 61, using cyclopentylpropionyl chloride as the raw material. 1H NMR(500MHz,CD3OD)δppm 1.17-1.18(m,2H),1.58-1.76(m,6H),1.84-2.00(m,10H),2.14-2.36(m,3H),2.59(t ,J=5.0Hz,2H),3.01-3.02(m,1H),3.17-3.36(m,4H),3.75(s,2H),4.22-4.32(m,2H), 4.50-4.66(m,4H),5.22(s,2H),5.25-5.36(m,1H),7.11(d,J=10.0Hz,2H),7.20(s,1H ),7.31-7.35(m,2H),7.48(d,J=10.0Hz,2H),7.85-7.88(m,1H),9.00(s,1H).m / z(ESI + ):875.5.

[0330] Synthesis of compound 70

[0331] The synthesis method of compound 70 refers to compound 61, using 2-hexyldecanoyl chloride as the raw material. 1 H NMR(500MHz,CD3OD)δppm 0.89(t,J=5.0Hz,6H),1.32-1.39(m,20H),1.58-1.60(m,2H),1.70-1.73(m,2H),1.82-1.8 9(m,3H),1.99-2.32(m,7H),2.58-2.60(m,1H),3.01-3.02(m,1H),3.19-3.35(m,4H),3.75( s,2H),4.22-4.31(m,2H),4.49-4.64(m,4H),5.23-5.36(m,3H),7.06(d,J=5.0Hz,2H),7.2 0(s,1H),7.30-7.34(m,2H),7.49(d,J=5.0Hz,2H),7.84-7.87(m,1H),9.00(s,1H).m / z(ESI + ):989.5.

[0332] Synthesis of compound 71

[0333] The synthesis method of compound 71 refers to compound 61, using dodecanoyl chloride as the starting material. 1H NMR(500MHz,CD3OD)δppm 0.87-0.93(m,3H),1.28-1.44(m,16H),1.67-1.76(m,2H),1.81-2.05(m,7H),2.11-2.37(m,3H),2.54 -2.60(m,2H),2.98-3.06(m,1H),3.13-3.29(m,3H),3.35(d,J=8.5Hz,1H),3.75(s,2H),4.19-4.34(m ,2H),4.44-4.54(m,2H),4.58-4.73(m,2H),5.22(s,2H),5.26(s,0.5H),5.37(s,1H),7.10(d,J=8.5H z,2H),7.20(s,1H),7.28-7.37(m,2H),7.48(d,J=8.5Hz,2H),7.83-7.89(m,1H),9.00(s,1H).m / z(ESI + ):933.5

[0334] Synthesis of compound 72

[0335] The synthesis method of compound 72 was based on compound 61, using hexadecanoyl chloride as the starting material. 1 H NMR(500MHz,CD3OD)δppm 0.85-0.93(m,3H),1.28-1.44(m,24H),1.66-1.77(m,2H),1.81-2.06(m,7H),2.11-2.40(m,3H),2.58( t,J=7.5Hz,2H),3.00-3.09(m,1H),3.13-3.29(m,3H),3.36(d,J=8.5Hz,1H),3.70-3.82(m,2H),4.20- 4.37(m,2H),4.45-4.55(m,2H),4.58-4.73(m,2H),5.18-5.29(m,2.5H),5.38(s,0.5H),7.11(d,J=8.5 Hz,2H),7.20(s,1H),7.29-7.38(m,2H),7.48(d,J=8.5Hz,2H),7.84-7.90(m,1H),9.01(s,1H).m / z(ESI + ):989.5

[0336] Synthesis of compound 73

[0337] The synthesis method of compound 73 was based on compound 61, using tetradecanoyl chloride as the starting material. 1H NMR(500MHz,DMSO-d6)δppm 10.18(s,1H),9.05(s,1H),7.99-7.81(m,1H),7.48-7.50(m,3H),7.42(s,1H),7.19(s,1H ),7.14-7.16(m,2H),5.27-5.38(m,1H),5.19(s,1H),4.60-4.61(m,1H),4.45(s,3H),4.20 -3.89(m,2H),3.78-3.63(m,2H),3.14(m,3H),2.89(s,1H),2.57-2.60(m,2H),2.12(m,3H) ,1.80-1.89(m,7H),1.63-1.64(m,2H),1.32(s,2H),1.29(s,20H),0.85-0.87(m,3H).(ESI + ):961.5.

[0338] Synthesis of compound 74

[0339] Triethylamine (10.41 mg, 0.102 mmol, 1.5 eq) was added to a solution of compound 69 (60 mg, 0.068 mmol, 1 eq) in dichloromethane (6 mL), followed by the addition of DMAP (0.84 mg, 0.007 mmol, 0.1 eq) and pivaloyl chloride (9.92 mg, 0.082 mmol, 1.2 eq). The reaction solution was stirred at room temperature for 1.5 hours, followed by the addition of dichloromethane and water. The separated organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was spin-dried, and the residue was purified by column chromatography (MeOH / DCM = 0% to 4%) to afford compound 74 (44 mg, 65.5% yield). 1H NMR(500MHz,CD3OD)δppm 9.05(s,1H),8.11(dd,J=9.0,5.5Hz,1H),7.89(d,J=2.5Hz,1H),7.55-7.47(m,3H),7.45(s,1H),7.13 (d,J=8.5Hz,2H),5.37(d,J=53.5Hz,1H),5.25(s,2H),4.84-4.58(m,2H),4.58-4.45(m,2H),4.43-4.2 6(m,2H),3.86-3.70(m,2H),3.50(d,J=8.0Hz,1H),3.17-3.03(m,1H),2.62(t,J=7.6Hz,2H),2.43-2. 15(m,3H),2.15-1.81(m,10H),1.81-1.54(m,6H),1.46-1.40(m,9H),1.19(d,J=11.0Hz,2H).m / z,(ESI + ):959.3.

[0340] Synthesis of compound 75

[0341] The synthesis method of compound 75 refers to compound 74, using compound 61 as the starting material. 1 H NMR(500MHz,CD3OD)δppm 9.07(s,1H),8.12(dd,J=9.1,5.7Hz,1H),7.89(d,J=2.2Hz,1H),7.55-7.48(m,3H),7.45(s ,1H),7.11(d,J=8.4Hz,2H),5.42(d,J=52.9Hz,1H),5.25(s,2H),4.78-4.61(m,2H),4.58- 4.36(m,4H),3.88-3.69(m,2H),3.64-3.41(m,4H),3.26-3.14(m,1H),2.56-2.22(m,3H),2 .20-2.09(m,2H),2.09-1.95(m,3H),1.93-1.78(m,2H),1.42(s,9H),1.38(s,9H).m / z(ESI + ):919.48.

[0342] Synthesis of compound 76

[0343] The synthesis method of compound 76 refers to compound 74, using compound 1 as the raw material, and the intermediates used refer to the synthesis of compound 51-4. 1H NMR(500MHz,CD3OD)δppm 0.80-0.88(m,6H),0.93-1.01(m,3H),1.20-1.36(m,20H),1.50-1.70(m,9H),1.82-2.08(m,7H) ,2.09-2.40(m,9H),2.99-3.07(m,1H),3.15-3.27(m,3H),3.51(d,J=7.0Hz,1H),3.68-3.84(m, 2H),4.18-4.35(m,4H),4.43-4.56(m,4H),4.59-4.76(m,2H),5.16-5.28(m,1.5H),5.37(s,0.5 H),6.81-6.90(m,1H),7.47-7.58(m,2H),8.00(s,1H),8.09-8.15(m,1H),9.05(s,1H).m / z(ESI + ):1157.6.

[0344] Synthesis of compound 77

[0345] The synthesis method of compound 77 refers to compound 76, using compound 3 as the starting material. 1 H NMR(500MHz,CD3OD)δppm 9.07(s,1H),8.12(dd,J=9.1,5.4Hz,1H),8.01(s,1H),7.59(d,J=2.3Hz,1H),7.52(t,J=8.8Hz,1H),6.92-6.81 (m,1H),5.34(d,J=54.4Hz,1H),5.27-5.22(m,1H),4.79-4.59(m,2H),4.58-4.42(m,4H),4.39-4.23(m,4H),3.9 4-3.65(m,2H),3.52(d,J=5.9Hz,1H),3.33-3.17(m,3H),3.11-2.99(m,1H),2.42-2.33(m,4H),2.32-2.14(m,3 H),2.14-1.98(m,7H),1.97-1.81(m,3H),1.69-1.52(m,7H),1.34-1.19(m,20H),0.86(t,J=5.2Hz,6H).m / z(ESI + ):1129.4.

[0346] The synthesis methods of other compounds are similar to those shown above and are identified by NMR and mass spectrometry. The obtained NMR and mass spectrometry data are shown in Table 3.

[0347] Table 3

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361] Biological assays

[0362] Experimental Example 1. Pharmacokinetic Experiment

[0363] Mouse experiments

[0364] A total of 126 male ICR mice weighing 30-34 g were randomly divided into 42 groups (oral and intravenous administration), with 3 mice per group. Blood samples were collected at 0.167, 0.5, 1, 2, 4, 6, 8, and 24 hours after oral administration and at 0.083, 0.25, 0.5, 1, 2, 4, 6, and 8 hours after intravenous administration. The test compounds were prepared in 5% DMSO, 5% Solutol, and 90% 20% SBE-β-CD.

[0365] After fasting for 12 hours, each compound was administered intravenously or orally via the tail vein of mice at a dose equivalent to 3 mg / kg for intravenous injection and 10 mg / kg for oral administration of Compound A1. Following administration, blood was collected at pre-set time points (approximately 50 μL / mouse). 20 μL of whole blood was quantitatively drawn into an EP tube pre-filled with 200 μL of acetonitrile containing the internal standard. The supernatant was collected after centrifugation at 12,000 rpm for 5 minutes at 4°C and stored at low temperature. The supernatant was analyzed by LC-MS / MS to determine the levels of the corresponding drug and metabolites in plasma.

[0366] Tables 4 and 5 show the AUC (area under the mean plasma concentration-time curve) data of different compounds after oral or intravenous administration.

[0367] Figures 1 to 4 The drug-dose time curves of A1 after administration of different compounds are shown in FIG.

[0368] Table 4 Average blood concentration-time area under the curve of compound A1 and the compounds of the present invention after oral administration of equimolar doses to ICR mice

[0369]

[0370]

[0371] As can be seen from Table 4, when the compounds provided by the present application are orally administered, the AUC of A1 in the plasma after the compounds enter the body is much higher than the AUC of A1 in the plasma when A1 (control compound) is directly orally administered; among them, after oral administration of compound 10, the AUC of A1 in the plasma increased to more than 8.5 times that of oral administration of A1, greatly improving the oral bioavailability of A1.

[0372] Table 5 Average blood concentration-time area under the curve of compound A1 and the compounds of the present invention after intravenous injection of equimolar doses into ICR mice

[0373]

[0374]

[0375] As can be seen from Table 5, after intravenous injection of the compounds provided by the present application, the AUC of A1 in plasma is higher than that of the control compound A1. Among them, the drug exposure of compounds 36, 39, 52, 53, and 56 is increased by more than 50% relative to the compounds, and compound 36 shows an advantage of nearly 4 times.

[0376] Figure 1 The drug-time curves of compound 1 and compound 61 of the present invention and positive control A1 when administered orally are shown.

[0377] Figure 2 The drug-time curves of compound 4, compound 17 and compound 69 of the present invention and the positive control A1 when orally administered are shown.

[0378] Figure 3 The graph shows the drug-time curves of compound 32, compound 39 and compound 52 of the present invention compared with the positive control A1 when administered by intravenous injection.

[0379] Figure 4 The graph shows the drug-time curves of Compound 55 and Compound 56 of the present invention compared with the positive control A1 when administered by intravenous injection.

[0380] Experimental Example 2. Tumor Proliferation Inhibition Experiment in AsPC-1 Mouse Model

[0381] (1) Study on the inhibitory effect of oral administration on tumor growth in mice

[0382] AsPC-1 human pancreatic cancer cells 5x10 6 Suspended in 0.1 mL PBS, implanted into 6-8 week old Balb / C6-8 nude mice, 13 animals were randomly divided into vehicle control group (4), compound A1 administration group (4) and compound 1 administration group (5) on the 11th day. Oral administration was performed twice a day with 100 mg / kg compound A1 and 126 mg / kg compound 1. The compound administration method and results are shown in Table 6. The long and short diameters of the tumor were measured with a vernier caliper twice a week, and the tumor volume was calculated (TV = (long diameter x short diameter x short diameter) / 2). The inhibition of tumor growth was evaluated by the tumor (volume) inhibition rate TGI. TGI = [1-(V t -V0(experimental group)) / (V t -V0 (vehicle control group))] x 100%.

[0383] As shown in Table 6, oral administration of 126 mg / kg Compound 1 for 16 days significantly inhibited tumor growth relative to the vehicle control group (P = 0.0146, TGI of 53.95%). Oral administration of 100 mg / kg Compound A1 for 12 days had no inhibitory effect on tumor growth relative to the vehicle control group, with A1's tumor inhibition TGI being only 9.07%. Furthermore, the inhibitory effect of Compound 1 on tumor growth was significantly different (P = 0.003). Neither treatment had an effect on the body weight of the animals.

[0384] Table 6 Administration and dosage of compounds

[0385]

[0386] Note: TGI = [1-(V t-V0(experimental group)) / (V t -V0 (vehicle control group))]×100%; P "mean ± SEM", P < 0.05 indicates a significant difference.

[0387] Figure 5 Graph 2 shows the comparative results of tumor growth inhibition effects in mice after oral administration of compound 1, positive control compound A1 and blank control.

[0388] (2) Study on the inhibitory effect of non-oral administration on tumor growth in mice

[0389] AsPC-1 human pancreatic cancer cells 5x10 6 Suspended in 0.1 mL PBS, the cells were implanted into 6-8 week old Balb / C6-8 nude mice. On the 11th day, 24 animals were randomly assigned to a vehicle control group (5 animals), a compound A1 intraperitoneal administration group (5 animals), a compound A1 tail vein administration group (3 animals), a compound 52 intraperitoneal administration group (5 animals) and a compound 52 tail vein administration group (6 animals). All administration groups were administered with an equimolar dose (Compound A1, 6 mg / kg), once a day for 27 consecutive days. The compound administration method and results are shown in Table 7. The long and short diameters of the tumor were measured with a vernier caliper twice a week, and the tumor volume was calculated (TV = (long diameter x short diameter x short diameter) / 2). The inhibition of tumor growth was evaluated by the tumor (volume) inhibition rate TGI.

[0390] TGI=[1-(V t -V0(experimental group)) / (V t -V0 (vehicle control group))]*100%.

[0391] Compared with the vehicle control group, all drug treatment groups had a certain inhibitory effect on tumor growth.

[0392] After 27 days of intraperitoneal administration of 6 mg / kg compound A1, the tumor growth inhibition rate TGI was 37.27%, P=0.018.

[0393] After 27 days of intraperitoneal administration of 13.44 mg / kg of compound 52, the tumor growth inhibition rate TGI was 36.12%, P=0.0047.

[0394] All mice died within 1 day after administration of 6 mg / kg compound A1 into the tail vein.

[0395] After 27 days of tail vein administration of 13.44 mg / kg of compound 52, the tumor growth inhibition rate (TGI) was 47.22%, P = 0.027. The results showed that the body weight of all test animals remained stable throughout the experiment.

[0396] Table 7: Administration and efficacy of compounds

[0397]

[0398] Note: Animal D died; TGI = [1-(V t -V0(experimental group)) / (V t -V0 (vehicle control group))] x 100%; *P < 0.05, **P < 0.01, ***P < 0.001.

[0399] Figure 6 The results of the comparison of tumor growth inhibition effects in mice after intraperitoneal administration of compound 52, intravenous administration of compound 52, intraperitoneal administration of positive control compound A1, intravenous administration of control compound A1 and vehicle control are shown in FIG. The compounds disclosed in this application have good KRAS G12D The inhibitory effect can be used to prepare a method for treating, inhibiting or preventing KRAS G12D Drugs for mutation-related diseases.

[0400] Experimental Example 3. Tumor Proliferation Inhibition Experiment in GP2D Mouse Model

[0401] (1) Study on the inhibitory effect of intraperitoneal administration (ip) on tumor growth in mice

[0402] GP2D human colon cancer cells 5x10 6 Suspended in 0.1 mL PBS, implanted into 6-8 week old Balb / C6-8 nude mice on the 11th day, 24 animals were randomly assigned to a vehicle control group (6), a compound A1 administration group (6), a compound 52 administration group (6) and a compound 53 administration group (6). 18 mg / kg of compound A1 was used for intraperitoneal administration once a day. The compound administration method and results are shown in Table 6. The long and short diameters of the tumor were measured with a vernier caliper twice a week, and the tumor volume was calculated (TV = (long diameter x short diameter x short diameter) / 2). The inhibition of tumor growth was evaluated by the tumor (volume) inhibition rate TGI. The specific results are shown in Table 8.

[0403] (2) Study on the inhibitory effect of (i) on tumor growth in mice after tail vein administration

[0404] GP2D human colon cancer cells 5x10 6Suspended in 0.1 mL PBS, the mixture was implanted into 6-8 week old Balb / C6-8 nude mice. On the 11th day, 24 animals were randomly divided into the compound A1 administration group (6 animals), the compound 52 administration group (18 mpk) (6 animals), the compound 52 administration group (12 mpk) (6 animals) and the compound 53 administration group (6 animals). Compound A1 was administered via the tail vein at a dose of 18 mg / kg once a day. The compound 52 administration group (18 mpk) was administered via the tail vein at a dose of 18 mg / kg A1 molar equivalent (actually measured 40.3 mpk) once a day. The compound 52 administration group (12 mpk) was administered via the tail vein at a dose of 12 mg / kg A1 molar equivalent (actually measured 27 mpk) once every three days. The compound 53 administration group was administered via the tail vein at a dose of 18 mg / kg A1 molar equivalent (actually measured 43 mpk) once every three days. TGI = [1-(V t -V0(experimental group)) / (V t -V0 (vehicle control group))] x 100%. Specific results are shown in Table 8.

[0405] Table 8: Administration and efficacy of compounds

[0406]

[0407] Note: qd, once a day; q.3d, once every 3 days.

[0408] It can be seen from Table 8 that the compounds provided by the present application have better tumor treatment effects when administered intraperitoneally at the same equivalent. When administered through the tail vein, it can still have a good therapeutic effect at a higher concentration. Among them, when compound 52 was administered through the tail vein at a dosage of 40.3 mg / kg (18 mg / kg of compound A1 molar equivalent), more than half of the mice died within 3 days. The dosage was adjusted to 27 mg / kg (12 mg / kg of compound A1 molar equivalent), and the drug was administered once every three days. The mice had no abnormalities and had a better therapeutic effect. When compound 53 was administered at a dosage of 43 mg / kg (18 mg / kg of compound A1 molar equivalent), the mice still had no abnormalities and had a relatively better therapeutic effect. The compounds disclosed in the present application have better KRAS G12D The inhibitory effect can be used to prepare a method for treating, inhibiting or preventing KRAS G12D Drugs for mutation-related diseases.

[0409] Although the present invention has been described in detail with reference to the embodiments of the present invention, these embodiments are provided to illustrate rather than limit the present invention. Other embodiments that can be obtained according to the principles of the present invention all fall within the scope defined by the claims of the present invention.

Claims

1. A compound selected from the following or a pharmaceutically acceptable salt thereof:

2. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 2, wherein At least one pharmaceutically acceptable excipient is also included.

4. The pharmaceutical composition according to claim 2, wherein At least one pharmaceutically acceptable carrier is also included.

5. The pharmaceutical composition according to claim 2, wherein At least one pharmaceutically acceptable diluent is also included.

6. The pharmaceutical composition according to claim 3, wherein The pharmaceutically acceptable excipients include one or more of a binder, a filler, a disintegrant, a lubricant and a glidant.

7. The pharmaceutical composition according to claim 4, wherein The pharmaceutically acceptable carrier includes a cream.

8. The pharmaceutical composition according to claim 4, wherein The pharmaceutically acceptable carrier includes one or more of emulsions, gels, liposomes and nanoparticles.

9. The pharmaceutical composition according to any one of claims 2 to 8, characterized in that The composition is suitable for oral administration or injection administration.

10. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to any one of claims 2 to 9 in the preparation of a medicament for treating, preventing or inhibiting a hyperproliferative disorder, wherein: The hyperproliferative disorder is KRAS G12D Mutation-related malignancies.

11. The use according to claim 10, wherein The malignant tumor is selected from: angiosarcoma, liposarcoma and teratoma; one or more of gastric cancer, liver cancer and colorectal adenocarcinoma.

12. The use according to claim 10, wherein The malignant tumor is selected from the group consisting of: bronchial squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, lung adenocarcinoma, alveolar carcinoma, bronchial adenoma, lung sarcoma, lung lymphoma, lung chondroma, lung mesothelioma; esophageal squamous cell carcinoma, esophageal adenocarcinoma, esophageal leiomyoma, esophageal lymphoma, gastric lymphoma, gastric leiomyoma, pancreatic ductal adenocarcinoma, insulinoma, pancreatic gastrinoma, pancreatic carcinoid tumor, pancreatic vasodilator peptide tumor, small intestinal adenocarcinoma, small intestinal lymphoma , small intestinal carcinoid tumor, small intestinal Kaposi's sarcoma, small intestinal hemangioma, large intestinal tubular adenoma, large intestinal chorioadenoma; renal adenocarcinoma, Wilms tumor, renal lymphoma, bladder and urethra squamous cell carcinoma, bladder and urethra transitional cell carcinoma, bladder and urethra adenocarcinoma, prostate adenocarcinoma, prostate sarcoma, seminoma, testicular teratoma, testicular embryonal carcinoma, testicular choriocarcinoma, testicular Leydig cell carcinoma, testicular fibroadenoma, testicular adenoid tumor; hepatocellular adenoma, hepatic hemangioma; Gallbladder cancer, bile duct cancer; osteosarcoma, fibrosarcoma of bone, malignant fibrous histiocytoma of bone, chondrosarcoma, Ewing's sarcoma, malignant lymphoma of bone, multiple myeloma, giant cell tumor of bone; skull osteoma, skull hemangioma, meningioma, glioma, retinoblastoma, spinal neurofibroma; endometrial cancer, mucinous bladder cancer, granulosa cell tumor of the uterus, uterine serotonin-stromal cell tumor, uterine malignant teratoma, vulvar squamous cell carcinoma, vulvar intraepithelial carcinoma, vulvar adenocarcinoma, vulvar fibrosarcoma, vulvar melanoma, vaginal clear cell carcinoma, vaginal squamous cell carcinoma, vaginal uveal sarcoma, fallopian tube cancer; acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma; One or more of the following: malignant melanoma of the skin, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, Kaposi's sarcoma of the skin, hemangioma of the skin; neuroblastoma of the adrenal gland.

13. The use according to claim 10, characterized in that The malignant tumor is selected from one or more of hepatocellular carcinoma, hepatic angiosarcoma, astrocytoma, medulloblastoma, glioblastoma or oligodendroglioma.

14. The use according to claim 10, characterized in that The malignant tumor is one or more of non-small cell lung cancer, small cell lung cancer, pancreatic cancer, colorectal cancer, bile duct cancer, cervical cancer, bladder cancer, liver cancer or breast cancer.

15. Kit for the preparation of a method for treating, inhibiting or preventing KRAS G12D Use in a drug for a disease associated with a mutation, wherein The kit comprises the compound or pharmaceutically acceptable salt according to claim 1 , or the pharmaceutical composition according to any one of claims 2 to 9 .

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