Modulators for promoting binding of lactolipoprotein 3A1 / 2A1

Abstract

Compounds of formula (I), or pharmaceutically acceptable salts, enantiomers, diastereoisomers, solvates, hydrates, polymorphs or isotopic variants thereof, can promote the binding of lactolipoproteins 3A1 / 2A1, where the definitions of the groups are as detailed in the description and claims, or pharmaceutically acceptable salts, enantiomers, diastereoisomers, solvates, hydrates, polymorphs or isotopic variants thereof. The invention also relates to pharmaceutical compositions containing the compounds of formula (I) and their use in clinical therapy. # imgabs0 #

Description

Modulators that promote butyrophilin 3A1 / 2A1 binding Technical Field

[0001] The present invention relates to a small molecule regulator, which promotes the binding of butyrophilin 3A1 (BTN3A1) and butyrophilin 2A1 (BTN2A1) in vivo, thereby exerting their biological functions, including applications in tumor treatment and infectious disease treatment. Background Art

[0002] Butyrophilin (BTN) is a class of transmembrane proteins that generally exert their specific biological functions by forming heteropolymers. Both butyrophilin 3A1 (BTN3A1) and butyrophilin 2A1 (BTN2A1) proteins consist of two extracellular domains (IgV and IgC), a transmembrane domain (TM), a proximal coiled-coil domain (JM), and an intracellular B30.2 domain. The intracellular B30.2 domain of BTN2A1 shares 50% homology with that of BTN3A1. However, in the intracellular B30.2 domain of BTN3A1 and its ligand-binding pocket, BTN2A1 lacks key basic amino acid residues. Therefore, only when the B30.2 domains of the two bind will the target cells be recognized by immune cells such as αβT cells and γδT cells.

[0003] For example, Vγ9Vδ2T cells are a common subtype of γδT cells, an important type of immune cell, and an important bridge between innate immunity and adaptive immunity. After activation, they can kill tumor cells and various pathogens, playing an important role in anti-infection and anti-tumor fields. Although BTN3A1 plays an important role in identifying and activating Vγ9Vδ2T cells, small molecules that bind to BTN3A1 alone do not have biological functions. Only when the small molecule can promote the binding of BTN3A1 to the intracellular segment of BTN2A1 can Vγ9Vδ2T cells be activated.

[0004] HMBPP is a naturally occurring small molecule produced within cells after pathogen infection. Its activity in activating BTN3A1 / BTN2A1 is over a thousand times greater than that of endogenous molecules such as IPP and DMAPP. Under physiological conditions, HMBPP carries two negative charges, making it difficult to enter cells on its own. Its activity is weak under short-term incubation (2-hour pulse stimulation), and its plasma stability is poor, making its druggability difficult. While C-HMBPP exhibits improved activity compared to HMBPP, its short-term stimulatory activity remains weak.

[0005] Patents WO2020008189 and WO2019182904 provide some new molecules. Apart from in vitro activity data, the in vivo activity of these molecules and subsequent clinical information have not yet been disclosed.

[0006] This patent describes a small molecule compound that can effectively promote the binding of the intracellular B30.2 domain of BTN3A1-BTN2A1, and its application in disease treatment. The molecule has high activity and good drugability.

[0007] Summary of the Invention

[0008] The present invention uses size exclusion chromatography-light scattering (SEC-MALS) and sedimentation velocity analytical ultracentrifugation (SV-AUC) tests to demonstrate that the BTN3A1B30.2 domain and the BTN2A1B30.2 domain do not bind in the absence of a modulator. Furthermore, the addition of a small molecule that only binds to the BTN3A1B30.2 domain does not lead to Vγ9Vδ2 T cell activation. However, only when a small molecule (such as those disclosed herein) can the B30.2 domains of the two proteins adhere together can Vγ9Vδ2 T cell activation be promoted.

[0009] The compounds provided herein have the ability to promote 3A1-2A1 binding, activating Vγ9Vδ2 T cells. Furthermore, some compounds provided herein have good stability, low clearance, and low plasma protein binding, which facilitates the generation of more free active drug in the blood. Furthermore, some compounds provided herein also possess excellent cytotoxic activity, extended human liver microsome stability, and low plasma protein binding, all of which combine to create a comprehensive set of properties suitable for drug development.

[0010] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variation thereof:

[0011] in,

[0012] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0013] R a Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl;

[0014] m = 1, 2, 3, 4, or 5;

[0015] X is O or CRR';

[0016] R1 is selected from H, F, Cl, CN or methyl, wherein methyl is optionally substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2;

[0017] R2 is selected from C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Halogenated alkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl, C 0-6 Alkylene-4-12 membered heterocyclic group or C 0-6 Alkylene-5-10 membered heteroaryl, wherein the C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Halogenated alkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl, C 0-6 Alkylene-4-12 membered heterocyclic group or C 0-6 Alkylene-5-10 membered heteroaryl is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Haloalkyl, -C(O)-C 2-6 Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10 membered cycloalkyl, -C(O)-4-10 membered heterocycloalkyl, -C(O)-C 6-10 aryl, -C(O)-5-10 membered heteroaryl, -CN and oxo substituents;

[0018] R3 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0019] in,

[0020] R and R' are independently selected from H or halogen;

[0021] R" is independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0022] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variation thereof:

[0023] in,

[0024] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0025] R a Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl.

[0026] m = 1, 2, 3, 4, or 5;

[0027] X is O or CRR';

[0028] R1 is selected from H, F, Cl, CN or methyl, wherein methyl is optionally substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2;

[0029] R2 is selected from C 5-6 Alkyl, C 5-6 Halogenated alkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-7 Cycloalkyl, C 0-6 Alkylene-4-7 membered heterocyclic group, C 0-6 Alkylene-C 6-10 Aryl or C 0-6 Alkylene-5-10 membered heteroaryl;

[0030] R3 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0031] in,

[0032] R and R' are independently selected from H or halogen;

[0033] R" is independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0034] In another aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variation thereof:

[0035] in,

[0036] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0037] R a Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl.

[0038] m = 1, 2, 3, 4, or 5;

[0039] X is O or CRR';

[0040] R1 is selected from H, F, Cl, CN or methyl, wherein methyl is substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2;

[0041] R2 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkylene-C 3-7 Cycloalkyl, C 0-6 Alkylene-3-7 membered heterocyclic group, C 0-6 Alkylene-C 6-10 Aryl or C 0-6 Alkylene-5-10 membered heteroaryl;

[0042] R3 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0043] in,

[0044] R and R' are independently selected from H or halogen;

[0045] R" is independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0046] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, and a pharmaceutically acceptable excipient.

[0047] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof and a pharmaceutically acceptable excipient, which further contains another therapeutic agent.

[0048] In another aspect, the present invention provides a kit comprising a compound of the present invention, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, and other therapeutic agents and a pharmaceutically acceptable carrier, adjuvant or vehicle.

[0049] In another aspect, the present invention provides use of a compound of the present invention, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, in the preparation of a medicament for treating and / or preventing a proliferative disease.

[0050] In another aspect, the present invention provides a method for treating and / or preventing a proliferative disease in a subject, comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, or a composition of the present invention.

[0051] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, or a composition of the present invention for use in treating and / or preventing a proliferative disease.

[0052] In a specific embodiment, proliferative diseases as described herein include but are not limited to cancer, cardiovascular disorders, infectious diseases, chronic inflammatory diseases, autoimmune disorders and other cell proliferation disorders. More specifically, the cancer includes but is not limited to solid tumors and hematological malignancies, such as breast cancer, neuroblastoma, malignant rhabdomyomas, well-differentiated and dedifferentiated liposarcoma, glioma, lung cancer, colorectal cancer, gastric cancer, gastrointestinal stromal tumor (GIST), hepatocellular carcinoma, prostate tumor, sarcoma, ovarian cancer, cervical cancer, pancreatic cancer, melanoma, thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, mesothelioma, lymphoma, leukemia, non-Hodgkin's lymphoma, mantle cell lymphoma, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma.

[0053] In another aspect, the present invention provides use of a compound of the present invention or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, or a composition of the present invention in the preparation of a medicament for promoting butyrophilin 3A1 / 2A1 binding.

[0054] In another aspect, the present invention provides a method of promoting butyrophilin 3A1 / 2A1 binding in a subject, comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, or a composition of the present invention.

[0055] In another aspect, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, or a composition of the present invention for use in promoting butyrophilin 3A1 / 2A1 binding.

[0056] Other objects and advantages of the present invention will be apparent to those skilled in the art from the following detailed description, examples and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1. Binding pattern of a small molecule compound (Compound 7) with BTN3A1 in vivo, showing that the R1 group of the general formula molecule is basically exposed to the solvent region, which has no effect on its binding with BTN3A1 and can be derivatized in various ways.

[0058] Figure 2. The binding pattern of a small molecule compound (Compound 7) with both BTN3A1 and BTN2A1 in vivo. This shows that the R1 structure of the general molecule is confined to a specific cavity. Only R1 with a specific spatial size can simultaneously bind to BTN3A1 and BTN2A1 and produce the corresponding biological effects.

[0059] Figures 1 and 2 illustrate that the requirements for small molecule ligands designed based on the BTN3A1 model (Figure 1) and the BTNA1-BTN2A1 model (Figure 2) are completely different. Only the model in Figure 2, where small molecules simultaneously bind to the cavity formed by both BTN3A1 and BTN2A1, can exert biological function. DETAILED DESCRIPTION

[0060] definition

[0061] Chemical definition

[0062] Definitions of specific functional groups and chemical terms are described in more detail below.

[0063] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-6 "Alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 and C 5-6 alkyl.

[0064] It should be understood that when described herein, any of the groups defined below may be substituted with a number of substituents, and that the corresponding definitions are within their scope listed below, including substituted groups. Unless otherwise stated, the term "substituted" is as defined below.

[0065] “C 1-10 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 10 carbon atoms. In some embodiments, C 1-8 In some embodiments, preferably C 1-6 Alkyl, which is also called "lower alkyl". In some embodiments, C 1-4 Alkyl. Examples of the alkyl group include, but are not limited to, methyl (C1), ethyl (C2), propyl (C3), butyl (C4), pentyl (C5), hexyl (C6), heptyl (C7), octyl (C8), nonyl (C9), and decyl (C10). 10). The alkyl group also includes any isomers of the above groups, for example, propyl (C3) includes n-propyl (C3) and isopropyl (C3), butyl (C4) includes n-butyl (C4), tert-butyl (C4), sec-butyl (C4) and isobutyl (C4), pentyl (C5) includes n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5) and tert-pentyl (C5), and the like. Unless otherwise specified, each of the alkyl groups is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents; for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkyl group is unsubstituted C 1-6 In some embodiments, the alkyl group is a substituted C 1-6 alkyl.

[0066] “C 2-10 "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). In some embodiments, C 2-6 In some embodiments, preferably C 2-4 Alkenyl. One or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). Examples of the alkenyl include, but are not limited to, vinyl (C2), propenyl (C3), butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. The alkenyl group also includes any isomer of the above groups, for example, propenyl (C3) includes 1-propenyl (C3), 2-propenyl (C3) and 1-propen-2-yl (C3), butenyl (C4) includes 1-butenyl (C4) and 2-butenyl (C4), C 10 Alkenyl groups include, for example, 1-decenyl (C 10 ), 2-decenyl (C 10 ), 3-decenyl (C 10 ), 4-decenyl (C 10 )、1,3-decenediyl (C 10 )、1,4-decenediyl (C 10 )、1,5-decenediyl (C 10 )、3,7-dimethylocta-2,6-dien-1-yl (C 10 ), and the like. Unless otherwise specified, each alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents; for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, an alkenyl group is an unsubstituted C2-6 In some embodiments, alkenyl is a substituted C 2-6 Alkenyl.

[0067] “C 2-10 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 10 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, or 3 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). In some embodiments, C 2-6 In some embodiments, preferably C 2-4 Alkynyl. In some embodiments, an alkynyl group does not contain any double bonds. The one or more carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). Examples of such alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), 3-methylbut-1-ynyl (C5), hexynyl (C6), and the like. Unless otherwise specified, each of the alkynyl groups is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted ("substituted alkynyl") with one or more substituents; for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, an alkynyl group is an unsubstituted C 2-6 In some embodiments, the alkynyl group is a substituted C 2-6 Alkynyl.

[0068] "Halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halogen group is -F, -Cl, or -Br. In some embodiments, the halogen group is -F or -Cl.

[0069] Therefore, “C 1-10 "Haloalkyl" refers to the above-mentioned "C 1-10 Alkyl", which is substituted by one or more halogen groups. In some embodiments, preferably C 1-6 Haloalkyl or C 1-4 Halogenated alkyl, more preferably C 1-2 Haloalkyl. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like.

[0070] “C 3-12 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 12 ring carbon atoms and zero heteroatoms, including fused rings, bridged rings, spiro rings, etc. In some embodiments, C3-7 Cycloalkyl, preferably C 3-6 Cycloalkyl, more preferably C 5-6 Cycloalkyl. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodec ... 10 ), cyclodecenyl (C 10 ), cycloundecyl (C 11 ), cycloundecenyl (C 11 ), cyclododecyl (C 12 ), cyclododecenyl (C 12 ), cyclotridecyl (C 13 ), cyclotridecenyl (C 13 ), adamantyl group, etc.

[0071] "3-12 membered heterocyclyl" refers to a 3 to 12 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, including fused rings, bridged rings, spiro rings, etc. In some embodiments, 3-7 membered heterocyclyl and 3-6 membered heterocyclyl are preferred, which are 3 to 6 membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms. In some embodiments, 4-7 membered heterocyclyl are preferred, which are 4 to 7 membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms. In some embodiments, 5-6 membered heterocyclyl are preferred, which are 5 to 6 membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms. Exemplary 3 membered heterocyclyls containing one heteroatom include, but are not limited to, aziridine, oxadiazine, and thiazole. Exemplary 4 membered heterocyclyls containing one heteroatom include, but are not limited to, azetidinyl, oxadiazine, and thiazole. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, hexahydrotriazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepane, and thiepanyl. In some embodiments, the 3-12 membered heterocyclic groups of the present invention include:

[0072] “C 6-10 "Aryl" refers to a group having a monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) with 6-10 ring carbon atoms and zero heteroatoms provided in the aromatic ring system. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C 10Unless otherwise specified, each aryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents.

[0073] "5-10 membered heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl is preferred, which is a group of a 5-6 membered monocyclic 4n+2 aromatic ring system (e.g., having 6 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur; in some embodiments, a 5 membered heteroaryl is preferred, which is a group of a 5 membered monocyclic 4n+2 aromatic ring system (e.g., having 6 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, 6-membered heteroaryl is preferably a group having a 6-membered monocyclic 4n+2 aromatic ring system (e.g., having 6 π electrons shared in a cyclic arrangement) of ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each of the heteroaryl groups is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") by one or more substituents. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively.

[0074] "Heteroatom" refers to non-metal atoms other than carbon atoms, preferably oxygen, nitrogen, phosphorus, sulfur, silicon and boron atoms, more preferably oxygen, nitrogen, phosphorus and sulfur atoms.

[0075] "-C 1-6 "Alkylene-" refers to the above-defined "C 1-6 Specifically refers to the divalent group of "alkyl". 1-6In some embodiments, C 1-4 Alkylene is particularly preferred. Unsubstituted alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylenes, for example, alkylenes substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0076] “C 0-6 "Alkylene" means a chemical bond and "C 1-6 "Alkylene".

[0077] When using chemical bonds at double bond positions in compounds When , it means that the cis isomer and the trans isomer of the compound coexist in any ratio, that is, it can be a cis isomer, a trans isomer or a mixture thereof.

[0078] Alkyl, alkenyl, alkynyl, aryl and heteroaryl, etc., as defined herein, are optionally substituted groups, regardless of whether or not there is the term "optionally substituted" in front. Generally, the term "substituted", regardless of whether or not there is the term "optionally" in front, refers to at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) being replaced by a permissible substituent, e.g., a substituent that produces a stable compound upon substitution, e.g., a compound that does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination or other reactions). Unless otherwise stated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent at each position is the same or different. The term "substituted" includes substitution with all permissible substituents of an organic compound (resulting in any substituent described herein that forms a stable compound). For the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatoms and result in the formation of a stable moiety.

[0079] Exemplary substituents on carbon atoms include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa 、-ON(R bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2, -CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NRbb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa )2、-B(ORcc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0080] Or the two geminal hydrogen atoms on the carbon atom are replaced by groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa 、=NNR bb C(=O)OR aa 、=NNR bb S(=O)2R aa 、=NR bb or = NOR cc replace;

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

[0082] R bb Each of the following is independently selected from: hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(Rcc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl, or two R bb The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0083] R cc Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0084] R dd Each of the is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee 、-ON(R ff )2、-N(R ff )2,、-N(R ff )3 + X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=O)N(R ff )2、-C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff)2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee 、-SO2N(R ff )2, -SO2R ee 、-SO2OR ee 、-OSO2R ee 、-S(=O)R ee 、-Si(R ee )3、-OSi(R ee )3、-C(=S)N(R ff )2, -C(=O)SR ee 、-C(=S)SR ee 、-SC(=S)SR ee 、-P(=O)2R ee 、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may combine to form =O or =S;

[0085] R ee Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0086] R ff Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R ff The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0087] R gg Each of the independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6Alkyl, -ON(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - 、-NH(C 1-6 Alkyl)2 + X - 、-NH2(C 1-6 alkyl) + X - 、-NH3 + X - 、-N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2、C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Perhalogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, C 6-10 Aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; wherein X - For the counter ion.

[0088] Exemplary substituents on nitrogen atoms include, but are not limited to, hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR bb )R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SRcc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R attached to the nitrogen atom cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd Group substituted, and wherein R aa 、R bb 、R cc and R dd As mentioned above.

[0089] When the chemical formula of a compound contains a chiral atom, such as a chiral carbon atom or a chiral phosphorus atom, the present invention encompasses all isomers related to the chiral atom, including R isomers, S isomers, (+) isomers, (-) isomers, mixtures thereof, and racemates. Furthermore, when a chiral atom is connected via a chemical bond "-" rather than a wedge-shaped bond, this merely indicates the connection between the two atoms and indicates that the compound does not specify a specific configuration, i.e., it may include all isomers, mixtures thereof, or racemates, and should not be understood as representing only racemates.

[0090] When a double bond is contained in the chemical formula of a compound, it only means that two atoms are connected by the double bond and that the compound has no specific configuration, that is, it may include (E) isomers, (Z) isomers and mixtures thereof.

[0091] Other definitions

[0092] The term "pharmaceutically acceptable salt" refers to salts that are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reaction, etc., and are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed with an amino group and inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or salts formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts formed using methods used in the art, such as ion exchange methods. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, if appropriate.

[0093] "Subjects" to be administered include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal.

[0094] As used herein, and unless otherwise indicated, the term "treating" includes actions that occur while a subject has a particular disease, disorder, or condition that reduce the severity of, or delay or slow the development of, the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject becomes ill with a particular disease, disorder, or condition ("prophylactic treatment").

[0095] Generally, an "effective amount" of a compound is an amount sufficient to elicit the desired biological response. As will be appreciated by those skilled in the art, the effective amount of a compound of the invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. An effective amount includes both therapeutic and prophylactic treatment effective amounts.

[0096] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, used alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of other therapeutic agents.

[0097] Unless otherwise specified, a "prophylactically effective amount" of a compound, as used herein, is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent the recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, used alone or in combination with other agents, that provides a prophylactic benefit in the prevention of a disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prevention, or an amount that enhances the prophylactic efficacy of other prophylactic agents.

[0098] Compound

[0099] As used herein, "compounds of the present invention" refers to compounds of the following formula or its subformulae, or pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, hydrates, polymorphs or isotopic variations thereof.

[0100] In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variation thereof:

[0101] in,

[0102] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0103] R a Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl;

[0104] m = 1, 2, 3, 4, or 5;

[0105] X is O or CRR';

[0106] R1 is selected from H, F, Cl, CN or methyl, wherein methyl is optionally substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2;

[0107] R2 is selected from C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Halogenated alkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl or C 0-6 Alkylene-4-12 membered heterocyclic group, wherein the C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Halogenated alkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl or C 0-6 Alkylene-4-12 membered heterocyclic group is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Haloalkyl, -C(O)-C 2-6 Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10 membered cycloalkyl, -C(O)-4-10 membered heterocycloalkyl, -C(O)-C 6-10aryl, -C(O)-5-10 membered heteroaryl, -CN and oxo substituents;

[0108] R3 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0109] in,

[0110] R and R' are independently selected from H or halogen;

[0111] R" is independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0112] In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variation thereof:

[0113] in,

[0114] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0115] R a Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl;

[0116] m = 1, 2, 3, 4, or 5;

[0117] X is O or CRR';

[0118] R1 is selected from H, F, Cl, CN or methyl, wherein methyl is optionally substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2;

[0119] R2 is selected from C 5-6 Alkyl, C 5-6 Halogenated alkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-7 Cycloalkyl, C 0-6 Alkylene-4-7 membered heterocyclic group, C0-6 Alkylene-C 6-10 Aryl or C 0-6 Alkylene-5-10 membered heteroaryl;

[0120] R3 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0121] in,

[0122] R and R' are independently selected from H or halogen;

[0123] R" is independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0124] In another embodiment, the present invention is directed to a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variation thereof:

[0125] in,

[0126] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0127] R a Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl;

[0128] m = 1, 2, 3, 4, or 5;

[0129] X is O or CRR';

[0130] R1 is selected from H, F, Cl, CN or methyl, wherein methyl is substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2;

[0131] R2 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkylene-C 3-7 Cycloalkyl, C 0-6Alkylene-3-7 membered heterocyclic group, C 0-6 Alkylene-C 6-10 Aryl or C 0-6 Alkylene-5-10 membered heteroaryl;

[0132] R3 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0133] in,

[0134] R and R' are independently selected from H or halogen;

[0135] R" is independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0136] Ring A

[0137] In one embodiment, Ring A is C 6-10 Aryl, preferably phenyl; in another embodiment, ring A is a 5-10 membered heteroaryl.

[0138] R a

[0139] In a specific embodiment, R a is H; in another embodiment, R a is halogen; in another embodiment, R a C 1-6 Alkyl; in another embodiment, R a C 1-6 haloalkyl; in another embodiment, R a is -OR"; in another embodiment, R a is NR"R"; in another embodiment, R a C 2-6 alkenyl; in another embodiment, R a C 2-6 Alkynyl.

[0140] m

[0141] In one embodiment, m=1; in another embodiment, m=2; in another embodiment, m=3; in another embodiment, m=4; in another embodiment, m=5.

[0142] X

[0143] In one embodiment, X is O; in another embodiment, X is CRR'; in another embodiment, X is CH2 or CF2.

[0144] R1

[0145] In one embodiment, R1 is H; in another embodiment, R1 is F; in another embodiment, R1 is Cl; in another embodiment, R1 is CN; in another embodiment, R1 is methyl substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2, such as CF3 or CH2OH; in another embodiment, R1 is methyl, wherein methyl is optionally substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2.

[0146] In a more specific embodiment, R1 is selected from H; in another more specific embodiment, R1 is selected from CF3 or CH2OH; in another more specific embodiment, R1 is selected from H or CF3; in another more specific embodiment, R1 is CF3; in another more specific embodiment, R1 is selected from H, F, Cl, CN, CH3, CF3 or CH2OH; in another more specific embodiment, R1 is selected from H, CH3 or CF3; in another more specific embodiment, R1 is selected from CH3 or CF3; in another more specific embodiment, R1 is CH3.

[0147] R2

[0148] In one embodiment, R2 is C 1-6 Alkyl, preferably C 1-4 Alkyl, preferably C 5-6 Alkyl, preferably isopropyl or 2-ethylbutyl; in another embodiment, R2 is C 1-6 Halogenated alkyl, preferably C 1-4 Halogenated alkyl, preferably C 5-6 In another embodiment, R2 is C 2-6 Alkenyl, preferably C 2-4 Alkenyl, preferably C 5-6 In another embodiment, R2 is C 2-6 Alkynyl, preferably C 2-4 Alkynyl, preferably C5-6 Alkynyl; In another embodiment, R2 is C 0-6 Alkylene-C 3-7 Cycloalkyl, preferably C 0-6 Alkylene-C 5-6 In another embodiment, R2 is C 0-6 Alkylene-3-7 membered heterocyclic group, preferably C 0-6 Alkylene-4-7 membered heterocyclic group, C 0-6 Alkylene-5-6 membered heterocyclic group, preferably tetrahydropyranyl; in another embodiment, R2 is C 0-6 Alkylene-C 6-10 Aryl; In another embodiment, R2 is C 0-6 Alkylene-5-10 membered heteroaryl.

[0149] In a more specific embodiment, R2 is C 1-6 Alkyl, C 0-6 Alkylene-C 3-7 Cycloalkyl, C 0-6 Alkylene-3-7 membered heterocyclic group, C 0-6 Alkylene-C 6-10 Aryl or C 0-6 In another more specific embodiment, R2 is isopropyl, 2-ethylbutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyridinyl or benzyl; In another more specific embodiment, R2 is 2-ethylbutyl, cyclopentyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl or benzyl; In another more specific embodiment, R2 is 2-ethylbutyl, In another more specific embodiment, R2 is 2-ethylbutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl or tetrahydropyridinyl; in another more specific embodiment, R2 is 2-ethylbutyl, cyclopentyl, tetrahydrofuranyl, tetrahydrothiophenyl or pyrrolidinyl; in another more specific embodiment, R2 is 2-ethylbutyl, cyclopentyl, tetrahydrofuranyl, tetrahydrothiophenyl or pyrrolidinyl; in another more specific embodiment, R2 is 2-ethylbutyl, cyclopentyl or tetrahydrofuranyl.

[0150] In another more specific embodiment, R2 is a 3-12 membered cycloalkyl or a 4-12 membered heterocyclyl, wherein said 3-12 membered cycloalkyl or 4-12 membered heterocyclyl is optionally substituted with one or more selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Haloalkyl, -C(O)-C 2-6 Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10 membered cycloalkyl, -C(O)-4-10 membered heterocycloalkyl, -C(O)-C 6-10 aryl, -C(O)-5-10 membered heteroaryl, -CN and oxo group; preferably, R2 is a 4-10 membered heterocyclic group, the 4-10 membered heterocyclic group is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 More preferably, R2 is a 4-7 membered heterocyclic group, wherein the heteroatom is an oxygen atom or a nitrogen atom, and the 4-7 membered heterocyclic group is optionally substituted by one or more selected from C 1-6 Alkyl and oxo groups are substituted by substituents; More preferably, the R2 is selected from:

[0151] R3

[0152] In one embodiment, R3 is C 1-6 Alkyl, such as methyl or isopropyl; in another embodiment, R3 is C 1-6 In another embodiment, R3 is C 2-6 In another embodiment, R3 is C 2-6 Alkynyl.

[0153] R and R'

[0154] In one embodiment, R and R' are H; in one embodiment, R and R' are halogen.

[0155] R”

[0156] In one embodiment, R" is C 1-6 Alkyl; in another embodiment, R" is C 1-6 In another embodiment, R" is C 0-6 Alkylene-C 6-10 Aryl; In another embodiment, R" is C 0-6 Alkylene-5-10 membered heteroaryl.

[0157] Any technical solution or any combination thereof in any of the above specific embodiments may be combined with any technical solution or any combination thereof in any other specific embodiment. For example, any technical solution or any combination thereof for X may be combined with any technical solution or any combination thereof for R1 to R3, R, R', and R". The present invention is intended to include all combinations of these technical solutions, but due to space limitations, they are not listed one by one.

[0158] In a preferred embodiment, the present invention relates to the following technical solutions:

[0159] Technical Solution 1. A compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof:

[0160] in,

[0161] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0162] R a Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl;

[0163] m = 1, 2, 3, 4, or 5;

[0164] X is O or CRR';

[0165] R1 is selected from H, F, Cl, CN or methyl, wherein methyl is optionally substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2;

[0166] R2 is selected from C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Halogenated alkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl, C 0-6 Alkylene-4-12 membered heterocyclic group or C 0-6 Alkylene-5-10 membered heteroaryl, wherein the C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Halogenated alkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl, C0-6 Alkylene-4-12 membered heterocyclic group or C 0-6 Alkylene-5-10 membered heteroaryl is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Haloalkyl, -C(O)-C 2-6 Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10 membered cycloalkyl, -C(O)-4-10 membered heterocycloalkyl, -C(O)-C 6-10 aryl, -C(O)-5-10 membered heteroaryl, -CN and oxo substituents;

[0167] R3 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0168] in,

[0169] R and R' are independently selected from H or halogen;

[0170] R" is independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0171] Technical Solution 2. The compound of formula (I) described in Technical Solution 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof:

[0172] in,

[0173] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0174] R a Selected from H, halogen, C 1-6 Alkyl, C 1-6Halogenated alkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl;

[0175] m = 1, 2, 3, 4, or 5;

[0176] X is O or CRR';

[0177] R1 is selected from H, F, Cl, CN or methyl, wherein methyl is optionally substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2;

[0178] R2 is selected from C 5-6 Alkyl, C 5-6 Halogenated alkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-7 Cycloalkyl, C 0-6 Alkylene-4-7 membered heterocyclic group or C 0-6 Alkylene-5-10 membered heteroaryl;

[0179] R3 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0180] in,

[0181] R and R' are independently selected from H or halogen;

[0182] R" is independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0183] Technical Solution 3. The compound of Technical Solution 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, which is a compound of formula (II):

[0184] in,

[0185] X is O or CRR';

[0186] R1 is selected from H, F, Cl, CN or methyl, wherein methyl is optionally substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2;

[0187] R2 is selected from C1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Halogenated alkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl or C 0-6 Alkylene-4-12 membered heterocyclic group, wherein the C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Halogenated alkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl or C 0-6 Alkylene-4-12 membered heterocyclic group is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Haloalkyl, -C(O)-C 2-6 Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10 membered cycloalkyl, -C(O)-4-10 membered heterocycloalkyl, -C(O)-C 6-10 aryl, -C(O)-5-10 membered heteroaryl, -CN and oxo substituents;

[0188] R3 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0189] in,

[0190] R and R' are independently selected from H or halogen.

[0191] Technical Solution 4. The compound of Technical Solution 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, which is a compound of formula (II):

[0192] in,

[0193] X is O or CRR';

[0194] R1 is selected from H, F, Cl, CN or methyl, wherein methyl is optionally substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2;

[0195] R2 is selected from C 5-6 Alkyl, C 5-6 Halogenated alkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-7 Cycloalkyl or C 0-6 Alkylene-4-7 membered heterocyclic group;

[0196] R3 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0197] in,

[0198] R and R' are independently selected from H or halogen.

[0199] Technical Solution 5. The compound of Technical Solution 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, which is a compound of formula (III):

[0200] in,

[0201] X is O or CRR';

[0202] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0203] R a Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl;

[0204] R2 is selected from C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Halogenated alkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl or C 0-6 Alkylene-4-12 membered heterocyclic group, wherein the C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6Halogenated alkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl or C 0-6 Alkylene-4-12 membered heterocyclic group is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Haloalkyl, -C(O)-C 2-6 Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10 membered cycloalkyl, -C(O)-4-10 membered heterocycloalkyl, -C(O)-C 6-10 aryl, -C(O)-5-10 membered heteroaryl, -CN and oxo substituents;

[0205] in,

[0206] R and R' are independently selected from H or halogen.

[0207] Technical Solution 6. The compound of any one of Technical Solutions 1-5, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein X is CRR', preferably CH2 or CF2.

[0208] Technical Solution 7. The compound of any one of Technical Solutions 1-4 and 6, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein R1 is selected from H, F, Cl, CN, CH3, CF3 or CH2OH, more preferably H, CH3, CH2OH or CF3, more preferably CH3 or CF3, more preferably CH3.

[0209] Technical Solution 8. The compound of any one of Technical Solutions 1-7, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein R2 is 2-ethylbutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl or tetrahydropyridinyl, preferably cyclopentyl, tetrahydrofuranyl, tetrahydrothiophenyl or pyrrolidinyl, more preferably cyclopentyl or tetrahydrofuranyl.

[0210] Technical Solution 9. The compound of any one of Technical Solutions 1-4 and 6-8, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein R3 is C 1-6 Alkyl, preferably methyl or isopropyl.

[0211] Technical Solution 10. The compound of Technical Solution 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, which is a compound of formula (IV):

[0212] Wherein ring A is C 6-10 aryl or 5-10 membered heteroaryl, such as phenyl or naphthalene ring,

[0213] R a Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl;

[0214] m = 1, 2, 3, 4, or 5;

[0215] R2 is a 3-12 membered cycloalkyl or a 4-12 membered heterocyclic group, wherein the 3-12 membered cycloalkyl or the 4-12 membered heterocyclic group is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Haloalkyl, -C(O)-C 2-6 Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10 membered cycloalkyl, -C(O)-4-10 membered heterocycloalkyl, -C(O)-C 6-10 The substituents are substituted with aryl, -C(O)-5-10 membered heteroaryl, -CN and oxo groups.

[0216] Technical Solution 11. The compound of Technical Solution 10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, which is a compound of formula (V):

[0217] wherein R2 is a 4-12 membered heterocyclic group, wherein the 4-12 membered heterocyclic group is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Haloalkyl, -C(O)-C 2-6 Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10 membered cycloalkyl, -C(O)-4-10 membered heterocycloalkyl, -C(O)-C 6-10 The substituents are substituted with aryl, -C(O)-5-10 membered heteroaryl, -CN and oxo groups.

[0218] Technical Solution 12. The compound of any one of Technical Solutions 1-11, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein R2 is a 4-10 membered heterocyclic group, and the 4-10 membered heterocyclic group is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 The substituents are substituted with hydroxyalkyl, -C(O)-3-10 membered cycloalkyl, -CN and oxo groups.

[0219] Technical Solution 13. The compound of any one of Technical Solutions 1-11, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein R2 is a 4-7 membered heterocyclic group, the heteroatom is an oxygen atom or a nitrogen atom, and the 4-7 membered heterocyclic group is optionally replaced by one or more selected from C 1-6 The substituents of the alkyl and oxo groups are substituted.

[0220] Technical Solution 14. The compound of any one of Technical Solutions 1-11, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein R2 is selected from:

[0221] Technical Solution 15. A compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof:

[0222] in,

[0223] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0224] R a Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl;

[0225] m = 1, 2, 3, 4, or 5;

[0226] X is O or CRR';

[0227] R1 is selected from H, F, Cl, CN or methyl, wherein methyl is substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2;

[0228] R2 is selected from C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Halogenated alkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl or C 0-6 Alkylene-4-12 membered heterocyclic group, wherein the C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Halogenated alkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl or C 0-6 Alkylene-4-12 membered heterocyclic group is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Haloalkyl, -C(O)-C 2-6 Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10 membered cycloalkyl, -C(O)-4-10 membered heterocycloalkyl, -C(O)-C6-10 aryl, -C(O)-5-10 membered heteroaryl, -CN and oxo; preferably, R2 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkylene-C 3-7 Cycloalkyl, C 0-6 Alkylene-3-7 membered heterocyclic group, C 0-6 Alkylene-C 6-10 Aryl or C 0-6 Alkylene-5-10 membered heteroaryl;

[0229] R3 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0230] in,

[0231] R and R' are independently selected from H or halogen;

[0232] R" is independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0233] Technical Solution 16. The compound of Technical Solution 15, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, which is a compound of formula (II):

[0234] in,

[0235] X is O or CRR';

[0236] R1 is selected from H, F, Cl, CN or methyl, wherein methyl is substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2;

[0237] R2 is selected from C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Halogenated alkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl or C 0-6Alkylene-4-12 membered heterocyclic group, wherein the C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Halogenated alkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl or C 0-6 Alkylene-4-12 membered heterocyclic group is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Haloalkyl, -C(O)-C 2-6 Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10 membered cycloalkyl, -C(O)-4-10 membered heterocycloalkyl, -C(O)-C 6-10 aryl, -C(O)-5-10 membered heteroaryl, -CN and oxo; preferably, R2 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkylene-C 3-7 Cycloalkyl, C 0-6 Alkylene-3-7 membered heterocyclic group, C 0-6 Alkylene-C 6-10 Aryl or C 0-6 Alkylene-5-10 membered heteroaryl;

[0238] R3 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0239] in,

[0240] R and R' are independently selected from H or halogen.

[0241] Technical Solution 17. The compound of Technical Solution 15 or 16, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein X is CRR', preferably CH2 or CF2.

[0242] Technical Solution 18. The compound of any one of Technical Solutions 15-17, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein R1 is selected from H, F, Cl, CN, CF3 or CH2OH, more preferably H or CF3, more preferably CF3.

[0243] Technical Solution 19. The compound of any one of Technical Solutions 15-18, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein R2 is C 1-6 Alkyl, C 0-6 Alkylene-C 3-7 Cycloalkyl, C 0-6 Alkylene-3-7 membered heterocyclic group, C 0-6 Alkylene-C 6-10 Aryl or C 0-6 Alkylene-5-10 membered heteroaryl, preferably isopropyl, 2-ethylbutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyridinyl or benzyl, more preferably 2-ethylbutyl, cyclopentyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl or benzyl, more preferably 2-ethylbutyl, cyclopentyl, tetrahydrofuranyl or benzyl.

[0244] Technical Solution 20. The compound of any one of Technical Solutions 15-19, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein R3 is C 1-6 Alkyl, preferably methyl or isopropyl.

[0245] Technical Solution 21. The compound of any one of Technical Solutions 15-20, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein R2 is a 3-12 membered cycloalkyl group or a 4-12 membered heterocyclic group, wherein the 3-12 membered cycloalkyl group or the 4-12 membered heterocyclic group is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Haloalkyl, -C(O)-C 2-6Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10 membered cycloalkyl, -C(O)-4-10 membered heterocycloalkyl, -C(O)-C 6-10 aryl, -C(O)-5-10 membered heteroaryl, -CN and oxo group; preferably, R2 is a 4-10 membered heterocyclic group, the 4-10 membered heterocyclic group is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 More preferably, R2 is a 4-7 membered heterocyclic group, wherein the heteroatom is an oxygen atom or a nitrogen atom, and the 4-7 membered heterocyclic group is optionally substituted by one or more selected from C 1-6 Alkyl and oxo groups are substituted with substituents; more preferably, R2 is selected from:

[0246] Technical Solution 22. A compound of formula (VI), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof:

[0247] in,

[0248] Ring A is C 6-12 Aryl or 5-12 membered heteroaryl;

[0249] R a Selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl;

[0250] m = 1, 2, 3, 4, or 5;

[0251] X is O or CRR';

[0252] R1 is selected from H, F, Cl, CN or methyl, wherein methyl is optionally substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2;

[0253] R2 is selected from C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Halogenated alkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl, C 0-6Alkylene-4-12 membered heterocyclic group or C 0-6 Alkylene-5-10 membered heteroaryl, wherein the C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Halogenated alkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl, C 0-6 Alkylene-4-12 membered heterocyclic group or C 0-6 Alkylene-5-10 membered heteroaryl is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Haloalkyl, -C(O)-C 2-6 Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10 membered cycloalkyl, -C(O)-4-10 membered heterocycloalkyl, -C(O)-C 6-10 aryl, -C(O)-5-10 membered heteroaryl, -CN and oxo substituents;

[0254] R3 and R3' are each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0255] in,

[0256] R and R' are independently selected from H or halogen;

[0257] R" is independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0258] Technical Solution 23. The compound of Technical Solution 22, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, which is a compound of formula (VII):

[0259] in,

[0260] X is O or CRR';

[0261] Ring A is C 6-12 Aryl or 5-12 membered heteroaryl;

[0262] R a Selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl;

[0263] m = 1, 2, 3, 4, or 5;

[0264] X is O or CRR';

[0265] R2 is selected from C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Halogenated alkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl, C 0-6 Alkylene-4-12 membered heterocyclic group or C 0-6 Alkylene-5-10 membered heteroaryl, wherein the C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Halogenated alkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl, C 0-6 Alkylene-4-12 membered heterocyclic group or C 0-6 Alkylene-5-10 membered heteroaryl is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C1-6 Haloalkyl, -C(O)-C 2-6 Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10 membered cycloalkyl, -C(O)-4-10 membered heterocycloalkyl, -C(O)-C 6-10 aryl, -C(O)-5-10 membered heteroaryl, -CN and oxo substituents;

[0266] R3 and R3' are each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0267] in,

[0268] R and R' are independently selected from H or halogen;

[0269] R" is independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0270] Technical Solution 24. The compound of Technical Solution 22 or 23, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein X is CRR', preferably CH2 or CF2.

[0271] Technical Solution 25. The compound of any one of Technical Solutions 22-24, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein R2 is C 1-6 Alkyl, C 0-6 Alkylene-C 3-7 Cycloalkyl, C 0-6 Alkylene-3-7 membered heterocyclic group, C 0-6 Alkylene-C 6-10 Aryl or C 0-6 Alkylene-5-10 membered heteroaryl, preferably isopropyl, 2-ethylbutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyridinyl or benzyl, more preferably 2-ethylbutyl, cyclopentyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl or benzyl, more preferably 2-ethylbutyl, cyclopentyl, tetrahydrofuranyl or benzyl.

[0272] Technical Solution 26. The compound of any one of Technical Solutions 22-25, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein R3 is C 1-6 Alkyl, preferably methyl or isopropyl.

[0273] Technical solution 27. The compound of any one of technical solutions 22-26, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein R2 is a 3-12 membered cycloalkyl group or a 4-12 membered heterocyclic group, wherein the 3-12 membered cycloalkyl group or the 4-12 membered heterocyclic group is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Haloalkyl, -C(O)-C 2-6 Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10 membered cycloalkyl, -C(O)-4-10 membered heterocycloalkyl, -C(O)-C 6-10 aryl, -C(O)-5-10 membered heteroaryl, -CN and oxo group; preferably, R2 is a 4-10 membered heterocyclic group, the 4-10 membered heterocyclic group is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 More preferably, R2 is a 4-7 membered heterocyclic group, wherein the heteroatom is an oxygen atom or a nitrogen atom, and the 4-7 membered heterocyclic group is optionally substituted by one or more selected from C 1-6 Alkyl and oxo groups are substituted by substituents; More preferably, the R2 is selected from:

[0274] Technical Solution 28. The compound of any one of Technical Solutions 1-27, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein the compound is selected from:

[0275] Technical Solution 29. The compound of any one of Technical Solutions 1-28, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein the compound is selected from:

[0276] Technical solution 30. A pharmaceutical composition comprising the compound of any one of Technical Solutions 1-29 or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

[0277] Technical Solution 31. Use of a compound of any one of Technical Solutions 1-29 or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof or the pharmaceutical composition of Technical Solution 30 in the preparation of a medicament for treating a proliferative disease.

[0278] Technical Solution 32. A compound of any one of Technical Solutions 1-29 or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, or a pharmaceutical composition of Technical Solution 30, for use in treating a proliferative disease.

[0279] Technical Solution 33. A method for treating a proliferative disease in a subject, the method comprising administering to the subject a compound of any one of Technical Solutions 1-29 or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof or the pharmaceutical composition of Technical Solution 14.

[0280] Technical Solution 34. The use of Technical Solution 31 or the use of the compound or pharmaceutical composition of Technical Solution 32 or the method of Technical Solution 33, wherein the proliferative disease is selected from cancer, cardiovascular disorders, infectious diseases, chronic inflammatory diseases, autoimmune disorders and other cell proliferative disorders; preferably, the cancer is selected from solid tumors and hematological malignancies, such as breast cancer, neuroblastoma, malignant rhabdomyomas, well-differentiated and dedifferentiated liposarcoma, glioma, lung cancer, colorectal cancer, gastric cancer, gastrointestinal stromal tumor (GIST), hepatocellular carcinoma, prostate tumor, sarcoma, ovarian cancer, cervical cancer, pancreatic cancer, melanoma, thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, mesothelioma, lymphoma, leukemia, non-Hodgkin's lymphoma, mantle cell lymphoma, anaplastic large cell lymphoma, acute myeloid leukemia (AML) and multiple myeloma; preferably, the proliferative disease is selected from multiple myeloma, non-Hodgkin's lymphoma, lung cancer, renal cancer and prostate cancer.

[0281] Technical Solution 35. Use of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof in the preparation of a medicament for promoting the binding of butyrophilin 3A1 / 2A1:

[0282] in,

[0283] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0284] R a Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl.

[0285] m = 1, 2, 3, 4, or 5;

[0286] X is O or CRR';

[0287] R1 is selected from H, F, Cl, CN or methyl, wherein methyl is optionally substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2;

[0288] R2 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkylene-C 3-7 Cycloalkyl, C 0-6 Alkylene-3-7 membered heterocyclic group, C 0-6 Alkylene-C 6-10 Aryl or C 0-6 Alkylene-5-10 membered heteroaryl;

[0289] R3 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0290] in,

[0291] R and R' are independently selected from H or halogen;

[0292] R" is independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10aryl or 5-10 membered heteroaryl.

[0293] Technical solution 36. A compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, for promoting the binding of butyrophilin 3A1 / 2A1:

[0294] in,

[0295] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0296] R a Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl.

[0297] m = 1, 2, 3, 4, or 5;

[0298] X is O or CRR';

[0299] R1 is selected from H, F, Cl, CN or methyl, wherein methyl is optionally substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2;

[0300] R2 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkylene-C 3-7 Cycloalkyl, C 0-6 Alkylene-3-7 membered heterocyclic group, C 0-6 Alkylene-C 6-10 Aryl or C 0-6 Alkylene-5-10 membered heteroaryl;

[0301] R3 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0302] in,

[0303] R and R' are independently selected from H or halogen;

[0304] R" is independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0305] Technical solution 37. A method for promoting butyrophilin 3A1 / 2A1 binding in a subject, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof:

[0306] in,

[0307] Ring A is C 6-10 Aryl or 5-10 membered heteroaryl;

[0308] R a Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl.

[0309] m = 1, 2, 3, 4, or 5;

[0310] X is O or CRR';

[0311] R1 is selected from H, F, Cl, CN or methyl, wherein methyl is optionally substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2;

[0312] R2 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkylene-C 3-7 Cycloalkyl, C 0-6 Alkylene-3-7 membered heterocyclic group, C 0-6 Alkylene-C 6-10 Aryl or C 0-6 Alkylene-5-10 membered heteroaryl;

[0313] R3 is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;

[0314] in,

[0315] R and R' are independently selected from H or halogen;

[0316] R" is independently selected from H, C 1-6 Alkyl, C1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl.

[0317] Technical Solution 38. The use of Technical Solution 35 or the use of the compound or pharmaceutical composition of Technical Solution 36 or the method of Technical Solution 37, wherein the compound is selected from the compound of any one of Technical Solutions 1-29 or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

[0318] Technical Solution 39. The use of Technical Solution 35 or the use of the compound or pharmaceutical composition of Technical Solution 36 or the method of Technical Solution 37, wherein the compound is selected from the following compounds or pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, hydrates, polymorphs or isotopic variants thereof:

[0319] The compounds of the present invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomers and / or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0320] The present invention also includes all suitable isotopic derivatives of the compounds of the present invention. An isotopic derivative of a compound of the present invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, for example, 2 H. 3 H. 13 C. 14 C. 15 N. 17 O. 18 O. 18 F. 31 P. 32 P. 35 S and 36Cl. Some isotopic derivatives of the compounds of the present invention, for example, those in which radioactive isotopes such as 3 H or 14 C, can be used for drug and / or substrate tissue distribution studies. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred because of their ease of preparation and detectability. In addition, isotopes (e.g., deuterium, i.e. 2 H) substitution may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some circumstances. Isotopic derivatives of the compounds of the invention can generally be prepared by conventional procedures, for example, by the illustrative methods or by the preparations described in the Examples hereinafter, using appropriate isotopic derivatives of suitable reagents.

[0321] The compounds of the present invention or their pharmaceutically acceptable salts can be in amorphous or crystalline form. In addition, the compounds of the present invention can exist in one or more crystalline forms. Therefore, the present invention includes all amorphous or crystalline forms of the compounds of the present invention within its scope. The term "polymorph" refers to the crystalline form (or its salt, hydrate or solvate) of a compound with a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature and other factors can lead to one crystalline form dominating. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0322] Those skilled in the art will appreciate that many organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are referred to as "solvates." When the solvent is water, the complex is referred to as a "hydrate." The present invention encompasses all solvates of the compounds of the present invention.

[0323] Pharmaceutical compositions, preparations and kits

[0324] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

[0325] Pharmaceutically acceptable excipients used in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0326] The present invention also includes kits (e.g., pharmaceutical packaging). The kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compound of the invention and other therapeutic agents. In some embodiments, the kit provided may also optionally include a third container containing a pharmaceutical excipient for diluting or suspending the compound of the invention and / or other therapeutic agents. In some embodiments, the compound of the invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0327] Example

[0328] The following examples are provided to provide those skilled in the art with a complete disclosure and description of how to perform, prepare, and evaluate the methods and compounds claimed herein and are intended to be illustrative only and not limiting of the scope of the invention. The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectroscopy (MS). NMR shifts (δ) were measured in 10 ‐6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). Tetramethylsilane (TMS) was used as the internal standard to set the zero point.

[0329] Preparation of intermediates

[0330] 4-Dichlorophosphorylbut-1-ene (Int-A)

[0331] The title compound was prepared according to the following scheme:

[0332] Experimental operation

[0333] Step 1: Diethyl but-3-en-1-yl phosphate (Int-A1)

[0334] To a solution of sodium hydride (5.21 g, 130.34 mmol, 60% w / w, 1.2 eq) in anhydrous tetrahydrofuran (300 mL) at 0°C under nitrogen was added diethyl phosphite (15 g, 108.62 mmol, 14.02 mL, 1 eq), and the mixture was stirred at 20°C for 1 hour. Subsequently, 4-bromo-1-butene (17.60 g, 130.34 mmol, 13.23 mL, 1.2 eq) was added, and the mixture was stirred at 60°C for 5 hours. After the reaction was complete, the mixture was cooled to room temperature and quenched by the addition of saturated ammonium chloride solution (300 mL). The mixture was extracted with ethyl acetate (300 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography using 0-55% petroleum ether / ethyl acetate to give diethyl 3-butenyl phosphate (18.4 g, 95.74 mmol, 88.14% yield) as a colorless oil.

[0335] 1 H NMR (400MHz, CDCl3) δ=5.82-5.75(m,1H),5.02-4.93(m,2H),4.06-4.00(m,4H),2.28-2.21(m,2H),1.80-1.71(m,2H),1.27(t,J=7.2Hz,6H);

[0336] 31 P NMR (162MHz, CDCl3) δ = 31.48.

[0337] Step 2: Bis(trimethylsilyl)but-3-en-1-ylphosphonate (Int-A2)

[0338] To a solution of diethyl but-3-en-1-yl phosphate (18.4 g, 95.74 mmol, 1 eq) in dichloromethane (600 mL) was added trimethylsilyl bromide (146.48 g, 957.4 mmol, 10 eq) dropwise at 20°C under nitrogen, and the mixture was stirred at 20°C for 4 hours. After the reaction, the mixture was concentrated under reduced pressure to remove the solvent to obtain bis(trimethylsilyl) but-3-en-1-ylphosphonate (25 g, 93% yield) as a yellow oil, which was used directly in the next reaction without further treatment.

[0339] 1H NMR (400MHz, CDCl3) δ=5.82-5.75(m,1H),5.04-4.95(m,2H),2.30-2.25(m,2H),1.86-1.80(m,2H),0.27(s,18H);

[0340] 31 P NMR (162MHz, CDCl3) δ = 14.94.

[0341] Step 3: 4-Dichlorophosphorylbut-1-ene (Int-A)

[0342] At 0°C under nitrogen, oxalyl chloride (34.0 g, 267.87 mmol, 3 eq) and anhydrous N,N-dimethylformamide (0.4 mL, 8.929 mmol) were added sequentially to a solution of bis(trimethylsilyl) but-3-en-1-ylphosphonate (25 g, 89.29 mmol) in dichloromethane (100 mL). The mixture was stirred at 20°C for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent, yielding 4-dichlorophosphorylbut-1-ene (14.5 g, 94% yield) as a yellow oil, which was used directly in the next reaction without further treatment.

[0343] ((But-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine isopropyl ester (Int-B)

[0344] The title compound was prepared according to the following scheme:

[0345] Experimental operation

[0346] Step 1: ((But-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine isopropyl ester (Int-B)

[0347] To a solution of 4-dichlorophosphorylbut-1-ene (5.0 g, 28.9 mmol, 1 eq) in dichloromethane (200 mL) at -78°C under nitrogen was added L-alanine isopropyl ester hydrochloride (4.85 g, 28.9 mmol, 1 eq) and triethylamine (5.85 g, 57.8 mmol, 2 eq). After stirring at -78°C for 5 minutes, phenol (2.72 g, 28.9 mmol, 1 eq) was added to the reaction solution. The mixture was stirred at -78°C for 0.5 hour, and then stirred at 20°C for 16 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography using 0-60% petroleum ether / ethyl acetate to give ((but-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine isopropyl ester (4.5 g, 13.83 mmol, 47.8% yield) as a colorless oil.

[0348] MS (ESI) m / z: calculated value 326.1 [M+H] + , measured value 326.0[M+H] + .

[0349] (Z)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-ol (Int-C)

[0350] The title compound was prepared according to the following scheme:

[0351] Experimental operation

[0352] Step 1: 3-(Benzyloxy)-1,1,1-trifluoropropan-2-ol (Int-C1)

[0353] To a reaction mixture of benzyl alcohol (19.11 g, 176.71 mmol, 1 eq) and boron trifluoride etherate (501.63 mg, 3.53 mmol, 0.02 eq) was added 1,1,1-trifluoro-2,3-epoxypropane (19.8 g, 176.71 mmol, 1 eq) at room temperature, and the mixture was stirred at 40°C for 16 hours. After the reaction, the reaction mixture was cooled to room temperature and quenched with an appropriate amount of water. The mixture was extracted with dichloromethane (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography using 20-40% petroleum ether / ethyl acetate as the eluent to obtain 3-(benzyloxy)-1,1,1-trifluoropropan-2-ol (30 g, 136.25 mmol, 77.1% yield) as a yellow oil.

[0354] 1H NMR (400MHz, CDCl3) δ=7.42-7.37(m,5H),4.63(s,2H),4.18-4.15(m,1H),3.77-3.74(m,1H),3.71-3.68(m,1H),3.36(d,J=6.4Hz,1H);

[0355] 19 F NMR (376MHz, CDCl3) δ=-77.61.

[0356] Step 2: 3-(Benzyloxy)-1,1,1-trifluoropropan-2-one (Int-C2)

[0357] To a solution of 3-(benzyloxy)-1,1,1-trifluoropropan-2-ol (21 g, 95.37 mmol, 1.0 eq) in dichloromethane (50 mL) was added dropwise Dess-Martin periodinane (DMP) (56.63 g, 133.52 mmol, 1.4 eq) at 20°C, and the mixture was stirred at 20°C for 16 hours. After the reaction, the mixture was diluted with dichloromethane, and the organic layer was washed with sodium thiosulfate and sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography using 20-40% petroleum ether / ethyl acetate as the eluent to obtain the desired 3-(benzyloxy)-1,1,1-trifluoropropan-2-one (11.0 g, 50.42 mmol, 52.8% yield) as a colorless oil.

[0358] 1 H NMR (400MHz, CDCl3) δ = 7.42-7.32 (m, 5H), 4.70 (s, 2H), 3.69 (s, 2H);

[0359] 19 F NMR (376MHz, CDCl3) δ=-85.13.

[0360] Step 3: Ethyl (Z)-3-((Benzyloxy)methyl)-4,4,4-trifluorobut-2-enoate (Int-C3)

[0361] Under nitrogen, 3-(Benzyloxy)-1,1,1-trifluoropropane-2-one (9.0 g, 41.26 mmol, 1 eq) was dissolved in an appropriate amount of benzene and refluxed to remove water. The reaction mixture was cooled to 25°C, and ethoxycarbonylmethyltriphenylphosphonium bromide (21.26 g, 49.51 mmol, 1.2 eq) and triethylamine (9.59 g, 94.90 mmol, 2.3 eq) were added to the reaction system. The mixture was stirred at 25°C for 16 hours. After completion of the reaction, an appropriate amount of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography using 20-30% petroleum ether / ethyl acetate to give (Z)-ethyl 3-((benzyloxy)methyl)-4,4,4-trifluorobut-2-enoate (4.8 g, 16.65 mmol, 40.3% yield) as a colorless oil.

[0362] 1 H NMR (400MHz, CDCl3) δ = 7.36-7.34 (m, 5H), 6.53 (s, 1H), 4.62 (s, 2H), 4.57 (s, 2H), 4.23 (q, J = 7.2Hz, 2H), 1.30 (t, J = 7.2Hz, 3H);

[0363] 19 F NMR (376MHz, CDCl3) δ=-67.23.

[0364] Step 4: (Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-enoic acid ethyl ester (Int-C4)

[0365] To a solution of ethyl (Z)-3-((benzyloxy)methyl)-4,4,4-trifluorobut-2-enoate (4.8 g, 16.64 mmol, 1 eq) in dichloromethane (80 mL) was added dropwise boron trichloride (1.0 M, 94.36 mL, 8.0 eq) at 0°C under nitrogen. The mixture was stirred at -78°C for 5 hours. After the reaction, the mixture was diluted with an appropriate amount of dichloromethane, and the organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography using 40-60% petroleum ether / ethyl acetate as the eluent to obtain ethyl (Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-enoate (2.1 g, 10.60 mmol, 63.70% yield) as a colorless oil.

[0366] 1H NMR (400MHz, CDCl3) δ = 6.47 (t, J = 1.6Hz, 1H), 5.01 (s, 1H), 4.35 (d, J = 0.8Hz, 2H), 4.26 (q, J = 7.2Hz, 2H), 1.31 (t, J = 7.2Hz, 3H);

[0367] 19 F NMR (377MHz, CDCl3) δ = -63.15, -65.07.

[0368] Step 5: (Z)-ethyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-enoate (Int-C5)

[0369] To a mixed solution of (Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-enoic acid ethyl ester (2.1 g, 10.60 mmol, 1 eq) and imidazole (1.08 g, 15.90 mmol, 1.5 eq) in dichloromethane (25 mL) was added dropwise tert-butyldimethylsilyl chloride (2.08 g, 13.78 mmol, 1.3 eq) at 0°C under nitrogen. The mixture was stirred at 20°C for 16 hours. After completion of the reaction, the reaction mixture was diluted with an appropriate amount of dichloromethane, and the organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography eluting with 40-60% petroleum ether / ethyl acetate to give (Z)-ethyl 3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-enoate (2.4 g, 7.69 mmol, 72.53% yield) as a colorless oil.

[0370] 1 H NMR (400MHz, CDCl3) δ = 6.44 (t, J = 2.4Hz, 1H), 4.32 (s, 2H), 4.26 (q, J = 7.2Hz, 2H), 1.32 (t, J = 7.2Hz, 3H), 0.93 (s, 9H), 0.12 (s, 6H);

[0371] 19 F NMR (376MHz, CDCl3) δ=-63.16.

[0372] Step 6: (Z)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-ol (Int-C)

[0373] To a solution of ethyl (Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-enoate (2.1 g, 6.73 mmol, 1 eq) in tetrahydrofuran (30 mL) was added red aluminum (1.0 M in toluene, 13.46 mL, 2.0 eq) dropwise at -78°C under nitrogen. The mixture was stirred at 0°C for 5 hours. After completion of the reaction, the mixture was diluted with an appropriate amount of dichloromethane, and the organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography eluting with 10-20% petroleum ether / ethyl acetate to give (Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-ol (0.65 g, 2.41 mmol, 35.81% yield) as a colorless oil.

[0374] 1 H NMR (400MHz, CDCl3) δ = 6.23-6.20 (m, 1H), 4.46-4.45 (m, 2H), 4.25 (s, 2H), 0.94-0.93 (m, 9H), 0.11-0.10 (m, 6H);

[0375] 19 F NMR (376MHz, CDCl3) δ = -60.92, -61.00.

[0376] (E)-(4-Methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pent-3-en-1-yl)phosphonate (trimethylsilyl) (Int-D)

[0377] The title compound was prepared according to the following scheme:

[0378] Experimental operation

[0379] Step 1-1: Diethyl (4-methyl-3-en-1-yl)phosphonate (Int-D1)

[0380] 5-Bromo-2-methyl-2-pentene (50 g, 0.31 mol) was added to triethyl phosphite (500 mL) at room temperature, and the mixture was refluxed and stirred at 150°C for 26 hours. After the reaction, the mixture was distilled at 150°C under atmospheric pressure, then cooled to 100°C and distilled under reduced pressure (0.1 MPa). The temperature was gradually increased to 140°C until no more solvent was evaporated, resulting in a yellow oily residue (38 g, 0.17 mol, 55.72% yield).

[0381] MS (ESI) m / z: Calculated value 221.1 [M+H]+ , measured value 221.1[M+H] + .

[0382] Step 2: (E)-diethyl (5-hydroxy-4-methylpent-3-en-1-yl)phosphonate (Int-D2)

[0383] To a solution of diethyl (4-methyl-3-en-1-yl)phosphonate (10 g, 52.05 mmol, 1 eq) in dichloromethane (100 mL) at 20°C under nitrogen was added selenium dioxide (2.89 g, 26.03 mmol, 0.5 eq), 4-hydroxybenzoic acid (0.72 g, 5.21 mmol, 0.1 eq), and tert-butyl hydroperoxide (5.5 M aqueous solution, 37.82 mL, 208.20 mmol, 4 eq). The mixture was stirred at 20°C for 16 hours. After completion of the reaction, saturated aqueous sodium bicarbonate (50 mL) was added to quench the reaction system. The mixture was extracted with dichloromethane (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield a residue (10 g, crude product). The crude product was dissolved in methanol (150 mL), and sodium borohydride (3.67 g, 104.10 mmol, 2 eq) was added portionwise at 0°C under nitrogen. The mixture was stirred at 0°C for 2 hours. After the reaction, saturated ammonium chloride solution (200 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (200 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography using 0-10% dichloromethane / methanol as the eluent and concentrated under reduced pressure to obtain crude diethyl (E)-(5-hydroxy-4-methylpent-3-en-1-yl)phosphonate (2.8 g, 11.86 mmol, 22.82% yield). It was a yellow oil.

[0384] MS (ESI) m / z: Calculated value 237.1 [M+H] + , measured value 219.2[M+H-H2O] + .

[0385] Step 3: Diethyl (E)-(4-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pent-3-en-1-yl)phosphonate (Int-D3)

[0386] To a solution of diethyl (E)-(5-hydroxy-4-methylpent-3-en-1-yl)phosphonate (3 g, 12.70 mmol, 1 eq) and pyridine p-toluenesulfonate (0.34 g, 1.27 mmol, 0.1 eq) in tetrahydrofuran (30 mL) was added 3,4-dihydropyran (3.21 g, 38.10 mmol, 3 eq), and the reaction mixture was stirred at 20°C for 5 hours. After completion of the reaction as determined by TLC, water (20 mL) was added for quenching, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography using 10-20% petroleum ether / ethyl acetate to give diethyl (E)-(4-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pent-3-en-1-yl)phosphonate (2.5 g, 7.81 mmol, 62.5% yield) as a light yellow oil.

[0387] MS (ESI) m / z: calcd. 321.2 [M+H] + , measured value 219.1[M+H-102] + .

[0388] Step 4: (E)-(4-Methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pent-3-en-1-yl)phosphonate (trimethylsilyl) (Int-D)

[0389] To a solution of (E)-5-diethoxyphospho-2-methyl-2-pent-1-yloctanoate (2.5 g, 7.81 mmol, 1 eq) in dichloromethane (25 mL) was added dropwise trimethylsilyl bromide (11.76 g, 78.10 mmol, 10 eq) at 0°C under nitrogen. The mixture was stirred at room temperature for 16 hours. After the disappearance of the starting material, the mixture was concentrated under reduced pressure to afford (E)-(4-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pent-3-en-1-yl)phosphonate (trimethylsilyl) (crude product) (2.5 g, 6.12 mmol, 78.56% yield) as a yellow oil, which was used directly in the next step.

[0390] MS (ESI) m / z: calcd. 409.2 [M+H] + , measured value 181.1[M+H-228] + .

[0391] Control compound 1:

[0392] (((E)-5-Hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine isopropyl ester (reference compound 1)

[0393] The title compound was prepared according to the following scheme:

[0394] Experimental operation

[0395] Step 1: (((E)-5-Hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine isopropyl ester (reference compound 1)

[0396] To a solution of ((but-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine isopropyl ester (300.00 mg, 922.12 μmol, 1 eq), 2-methylallyl alcohol (134.97 mg, 1.87 mmol, 2 eq), and p-benzoquinone (12.00 mg, 111.01 μmol, 0.12 eq) in dichloromethane (20 mL) was added the second-generation Hoveyda-Grubbs catalyst (43.35 mg, 69.15 μmol, 0.075 eq). At t = 0, 2, and 4 hours during the reaction, the catalyst was added in three equal portions, each (14.45 mg, 23.05 μmol, 0.025 eq). The solution was then heated to reflux at 45°C under a nitrogen atmosphere for 18 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure to yield a residue. The residue was purified by preparative HPLC (FA conditions) to give (((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine isopropyl ester (127.6 mg, 345.43 μmol, 37.4% yield) as the desired product as a colorless oil.

[0397] 1 H NMR (400MHz, CDCl3) δ=7.31-7.29(m,2H),7.28-7.27(m,2H),7.21-7.19(m,1H),5.50-5.46(s,1H),5.00-4.96(m,1H),4.05-3.9 4(m,3H),3.50-3.29(m,1H),2.48-2.44(m,2H),2.00-1.93(m,2H),1.70(d,J=4.4Hz,3H),1.30-1.29(m,3H),1.23-1.19(m,6H);

[0398] 31 P NMR (162MHz, CDCl3) δ = 31.34, 30.98;

[0399] MS (ESI) m / z: calcd. 370.2 [M+H] + , measured value 352.1[M+H-H2O] + .

[0400] Example 1:

[0401] ((5-Hydroxy-4-(hydroxymethyl)pent-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine isopropyl ester (Compound 1)

[0402] The title compound was prepared according to the following scheme:

[0403] Steps:

[0404] ((5-Hydroxy-4-(hydroxymethyl)pent-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine isopropyl ester (Compound 1)

[0405] To a solution of ((but-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine isopropyl ester (1 g, 3.36 mmol, 1 eq), 2-methylene-1,3-propanediol (541.62 mg, 6.15 mmol, 2 eq), and p-benzoquinone (39.87 mg, 368.85 μmol, 0.12 eq) in dichloromethane (30 mL) was added the second-generation Hoveyda-Grubbs catalyst (144.45 mg, 230.52 μmol, 0.075 eq). At t = 0, 2, and 4 hours during the reaction, the catalyst was added in three equal portions, each (48.15 mg, 76.84 μmol, 0.025 eq). The solution was then heated to reflux at 45°C under a nitrogen atmosphere for 18 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure to yield a residue. The residue was purified by preparative HPLC (FA conditions) to give ((5-hydroxy-4-(hydroxymethyl)pent-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine isopropyl ester (0.04 g, 117.19 μmol, 3.48% yield) as the desired product as a colorless oil.

[0406] 1H NMR (400MHz, CDCl3) δ=7.34-7.32(m,2H),7.30-7.27(m,2H),7.22-7.29(m,1H),5.62-5.58(m,1H),5.01-4.96(m,1H),4.31-4 .19(m,4H),4.06-3.87(m,1H),3.77-3.58(m,1H),3.42-2.73(m,2H),2.59-2.54(m,2H),2.09–2.04(m,2H),1.28-1.21(m,9H);

[0407] 31 P NMR (162MHz, CDCl3) δ = 32.08, 31.86;

[0408] MS (ESI) m / z: calcd. 386.2 [M+H] + , measured value 368.2[M+H-H2O] + .

[0409] Example 2:

[0410] (((E)-5-Hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine 2-ethylbutyl ester (Compound 2)

[0411] The title compound was prepared according to the following scheme:

[0412] Experimental operation

[0413] Step 1: (tert-Butyloxycarbonyl)-L-alanine 2-ethylbutyl ester (Compound 2-1)

[0414] To a mixed solution of N-tert-butyloxycarbonyl-L-alanine (2.22 g, 11.74 mmol, 1.2 eq) and 2-ethyl-1-butanol (1.0 g, 9.79 mmol, 1 eq) in dichloromethane (50 mL) was added 4-dimethylaminopyridine (1.79 g, 14.68 mmol, 1.5 eq), triethylamine (1.19 g, 11.74 mmol, 1.2 eq), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.97 g, 10.28 mmol, 1.05 eq) at 25°C. The mixture was stirred at 25°C for 16 hours. After completion of the reaction, an appropriate amount of water was added to quench the reaction. The mixture was extracted with dichloromethane (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography using 0-40% petroleum ether / ethyl acetate to give (tert-butoxycarbonyl)-L-alanine 2-ethylbutyl ester (1.6 g, 5.85 mmol, 59.80% yield) as a colorless oil.

[0415] MS (ESI) m / z: Calculated value 274.2 [M+H] + , measured value 296.0[M+Na] + .

[0416] Step 2: L-Alanine 2-ethylbutyl ester hydrochloride (Compound 2-2)

[0417] At 25°C, (tert-Butyloxycarbonyl)-L-alanine 2-ethylbutyl ester (1.6 g, 5.85 mmol, 1.0 eq) was added to a solution of hydrogen chloride in 1,4-dioxane (4 M, 15 mL), and the mixture was stirred at 25°C for 1 hour. After the reaction, the solvent was removed by concentration under reduced pressure to obtain L-alanine 2-ethylbutyl ester hydrochloride (1.2 g, 98% yield) as a white solid, which was used directly in the next reaction without further treatment.

[0418] MS (ESI) m / z: Calculated value 174.2 [M+H] + , measured value 174.2[M+H] + .

[0419] Step 3: ((But-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine 2-ethylbutyl ester (Compound 2-3)

[0420] To a solution of 4-dichlorophosphorylbut-1-ene (1 g, 5.78 mmol, 1 eq) in dichloromethane (50 mL) was added triethylamine (1.17 g, 11.56 mmol, 2 eq) at -78°C under nitrogen, and the mixture was stirred at -78°C for 5 minutes. L-alanine 2-ethylbutyl ester hydrochloride (1.20 g, 5.78 mmol, 1 eq) and phenol (0.54 g, 5.78 mmol, 1 eq) were then added to the mixture under nitrogen at -78°C, and the mixture was stirred at 20°C for 16 hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain a residue. The residue was purified by silica gel column chromatography eluting with 10-30% petroleum ether / ethyl acetate to give ((but-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine 2-ethylbutyl ester (210 mg, 0.57 mmol, 9.89% yield) as a colorless oil.

[0421] MS (ESI) m / z: calcd. 368.2 [M+H] + , measured value 368.2[M+H] + .

[0422] Step 4: (((E)-5-Hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine 2-ethylbutyl ester (Compound 2)

[0423] To a solution of ((but-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine 2-ethylbutyl ester (0.15 g, 408.25 μmol, 1 eq), 2-methylallyl alcohol (58.87 mg, 816.51 μmol, 2 eq), and p-benzoquinone (5.30 mg, 48.99 μmol, 0.12 eq) in dichloromethane (50 mL) was added the second-generation Hoveyda-Grubbs catalyst (19.17 mg, 30.63 μmol, 0.075 eq). At t = 0, 2, and 4 hours during the reaction, the catalyst was added in three equal portions, each (6.39 mg, 10.21 μmol, 0.025 eq). The solution was then heated to reflux at 45°C under a nitrogen atmosphere for 18 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated in vacuo to yield a residue. The residue was purified by preparative HPLC (FA conditions) to give (((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine 2-ethylbutyl ester (8.8 mg, 21.40 μmol, 5.24% yield) as the desired product as a colorless oil.

[0424] 1H NMR (400MHz, CDCl3) δ=7.33-7.31(m,2H),7.30-7.29(m,2H),7.22-7.14(m,1H),5.48(q,J=7.2Hz,1H),4.15-3.98(m,5H),3.48-3.2 8(m,1H),2.50-2.46(m,2H),2.06-1.89(m,2H),1.71(d,J=4.4Hz,3H),1.54-1.44(m,1H),1.35-1.20(m,7H),0.88(t,J=7.2Hz,6H);

[0425] 31 P NMR (162MHz, CDCl3) δ = 31.53, 31.15;

[0426] MS (ESI) m / z: Calculated value 412.2 [M+H] + , measured value 412.2[M+H] + .

[0427] Example 3:

[0428] ((Phenoxy)(((Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-en-1-yl)oxy)phosphoryl)-L-alanine isopropyl ester (Compound 3)

[0429] The title compound was prepared according to the following scheme:

[0430] Experimental operation

[0431] Step 1: ((((Z)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-yl)oxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester (Compound 3-1)

[0432] To a solution of phenyl dichlorophosphate (300 mg, 1.43 mmol, 1 eq) in dichloromethane (5 mL) was added triethylamine (289.20 mg, 2.86 mmol, 2 eq) at -78°C under nitrogen, and the mixture was stirred at -78°C for 5 minutes. Subsequently, L-alanine isopropyl ester hydrochloride (238.91 mg, 1.43 mmol, 1 eq) and (Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-ol (386.29 mg, 1.43 mmol, 1 eq) were added, and the mixture was stirred at 20°C for 16 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (NH4HCO3 conditions) to give ((((Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-yl)oxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester (21.8 mg, 40.43 μmol, 2.83% yield) as a colorless oil.

[0433] 1 H NMR (400MHz, CDCl3) δ=7.35-7.31(m,2H),7.24-7.16(m,3H),6.20(q,J=6.0Hz,1H),5.05-4.98(m,1H),4.91-4.90(m,2H),4.2 4(s,2H),4.01-3.96(m,1H),3.60(t,J=10.4Hz,1H),1.38(dd,J=6.8,4.4Hz,3H),1.26-1.21(m,6H),0.92(s,9H),0.09(s,6H);

[0434] 31 P NMR (162MHz, CDCl3) δ = 2.38;

[0435] 19 F NMR (376MHz, CDCl3) δ = -61.40;

[0436] MS (ESI) m / z: calculated value 540.1 [M+H] + , measured value 540.1[M+H] + .

[0437] Step 2: ((Phenoxy)(((Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-en-1-yl)oxy)phosphoryl)-L-alanine isopropyl ester (Compound 3)

[0438] To a solution of ((((Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-yl)oxy)(phenoxy)phosphoryl)-L-alanine isopropyl ester (10.0 mg, 18.53 μmol, 1.0 eq) in acetonitrile (3 mL) was added p-toluenesulfonic acid (6.38 mg, 37.06 μmol, 2.0 eq), and the mixture was stirred at 25°C for 2 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (NH4HCO3 conditions) to give the desired product ((phenoxy)(((Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-en-1-yl)oxy)phosphoryl)-L-alanine isopropyl ester (2.7 mg, 6.35 μmol, 34.27% yield), which was the target product as a colorless oil.

[0439] 1 H NMR (400MHz, CDCl3) δ=7.36-7.32(m,2H),7.23-7.18(m,3H),6.27-6.21(m,1H),5.05-4.99(m,1H),4.91-4.87(m ,2H),4.24(s,2H),4.01-3.95(m,1H),3.68-3.60(m,1H),2.63(s,1H),1.37(t,J=7.2Hz,3H),1.25-1.22(m,6H);

[0440] 31 P NMR (162MHz, CDCl3) δ = 2.56, 2.38;

[0441] 19 F NMR (376MHz, CDCl3) δ = 61.20;

[0442] MS (ESI) m / z: Calculated value 426.1 [M+H] + , measured value 426.0[M+H] + .

[0443] Example 4:

[0444] (((E)-5-Hydroxy-4-ethylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine isopropyl ester (Compound 4)

[0445] The title compound was prepared according to the following scheme:

[0446] Experimental operation

[0447] Step 1: (((E)-5-Hydroxy-4-ethylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine isopropyl ester (Compound 4)

[0448] To a solution of (but-3-en-1-yl(phenoxy)phosphoryl)-L-alanine isopropyl ester (300 mg, 0.92 mmol, 1 eq), 2-methylenebutan-1-ol (237.72 mg, 2.76 mmol, 3 eq), and p-benzoquinone (11.89 mg, 0.11 mmol, 0.12 eq) in dichloromethane (10 mL) was added the second-generation Hoveyda-Grubbs catalyst (43.2 mg, 69 μmol, 0.075 eq). At t = 0, 2, and 4 hours during the reaction, the catalyst was added in three equal portions (14.4 mg, 23 μmol, 0.025 eq). The solution was then heated to reflux at 45°C under a nitrogen atmosphere for 18 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure to yield a residue. The residue was purified by preparative HPLC (NH4HCO3 conditions) to give (((E)-5-hydroxy-4-ethylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine isopropyl ester (2.8 mg, 7.30 μmol, 7.93% yield) as the target product in the form of a colorless oil.

[0449] 1 H NMR (400MHz, CDCl3) δ=7.34-7.30(m,2H),7.22(d,J=7.6Hz,2H),7.16-7.14(m,1H),5.45-5.42(m,1H),5.02–4.96(m,1H),4.07(s,2H) ,3.44-3.27(m,1H),2.50-2.45(m,2H),2.18-2.14(m,2H),2.00-1.89(m,2H),1.32-1.20(m,3H),1.25-1.23(m,6H),1.04-1.00(m,3H);

[0450] 31 P NMR (162MHz, CDCl3): δ31.40, 30.99;

[0451] MS (ESI) m / z: calcd. 384.2 [M+H] + , measured value 384.2[M+H] + .

[0452] Example 5:

[0453] (((E)-5-Hydroxypent-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine isopropyl ester (Compound 5)

[0454] The title compound was prepared according to the following scheme:

[0455] Experimental operation

[0456] Step 1: (((E)-5-Hydroxypent-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine isopropyl ester (Compound 5)

[0457] To a solution of ((but-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine isopropyl ester (200 mg, 0.62 mmol, 1 eq), allyl alcohol (83.90 mg, 1.45 mmol, 2.35 eq), and p-benzoquinone (8.04 mg, 0.74 mmol, 0.12 eq) in dichloromethane (10 mL) was added the second-generation Hoveyda-Grubbs catalyst (29.16 mg, 46.5 μmol, 0.075 eq). At t = 0, 2, and 4 hours during the reaction, the catalyst was added in three equal portions, each (9.72 mg, 15.5 μmol, 0.025 eq). The solution was then heated to reflux at 45°C under a nitrogen atmosphere for 18 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (FA conditions) to give (((E)-5-hydroxypent-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine isopropyl ester (16.8 mg, 47.30 μmol, 7.63% yield) as the desired product as a colorless oil.

[0458] 1 H NMR (400MHz, CDCl3) δ=7.34-7.30(m,2H),7.23(d,J=8.4Hz,2H),7.28-7.14(m,1H),5.77-5.75(m,2H),4.98(dt,J=12.4,6.4Hz,1H),4.1 2(d,J=2.4Hz,2H),4.00-3.93(m,1H),3.41-3.36(m,1H),2.49-2.45(m,2H),2.01-1.97(m,2H),1.30(d,J=7.2Hz,3H),1.24-1.20(m,6H);

[0459] 31 P NMR (162MHz, CDCl3) δ = 30.73;

[0460] MS (ESI) m / z: calcd. 356.1 [M+H] + , measured value 338.1[M+H-H2O] + .

[0461] Example 6:

[0462] (((E)-5-Hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine cyclopentyl ester (Compound 6)

[0463] Example 6 was synthesized using benzyloxycarbonyl-L-alanine and cyclopentanol as raw materials using the same method as Example 2.

[0464] 1 H NMR (400MHz, CDCl3) δ=7.34-7.30(m,2H),7.21(d,J=8.4Hz,2H),7.16-7.12(m,1H),5.47(t,J=7.2Hz,1H),5.17-5.13(m,1H),4.02(s,2H),3.99-3 .93(m,1H),3.43-3.27(m,1H),2.53-2.39(m,2H),2.00-1.92(m,2H),1.8 9-1.79(m,2H),1.73-1.70(m,3H),1.68-1.64(m,6H),1.31-1.18(m,3H);

[0465] 31 P NMR (162MHz, CDCl3) δ = 31.51, 31.11;

[0466] MS (ESI) m / z: calcd. 396.2 [M+H] + , measured value 396.4[M+H] + .

[0467] Example 7:

[0468] (((E)-5-Hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine (R)-tetrahydrofuran-3-yl ester (Compound 7)

[0469] Example 7 was synthesized using benzyloxycarbonyl-L-alanine and (R)-tetrahydrofuran-3-ol as raw materials using the same method as Example 2.

[0470] 1H NMR(400MHz, CDCl3)δ=7.32-7.29(m,2H),7.22-7.20(m,2H),7.19-7.14(m, 1H),5.53-5.42(m,1H),5.33-5.20(m,1H),4.14-4.02(m,1H),4.01(s,2H),3 .92-3.79(m,3H),3.76-3.67(m,1H),3.44-3.22(m,1H),2.54-2.39(m,2H), 2.22-2.10(m,1H),2.04-1.89(m,3H),1.71-1.68(m,3H),1.33-1.20(m,3H);

[0471] 31 P NMR (162MHz, CDCl3) δ = 31.40, 31.00;

[0472] MS (ESI) m / z: calcd. 398.1 [M+H] + , measured value 380.1[M+H-H2O] + .

[0473] Example 8:

[0474] (((E)-5-Hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine (S)-tetrahydrofuran-3-yl ester (Compound 8)

[0475] Example 8 was synthesized using benzyloxycarbonyl-L-alanine and (S)-tetrahydrofuran-3-ol as raw materials using the same method as Example 2.

[0476] 1 H NMR(400MHz, CDCl3)δ=7.34-7.29(m,2H),7.21-7.19(m,2H),7.16-7.14(m,1H) ,5.50-5.45(m,1H),5.25(t,J=5.2Hz,1H),4.14-4.02(m,1H),4.00(s,2H),3.90 -3.84(m,3H),3.83-3.74(m,1H),3.45-3.25(m,1H),2.45(J=14.8,7.6Hz,2H), 2.22-2.12(m,1H),2.01-1.91(m,3H),1.70(d,J=4.0Hz,3H),1.33-1.21(m,3H);

[0477] 31P NMR (162MHz, CDCl3) δ = 31.40, 31.00;

[0478] MS (ESI) m / z: calcd. 398.1 [M+H] + , measured value 380.1[M+H-H2O] + .

[0479] Example 9:

[0480] ((Phenoxy)(((Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-en-1-yl)oxy)phosphoryl)-L-alanine cyclopropylmethyl ester (Compound 9)

[0481] The title compound was prepared according to the following scheme:

[0482] Experimental operation

[0483] Step 1: (tert-Butyloxycarbonyl)-L-alanine cyclopropylmethyl ester (Compound 9-1)

[0484] To a mixed solution of N-tert-butyloxycarbonyl-L-alanine (5.00 g, 26.43 mmol, 1 eq) and hydroxymethylcyclopropane (2.29 g, 31.72 mmol, 1.2 eq) in acetonitrile (50 mL) at 0°C were added 4-dimethylaminopyridine (4.84 g, 39.65 mmol, 1.5 eq) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.32 g, 27.75 mmol, 1.05 eq). The mixture was stirred at 25°C for 3 hours. After completion of the reaction, an appropriate amount of water was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography using 0-20% petroleum ether / ethyl acetate to give (tert-butoxycarbonyl)-L-alanine cyclopropylmethyl ester (3.5 g, 14.39 mmol, 54.45% yield) as a colorless oil.

[0485] 1 H NMR (400MHz, CDCl3) δ = 5.07 (d, J = 2.4Hz, 1H), 4.35-4.31 (m, 1H), 4.02-3.95 (m, 2H), 1.46 (s,9H),1.40(d,J=7.2Hz,3H),1.16-1.12(m,1H),0.59-0.57(m,2H),0.31-0.27(m,2H).

[0486] Step 2: L-Alanine cyclopropyl methyl ester trifluoroacetate (Compound 9-2)

[0487] Trifluoroacetic acid (1 mL) was added to a solution of (tert-butyloxycarbonyl)-L-alanine cyclopropyl methyl ester (0.5 g, 2.06 mmol, 1 eq) in dichloromethane (5 mL) at 25°C, and the mixture was stirred at 25°C for 1 hour. After the reaction, the solvent was removed by concentration under reduced pressure to obtain L-alanine cyclopropyl methyl ester trifluoroacetate (0.46 g, 92.7% yield) as a bright yellow oil, which was used directly in the next reaction without further treatment.

[0488] 1H NMR (400MHz, CDCl3) δ = 9.85 (s, 2H), 4.15-4.13 (m, 1H), 4.07–4.01 (m, 2H), 1.63 (d,J=7.2Hz,3H),1.16-1.12(m,1H),0.64-0.60(m,2H),0.30(q,J=4.8Hz,2H).

[0489] Step 3: ((((Z)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-yl)oxy)(phenoxy)phosphoryl)-L-alanine cyclopropylmethyl ester (Compound 9-3)

[0490] To a solution of phenyl dichlorophosphate (300 mg, 1.43 mmol, 1 eq) in dichloromethane (10 mL) at -78°C under nitrogen was added triethylamine (718.2 mg, 7.1 mmol, 5 eq). The mixture was stirred at -78°C for 5 minutes. L-alanine cyclopropylmethyl ester trifluoroacetate (365.11 mg, 1.42 mmol, 1 eq) and (Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-ol (383.78 mg, 1.42 mmol, 1 eq) were then added. The mixture was stirred at 25°C for 16 hours. After completion of the reaction, an appropriate amount of water was added to quench the reaction. The mixture was extracted with dichloromethane (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography eluting with 0-55% petroleum ether / ethyl acetate to give ((((Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-yl)oxy)(phenoxy)phosphoryl)-L-alanine cyclopropylmethyl ester (70 mg, 126.90 μmol, 8.94% yield) as a yellow oil.

[0491] MS (ESI) m / z: calculated value 552.2 [M+H] + , measured value 552.2[M+H] + .

[0492] Step 4: ((Phenoxy)(((Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-en-1-yl)oxy)phosphoryl)-L-alanine cyclopropylmethyl ester (Compound 9)

[0493] To a solution of ((((Z)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-yl)oxy)(phenoxy)phosphoryl)-L-alanine cyclopropylmethyl ester (70 mg, 126.90 μmol, 1 eq) in acetonitrile (3 mL) was added p-toluenesulfonic acid (43.69 mg, 253.8 μmol, 2 eq), and the mixture was stirred at 25°C for 16 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (NH4HCO3 conditions) to give ((phenoxy)(((Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-en-1-yl)oxy)phosphoryl)-L-alanine cyclopropylmethyl ester (0.5 mg, 1.14 μmol, 0.90% yield) as the desired product as a colorless oil.

[0494] 1 H NMR (400MHz, CDCl3) δ=7.36-7.33(m,2H),7.24-7.18(m,3H),6.23(dt,J=11 .6,5.6Hz,1H),4.92-4.90(m,2H),4.25(s,2H),4.11-4.00(m,1H),3.99-3.9 4(m,2H),3.74(q,J=7.2Hz,1H),3.72-3.57(m,1H),1.41(t,J=7.2Hz,3H),1. 25(t,J=7.2Hz,1H)1.13-1.11(m,1H),0.60-0.56(m,2H),0.30-0.27(m,2H);

[0495] 31 P NMR (162MHz, CDCl3) δ = 2.29;

[0496] 19 F NMR (376MHz, CDCl3) δ = -61.19;

[0497] MS (ESI) m / z: Calculated value 438.1 [M+H] +, measured value 438.1[M+H] + .

[0498] Example 10:

[0499] ((Phenoxy)(((Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-en-1-yl)oxy)phosphoryl)-L-alanine 2-ethylbutyl ester (Compound 10)

[0500] Example 10 was synthesized using N-tert-butyloxycarbonyl-L-alanine and 2-ethyl-1-butanol as raw materials using the same method as Example 9.

[0501] 1 H NMR (400MHz, CDCl3) δ=7.37-7.33(m,2H),7.25-7.19(m,3H),6.25(dt,J=11.6,5.6Hz,1H),4.91(dd,J=4.4,2.0Hz ,2H),4.25(s,2H),4.10-4.04(m,3H),3.72-3.66(m,1H),1.56-1.48(m,1H),1.42-1.34(m,7H),0.93-0.88(m,6H);

[0502] 31 P NMR (162MHz, CDCl3) δ = 2.51;

[0503] 19 F NMR (376MHz, CDCl3) δ = -61.24;

[0504] MS (ESI) m / z: Calculated value 468.2 [M+H] + , measured value 468.2[M+H] + .

[0505] Example 11:

[0506] ((Phenoxy)(((Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-en-1-yl)oxy)phosphoryl)-L-alanine cyclopentyl ester (Compound 11)

[0507] Example 11 was synthesized using N-benzyloxycarbonyl-L-alanine and cyclopentanol as raw materials using the same method as Example 9.

[0508] 1H NMR (400MHz, CDCl3) δ=7.36-7.32(m,2H),7.23-7.18(m,3H),6.26-6.22(m,1H),5.20-5.17(m,1H),4.91-4.88(m,2H),4.25( s,2H),3.99-3.95(m,1H),3.60-3.57(m,1H),2.48-2.47(m,1H),1.88-1.84(m,2H),1.72-1.67(m,6H),1.36(t,J=7.6Hz,3H);

[0509] 31 P NMR (162MHz, CDCl3) δ = 2.35;

[0510] 19 F NMR (376MHz, CDCl3) δ = -61.24;

[0511] MS (ESI) m / z: calcd. 452.1 [M+H] + , measured value 452.1[M+H] + .

[0512] Example 12:

[0513] ((Phenoxy)(((Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-en-1-yl)oxy)phosphoryl)-L-alanine (S)-tetrahydrofuran-3-yl ester (Compound 12)

[0514] Example 12 was synthesized using N-benzyloxycarbonyl-L-alanine and (S)-3-hydroxytetrahydrofuran as raw materials using the same method as Example 9.

[0515] 1 H NMR (400MHz, CDCl3) δ=7.36-7.32(m,2H),7.23-7.18(m,3H),6.26-6.21(m,1H),5.31-5.29(m,1H),4.92-4.90(m,2H),4.23(s,2 H),4.08-3.97(m,1H),3.93-3.81(m,3H),3.78-3.64(m,2H),2.22-2.15(m,1H),2.00-1.97(m,1H),1.38(dd,J=6.8,3.2Hz,3H);

[0516] 31 P NMR (162MHz, CDCl3) δ = 2.38, 2.15;

[0517] 19 F NMR (376MHz, CDCl3) δ = -61.18, -61.19;

[0518] MS (ESI) m / z: Calculated value 454.1 [M+H] + , measured value 454.0[M+H] + .

[0519] Example 13: Compound 13

[0520] Example 13 was synthesized using N-benzyloxycarbonyl-L-alanine and (R)-3-hydroxytetrahydrofuran as raw materials using the same method as Example 9.

[0521] 1 H NMR(400MHz, CDCl3)δ=7.36-7.32(m,2H),7.24-7.18(m,3H),6.25-6.18(m,1H),5.31-5.29(m,1H),4.92-4.90(m,2H), 4.24(s,2H),4.06-3.78(m,5H),3.67-3.57(m,1H),2.22-2.15(m,1H),2.02-1.95(m,1H),1.38(dd,J=7.2,3.6Hz,3H);

[0522] 31 P NMR (162MHz, CDCl3) δ = 2.40, 1.95;

[0523] 19 F NMR (376MHz, CDCl3) δ = -61.19, -61.27;

[0524] MS (ESI) m / z: Calculated value 454.1 [M+H] + , measured value 454.2[M+H] + .

[0525] Example 14: Compound 14

[0526] The title compound was prepared according to the following scheme:

[0527] Experimental operation

[0528] Step 1: 1-naphthyl dichlorophosphate (Compound 14-1)

[0529] Phosphorus oxychloride (1.06 g, 6.94 mmol, 1 eq) was added to a solution of 1-naphthol (1 g, 6.94 mmol, 1 eq) in tetrahydrofuran (40 mL) at -78°C under nitrogen. Triethylamine (701.87 mg, 6.94 mmol, 1 eq) was then added dropwise to the mixture at -78°C under nitrogen. The mixture was stirred at 25°C for 16 hours. After the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent, yielding 1-naphthyl dichlorophosphate (1.2 g, 66.7% yield) as a colorless oil that was used directly in the next reaction without further treatment.

[0530] Step 2: ((((Z)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-yl)oxy)(naphthyloxy)phosphoryl)-L-alanine isopropyl ester (Compound 14-2)

[0531] To a solution of 1-naphthyl dichlorophosphate (300 mg, 1.15 mmol, 1 eq) in dichloromethane (5 mL) was added triethylamine (465.31 mg, 4.6 mmol, 4 eq) at -78°C under nitrogen. The mixture was stirred at -78°C for 5 minutes. L-alanine isopropyl ester hydrochloride (192.72 mg, 1.15 mmol, 1 eq) and (Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-ol (310.81 mg, 1.15 mmol, 1 eq) were then added. The mixture was stirred at 25°C for 16 hours. After completion of the reaction, an appropriate amount of water was added to quench the reaction. The mixture was extracted with dichloromethane (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography eluting with 0-50% petroleum ether / ethyl acetate to give ((((Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-yl)oxy)(naphthyloxy)phosphoryl)-L-alanine isopropyl ester (25 mg, 42.4 μmol, 3.69% yield) as a colorless oil.

[0532] MS (EI) m / z: calculated value 590.2 [M+H] + , measured value 590.2[M+H] + .

[0533] Step 3: ((Naphthyloxy)(((Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-en-1-yl)oxy)phosphoryl)-L-alanine isopropyl ester (Compound 14)

[0534] To a solution of ((((Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-yl)oxy)(naphthyloxy)phosphoryl)-L-alanine isopropyl ester (20 mg, 33.92 μmol, 1 eq) in acetonitrile (2 mL) was added p-toluenesulfonic acid (11.68 mg, 67.84 μmol, 2.0 eq), and the mixture was stirred at 25°C for 16 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (NH3.H2O conditions) to obtain ((naphthyloxy)(((Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-en-1-yl)oxy)phosphoryl)-L-alanine isopropyl ester (1.4 mg, 2.94 μmol, 8.67% yield) as the desired product as a colorless oil.

[0535] 1 H NMR (400MHz, CDCl3) δ = 8.11 (dd, J = 6.4, 3.2Hz, 1H), 7.86-7.84 (m, 1H), 7.67 (dd, J = 8.4, 1.6Hz,1H),7.54-7.52(m,3H),7.41(td,J=8.0,3.2Hz,1H),6.23-6.18(m,1H),4.98-4. 93(m,3H),4.21(s,2H),4.06-4.04(m,1H),3.69-3.62(m,1H),2.10-2.04(m,1H),1.33( ddd,J=12.8,7.2,3.2Hz,3H),1.23(dt,J=6.4,3.2Hz,3H),1.18(td,J=6.4,3.2Hz,3H);

[0536] 31 P NMR (162MHz, CDCl3) δ = 2.82;

[0537] 19 F NMR (376MHz, CDCl3) δ = -61.21;

[0538] MS (ESI) m / z: Calculated value 476.1 [M+H] + , measured value 476.1[M+H] + .

[0539] Example 15:

[0540] (R)-Tetrahydrofuran-3-yl((4-chlorophenoxy)(E)-5-hydroxy-4-methylpent-3-en-1-yl)phosphoryl)-L-propylaminoester (Compound 15)

[0541] The title compound was prepared according to the following scheme:

[0542] Example 15 uses benzyloxycarbonyl-L-alanine and (R)-3-hydroxytetrahydrofuran as raw materials, replaces phenol with p-chlorophenol in step 3 of Example 2, and is synthesized using the same method as Example 2.

[0543] 1 H NMR (400MHz, CDCl3) δ=7.29-7.28(m,2H),7.18-7.16(m,2H),5.49-5.47(m,1H),5.28-5.24(m,1H),4.12-4.02(m,3H),3.90-3.85(m, 3H),3.77-3.71(m,1H),3.36-3.24(m,1H),2.48-2.45(m,2H),2.23-2.13(m,1H),1.99-1.92(m,3H),1.71(s,3H),1.35-1.23(m,3H);

[0544] 31 P NMR (162MHz, CDCl3) δ = 31.57, 31.49

[0545] MS (ESI) m / z: calculated value 432.1 [M ( 35 Cl)+H] + ,434.1[M( 37 Cl)+H] + , the measured value is 432.1[M( 35 Cl)+H] + ,434.1[M( 37 Cl)+H] +

[0546] Example 16:

[0547] (R)-Tetrahydrofuran-3-yl((E)-5-hydroxy-4-methylpent-3-en-1-yl)(p-methoxy)phosphoryl)-L-propylaminoester (Compound 16)

[0548] The title compound was prepared according to the following scheme:

[0549] Example 16 uses benzyloxycarbonyl-L-alanine and (R)-3-hydroxytetrahydrofuran as raw materials, replaces phenol with p-methylphenol in step 3 of Example 2, and adopts the same method as Example 2 to synthesize.

[0550] 1H NMR (400MHz, CDCl3) δ=7.12-7.07(m,4H),5.50-5.46(m,1H),5.27-5.25(m,1H),4.03-4.01(m,3H),3.90-3.83(m,3H),3.78-3.71 (m,1H),3.36-3.20(m,1H),2.47-2.43(m,2H),2.31(s,3H),2.21-2.11(m,1H),1.96-1.89(m,3H),1.70(s,3H),1.34-1.23(m,3H);

[0551] 31 P NMR (162MHz, CDCl3) δ = 30.86, 30.82

[0552] MS (ESI) m / z: Calculated value 412.2 [M+H] + , measured value 394.2 [M+H–H2O] + .

[0553] Example 17:

[0554] (R)-Tetrahydrofuran-3-yl((E)-5-hydroxy-4-methylpent-3-en-1-yl)(naphthalen-1-yloxy)phosphoryl)-L-propylaminate (Compound 17)

[0555] The title compound was prepared according to the following scheme:

[0556] Example 17 uses benzyloxycarbonyl-L-alanine and (R)-3-hydroxytetrahydrofuran as raw materials, replaces phenol with 1-naphthol in step 3 of Example 2, and adopts the same method as Example 2 to synthesize.

[0557] 1 H NMR (400MHz, CDCl3) δ = 8.08-8.06 (m, 1H), 7.86-7.84 (m, 1H), 7.64 (d, J = 8.0Hz, 1H), 7.59 (d, J=7.6Hz,1H),7.60-7.52(m,2H),7.43-7.39(m,1H),5.51-5.48(m,1H),5.17-5.14(m,1H),4 .10-4.04(m,1H),4.01(s,2H),3.83-3.78(m,3H),3.67-3.62(m,1H),3.47-3.28(m,1H),2.5 5-2.50(m,2H),2.12-2.05(m,3H),1.83-1.80(m,1H),1.71-1.69(m,3H),1.29–1.26(m,3H);

[0558] 31 P NMR (162MHz, CDCl3) δ = 31.44, 31.39;

[0559] MS (ESI) m / z: calcd. 448.2 [M+H] + , measured value 470.0[M+Na] + .

[0560] Example 18:

[0561] (R)-Tetrahydrofuran-3-yl((S)-((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-propylaminate (Compound 18) & (R)-Tetrahydrofuran-3-yl((S)-((R)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-propylaminate (Compound 19)

[0562] The title compound was prepared according to the following scheme:

[0563] Compound 7 from Example 7 was resolved by SFC.

[0564] (R)-Tetrahydrofuran-3-yl((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-propylaminoester (600 mg, 1.51 mmol, 1 eq) was purified by supercritical fluid chromatography (SFC) and normal phase high pressure liquid chromatography (DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 μm); mobile phase: [CO2-EtOH]; B%: 25%, isocratic elution). The first elution obtained was compound 18 (305.56 mg, 768.90 μmol, 50.92% yield), and the second elution was compound 19 (137.6 mg, 346.25 μmol, 22.93% yield), both of which were the target products as colorless oils.

[0565] The characterization data of compound 18 are as follows:

[0566] 1H NMR (400MHz, CDCl3) δ = 7.34-7.30 (m, 2H), 7.21 (d, J = 8.0Hz, 2H), 7.17-7.15 (m, 1 H),5.47(t,J=6.8Hz,1H),5.27-5.24(m,1H),4.07-4.05(m,1H),4.02(s,2H),3.9 0-3.84(m,3H),3.73(d,J=10.4Hz,1H),3.35(t,J=10.4Hz,1H),2.48–2.43(m,2H) ,2.22-2.12(m,1H),2.04-1.86(m,3H),1.71-1.69(m,3H),1.33(d,J=7.2Hz,3H);

[0567] 31 P NMR (162MHz, CDCl3) δ = 30.88;

[0568] MS (EI) m / z: calcd. 398.2 [M+H] + , measured value 398.1[M+H] + .

[0569] The characterization data of compound 19 are as follows:

[0570] 1 H NMR (400MHz, CDCl3) δ = 7.35-7.31 (m, 2H), 7.21 (d, J = 8.4Hz, 2H), 7.17-7.15 (m, 1H),5.49(t,J=6.8Hz,1H),5.27-5.25(m,1H),4.14-4.08(m,1H),4.02(s,2H),3 .91-3.84(m,3H),3.79-3.76(m,1H),3.25(t,J=10.4Hz,1H),2.49–2.45(m,2H), 2.21-2.17(m,1H),2.03-1.86(m,3H),1.77-1.72(m,3H),1.22(d,J=7.2Hz,3H);

[0571] 31 P NMR (162MHz, CDCl3) δ = 31.31;

[0572] MS (EI) m / z: calcd. 398.2 [M+H] + , measured value 398.1[M+H] + .

[0573] Example 20:

[0574] Tetrahydro-2H-pyran-4-yl-((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-propylaminate (Compound 20)

[0575] The product was synthesized using the same method as in Example 2 using benzyloxycarbonyl-L-alanine and tetrahydro-2H-pyran-4-ol as raw materials.

[0576] 1 H NMR (400MHz, CDCl3) δ=7.33-7.31(m,2H),7.23-7.20(m,2H),7.15-7.13(m,1H),5.51-5.4 3(m,1H),4.96-4.88(m,1H),4.05-4.03(m,1H),4.01(s,2H),3.91-3.83(m,2H),3.55-3.4 9(m,2H),3.42-3.33(m,0.6H),3.30–3.25(m,0.4H),2.53-2.40(m,2H),2.04-1.92(m,2H) ,1.90-1.84(m,4H),1.71(s,1.5H),1.70(s,1.5H),1.67-1.60(m,2H),1.34-1.31(m,3H);

[0577] 31 P NMR (162MHz, CDCl3) δ = 31.42, 31.04;

[0578] MS (ESI) m / z: Calculated value 412.2 [M+H] + , measured value 394.2[M+H-H2O] + ,434.1[M+Na] + ;

[0579] Examples 21 and 22:

[0580] Tetrahydro-2H-pyran-4-yl((S)-((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine (Compound 21) & Tetrahydro-2H-pyran-4-yl((R)-((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine (Compound 22)

[0581] The title compound was prepared according to the following scheme:

[0582] Compound 20 (90 mg, 218.75 μmol, 1 eq) was purified by supercritical fluid chromatography (DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 μm); mobile phase: [CO2-EtOH / ACN]; B%: 35%, isocratic elution mode) and preparative HPLC (Waters Xbridge C18 150*50 mm*10 μm; mobile phase: [water(NH4HCO3)-ACN]; gradient: 17%-47% B over 10 min) to obtain the first compound 21 (10 mg, 24.31 μmol, 11.11% yield) and the second compound 22 (5 mg, 12.15 μmol, 5.55% yield), both of which were colorless oily target products.

[0583] The characterization of compound 21 is as follows:

[0584] 1 H NMR(400MHz, CDCl3)δ=7.33-7.29(m,2H),7.23-7.20(m,2H),7.16-7.14(m,1H),5.4 9-5.45(m,1H),4.95-4.90(m,1H),4.05-4.03(m,1H),4.01(s,2H),3.90-3.85(m,2H ),3.55-3.49(m,2H),3.40(t,J=10.4Hz,1H),2.46(dq,J=14.8,7.2Hz,2H),1.99-1. 92(m,2H),1.87-1.86(m,2H),1.70(s,3H),1.67-1.58(m,2H),1.34(d,J=7.2Hz,3H);

[0585] 31 P NMR (162MHz, CDCl3) δ = 31.02;

[0586] MS (ESI) m / z: Calculated value 412.2 [M+H] + , measured value 394.2[M+H-H2O] + .

[0587] The characterization of compound 22 is as follows:

[0588] 1H NMR(400MHz, CDCl3)δ=7.34-7.30(m,2H),7.22-7.20(m,2H),7.17-7.13(m,1H),5 .49(t,J=6.8Hz,1H),4.94-4.90(m,1H),4.13-4.10(m,1H),4.01(s,2H),3.90-3.8 6(m,2H),3.55-3.50(m,2H),3.29(t,J=10.8Hz,1H),2.53-2.41(m,2H),2.04-1.98 (m,2H),1.88-1.87(m,2H),1.71(s,3H),1.65-1.63(m,2H),1.22(d,J=7.2Hz,3H);

[0589] 31 P NMR (162MHz, CDCl3) δ = 31.42;

[0590] MS (ESI) m / z: Calculated value 412.2 [M+H] + , measured value 394.2[M+H-H2O] + .

[0591] Example 23:

[0592] Isopropyl (((Z)-4-fluoro-5-hydroxy-3-en-1-yl)(phenoxy)phosphoryl)-L-propylamino ester (Compound 23)

[0593] The title compound was prepared according to the following scheme:

[0594] Experimental operation

[0595] Step 1: Isopropyl (((E)-5-oxo-3-en-1-yl)(phenoxy)phosphoryl)-L-propylamino ester (Compound 23-1)

[0596] To a solution of isopropyl(but-3-en-1-yl(phenoxy)phosphoryl)-L-propylaminoester (13 g, 39.96 mmol, 1 eq), acrolein (9.81 g, 319.68 mmol, 8 eq), and 1,4-benzoquinone (367.54 mg, 3.40 mmol, 0.1 eq) in dichloromethane (150 mL) was added second-generation Hoveyda-Grubbs catalyst (2.13 g, 3.40 mmol, 0.1 eq). At t = 0, 2, and 4 hours during the reaction, the catalyst was added in three equal portions, each containing 710 mg, 1.13 mmol. The solution was then heated to reflux at 45°C under a nitrogen atmosphere for 18 hours. LCMS indicated complete reaction of the starting material, with product detected. The mixture was filtered, and the filtrate was concentrated in vacuo to yield a residue. The residue was purified by silica gel column chromatography eluting with 10% ethyl acetate / methanol to give isopropyl (((E)-5-oxo-3-en-1-yl)(phenoxy)phosphoryl)-L-propylaminate (7.5 g, 21.23 mmol, 53.13% yield) as the desired product as a brown oil.

[0597] MS (ESI) m / z: calcd. 354.2 [M+H] + , measured value 354.1[M+H] + .

[0598] Step 2: Isopropyl (((Z)-4-fluoro-5-oxo-3-en-1-yl)(phenoxy)phosphoryl)-L-propylamino ester (Compound 23-2)

[0599] Under a nitrogen atmosphere, to a solution of isopropyl (((E)-5-oxo-3-en-1-yl)(phenoxy)phosphoryl)-L-propylamino ester (6 g, 16.98 mmol, 1 eq), L-proline (1.95 g, 16.98 mmol, 1 eq), sodium acetate (1.39 g, 16.98 mmol, 1 eq), and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (12.03 g, 33.96 mmol, 2 eq) in methanol (60 mL) was added nitromethane (57.23 g, 937.58 mmol, 55.2 eq). The solution was then stirred at 65°C under a nitrogen atmosphere for 16 hours. LCMS indicated complete reaction of the starting material and the product was detected. The mixture was cooled to room temperature and quenched by the addition of saturated ammonium chloride solution (100 mL). The mixture was extracted with dichloromethane (80 mL * 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography using 10% ethyl acetate / methanol as eluent to obtain isopropyl (((Z)-4-fluoro-5-oxo-3-en-1-yl)(phenoxy)phosphoryl)-L-propylaminate (720 mg, 1.94 mmol, 11.42% yield) as the desired product as a brown oil.

[0600] MS (ESI) m / z: calcd. 372.1 [M+H] + , measured value 372.1[M+H] + .

[0601] Step 7: Isopropyl (((Z)-4-fluoro-5-hydroxy-3-en-1-yl)(phenoxy)phosphoryl)-L-propylamino ester (Compound 23)

[0602] To a solution of isopropyl (((Z)-4-fluoro-5-oxo-3-en-1-yl)(phenoxy)phosphoryl)-L-propylamino ester (360 mg, 969.46 μmol, 1 eq) in methanol (5 mL) was slowly added sodium borohydride (73.39 mg, 1.94 mmol, 2 eq) at 0°C under a nitrogen atmosphere. The solution was then stirred at 0°C under a nitrogen atmosphere for 1 hour. LCMS showed that the starting material reaction was complete and product was detected. Saturated ammonium chloride solution (10 mL) was added to the mixture to quench it. The mixture was extracted with dichloromethane (50 mL*2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography eluting with 10% ethyl acetate / methanol, and then purified by preparative HPLC (Phenomenex Synergi C18 150*25mm*10μm; mobile phase: [water (0.1% FA)-ACN]; B%: 40%-50%, 2 min) to give isopropyl (((Z)-4-fluoro-5-hydroxy-3-en-1-yl)(phenoxy)phosphoryl)-L-propylaminate (3.08 mg, 8.25 μmol, 0.85% yield) as the desired product in the form of a colorless oil.

[0603] 1 H NMR(400MHz, CDCl3)δ=7.34-7.30(m,2H),7.22-7.20(m,2H),7.15-7.14(m,1H),5.04-4.95(m,2H),4.14-4 .04(m,2H),3.97–3.95(m,1H),3.41-3.27(m,1H),2.55-2.51(m,2H),2.06-2.00(m,2H),1.32-1.20(m,9H); 31 P NMR (162MHz, CDCl3) δ = 30.64, 30.39; 19 F NMR (376 MHz, CDCl3) δ = -118.43, -118.49; MS (ESI) m / z: calculated value 374.2 [M+H] + , measured value 374.1[M+H] + .

[0604] Example 24:

[0605] Isopropyl (((Z)-4-fluoro-5-hydroxy-3-en-1-yl)(phenoxy)phosphoryl)-L-propylamino ester (Compound 24)

[0606] The title compound was prepared according to the following scheme:

[0607] Experimental operation

[0608] Step 1: 3-(Benzyloxy)-1,1,1-trifluoropropan-2-ol (Compound 24-2)

[0609] To a reaction mixture of benzyl alcohol (30 g, 267.70 mmol, 1 eq) and boron trifluoride etherate (3.8 g, 26.77 mmol, 0.1 eq) was added 1,1,1-trifluoro-2,3-epoxypropane (29 g, 267.70 mmol, 1 eq) at room temperature, and the mixture was stirred at 40°C for 16 hours. After the reaction, the reaction mixture was cooled to room temperature and quenched with an appropriate amount of water. The mixture was extracted with dichloromethane (300 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography using 20-40% petroleum ether / ethyl acetate as the eluent to obtain 3-(benzyloxy)-1,1,1-trifluoropropan-2-ol (35 g, 206.20 mmol, 57.08% yield) as a yellow oil.

[0610] 1 H NMR (400MHz, CDCl3) δ = 7.40-7.32 (m, 5H), 4.61 (s, 2H), 4.18-4.14 (m, 1H), 3.76-3.65 (m, 2H), 2.88 (d, J = 4.0Hz, 1H).

[0611] Step 2: 3-(Benzyloxy)-1,1,1-trifluoropropan-2-one (Compound 24-3)

[0612] To a solution of 3-(benzyloxy)-1,1,1-trifluoropropan-2-ol (24 g, 116.40 mmol, 1.0 eq) in dichloromethane (500 mL) was added dropwise Dess-Martin periodinane (DMP) (64.18 g, 151.32 mmol, 1.3 eq) at 20°C, and the mixture was stirred at 20°C for 16 hours. After the reaction, the mixture was diluted with dichloromethane, and the organic layer was washed with sodium thiosulfate and sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography using 20-40% petroleum ether / ethyl acetate as the eluent to obtain the desired 3-(benzyloxy)-1,1,1-trifluoropropan-2-one (e) (15 g, 66.10 mmol, 56.79% yield) as a colorless oil.

[0613] 1 H NMR (400MHz, CDCl3) δ = 7.39-7.37 (m, 5H), 4.70 (s, 2H), 3.68 (s, 2H).

[0614] Step 3: Ethyl 3-((Benzyloxy)methyl)-4,4,4-trifluorobut-2-enoate (Compound 24-5)

[0615] Under nitrogen, 3-(Benzyloxy)-1,1,1-trifluoropropan-2-one (20 g, 91.70 mmol, 1 eq) was dissolved in an appropriate amount of benzene and refluxed to remove water. The reaction mixture was cooled to 25°C, and ethoxycarbonylmethyltriphenylphosphonium bromide (47.18 g, 109.92 mmol, 1.2 eq) and triethylamine (10.66 g, 210.68 mmol, 2.3 eq) were added to the reaction system. The mixture was stirred at 25°C for 16 hours. After completion of the reaction, an appropriate amount of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography using 20-30% petroleum ether / ethyl acetate to give ethyl 3-((benzyloxy)methyl)-4,4,4-trifluorobut-2-enoate (15 g, 52.03 mmol, 51.09% yield) as a colorless oil.

[0616] 1 H NMR (400MHz, CDCl3) δ=7.39-7.32(m,5H),6.52-6.48(m,1H),4.60(s,2H),4.28-4.21(m,2H),4.18(s,2H),1.33-1.26(m,3H).

[0617] Step 4: 3-((Benzyloxy)methyl)-4,4,4-trifluorobut-2-en-1-ol (Compound 24-6)

[0618] To a solution of ethyl 3-((benzyloxy)methyl)-4,4,4-trifluorobut-2-enoate (6 g, 20.80 mmol, 1 eq) in tetrahydrofuran (50 mL) was added dropwise DIBALH (1.0 M, 41.60 mL, 2.0 eq) at -60°C under nitrogen. The mixture was slowly warmed to room temperature and stirred at room temperature for 15 hours. After the reaction, the mixture was diluted with dichloromethane (100 mL), and the organic layer was washed with saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography using 10-20% petroleum ether / ethyl acetate as the eluent to afford 3-((benzyloxy)methyl)-4,4,4-trifluorobut-2-en-1-ol (3.8 g, 13.90 mmol, 66.8% yield) as a colorless oil.

[0619] 1 H NMR (400MHz, CDCl3) δ = 7.37-7.30 (m, 5H), 6.55-6.52 (m, 0.6H), 6.25-6.22 (m, 0.4H), 4.54 (s ,0.7H),4.53(s,1.3H),4.46(s,0.7H),4.34(s,1.3H),4.17(s,1.3H),4.14-4.09(m,0.7H).

[0620] Step 5: (((4-bromo-2-(trifluoromethyl)but-2-en-1-yl)oxy)methyl)benzene (Compound 24-7)

[0621] To a solution of 3-((benzyloxy)methyl)-4,4,4-trifluorobut-2-en-1-ol (3.5 g, 14.20 mmol, 1 eq) in dichloromethane (20 mL) was added triphenylphosphine (4.47 g, 17.04 mmol, 1.2 eq) and carbon tetrabromide (5.18 g, 15.62 mmol, 1.1 eq) at 0°C under nitrogen. The resulting mixture was stirred at 0°C for 2 hours. After completion of the reaction, the reaction mixture was diluted with an appropriate amount of dichloromethane, and the organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography using 40-60% petroleum ether / ethyl acetate as the eluent to afford compound 24-7 (3.6 g, 32.65 mmol, 98.02% yield) as a colorless oil.

[0622] 1 H NMR (400MHz, CDCl3) δ=7.39-7.32(m,5H),6.58-6.56(m,0.6H),6.36-6.31(m,0.4H),4.56(s,0.7H),4.54 (s,1.3H)4.20(s,0.2H),4.19(s,1.1H),4.14-4.11(m,1.4H),4.09-4.08(m,0.7H),4.07-4.06(m,0.6H).

[0623] 19 F NMR (376MHz, CDCl3) δ = -60.38, -67.68.

[0624] Step 6: 4-Bromo-2-(trifluoromethyl)but-2-en-1-ol (Compound 24-8)

[0625] To a solution of (((4-bromo-2-(trifluoromethyl)but-2-en-1-yl)oxy)methyl)benzene (2.9 g, 52.03 mmol, 1 eq) in dichloromethane (150 mL) was added dropwise boron trichloride (1.0 M, 75.20 mL, 8.0 eq) at -78°C under nitrogen. The resulting mixture was gradually warmed to 20°C and stirred for 5 hours. After the reaction, the mixture was diluted with dichloromethane (150 mL), and the organic layer was washed with saturated sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography using 40-60% petroleum ether / ethyl acetate as the eluent to afford 24-8 (1.20 g, 4.90 mmol, 52.13% yield) as a colorless oil.

[0626] 1 H NMR (400MHz, CDCl3) δ = 6.58-6.54 (m, 0.7H), 6.36-6.531 (m, 0.3H), 4.38 (s, 1.5H), 4.31 (s, 0.5H) 4.15-4.13 (m, 1.5H) 4.13-4.12 (m, 0.5H).

[0627] Step 7: 2-((4-bromo-2-(trifluoromethyl)but-2-en-1-yl)oxy)tetrahydro-2H-pyran (Compound 24-9)

[0628] To a solution of 4-bromo-2-(trifluoromethyl)but-2-en-1-ol (1.50 g, 6.80 mmol, 1 eq) and pyridine p-toluenesulfonate (0.17 g, 0.06 mmol, 0.1 eq) in tetrahydrofuran (40 mL) was added 3,4-dihydropyran (1.71 g, 20.30 mmol, 3 eq), and the reaction mixture was stirred at 20°C for 2 hours. After completion of the reaction, water (20 ml) was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography eluting with 10-20% petroleum ether / ethyl acetate to give 2-((4-bromo-2-(trifluoromethyl)but-2-en-1-yl)oxy)tetrahydro-2H-pyran (1.5 g, 4.97 mmol, 73.1% yield) as a colorless oil.

[0629] 1H NMR(400MHz, CDCl3)δ=6.59-6.55(m,0.6H),6.35-6.30(m,0.4H),4.68-4.66(m,0.4H),4.65-4.64(m,0.6H),4.42-4.39(m,0.6H),4.38-4.34(m, 0.4H),4.22-4.19(m,0.6H),4.15-4.10(m,2H),4.10-4.06(m,0.4H),3.8 7-3.80(m,1H),3.58-3.53(m,1H),1.82-1.69(m,3H),1.67-1.54(m,3H).

[0630] Step 8: Dimethyl (5,5,5-trifluoro-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pent-3-en-1-yl)phosphonate (Compound 24-12)

[0631] To a solution of dimethyl methylphosphonate (135 mg, 1.08 mmol, 1 eq) in tetrahydrofuran (15 mL) at -78°C under nitrogen was added a 2.4 M solution of n-butyllithium in n-hexane (0.50 mL, 1.30 mmol, 1.2 eq). The reaction was stirred at -78°C for 0.5 hour. A solution of 2-((4-bromo-2-(trifluoromethyl)but-2-en-1-yl)oxy)tetrahydro-2H-pyran (330 mg, 1.08 mmol, 1.0 eq) in tetrahydrofuran (1 mL) was then added dropwise. The reaction system was slowly heated and stirred at 20°C for 16 hours. After completion of the reaction, saturated aqueous ammonium chloride (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield a residue. The residue was purified by silica gel column chromatography eluting with 0-10% ethyl acetate / methanol to afford dimethyl (5,5,5-trifluoro-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pent-3-en-1-yl)phosphonate (94 mg, 0.29 mmol, 26.90% yield) as a yellow oil.

[0632] MS (ESI) m / z: calcd. 347.3 [M+H] + , measured value 263.0[M-THP+H] + .

[0633] Step 9: Bis(trimethylsilyl)-(5,5,5-trifluoro-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pent-3-en-1-yl)phosphonate (Compound 24-13)

[0634] To a solution of (E)-5-diethoxyphospho-2-methyl-2-pent-1-yloctanoate (1.13 g, 3.12 mmol, 1 eq) in dichloromethane (500 mL) was added TMSBr (4.77 g, 31.20 mmol, 10 eq) dropwise at 0°C, and the mixture was stirred at room temperature for 16 hours. TLC spot plate analysis (PE:EA = 1:5) was performed. After completion of the reaction, the mixture was concentrated under reduced pressure. This afforded bis(trimethylsilyl)-(5,5,5-trifluoro-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pent-3-en-1-yl)phosphonate (crude product) (90 mg, 0.21 mmol, 67.94% yield) as a yellow oil, which was used directly in the next step.

[0635] Step 10: Isopropyl(phenoxy(-5,5,5-trifluoro-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pent-3-en-1-yl)phosphoryl)-L-alanine (Compound 24-16)

[0636] Under nitrogen, to a solution of bis(trimethylsilyl)-(5,5,5-trifluoro-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pent-3-en-1-yl)phosphonate (90 mg, 0.19 mmol, 1 eq) in pyridine (5 mL) were added isopropyl (2S)-2-aminopropionate (26 mg, 0.19 mmol, 1 eq), phenol (110 mg, 1.16 mmol, 6 eq), triethylamine (295 mg, 2.92 mmol, 15 eq), triphenylphosphine (306 mg, 1.17 mmol, 6 eq), and 1,2-bis(pyridin-2-yl)disulfane (257 mg, 1.17 mmol, 6 eq). The mixture was stirred at 50°C for 16 hours. After completion of the reaction, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by TLC preparative to give isopropyl(phenoxy((Z)-5,5,5-trifluoro-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pent-3-en-1-yl)phosphoryl)-L-alanine (10 mg, 0.02 mmol, 8.65% yield) as the desired product as a white solid.

[0637] MS (ESI) m / z: calcd. 508.2 [M+H] + , measured value 508.1[M+H] + .

[0638] Step 11: (Phenoxy((Z)-5,5,5-trifluoro-4-(hydroxymethyl)pent-3-en-1-yl)phosphoryl)-L-alanine isopropyl ester) (Compound 24)

[0639] To a solution of (phenoxy(-5,5,5-trifluoro-4-(hydroxymethyl)pent-3-en-1-yl)phosphoryl)-L-alanine isopropyl ester (10 mg, 0.02 mmol, 1 eq) in water (2 mL) was added dropwise a 1N hydrochloric acid solution until the pH reached 4-5, and the mixture was stirred at 25°C for 2 hours. After the reaction, the reaction solution was purified by preparative HPLC (Col μmn: Gemini-C18 150 x 21.2 mm, 5 μm, mobile phase: ACN / H2O from 25% to 50% over 40 minutes) to obtain (phenoxy((Z)-5,5,5-trifluoro-4-(hydroxymethyl)pent-3-en-1-yl)phosphoryl)-L-alanine isopropyl ester (3.1 mg, 37.16% yield).

[0640] 1 H NMR(400MHz, CDCl3)δ=7.34-7.30(m,2H),7.20-7.14(m,3H),6.18-6.15(m,1H),4.99-4.94(m,1H),4.23(s,2H),4.0 6-3.90(m,1H),3.49-3.42(m,0.5H),3.25–3.21(m,0.5H),2.78–2.68(m,2H),2.12–1.96(m,2H),1.30–1.18(m,9H);

[0641] 31 P NMR (162MHz, CDCl3) δ = 29.94, 29.75;

[0642] 19 F NMR (376MHz, CDCl3) δ = -60.09, -59.98;

[0643] MS (ESI) m / z: Calculated value 424.1 [M+H] + , measured value 424.1[M+H] + .

[0644] Example 25:

[0645] 2-Hydroxyethyl(((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine (Compound 25)

[0646] The title compound was prepared according to the following scheme:

[0647] Experimental operation

[0648] Step 1: 2-((4-methoxybenzyl)oxy)ethan-1-ol (Compound 25-2)

[0649] To a solution of ethylene glycol (5.94 g, 95.78 mmol, 1 eq) in tetrahydrofuran (60 mL) at 0°C under nitrogen was added sodium hydride (3.84 g, 95.78 mmol, 60% w / w, 1 eq) portionwise, and the mixture was stirred at 20°C for 0.5 hours. p-Methoxybenzyl chloride (15.0 g, 95.78 mmol, 1 eq) and tetrabutylammonium iodide (3.54 g, 9.58 mmol, 0.1 eq) were added to the reaction mixture at 20°C under nitrogen, and the mixture was stirred at 60°C for 5 hours. TLC (PE:EA = 1:1) indicated the reaction was complete and a new, less polar spot was observed. The mixture was cooled to room temperature and quenched by the addition of saturated ammonium chloride solution (100 mL). The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography eluting with 0-50% petroleum ether / ethyl acetate to give 2-((4-methoxybenzyl)oxy)ethan-1-ol (13 g, 71.34 mmol, 74.48% yield) as a yellow oil.

[0650] 1 H NMR (400MHz, CDCl3) δ=7.29-7.27(m,2H), 6.91-6.88(m,2H), 4.50(s,2H), 3.81(s,3H), 3.76-3.74(m,2H), 3.59-3.57(m,2H).

[0651] Step 2: 2-((4-methoxybenzyl)oxy)ethyl(tert-butoxycarbonyl)-L-propylamino ester (Compound 25-4)

[0652] To a solution of 2-((4-methoxybenzyl)oxy)ethan-1-ol (12.0 g, 65.85 mmol, 1 eq) in acetonitrile (100 mL) at 20°C under nitrogen was added BOC-L-alanine (14.95 g, 79.02 mmol, 1.2 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (13.89 g, 72.44 mmol, 1.1 eq), and 4-dimethylaminopyridine (8.85 g, 72.44 mmol, 1.1 eq). The mixture was stirred at 20°C for 16 hours. TLC (PE:EA = 1:1) indicated the reaction was complete and a new, less polar spot was observed. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography using 0-60% petroleum ether / ethyl acetate to give 2-((4-methoxybenzyl)oxy)ethyl(tert-butoxycarbonyl)-L-propylaminate (12.4 g, 35.09 mmol, 53.29% yield) as a yellow oil.

[0653] 1 H NMR(400MHz, CDCl3)δ=7.20-7.18(m,2H),6.83-6.80(m,2H),4.42(s,2H),4.29-4.23(m, 3H), 3.74-3.73 (m, 3H), 3.59 (t, J = 4.8Hz, 2H), 1.39-1.38 (m, 9H), 1.33 (d, J = 7.2Hz, 3H).

[0654] Step 3: 2-((4-methoxybenzyl)oxy)L-alanine ethyl ester (Compound 25-5)

[0655] To a solution of 2-((4-methoxybenzyl)oxy)ethyl(tert-butoxycarbonyl)-L-propylaminoester (5.0 g, 14.15 mmol, 1 eq) in tetrahydrofuran (40 mL) at 20°C under nitrogen was added p-toluenesulfonic acid monohydrate (9.75 g, 56.60 mmol, 4 eq), and the mixture was stirred at 60°C for 4 hours. LCMS indicated complete reaction of the starting material and the presence of product. The reaction mixture was diluted with ethyl acetate, quenched with water, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a residue. The residue was purified by preparative HPLC (Waters Xbridge C18 150*50mm*10μm; mobile phase: [water(NH4HCO3)-ACN]; gradient: 30%-45% B over 5min) to give ethyl 2-((4-methoxybenzyl)oxy)L-alaninate (0.6 g, 2.37mmol, 16.75% yield) as a colorless oil.

[0656] MS (ESI) m / z: Calculated value 254.1 [M+H] + , measured value 254.1[M+H] + .

[0657] Step 4: Diphenylbutyl-3-en-1-ylphosphonate (Compound 25-6)

[0658] To a solution of 4-dichlorophosphorylbut-1-ene (20 g, 115.62 mmol, 1 eq) in dichloromethane (200 mL) was added triethylamine (23.40 g, 231.24 mmol, 2 eq) at -78°C under nitrogen, and the mixture was stirred at -78°C for 5 minutes. A solution of phenol (23.94 g, 254.37 mmol, 2.2 eq) in dichloromethane (200 mL) was slowly added dropwise at -78°C under nitrogen. The mixture was then stirred at 20°C for 16 hours. LCMS indicated complete reaction of the starting material, with product detected. After completion of the reaction, the mixture was concentrated under reduced pressure to yield a residue. The residue was purified by silica gel column chromatography using 0-20% petroleum ether / ethyl acetate to give diphenylbutyl-3-en-1-ylphosphonate (28.0 g, 97.13 mmol, 84.01% yield) as a colorless oil.

[0659] MS (ESI) m / z: Calculated value 289.1 [M+H] + , measured value 289.0[M+H] + .

[0660] Step 5: Phenylhydrobutyl-3-en-1-ylphosphonate (Compound 25-7)

[0661] To a solution of diphenylbutyl-3-en-1-ylphosphonate (28.0 g, 97.13 mmol, 1 eq) in acetonitrile (300 mL) at 0°C under nitrogen was added aqueous sodium hydroxide (2 M, 485.65 mL, 10 eq). The mixture was stirred at 20°C for 16 hours. LCMS indicated complete reaction of the starting material, with product detected. The mixture was concentrated under reduced pressure to yield a residue. The residue was purified by preparative HPLC (Waters Xbridge C18 150*50 mm*10 μm; mobile phase: [water(NH3·H2O)-ACN]; gradient: 20%-30% B over 5 min) to afford phenylhydrobutyl-3-en-1-ylphosphonate (13.0 g, 61.27 mmol, 63.08% yield) as a colorless oil.

[0662] MS (ESI) m / z: Calculated value 213.1 [M+H] + , measured value 213.0[M+H] + .

[0663] Step 6: Phenylbut-3-en-1-ylphosphonochloridate (Compound 25-8)

[0664] Under nitrogen protection, thionyl chloride (19.62g, 164.95mmol, 5eq) is added to a toluene (50mL) solution of phenyl hydrogen butyl-3-ene-1-yl phosphonate (7.0g, 32.99mmol, 1eq). The mixture is stirred at 75°C for 2 hours. LCMS shows that the raw material reaction is complete and the product is monitored. The reaction mixture is cooled to room temperature and concentrated under reduced pressure to remove the solvent to obtain phenyl but-3-ene-1-yl phosphonyl chloride (7.0g, crude product), which is a yellow oil and is directly used in the next step reaction without further treatment.

[0665] Step 7: 2-((4-methoxybenzyl)oxy)ethyl(but-3-en-1-yl(phenoxy)phosphoryl)-L-propylaminoester (Compound 25-9)

[0666] To a solution of phenylbut-3-en-1-ylphosphonochloridate (500 mg, 2.17 mmol, 1 eq) in dichloromethane (10 mL) at 0°C under nitrogen was added triethylamine (438.76 mg, 4.34 mmol, 2 eq), and the mixture was stirred at 0°C for 5 minutes. A solution of ethyl 2-((4-methoxybenzyl)oxy)L-alaninate (549.14 mg, 2.17 mmol, 1 eq) in dichloromethane (2 mL) was slowly added dropwise to the mixture at 0°C under nitrogen. The mixture was then stirred at 20°C for 16 hours. LCMS indicated complete reaction of the starting material, with product detected. The mixture was concentrated under reduced pressure to yield a residue. The residue was purified by silica gel column chromatography eluting with 50-80% petroleum ether / ethyl acetate to give 2-((4-methoxybenzyl)oxy)ethyl(but-3-en-1-yl(phenoxy)phosphoryl)-L-propylaminate (300 mg, 670.45 μmol, 30.92% yield) as a colorless oil.

[0667] MS (ESI) m / z: calcd. 448.2 [M+H] + , measured value 448.2[M+H] + .

[0668] Step 8: 2-((4-methoxybenzyl)oxy)ethyl((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-propylaminoester (Compound 25-10)

[0669] To a solution of 2-((4-methoxybenzyl)oxy)ethyl(but-3-en-1-yl(phenoxy)phosphoryl)-L-propylaminate (300 mg, 670.45 μmol, 1 eq), 2-methylprop-2-en-1-ol (386.75 mg, 5.36 mmol, 8 eq), and 1,4-benzoquinone (7.25 mg, 67.05 μmol, 0.1 eq) in dichloromethane (6 mL) was added second-generation Hoveyda-Grubbs catalyst (84.02 mg, 134.09 μmol, 0.2 eq). At t = 0, 2, and 4 hours during the reaction, the catalyst was added in three equal portions, each (28.01 mg, 44.70 μmol). The solution was then heated to reflux at 45°C under a nitrogen atmosphere for 18 hours. LCMS indicated complete reaction of the starting material, with product detected. The mixture was concentrated under reduced pressure to yield a residue. The residue was purified by silica gel column chromatography using 0-10% ethyl acetate / methanol to give 2-((4-methoxybenzyl)oxy)ethyl((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-propylaminate (160 mg, 325.52 μmol, 48.55% yield) as the desired product in the form of a colorless oil.

[0670] MS (ESI) m / z: calcd. 492.2 [M+H] + , measured value 492.2[M+H] + .

[0671] Step 9: 2-Hydroxyethyl(((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine

[0672] To a mixed solution of 2-((4-methoxybenzyl)oxy)ethyl((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-propylaminoester (130 mg, 264.49 μmol, 1 eq) in dichloromethane (4 mL) and water (0.4 mL) was added dichlorodicyanobenzoquinone (72.05 mg, 317.39 μmol, 1.2 eq) at 0°C under nitrogen. The mixture was stirred at 0°C for 1 hour. LCMS showed that the starting material was completely reacted and product was detected. The reaction mixture was diluted with dichloromethane, quenched with water, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (Phenomenex Synergi C18 150*25mm*10μm; mobile phase: [water (0.1% FA)-ACN]; B%: 30%-45%, 2 min) to give 2-hydroxyethyl (((E)-5-hydroxy-4-methylpent-3-en-1-yl) (phenoxy)phosphoryl)-L-alanine (12.79 mg, 34.46 μmol, 13.03% yield) as the target product.

[0673] 1 H NMR(400MHz, CDCl3)δ=7.35-7.30(m,2H),7.21-7.14(m,3H),5.52-5.28(m,1H),4.21-4.09(m,3H),4.00-3.92(m,2H) ),3.78-3.75(m,2H),3.44-3.39(m,1H),2.50-2.45(m,2H),2.03-1.99(m,2H),1.82-1.68(m,3H),1.32-1.24(m,3H);

[0674] 31 P NMR (162MHz, CDCl3) δ = 32.89, 32.35;

[0675] MS (ESI) m / z: calcd. 372.2 [M+H] + , measured value 394.1[M+Na] + ;

[0676] Example 26:

[0677] (R)-Tetrahydrofuran-3-yl 2-((((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)amino)-2-methylpropanoate (Compound 26)

[0678] The title compound was prepared according to the following scheme:

[0679] Experimental operation

[0680] Step (R)-Tetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate (26-1)

[0681] To a solution of 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (5 g, 22.5 mmol, 1.0 eq) in tetrahydrofuran (50 mL) at 0°C under nitrogen was added 4-dimethylaminopyridine (3.01 g, 2.46 mmol, 1.0 eq) and carbodiimide hydrochloride (9.35 g, 24.6 mmol, 1.0 eq). The resulting mixture was stirred at 0°C under nitrogen for 0.5 h. (R)-tetrahydrofuran-3-ol (2.38 g, 27.0 mmol, 1.1 eq) was then added to the reaction system, and stirring continued for 16 h. After completion of the reaction, the mixture was quenched by the addition of water (100 mL). The mixture was extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The resulting residue was purified by silica gel chromatography using 0-10% petroleum ether / ethyl acetate to give (R)-tetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate (5 g, 16.5 mmol, 67% yield) as a light yellow oil.

[0682] MS (ESI) m / z: Calculated value 274.2 [M+H] + , measured value 174.2[M+H-100] + .

[0683] Step 1-2: (R)-tetrahydrofuran-3-yl 2-amino-2-methylpropanoate (26-2)

[0684] (R)-tetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate (5 g, 18.2 mmol) was dissolved in ethyl acetate hydrochloride (2 mmol / mL, 10 mL) at 20°C, and the resulting mixture was stirred at 20°C for 1 hour. After the reaction was completed, saturated aqueous sodium bicarbonate (10 mL) was added to the reaction system to quench the reaction. The mixture was extracted with ethyl acetate (50 mL*2), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (R)-tetrahydrofuran-3-yl 2-amino-2-methylpropanoate (4.2 g, crude product). It was obtained as a white solid.

[0685] MS (ESI) m / z: Calculated value 174.2 [M+H] + , measured value 174.2[M+H]+ .

[0686] Step 1: (R)-tetrahydrofuran-3-yl 2-((but-3-en-1-yl(phenoxy)phosphoryl)amino)-2-methylpropanoate (26-3)

[0687] To a solution of but-3-en-1-ylphosphine dichloride (500 mg, 2.89 mmol, 1 eq) in dichloromethane (10 mL) at -78°C under nitrogen was added (R)-tetrahydrofuran-3-yl 2-amino-2-methylpropanoate (500 mg, 2.89 mmol, 1 eq) and triethylamine (584 mg, 5.78 mmol, 2 eq). The resulting mixture was stirred at room temperature under nitrogen for 6 hours. The reaction mixture was then cooled to -78°C, and phenol (109 mg, 1.16 mmol, 1 eq) and triethylamine (584 mg, 5.78 mmol, 2 eq) were added. The resulting mixture was stirred at room temperature under nitrogen for 16 hours. After completion of the reaction, the reaction mixture was quenched by the addition of water (20 mL). The mixture was extracted with dichloromethane (20 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The resulting residue was purified by silica gel chromatography eluting with 20-40% petroleum ether / ethyl acetate to give (R)-tetrahydrofuran-3-yl 2-((but-3-en-1-yl(phenoxy)phosphoryl)amino)-2-methylpropanoate (150 mg, 0.41 mmol, 14.2% yield) as a yellow oil.

[0688] MS (ESI) m / z: calcd. 368.2 [M+H] + , measured value 368.2[M+H] + .

[0689] Step 2: (R)-tetrahydrofuran-3-yl 2-((((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)amino)-2-methylpropanoate (Compound 26)

[0690] To a solution of (R)-tetrahydrofuran-3-yl 2-((but-3-en-1-yl(phenoxy)phosphoryl)amino)-2-methylpropanoate (150 mg, 0.41 mmol, 1 eq) in dichloromethane (5 mL) at 20°C under nitrogen was added 2-methylprop-2-en-1-ol (58.9 mg, 0.82 mmol, 2 eq), HOVEYDA-GRUBBS catalyst (25.6 mg, 0.04 mmol, 0.1 eq), and p-benzoquinone (1 mg, 0.01 mmol, 0.1 eq). The resulting mixture was stirred at 40°C under nitrogen for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by HPLC: chromatographic column: Gemini-C18 150 x 21.2 mm, 5 μm mobile phase: ACN-H2O, gradient: 27%-95%, flow rate: 20 ml / min, ACN (%): 45, elution time: 13 min to give the title compound (12.7 mg, 0.03 mmol, 7.5% yield) as a colorless oil.

[0691] 1 H NMR (400MHz, CDCl3) δ7.34-7.30(m,2H),7.23–7.21(m,2H),7.16-7.12(m,1H),5.50-5.46(m,1H),5.31–5.29(m,1H),4.01(s,2H),3.90-3.86( m,3H),3.81–3.77(m,1H),3.66–3.64(m,1H),2.46-2.39(m,2H),2.19- 2.13(m,1H),1.98–1.91(m,3H),1.70(s,3H),1.55(s,3H),1.45(s,3H).

[0692] 31 P NMR (162MHz, CDCl3) δ = 30.51;

[0693] MS (ESI) m / z: Calculated value 412.2 [M+H] + , measured value 412.1[M+H] + .

[0694] Example 27:

[0695] (R)-Tetrahydrofuran-3-yl(phenoxy((Z)-5,5,5-trifluoro-4-(hydroxymethyl)pent-3-en-1-yl)phosphoryl)-L-alaninate (Compound 27)

[0696] Example 27 was synthesized using benzyloxycarbonyl-L-alanine and (R)-3-hydroxytetrahydrofuran as raw materials according to the method of Example 24.

[0697] 1 H NMR (400MHz, CDCl3) δ7.34-7.30(m,2H),7.21–7.13(m,3H),6.17–6.14(m,1 H),5.27–5.23(m,1H),4.21(s,2H),4.09–4.00(m,1H),3.90–3.80(m,3H),3. 74–3.72(m,1H),3.43(t,J=20Hz,0.5H),3.23(t,J=20Hz,0.5H),2.74–2.64( m,3H),2.19-1.88(m,4H),1.31(d,J=7.2Hz,1.5H),1.22(d,J=7.2Hz,1.5H).

[0698] 31 P NMR (162MHz, CDCl3) δ = 29.72, 29.42;

[0699] 19 F NMR (376.5MHz, CDCl3) δ = -60.00, -60.10;

[0700] MS (ESI) m / z: calcd. 452.1 [M+H] + , measured value 452.1[M+H] + .

[0701] Example 28:

[0702] 1,1-Dioxotetrahydro-2H-thiopyran-4-yl(((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 28)

[0703] Example 28 was synthesized using benzyloxycarbonyl-L-alanine and 4-hydroxytetrahydro-2H-thiopyran-1,1-dioxide as raw materials according to the method of Example 2.

[0704] 1H NMR(400MHz, CDCl3)δ7.34-7.28(m,2H),7.20–7.11(m,3H),5.50–5.43(m,1H),5.06–5 .04(m,0.5H),5.01–4.99(m,0.5H),4.16–4.08(m,1H),4.00(s,2H),3.16–3.09(m,2H), 2.96–2.91(m,2H),2.49–2.39(m,2H),2.36–2.18(m,4H),2.03-1.90(m,2H),1.81(brs ,1H),1.70(s,1.5H),1.69(s,1.5H),1.35(d,J=6.8Hz,1.5H),1.22(d,J=7.2Hz,1.5H).

[0705] 31 P NMR (162MHz, CDCl3) δ = 32.03, 31.73;

[0706] MS (ESI) m / z: Calculated value 460.2 [M+H] + , measured value 460.2[M+H] + .

[0707] Example 29:

[0708] Compound 29

[0709] Example 29 was synthesized using benzyloxycarbonyl-L-alanine and 4-hydroxypiperidine as raw materials according to the method of Example 2.

[0710] 1 H NMR (400MHz, CDCl3) δ7.32-7.27(m,2H),7.19–7.10(m,3H),5.48–5.42(m,1H),4.98–4.89(m,1H),4.14–4.01(m,1H),3.99(s,3H),3.82–3.75( m,1H),3.60–3.53(m,2H),3.44–3.25(m,3H),2.51–2.38(m,2H),2.07( s,3H),1.86–1.78(m,2H),1.69(s,1.5H),1.68(s,1.5H),1.61–1.55(m, 2H),1.33–1.30(m,1.5H),1.21–1.18(m,1.5H).

[0711] 31 P NMR (162MHz, CDCl3) δ = 32.05, 31.98, 31.66, 31.62;

[0712] MS (ESI) m / z: Calculated value 453.2 [M+H] + , measured value 453.2[M+H] + .

[0713] Example 30:

[0714] 2-Oxaspiro[3.3]heptan-6-yl(((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 30)

[0715] Example 30 was synthesized using benzyloxycarbonyl-L-alanine and 2-oxaspiro[3.3]heptane-6-ol as raw materials according to the method of Example 2.

[0716] 1 H NMR (400MHz, CDCl3) δ7.32-7.27(m,2H),7.19–7.11(m,3H),5.45(q,J=8.0Hz,1H),4.81–4. 76(m,1H),4.67(s,2H),4.64–4.60(m,2H),4.08–3.95(m,3H),3.31(t,J=10.4Hz,0.4H),3. 20(t,J=10.8Hz,0.6H),2.69–2.64(m,2H),2.48-2.40(m,2H),2.23-2.13(m,2H),2.01–1.8 3(m,2H),1.69(s,1.8H),1.68(s,1.2H),1.31(d,J=6.8Hz,1.2H),1.22(d,J=6.8Hz,1.8H).

[0717] 31 P NMR (162MHz, CDCl3) δ = 31.98, 31.56;

[0718] MS (ESI) m / z: Calculated value 424.2 [M+H] + , measured value 424.0[M+H] + .

[0719] Example 31:

[0720] Compound 31

[0721] Example 31 was synthesized using benzyloxycarbonyl-L-alanine and 4-hydroxypiperidine as raw materials according to the method of Example 2.

[0722] 1H NMR (400MHz, CDCl3) δ7.34-7.29 (m, 2H), 7.21–7.12 (m, 3H), 5.47 (dd, J1=7.6Hz, J2=7.6Hz, 1H), 4.84–4.78(m,1H),4.14–4.03(m,1H),4.01(s,2H),3.43(t,J=10Hz,0.5H),3.31(t,J=10.4Hz,0. 5H),3.08–3.06(m,2H),2.88(brs,2H),2.68(brs,2H),2.55-2.40(m,2H),2.03-1.86(m,4H),1.8 0-1.74(m,2H),1.71(s,1.5H),1.70(s,1.5H),1.33(d,J=7.2Hz,1.5H),1.21(d,J=7.2Hz,1.5H).

[0723] 31 P NMR (162MHz, CDCl3) δ = 31.44, 31.10;

[0724] MS (ESI) m / z: calcd. 493.2 [M+H] + , measured value 493.1[M+H] + .

[0725] Example 32:

[0726] (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl(((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 32)

[0727] Example 32 was synthesized using benzyloxycarbonyl-L-alanine and (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol as raw materials according to the method of Example 2.

[0728] 1H NMR (400MHz, CDCl3) δ7.30–7.29(m,2H),7.20-7.19(m,2H),7.16-7.14(t,J=6.7Hz,1H),5.71(d,J=4.8Hz,1H), 5.52–5.35(m,1H),5.13(p,J=6.6Hz,1H),4.17–4.07(m,1H),4.06–4.00(m,1H),3.98(s,2H),3.93(m,1H),3.85( p,J=8.5,7.7Hz,1H),3.77–3.67(m,1H),3.58(d,J=9.7Hz,0.5H),3.43(d,J=9.8Hz,0.5H),3.03(m,1H),2.71-2. 61(m,1H),2.44-2.41(m,2H),1.97–1.81(m,4H),1.68(s,3H),1.36(d,J=6.9Hz,1.5H),1.24(d,J=6.6Hz,1.5H).

[0729] 31 P NMR (162MHz, CDCl3) δ = 31.48, 31.16;

[0730] MS (ESI) m / z: Calculated value 440.2 [M+H] + , measured value 422.2[M+H-H2O] + .

[0731] Example 33:

[0732] Compound 33

[0733] Example 33 was synthesized using benzyloxycarbonyl-L-alanine and (2R,4R)-2-methyloxan-4-ol as raw materials according to the method of Example 2.

[0734] 1H NMR (400MHz, CDCl3) δ7.31–7.27(m,2H),7.20-7.17(m,2H),7.14–7.10(m,1H),5.46– 5.42(m,1H),4.84–4.78(m,1H),4.06-4.00(m,1H),3.99(s,2H),3.97-3.95(m,1H),3. 46–3.26(m,3H),2.49–2.40(m,2H),2.01–1.77(m,4H),1.69(s,1.5H),1.68(s,1.5H) ,1.62–1.46(m,1H),1.29(d,J=7.0Hz,1.5H),1.28–1.21(m,1H),1.20–1.16(m,4.5H).

[0735] 31 P NMR (162MHz, CDCl3) δ = 31.99, 31.59;

[0736] MS (ESI) m / z: Calculated value 426.2 [M+H] + , measured value 408.1[M+H-H2O] + .

[0737] Example 34:

[0738] (2R,4r,6S)-2,6-Dimethyltetrahydro-2H-pyran-4-yl(((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 34)

[0739] The title compound was prepared according to the following scheme:

[0740] Experimental operation

[0741] Step 1-1: (2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-ol (34-2)

[0742] To a solution of 2,6-dimethyl-4H-pyran-4-one (4.00 g, 32.2 mmol, 1 eq) in ethanol (40 mL) was added 10% Pd(OH)2 / C (3.39 g, 6.45 mmol, 0.1 eq) at room temperature. The resulting mixture was placed in an autoclave under 50 psi of hydrogen. The reaction system was stirred at 35°C for 19 hours. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure to afford crude (2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-ol (3.2 g, 24.61 mmol, 76.92% yield) as a pale yellow oil.

[0743] 1 H NMR (400MHz, CDCl3) δ3.68–3.77(m,1H),3.37-3.45(m,2H),2.11(s,1H),1.87(dd,J=12.1,J=4.7Hz,2H),1.18(d,J=6.2Hz,6H),1.05–1.15(m,2H).

[0744] Step 1: (2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl((benzyloxy)carbonyl)-L-alaninate (34-3)

[0745] To a solution of ((benzyloxy)carbonyl)-L-alanine (2.00 g, 8.97 mmol, 1 eq) and (2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-ol (1.28 g, 9.87 mmol, 1.1 eq) in dichloromethane (20 mL) at room temperature under nitrogen was added 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.70 g, 13.46 mmol, 1.5 eq) and 4-dimethylaminopyridine (0.22 g, 1.79 mmol, 0.2 eq). The resulting mixture was stirred at room temperature under nitrogen for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 10% petroleum ether / ethyl acetate to give (2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl((benzyloxy)carbonyl)-L-alaninate (1.80 g, 5.37 mmol, 60.37% yield) as a colorless oil.

[0746] MS (ESI) m / z: calcd. 336.2 [M+H] + , measured value 336.0[M+H] + .

[0747] Step 2: (2R,4R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl L-alaninate (34-4)

[0748] To a solution of (2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl((benzyloxy)carbonyl)-L-alaninate (1.80 g, 5.37 mmol, 1 eq) in tetrahydrofuran (20 mL) was added 20% palladium hydroxide on carbon (0.75 g, 1.34 mmol, 0.25 eq) at room temperature, and the hydrogen atmosphere was replaced three times. The resulting mixture was stirred at 35°C under hydrogen protection for 3 hours. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure to afford (2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl((benzyloxy)carbonyl)-L-alaninate (0.91 g, 4.50 mmol, 83.89% yield) as a colorless oil.

[0749] MS (ESI) m / z: Calculated value 202.1 [M+H] + , measured value 202.2[M+H] + .

[0750] Step 3: (2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl(((E)-4-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (34-5)

[0751] To a solution of (E)-(4-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pent-3-en-1-yl)phosphonate (trimethylsilyl) (500 mg, 1.22 mmol, 1 eq) in pyridine (5 mL) were added (2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl L-alaninate (248.46 mg, 1.23 mmol, 1 eq), phenol (691 mg, 7.35 mmol, 6 eq), triethylamine (1.86 g, 18.38 mmol, 15 eq), triphenylphosphine (1.93 mg, 7.35 mmol, 6 eq) and 1,2-di(pyridin-2-yl)disulfane (1.62 g, 7.35 mmol, 6 eq) under nitrogen, and the resulting mixture was stirred at 50° C. for 16 hours. After the reaction is completed, the reaction is filtered and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using 50-100% petroleum ether / ethyl acetate as eluent to give a crude product of (2R, 4r, 6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl(((E)-4-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (230 mg, 0.44 mmol, 35.98% yield) as a light yellow oil.

[0752] MS (ESI) m / z: calcd. 524.3 [M+H]+ , measured value 546.2[M+Na] + .

[0753] Step 4: (2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl(((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 34)

[0754] To a solution of (2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl(((E)-4-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (230 mg, 0.44 mmol) in dichloromethane (5 mL) was added dropwise a 2N hydrochloric acid in ethyl acetate solution (1 ml) at room temperature, and the resulting mixture was stirred at 25°C for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the crude product was purified by preparative HPLC (Colμmn: Gemini-C18 150x 21.2mm, Flow Rate: 20ml / min, mobile phase: ACN / H2O from 0% to 60% over 7mins) to give (2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl(((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (82.60 mg, 0.19 mmol, 43.18% yield) as a colorless oil.

[0755] 1 H NMR (400MHz, CDCl3) δ7.33–7.27(m,2H),7.21(d,J=8.7Hz,2H),7.14(td,J=7.5,J=3.2Hz, 1H),5.47(m,1H),4.88-4.82(m,1H),4.08–4.04(m,0.6H),4.01(s,2H),3 .99-3.96(m,,0.4H),3.53-3.46(m,2H),3.37(t,J=10.6Hz,0.5H),3.27( t,J=10.6Hz,0.5H),2.51-2.40(m,2H),2.01–1.93(m,2H),1.91–1.85(m, 2H),1.71(d,J=5.4Hz,3H),1.31(d,J=7.0Hz,1.5H),1.23–1.14(m,9.5H).

[0756] 31P NMR (162MHz, CDCl3) δ = 31.35, 30.97;

[0757] MS (ESI) m / z: Calculated value 440.2 [M+H] + , measured value 440.3[M+H] + .

[0758] Example 35:

[0759] (R)-2-Piperidon-4-yl(((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 35)

[0760] Example 35 was synthesized using benzyloxycarbonyl-L-alanine and (R)-4-hydroxypiperidin-2-one as raw materials according to the method of Example 34.

[0761] 1 H NMR (400MHz, CDCl3) δ7.32(t,J=7.8Hz,2H),7.25–7.18(m,2H),7.15(t,J=7.3Hz,1H),6.64(s,1H),5.5 2–5.39(m,1H),5.17-5.15(m,1H),4.15–3.95(m,3H),3.67(t,J=10.2Hz,0.6H),3.51–3.45(m,0.4H),3. 44–3.41(m,1H),3.35–3.24(m,1H),2.67(d,J=5.2Hz,0.4H),2.63(d,J=4.8Hz,0.4H),,2.49–2.39(m,3 H),2.02–1.84(m,4H),1.70(s,1.2H),1.68(s,1.8H),1.30(d,J=7.0Hz,1.8H),1.24(d,J=7.1Hz,1.2H).

[0762] 31 P NMR (162MHz, CDCl3) δ = 31.51, 31.12;

[0763] MS (ESI) m / z: Calculated value 425.2 [M+H] + , measured value 424.8[M+H] + .

[0764] Example 36:

[0765] 1-Cyanocyclopentyl(((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 36)

[0766] Example 36 was synthesized using benzyloxycarbonyl-L-alanine and 1-hydroxycyclopentane-1-carbonitrile as raw materials according to the method of Example 34.

[0767] 1 H NMR (400MHz, CDCl3) δ7.32–7.27(m,2H),7.19–7.17(m,2H),7.14–7.10(m,1H),5.45(q,J=7.8 ,7.4Hz,1H),4.15-4.03(m,1H),3.992(s,1H),3.985(s,1H),3.44–3.37(m,0.5H),3.28–3.22 (m,0.5H),2.48–2.38(m,2H),2.36–2.23(m,2H),2.21–2.04(m,2H),2.01–1.87(m,3H),1.83– 1.71(m,3H),1.68(s,1.5H),1.67(s,1.5H),1.32(d,J=7.1Hz,1.5H),1.20(d,J=7.2Hz,1.5H).

[0768] 31 P NMR (162MHz, CDCl3) δ = 32.00, 31.58;

[0769] MS (ESI) m / z: Calculated value 421.2 [M+H] + , measured value 403.1[M+H-H2O] + .

[0770] Example 37:

[0771] Tetrahydro-2H-pyran-4-yl(((E)-1,1-difluoro-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 37)

[0772] The title compound was prepared according to the following scheme:

[0773] Step 1: (1,1-difluorobut-3-en-1-yl)phosphonic acid diethyl ester (Compound 37-1)

[0774] Under nitrogen, diethyl bromofluoromethylphosphonate (3.3 mL, 18.6 mmol) was added dropwise to a solution of activated zinc powder (1.22 g, 18.7 mmol) in anhydrous N,N-dimethylformamide (9.5 mL). The resulting mixture was stirred at room temperature under nitrogen for 3 hours, followed by the addition of cuprous bromide (2.66 g, 18.5 mmol). Allyl bromide (2.26 g, 18.5 mmol) was then slowly added dropwise to the reaction system with stirring at room temperature. The resulting mixture was stirred at room temperature for 16 hours, then filtered, and the filtrate was dried by rotary evaporation. The crude product was purified by silica gel column chromatography using 60-70% petroleum ether / ethyl acetate as the eluent to afford diethyl (1,1-difluorobut-3-en-1-yl)phosphonate (1.70 g, 7.46 mmol, 40.09% yield) as a yellow oil.

[0775] 1 H NMR (400MHz, CDCl3) δ5.86–5.8(m,1H),5.3–5.26(m,2H),4.27-4.24(m,4H),2.87-2.78(m,2H),1.38-1.24(m,6H).

[0776] 31 P NMR (400MHz, CDCl3) δ = -111.12, -111.40;

[0777] MS (ESI) m / z: Calculated value 229.1 [M+H] + , measured value 229.1[M+H] + .

[0778] Steps 2 & 3: (1,1-difluorobut-3-en-1-yl)phosphonic acid dichloride (Compound 37-3)

[0779] To a solution of diethyl (1,1-difluorobut-3-en-1-yl)phosphonate (4.00 g, 17.54 mmol, 1 eq) in dichloromethane (15 mL) at 0°C under nitrogen was added TMSBr (26.84 g, 175.44 mmol, 10 eq). The resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The mixture was dissolved in anhydrous dichloromethane (50 mL), the reaction mixture was cooled to 0°C, and two drops of DMF and oxalyl chloride (6.68 g, 52.62 mmol, 3 eq) were added to the reaction system under nitrogen. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to yield 3.6 g of crude (1,1-difluorobut-3-en-1-yl)phosphonic acid dichloride as a yellow-brown oily-solid mixture.

[0780] Step 4: (R)-tetrahydrofuran-3-yl((1,1-difluorobut-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 37-4)

[0781] To a solution of (1,1-difluorobut-3-en-1-yl)phosphine dichloride (2.30 g, 11.06 mmol, 1 eq) in dichloromethane (40 mL) at -78°C under nitrogen was added (R)-tetrahydrofuran-3-yl L-alaninate (1.76 g, 11.06 mmol, 1 eq) and triethylamine (2.23 g, 22.12 mmol, 2 eq). The resulting mixture was stirred at room temperature for 6 hours. The temperature was then lowered to -78°C, and phenol (1.048 g, 11.06 mmol, 1 eq) and triethylamine (2.23 g, 22.12 mmol, 2 eq) were added. The resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was quenched by the addition of water (30 mL). The mixture was extracted with dichloromethane (30 mL x 3), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography eluting with 10-40% petroleum ether / ethyl acetate to give (R)-tetrahydrofuran-3-yl((1,1-difluorobut-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (1.30 g, 3.34 mmol, 30.20% yield) as a yellow oil.

[0782] MS (ESI) m / z: calculated value 390.1 [M+H] + , measured value 390.1[M+H] + .

[0783] Step 5: (R)-tetrahydrofuran-3-yl(((E)-1,1-difluoro-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 37)

[0784] To a solution of (R)-tetrahydrofuran-3-yl((1,1-difluorobut-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (1.30 g, 3.34 mmol, 1 eq) and 2-methylprop-2-en-1-ol (387 mg, 6.68 mmol, 2 eq) in dichloromethane (40 mL) was added dropwise HOVEYDA-GRUBBS catalyst (232.12 mg, 0.33 mmol, 0.1 eq) and p-benzoquinone (80.35 mg, 0.668 mmol, 0.2 eq) under nitrogen. The resulting mixture was stirred at 45°C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography using 40-100% petroleum ether / ethyl acetate as eluent. The crude product was purified by preparative HPLC: Column: Gemini-C18 150 x 21.2 mm, 5 μm Mobile phase: ACN-H2O gradient: 30%-95%, flow rate: 20 ml / min, peak time: 10.5 min,

[0785] (R)-tetrahydrofuran-3-yl(((E)-1,1-difluoro-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (680 mg, 1.57 mmol, 47.01%, yield) was obtained as a colorless oily solid mixture.

[0786] 1 H NMR(400MHz,DMSO-d6)δ7.39–7.34(m,2H),7.25–7.17(m,3H),6.64-6.57(m,1H),5.45(t ,J=7.1Hz,1H),5.16-5.12(m,1H),4.83(td,J=5.5,2.0Hz,1H),3.94-3.86(m,1H),3.80(d ,J=8.0Hz,2H),3.78–3.62(m,3H),3.55(d,J=10.4Hz,1H),2.93–2.80(m,2H),2.10–2.02( m,1H),1.77–1.71(m,1H),1.54(s,3H),1.21(d,J=7.2Hz,1.5H),1.18(d,J=7.2Hz,1.5H).

[0787] 31 P NMR (400MHz, DMSO-d6) δ = 11.22, 10.76, 10.57, 10.13, 9.92, 9.47;

[0788] MS (ESI) m / z: Calculated value 434.1 [M+H] +, measured value 416.0[M+H-H2O] + .

[0789] Example 38: Compound 38

[0790] Example 38 was synthesized using benzyloxycarbonyl-L-alanine and 4-hydroxytetrahydropyran as raw materials according to the method of Example 37.

[0791] 1 H NMR (400MHz, CDCl3) δ7.35–7.31(m,2H),7.27–7.18(m,3H),5.56–5.54(m,1 H),4.96–4.92(m,1H),4.19–4.11(m,1H),4.02(s,2H),3.91-3.87(m,3H),3. 54-3.48(m,2H),3.03–2.86(m,2H),2.36-2.29(m,1H),1.92–1.84(m,2H),1 .69(s,3H),1.66-1.59(m,2H),1.35(d,7.2Hz,1.5H),1.34(d,J=6.8,1.5H).

[0792] 31 P NMR (162MHz, CDCl3) δ9.79,9.21,9.15,9.09,8.59,8.51,8.45,7.89;

[0793] MS (ESI) m / z: calcd. 448.2 [M+H] + , measured value 470.2[M+Na] + .

[0794] Example 39: Control Compound 2

[0795] Example 39 was synthesized using benzyloxycarbonyl-L-alanine and benzyl alcohol as raw materials according to the method of Example 2.

[0796] 1H NMR(400MHz, CDCl3)δ=7.35-7.29(m,7H),7.20-7.12(m,3H),5.47–5.41(m,1H),5.10(s,2H),4.20-4.04(m,1H),4.01(s,2H),3.39– 3.23(m,1H),2.49–2.38(m,2H),2.02–1.85(m,2H),1.70(s,1.5H),1.69(s,1.5H)1.33(d,J=6.8Hz,1.5H),1.21(d,J=7.2Hz,1.5H);

[0797] 31 P NMR (162MHz, CDCl3) δ = 31.36, 30.94;

[0798] MS (ESI) m / z: Calculated value 418.2 [M+H] + , measured value 418.2[M+H] +

[0799] Biological Examples

[0800] Experimental Example 1: Small molecules activate γδT cells to kill tumor cells EC 50 Determination

[0801] γδT cells and MIApaca / FG2 tumor cell lines were expanded and cultured in vitro. MIApaca / FG2 cells were digested and counted, resuspended in DMEM complete medium, and the cell suspension density was adjusted to 5E3 / 50μL / well. The suspension was added to a 96-well plate and cultured overnight. The next day, the test compound and control compound were diluted 10-fold in γδT complete medium. 50μL was transferred to the corresponding well plate containing tumor cells. The actual detection concentration range was 10 -12 -10 -5 M. γδT cells were resuspended in γδT complete medium, and the cell suspension density was adjusted according to the effector-target ratio E:T = 2:1. 1E4 / 50μL / well was added to the corresponding well plate. After co-culture at 37°C, 5% CO2 for 20 hours, centrifugation was performed. The supernatant was aspirated, and 50μL of cell lysate containing fluorescein substrate was added to each well. After standing in the dark for 18 minutes, the chemiluminescence signal was detected. The value corresponding to the well with only tumor cells was the minimum killing value, and the value corresponding to the well without tumor cells was the maximum killing value. The EC was calculated by four-parameter fitting. 50 The following is the killing data of MIApaca / FG2 cells:

[0802] γδT cells and the MIApaca / FG2 tumor cell line were expanded in vitro. MIApaca / FG2 cells were digested and counted, then resuspended in complete DMEM medium. The suspension density was adjusted to 5E3 cells / 100 μL / well and plated into a 96-well plate for overnight incubation. The next day, test and control compounds were diluted 3-fold in DMSO. 4 μL of each dilution was added to 96 μL of culture medium for a 25-fold dilution. 5 μL was transferred to the corresponding wells of the plate seeded with tumor cells. The actual test concentration range was 0.05-100 nM. γδT cells were resuspended in complete γδT medium, the suspension density was adjusted to an effector-target ratio (E:T) of 2:1, and plated into the corresponding wells at 1E4 cells / 100 μL / well. Incubated at 37°C, 5% CO2 for 20 hours, the cells were centrifuged. The supernatant was removed and 50 μL of cell lysate containing fluorescein substrate was added to each well. After standing in the dark for 18 minutes, the chemiluminescence signal was detected. The value corresponding to the well with only tumor cells was the minimum killing value, and the value corresponding to the well without tumor cells was the maximum killing value. EC was calculated by four-parameter fitting. 50 The following is the killing data of MIApaca / FG2 cells:

[0803] γδT cells and Huh7 / FG2 tumor cell lines were expanded in vitro. Huh7 / FG2 cells were digested and counted, then resuspended in complete DMEM medium. The cell suspension density was adjusted to 5E3 / 100 μL / well and plated into a 96-well plate for overnight incubation. The next day, test and control compounds were diluted 3-fold in DMSO. 4 μL of each dilution was added to 96 μL of culture medium for a 25-fold dilution. 5 μL was transferred to the corresponding wells of the plate containing tumor cells. The actual test concentration range was 0.05-100 nM. γδT cells were resuspended in complete γδT medium and the cell suspension density was adjusted to an effector-target ratio of 5:1. 2.5E4 / 100 μL / well was plated into the corresponding wells of the plate. Incubate at 37°C, 5% CO2 for 20 hours, followed by centrifugation. The supernatant was removed and 50 μL of cell lysate containing fluorescein substrate was added to each well. After standing in the dark for 18 minutes, the chemiluminescence signal was detected. The value corresponding to the well with only tumor cells was the minimum killing value, and the value corresponding to the well without tumor cells was the maximum killing value. EC was calculated by four-parameter fitting. 50 value.

[0804] The following is the Huh7 cell killing data

[0805] γδT cells and SKOV3 / ELP tumor cell lines were expanded in vitro. SKOV3 / ELP cells were digested and counted, then resuspended in complete MC5A medium. The suspension density was adjusted to 5E3 cells / 100 μL / well and plated into a 96-well plate for overnight culture. The next day, test and control compounds were diluted 3-fold in DMSO. 4 μL of each dilution was added to 96 μL of culture medium for a 25-fold dilution. 5 μL was transferred to the corresponding wells of the plate seeded with tumor cells. The actual test concentration range was 0.05-100 nM. γδT cells were resuspended in complete γδT medium, the suspension density was adjusted to an effector-target ratio of 2:1, and 1E4 cells / 100 μL / well were plated into the corresponding wells. Incubate at 37°C, 5% CO2 for 20 hours, followed by centrifugation. The supernatant was removed and 50 μL of cell lysate containing fluorescein substrate was added to each well. After standing in the dark for 18 minutes, the chemiluminescence signal was detected. The value corresponding to the well with only tumor cells was the minimum killing value, and the value corresponding to the well without tumor cells was the maximum killing value. EC was calculated by four-parameter fitting. 50 value.

[0806] The following is the SKOV3 cell killing data

[0807] γδT cells and the MV4-11-luc tumor cell line were expanded in vitro. MV4-11-luc cells were digested and counted, then resuspended in complete IMDM medium. The suspension density was adjusted to 5E3 cells / 100 μL / well and plated into a 96-well plate for overnight incubation. The next day, test and control compounds were diluted 3-fold in DMSO. 4 μL of each dilution was added to 96 μL of culture medium for a 25-fold dilution. 5 μL was transferred to the corresponding wells of the plate seeded with tumor cells. The actual test concentration range was 0.05-100 nM. γδT cells were resuspended in complete γδT medium, the suspension density was adjusted to an effector-target ratio (E:T) of 2:1, and plated into the corresponding wells at 1E4 cells / 100 μL / well. Incubate at 37°C, 5% CO2 for 20 hours, then centrifuge. The supernatant was removed and 50 μL of cell lysate containing fluorescein substrate was added to each well. After standing in the dark for 18 minutes, the chemiluminescence signal was detected. The value corresponding to the well with only tumor cells was the minimum killing value, and the value corresponding to the well without tumor cells was the maximum killing value. EC was calculated by four-parameter fitting. 50 value.

[0808] The following is the MV4-11 cell killing data

[0809] Test Example 2: Stability test of the compound in human plasma

[0810] Human plasma stored in a refrigerator was thawed in a 37°C water bath. The solution was centrifuged at 4000 rpm for 5 minutes, and the solution was collected. Using an Apricot automated workstation, 98 μL of plasma was added to each well of a 96-well plate, with each sample prepared in duplicate. 2 μL of a 100 μM small molecule solution was then added. After incubation for 0, 10, 30, 60, 120 minutes, 6 hours, and 24 hours, 500 μL of quenching solution was added to precipitate the protein. After shaking for 20 minutes, the sample was centrifuged at 4000 rpm for 20 minutes at 4°C. The supernatant was analyzed by LC-MS / MS.

[0811] Test Example 3: Stability test of the compound in human whole blood

[0812] (1) Take an appropriate amount of blank whole blood into an EP tube containing sodium heparin, then add the working solution of the test substance to a final concentration of 1 μM and vortex to mix;

[0813] (2) Place the sample in a 37℃ water bath, in parallel with 2 replicates; the time points are 0h, 0.5h, 1h, 2h, and 4h; perform an absolute zero point test separately and compare it with the 0 point.

[0814] (3) Take out an appropriate amount of sample from the incubation system and add 300 μL of internal standard precipitant to precipitate the protein; (4) Centrifuge all samples at 6°C for 10 min (15700×g).

[0815] (5) Take 150 μL of the supernatant and add 150 μL of water, vortex mix, and analyze by LC-MS / MS. The stability data of the compound in human whole blood are as follows:

[0816] Test Example 4: Stability test of compounds in human liver microsomes

[0817] The compound was prepared into a 10 mM stock solution in DMSO and then diluted into a 100 μM working solution in 80% acetonitrile-water for later use. Human liver microsomes were obtained from BIOIVT.

[0818] (1) Take out the liver microsomes from the refrigerator, place them in a 37℃ water bath constant temperature oscillator and pre-incubate for 5 minutes, and melt them for use.

[0819] (2) Weigh a certain amount of NADPH and dissolve it into a 2mM solution by adding an appropriate amount of magnesium chloride solution. (3) Prepare the mixed solution of the incubation system (excluding β-NADPH) according to the proportions in the "Composition of the Experimental Incubation System" above and dispense it into 165μL / tubes (45μL / tube for the negative control group and 120μL / tube for the positive control group).

[0820] (4) 0 min sample: add 200 μL of internal standard working precipitant and then add 30 μL of NADPH solution.

[0821] (5) Other samples: Add 135 μL NADPH solution to start the reaction (add 45 μL magnesium chloride solution to the negative control group), incubate in a 37°C water bath for 5, 15, 30, and 60 min (incubate in a 37°C water bath for 60 min for the negative control group), then take out 60 μL and add 200 μL of internal standard precipitant.

[0822] (6) Positive control group: Add 90 μL NADPH solution to start the reaction, incubate in a 37°C water bath for 5. After 15 minutes, take out 60 μL and add 200 μL of internal standard precipitant.

[0823] (7) Neat sample: aspirate 297 μL of water, add 1000 μL of internal standard working solution, and add 3 μL of test compound working solution.

[0824] (8) All samples were vortexed and centrifuged.

[0825] (9) Take 150 μL of the supernatant and add 150 μL of water, vortex mix, and analyze by LC-MS / MS. The following is the half-life stability data of human liver microsomes:

[0826] Test Example 5: Compound Binding Rate to Human Plasma Protein

[0827] (1) Soak the dry dialysis membrane in ultrapure water for 20 minutes or more, then soak it in 20% ethanol for 30 minutes to 1 hour, rinse the membrane 2-3 times with ultrapure water, and finally soak it in ultrapure water for 20 minutes before use.

[0828] (2) Thaw the frozen plasma in a 37°C water bath.

[0829] (3) The test compound was diluted into plasma preheated to 37°C to a final concentration of 1 μM. The final concentration of the control compound, warfarin, in plasma was 2 μM.

[0830] (4) Assemble the pretreated dialysis membrane into the dialysis plate according to the product instructions, and add 120 μL of receiving solution (100 mM phosphate buffer solution plus 0.002% Tween 80) to one side of the dialysis membrane in each dialysis well.

[0831] (5) Dispense 20 μL of each final solution of the test compound and the control compound into a 96-well sample plate, duplicate, to obtain the T0 sample, and store in a -20°C refrigerator. Dispense another 20 μL of the final solution onto the other side of the dialysis device membrane, duplicate, and incubate at 37°C with constant shaking for 6 h.

[0832] (6) After 6 h of incubation, 20 μL of the dialyzed receiving solution and 20 μL of the administered plasma were collected in duplicate to obtain samples B and A. The corresponding volume of blank plasma or receiving solution was added to sample B and sample A, respectively, so that the plasma to buffer volume ratio in each sample well was 1:1. 300 μL of acetonitrile solution containing the internal standard was added to all sample wells, mixed, and centrifuged.

[0833] (7) Add 200 μL of ultrapure water (150 μL for the control group) to the corresponding sample wells of the 96-well sample plate, take 300 μL of the supernatant (150 μL for the control group) to the sample wells, mix well, and then inject the sample for analysis. The free percentage and recovery rate of the compound in plasma were calculated using the following formula: Plasma protein binding rate (%) = 1-free percentage, free percentage (%) = C B / C A

[0834] Among them, C B is the concentration of the compound in the receiving fluid after equilibrium dialysis, C A is the concentration of the compound in plasma after equilibrium dialysis, and CT0 is the initial concentration of the compound in plasma. The following is the human plasma protein binding rate data:

[0835] Test Example 6: Compound and CYPs inhibition rate test

[0836] (1) 100× specific inhibitor: dilute the corresponding stock solution with 50% acetonitrile-water to prepare the inhibitor working solution of the corresponding concentration;

[0837] (2) 200× compound: dilute the compound stock solution with acetonitrile to a 2000 μM working solution;

[0838] (3) 200× substrate: dilute the corresponding stock solution with 50% acetonitrile-water to prepare the substrate working solution of the corresponding concentration;

[0839] (4) Prepare a 4 mM NADPH solution using PB solution as solvent;

[0840] (5) Liver microsome substrate solution: Take a certain amount of PB into a centrifuge tube, add a certain amount of MgCl2-PB solution, then add human liver microsome solution, add each subtype substrate working solution respectively, vortex to mix, and distribute into 148 μL / tube.

[0841] (6) Add 1 μL of inhibitor / test compound working solution in 50% acetonitrile-water to each tube, then pre-incubate in a 37°C water bath for 5 min. Pre-incubate NADPH in a 37°C water bath for 5 min. (7) Add 50 μL / well of NADPH working solution and incubate for 30 min (2C19) and 10 min (other isoforms).

[0842] (8) Take out 100 μL of sample and add 300 μL / well of ice-cold internal standard working solution, vortex for 5 min to terminate the reaction, and centrifuge;

[0843] (9) Take 100 μL of the supernatant and add 300 μL of water (1A2, 2C8), take 150 μL of the supernatant and add 150 μL of water (other subtypes), vortex mix, and inject for LC-MS / MS analysis. Use Excel to calculate the enzyme inhibition rate of the analyte and the control on the metabolic rate of each specific probe substrate at the test concentration. The calculation method is: enzyme inhibition rate % = 100-average residual enzyme activity % Residual enzyme activity % = metabolite peak area ratio of the probe substrate after adding inhibitor / metabolite peak area ratio of the probe substrate without adding inhibitor * 100%

[0844] Test Example 7: Compound Kinetic Solubility Test

[0845] The test substance was prepared into 10 mM stock solution with DMSO and set aside.

[0846] (1) Add the stock solution of the substance to be tested to a buffer solution with a pH value of 7.4 at a ratio of 1:49.

[0847] (2) Oscillate thoroughly for 24 hours.

[0848] (3) Centrifuge (15700g, 20min), take the clear liquid in the middle layer, dilute it 2000 times with 80% acetonitrile-water, mix well and then inject it into the sample for analysis.

[0849] Test Example 8: Caco2 membrane permeability test

[0850] 1. Dilute the test substance to a 5 μM test solution using the appropriate transport buffer. The final content of organic reagent in the incubation system should be less than 1%.

[0851] 2. Determine the rate of compound transport from the apical to the basolateral side. Add 75 μL of the dosing solution to each well of the upper chamber (apical side) and 250 μL of the receiving solution to each well of the lower chamber (basolateral side). Determine the rate of compound transport from the basolateral to the apical side. Add 75 μL of the receiving solution to each well of the upper chamber (apical side) and 250 μL of the dosing solution to each well of the lower chamber (basolateral side). Close the plate and incubate in a 37°C incubator for 120 min.

[0852] 3. After incubation, take samples and finally mix all samples and add 600 μL of stop solution containing internal standard.

[0853] 4. Mix on a shaker and centrifuge. Finally, take 200 μL of the supernatant of all samples, add 200 μL of water, vortex mix, and inject for LC-MS / MS analysis.

[0854] 5. Use the leakage of fluorescent yellow to evaluate the integrity of the cell monolayer membrane after incubation for 2 hours. Dilute the fluorescent yellow stock solution with transport buffer to a final concentration of 100 μM. Add 75 μL of fluorescent yellow solution to each well of the upper Transwell insert and 250 μL of transport buffer to each well of the lower receiving plate. After incubation for 120 minutes, aspirate 10 μL of solution from the upper layer of each well and add 90 μL of transport buffer to a new 96-well plate. Aspirate 100 μL of solution from the lower layer to a new 96-well plate. Use a microplate reader to measure fluorescence under the conditions of excitation wavelength 428 nm and emission wavelength 528 nm.

[0855] Apparent permeability coefficient (P app , unit: cm / s 10 -6 ) is calculated using the following formula: P app =(dCr / dt)x Vr / (A x C0)

[0856] where dCr / dt is the cumulative concentration of the compound in the receptor compartment as a function of time (μM / s); Vr is the volume of the solution at the receptor end (0.075 mL at the apical end and 0.25 mL at the basolateral end); and A is the surface area, i.e., the cell monolayer area is 0.0804 cm 2 ; C0 is the initial concentration at the drug administration end (μM).

[0857] The efflux ratio is calculated using the following formula: Efflux Ratio = P app (BA) / P app (AB)

[0858] Recovery is calculated using the following formula: % Recovery = 100 x [(Vr x Cr) + (Vd x Cd)] / (Vd x C0)

[0859] where Vd is the volume of the dosing end (0.075 mL at the apical end and 0.25 mL at the basolateral end); Cd and Cr are the final concentrations of the transported compound in the dosing end and the receiving end, respectively.

[0860] Test Example 9: Pharmacokinetic Test in Cynomolgus Monkeys

[0861] The control compound 2 and compound 19 were prepared into a 1 mg / mL solution in 10% DMSO / 90% PBS. Cynomolgus monkeys were obtained from Suzhou Leo Biotechnology Co., Ltd. The control compound 2 and compound 19 were administered intravenously at 2 mg / kg, respectively. Blood was collected before administration and recorded as zero point. 1 mL of blood was then collected at eight time points: 0.083, 0.15, 0.5, 1.0 2.0, 4.0, 8.0, and 24.0. The collected 1 mL of whole blood was placed in a labeled EDTA-2K anticoagulant tube. After gently inverting the blood to fully mix the anticoagulant (EDTA-2K), it was immediately placed in wet ice and centrifuged within 30 minutes to separate the plasma. The centrifugation conditions were set at 4°C, 2200g, and 6 minutes. The plasma separated after centrifugation was placed in a labeled EP tube, and the content of compound 19 and control compound 2 in the plasma samples at different time points was detected and analyzed. There were 3 male cynomolgus monkeys in each group.

[0862] Plasma concentrations and PK parameters of the unchanged drug in cynomolgus monkeys after intravenous injection of 2 mg / kg

[0863] After intravenous injection, the exposure of the prototype compound of the present application is more than 3 times that of the control compound, indicating that the compound of the present application can provide better active substance exposure and therapeutic effect for the subjects.

[0864] Experimental Example 10: Molecular Binding Experiment

[0865] (A) Potential diagram of the BTN3A1B30.2-HMBPP crystal structure (PDB ID: 5ZXK). Basic regions are shown in blue, and acidic regions are shown in red. HMBPP and amino acids are shown as sphere models.

[0866] (B) Crystal structure of BTN2A1B30.2–HMBPP-BTN3A1B30.2 (PDB ID: 7YGJ). BTN3A1B30.2 is shown as a potential map. Chains A and B of 2A1B30.2 are shown as cartoon models. HMBPP and amino acids are shown as globular models.

[0867] Image output from Pymol.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof: in, Ring A is C 6-10 Aryl or 5-10 membered heteroaryl; R a Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl; m = 1, 2, 3, 4 or 5; X is O or CRR'; R1 is selected from H, F, Cl, CN or methyl, wherein methyl is optionally substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2; R2 is selected from C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Haloalkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl, C 0-6 Alkylene-4-12 membered heterocyclic group or C 0-6 Alkylene-5-10 membered heteroaryl, wherein the C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Haloalkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl, C 0-6 Alkylene-4-12 membered heterocyclic group or C 0-6 Alkylene-5-10 membered heteroaryl is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Haloalkyl, -C(O)-C 2-6 Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10-membered cycloalkyl, -C(O)-4-10-membered heterocycloalkyl, -C(O)-C 6-10 Substitution with aryl, -C(O)-5-10 membered heteroaryl, -CN and oxo; R3 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; in, R and R' are independently selected from H or halogen; R" is independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof: in, Ring A is C 6-10 Aryl or 5-10 membered heteroaryl; R a Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl; m = 1, 2, 3, 4 or 5; X is O or CRR'; R1 is selected from H, F, Cl, CN or methyl, wherein methyl is optionally substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2; R2 is selected from C 5-6 Alkyl, C 5-6 Haloalkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-7 Cycloalkyl, C 0-6 Alkylene-4-7 membered heterocyclic group or C 0-6 Alkylene-5-10 membered heteroaryl; R3 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; in, R and R' are independently selected from H or halogen; R" is independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl.

3. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, which is a compound of formula (II): in, X is O or CRR'; R1 is selected from H, F, Cl, CN or methyl, wherein methyl is optionally substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2; R2 is selected from C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Haloalkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl or C 0-6 Alkylene-4-12 membered heterocyclic group, wherein the C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Haloalkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl or C 0-6 Alkylene-4-12 membered heterocyclic radicals are optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Haloalkyl, -C(O)-C 2-6 Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10 membered cycloalkyl, -C(O)-4-10 membered heterocycloalkyl, -C(O)-C 6-10 Substitution with aryl, -C(O)-5-10 membered heteroaryl, -CN and oxo; R3 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; in, R and R' are independently selected from H or halogen.

4. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, which is a compound of formula (II): in, X is O or CRR'; R1 is selected from H, F, Cl, CN or methyl, wherein methyl is optionally substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2; R2 is selected from C 5-6 Alkyl, C 5-6 Haloalkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-7 Cycloalkyl or C 0-6 Alkylene-4-7 membered heterocyclic group; R3 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; in, R and R' are independently selected from H or halogen.

5. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, which is a compound of formula (III): in, X is O or CRR'; Ring A is C 6-10 Aryl or 5-10 membered heteroaryl; R a Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl; R2 is selected from C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Haloalkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl or C 0-6 Alkylene-4-12 membered heterocyclic group, wherein the C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Haloalkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl or C 0-6 Alkylene-4-12 membered heterocyclic radicals are optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Haloalkyl, -C(O)-C 2-6 Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10 membered cycloalkyl, -C(O)-4-10 membered heterocycloalkyl, -C(O)-C 6-10 Substitution with aryl, -C(O)-5-10 membered heteroaryl, -CN and oxo; in, R and R' are independently selected from H or halogen.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein: X is CRR', preferably CH2 or CF2.

7. The compound of any one of claims 1 to 4 and 6, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein: R1 is selected from H, F, Cl, CN, CH3, CF3 or CH2OH, more preferably H, CH3, CH2OH or CF3, more preferably CH3 or CF3, more preferably CH3.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein: R2 is 2-ethylbutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl or tetrahydropyridinyl, preferably cyclopentyl, tetrahydrofuranyl, tetrahydrothienyl or pyrrolidinyl, more preferably cyclopentyl or tetrahydrofuranyl.

9. The compound of any one of claims 1-4 and 6-8, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein: R3 is C 1-6 The alkyl group is preferably a methyl group or an isopropyl group.

10. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, which is a compound of formula (IV): Where ring A is C 6-10 aryl or 5-10 membered heteroaryl, such as phenyl or naphthalene ring, R a Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl; m = 1, 2, 3, 4 or 5; R2 is a 3-12 membered cycloalkyl or a 4-12 membered heterocyclic group, wherein the 3-12 membered cycloalkyl or the 4-12 membered heterocyclic group is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Haloalkyl, -C(O)-C 2-6 Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10-membered cycloalkyl, -C(O)-4-10-membered heterocycloalkyl, -C(O)-C 6-10 The substituents of the aryl group, -C(O)-5-10 membered heteroaryl group, -CN and oxo group are substituted.

11. The compound of claim 10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, which is a compound of formula (V): Wherein R2 is a 4-12 membered heterocyclic group, wherein the 4-12 membered heterocyclic group is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Haloalkyl, -C(O)-C 2-6 Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10 membered cycloalkyl, -C(O)-4-10 membered heterocycloalkyl, -C(O)-C 6-10 The substituents of the aryl group, -C(O)-5-10 membered heteroaryl group, -CN and oxo group are substituted.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein R2 is a 4-10 membered heterocyclic group, the 4-10 membered heterocyclic group being optionally substituted with one or more selected from halogen, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 The substituents are substituted with hydroxyalkyl, -C(O)-3-10 membered cycloalkyl, -CN and oxo groups.

13. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein R2 is a 4-7 membered heterocyclic group, wherein the heteroatom is an oxygen atom or a nitrogen atom, and the 4-7 membered heterocyclic group is optionally substituted by one or more selected from C 1-6 The substituents of the alkyl and oxo groups are substituted.

14. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein R2 is selected from:

15. A compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof: in, Ring A is C 6-10 Aryl or 5-10 membered heteroaryl; R a Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl; m = 1, 2, 3, 4 or 5; X is O or CRR'; R1 is selected from H, F, Cl, CN or methyl, wherein the methyl is substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2; R2 is selected from C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Haloalkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl or C 0-6 Alkylene-4-12 membered heterocyclic group, wherein the C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Haloalkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl or C 0-6 Alkylene-4-12 membered heterocyclic radicals are optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Haloalkyl, -C(O)-C 2-6 Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10-membered cycloalkyl, -C(O)-4-10-membered heterocycloalkyl, -C(O)-C 6-10 Substitution with aryl, -C(O)-5-10 membered heteroaryl, -CN and oxo; R3 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; in, R and R' are independently selected from H or halogen; R" is independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl.

16. The compound of claim 15, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, which is a compound of formula (II): in, X is O or CRR'; R1 is selected from H, F, Cl, CN or methyl, wherein the methyl is substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2; R2 is selected from C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Haloalkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl or C 0-6 Alkylene-4-12 membered heterocyclic group, wherein the C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Haloalkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl or C 0-6 Alkylene-4-12 membered heterocyclic radicals are optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Haloalkyl, -C(O)-C 2-6 Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10-membered cycloalkyl, -C(O)-4-10-membered heterocycloalkyl, -C(O)-C 6-10 Substitution with aryl, -C(O)-5-10 membered heteroaryl, -CN and oxo; R3 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; in, R and R' are independently selected from H or halogen.

17. The compound of claim 15 or 16, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein: X is CRR', preferably CH2 or CF2.

18. The compound of any one of claims 15-17, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein: R1 is selected from H, F, Cl, CN, CF3 or CH2OH, more preferably H or CF3, more preferably CF3.

19. The compound of any one of claims 15 to 18, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein: R2 is C 1-6 Alkyl, C 0-6 Alkylene-C 3-7 Cycloalkyl, C 0-6 Alkylene-3-7 membered heterocyclic group, C 0-6 Alkylene-C 6-10 Aryl or C 0-6 Alkylene-5-10 membered heteroaryl, preferably isopropyl, 2-ethylbutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyridinyl or benzyl, more preferably 2-ethylbutyl, cyclopentyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl or benzyl, more preferably cyclopentyl, tetrahydrofuranyl or benzyl.

20. The compound of any one of claims 15 to 19, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein: R3 is C 1-6 The alkyl group is preferably a methyl group or an isopropyl group.

21. The compound of any one of claims 15 to 20, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein said R2 is a 3-12 membered cycloalkyl or a 4-12 membered heterocyclyl, wherein said 3-12 membered cycloalkyl or 4-12 membered heterocyclyl is optionally substituted with one or more selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Haloalkyl, -C(O)-C 2-6 Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10-membered cycloalkyl, -C(O)-4-10-membered heterocycloalkyl, -C(O)-C 6-10 aryl, -C(O)-5-10 membered heteroaryl, -CN and oxo; preferably, R2 is a 4-10 membered heterocyclic group, the 4-10 membered heterocyclic group is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 More preferably, R2 is a 4-7 membered heterocyclic group, wherein the heteroatom is an oxygen atom or a nitrogen atom, and the 4-7 membered heterocyclic group is optionally substituted by one or more selected from C 1-6 The substituents of the alkyl and oxo groups are substituted; more preferably, the R2 is selected from:

22. A compound of formula (VI), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof: in, Ring A is C 6-12 Aryl or 5-12 membered heteroaryl; R a Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl; m = 1, 2, 3, 4 or 5; X is O or CRR'; R1 is selected from H, F, Cl, CN or methyl, wherein methyl is optionally substituted by 1-3 independently selected from halogen, CN, OH and NH2 Substituent substitution; R2 is selected from C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Haloalkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl, C 0-6 Alkylene-4-12 membered heterocyclic group or C 0-6 Alkylene-5-10 membered heteroaryl, wherein the C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Haloalkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl, C 0-6 Alkylene-4-12 membered heterocyclic group or C 0-6 Alkylene-5-10 membered heteroaryl is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Haloalkyl, -C(O)-C 2-6 Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10 membered cycloalkyl, -C(O)-4-10 membered heterocycloalkyl, -C(O)-C 6-10 Substitution with aryl, -C(O)-5-10 membered heteroaryl, -CN and oxo; R3 and R3' are each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; in, R and R' are independently selected from H or halogen; R" is independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl.

23. The compound of claim 22, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, which is a compound of formula (VII): in, X is O or CRR'; Ring A is C 6-12 Aryl or 5-12 membered heteroaryl; R a Selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl; m = 1, 2, 3, 4 or 5; X is O or CRR'; R2 is selected from C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Haloalkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl, C 0-6 Alkylene-4-12 membered heterocyclic group or C 0-6 Alkylene-5-10 membered heteroaryl, wherein the C 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Haloalkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl, C 0-6 Alkylene-4-12 membered heterocyclic group or C 0-6 Alkylene-5-10 membered heteroaryl is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Haloalkyl, -C(O)-C 2-6 Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10-membered cycloalkyl, -C(O)-4-10-membered heterocycloalkyl, -C(O)-C 6-10 Substitution with aryl, -C(O)-5-10 membered heteroaryl, -CN and oxo; R3 and R3' are each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; in, R and R' are independently selected from H or halogen; R" is independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl.

24. The compound of claim 22 or 23, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein: X is CRR', preferably CH2 or CF2.

25. The compound of any one of claims 22-24, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein: R2 is C 1-6 Alkyl, C 0-6 Alkylene-C 3-7 Cycloalkyl, C 0-6 Alkylene-3-7 membered heterocyclic group, C 0-6 Alkylene-C 6-10 Aryl or C 0-6 Alkylene-5-10 membered heteroaryl, preferably isopropyl, 2-ethylbutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyridinyl or benzyl, more preferably 2-ethylbutyl, cyclopentyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl or benzyl, more preferably cyclopentyl, tetrahydrofuranyl or benzyl.

26. The compound of any one of claims 22-25, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein: R3 is C 1-6 The alkyl group is preferably a methyl group or an isopropyl group.

27. The compound of any one of claims 22 to 26, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein said R2 is a 3-12 membered cycloalkyl or a 4-12 membered heterocyclyl, wherein said 3-12 membered cycloalkyl or 4-12 membered heterocyclyl is optionally substituted with one or more selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-10 membered cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Hydroxyalkyl, -C(O)-C 1-6 Haloalkyl, -C(O)-C 2-6 Alkenyl, -C(O)-C 2-6 Alkynyl, -C(O)-3-10-membered cycloalkyl, -C(O)-4-10-membered heterocycloalkyl, -C(O)-C 6-10 aryl, -C(O)-5-10 membered heteroaryl, -CN and oxo; preferably, R2 is a 4-10 membered heterocyclic group, the 4-10 membered heterocyclic group is optionally substituted by one or more selected from halogen, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 More preferably, R2 is a 4-7 membered heterocyclic group, wherein the heteroatom is an oxygen atom or a nitrogen atom, and the 4-7 membered heterocyclic group is optionally substituted by one or more selected from C 1-6 The substituents of the alkyl and oxo groups are substituted; more preferably, the R2 is selected from:

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein the compound is selected from:

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein the compound is selected from:

30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

31. Use of a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, or a pharmaceutical composition according to claim 30 in the preparation of a medicament for treating a proliferative disease.

32. A compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, or a pharmaceutical composition according to claim 30 for use in treating a proliferative disease.

33. A method of treating a proliferative disease in a subject, the method comprising administering to the subject a compound of any one of claims 1-29, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, or a pharmaceutical composition of claim 14.

34. The use of claim 31 or the use of the compound or pharmaceutical composition of claim 32 or the method of claim 33, wherein the proliferative disease is selected from cancer, cardiovascular disorders, infectious diseases, chronic inflammatory diseases, autoimmune disorders and other cell proliferative disorders; preferably, wherein the cancer is selected from solid tumors and hematological malignancies, such as breast cancer, neuroblastoma, malignant rhabdoid tumor, well-differentiated and dedifferentiated liposarcoma, glioma, lung cancer, colorectal cancer, gastric cancer, gastrointestinal stromal tumor (GIST), hepatocellular carcinoma, prostate tumor, sarcoma, ovarian cancer, cervical cancer, pancreatic cancer, melanoma, thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, mesothelioma, lymphoma, leukemia, non-Hodgkin's lymphoma, mantle cell lymphoma, anaplastic large cell lymphoma, acute myeloid leukemia (AML) and multiple myeloma; preferably, wherein the proliferative disease is selected from multiple myeloma, non-Hodgkin's lymphoma, lung cancer, renal cancer and prostate cancer.

35. Use of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof in the preparation of a medicament for promoting the binding of butyrophilin 3A1 / 2A1: in, Ring A is C 6-10 Aryl or 5-10 membered heteroaryl; R a Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl; m = 1, 2, 3, 4 or 5; X is O or CRR'; R1 is selected from H, F, Cl, CN or methyl, wherein methyl is optionally substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2; R2 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkylene-C 3-7 Cycloalkyl, C 0-6 Alkylene-3-7 membered heterocyclic group, C 0-6 Alkylene-C 6-10 Aryl or C 0-6 Alkylene-5-10 membered heteroaryl; R3 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; in, R and R' are independently selected from H or halogen; R" is independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl.

36. A compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof for use in promoting the binding of butyrophilin 3A1 / 2A1: in, Ring A is C 6-10 Aryl or 5-10 membered heteroaryl; R a Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl; m = 1, 2, 3, 4 or 5; X is O or CRR'; R1 is selected from H, F, Cl, CN or methyl, wherein methyl is optionally substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2; R2 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkylene-C 3-7 Cycloalkyl, C 0-6 Alkylene-3-7 membered heterocyclic group, C 0-6 Alkylene-C 6-10 Aryl or C 0-6 Alkylene-5-10 membered heteroaryl; R3 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; in, R and R' are independently selected from H or halogen; R" is independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl.

37. A method of promoting butyrophilin 3A1 / 2A1 binding in a subject, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof: in, Ring A is C 6-10 Aryl or 5-10 membered heteroaryl; R a Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR", NR"R", C 2-6 Alkenyl or C 2-6 Alkynyl; m = 1, 2, 3, 4 or 5; X is O or CRR'; R1 is selected from H, F, Cl, CN or methyl, wherein methyl is optionally substituted with 1-3 substituents independently selected from halogen, CN, OH and NH2; R2 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkylene-C 3-7 Cycloalkyl, C 0-6 Alkylene-3-7 membered heterocyclic group, C 0-6 Alkylene-C 6-10 Aryl or C 0-6 Alkylene-5-10 membered heteroaryl; R3 is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; in, R and R' are independently selected from H or halogen; R" is independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl.

38. The use of claim 35 or the use of the compound or pharmaceutical composition of claim 36 or the method of claim 37, wherein the compound is selected from the compound of any one of claims 1 to 29 or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

39. The use of claim 35 or the use of the compound or pharmaceutical composition of claim 36 or the method of claim 37, wherein the compound is selected from the following compounds or pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, hydrates, polymorphs or isotopic variations thereof:

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