Modulators for promoting butyrophilin 3A1 / 2A1 binding

Abstract

The present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, solvate, hydrate, polymorph, or isotopic variant thereof, which can promote the binding of butyrophilin 3A1 / 2A1, and the definitions of each group in formula (I) are as detailed in the specification and claims. The present invention also relates to pharmaceutical compositions containing the compound of formula (I) and their use in clinical treatment. [C1] TIFF2026503047000176.tif29156

Description

[Technical Field]

[0001] The present disclosure relates to small molecule modulators that promote the binding of butyrophilin 3A1 (BTN3A1) and butyrophilin 2A1 (BTN2A1) in vivo, thereby exerting their respective biological functions, including applications in the treatment of tumors and infectious diseases. [Background technology]

[0002] Butyrophilins (BTNs) are a class of transmembrane proteins that generally exert their specific biological functions by forming heteropolymers. Both butyrophilin 3A1 (BTN3A1) and butyrophilin 2A1 (BTN2A1) proteins contain 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 up to 50% homology with that of BTN3A1. However, BTN2A1 lacks key basic amino acids in its ligand-binding pocket, and target cells are only recognized by immune cells, such as αβ and γδ T cells, when the B30.2 domain of BTN3A1 binds to the B30.2 domain of BTN2A1.

[0003] For example, γ9Vδ2 T cells are a common subtype of γδ T cells, an important type of immune cell, and play a key role in linking innate and adaptive immunity. After activation, Vγ9Vδ2 T cells can produce killing effects against tumor cells and multiple pathogens. Vγ9Vδ2 T cells play important roles in anti-infective and anti-tumor applications. Although BTN3A1 plays a key role in the identification and activation of Vγ9Vδ2 T cells, small molecules that bind only to BTN3A1 have no biological function. Only when a small molecule can promote the binding of the intracellular segment of BTN3A1 to BTN2A1 can it activate Vγ9Vδ2 T cells.

[0004] HMBPP is a naturally occurring small molecule produced within cells after infection with an infectious agent. Its activity in activating BTN3A1 / BTN2A1 is thousands of times greater than that of endogenous molecules such as IPP and DMAPP. Under physiological conditions, HMBPP carries two negative charges, making it difficult for it to enter cells by itself. Its activity is weak after short incubation periods (2-hour pulse stimulation). At the same time, HMBPP has poor plasma stability and poor druggability. Although the activity of C-HMBPP has shown some improvement compared to HMBPP, its short-term stimulatory activity remains weak.

[0005] Both patents WO2020008189 and WO2019182904 provide several new molecules. Other than in vitro activity data, the in vivo activity and subsequent clinical information of these molecules have not yet been disclosed.

[0006] This disclosure describes a small molecule compound that can effectively promote the binding of the intracellular B30.2 domain of BTN3A1-BTN2A1 and its use in the treatment of diseases. This molecule has high activity and good druggability. Summary of the Invention [Problem to be solved by the invention]

[0007] The present disclosure demonstrates, using size-exclusion chromatography-multi-angle light scattering (SEC-MALS) and sedimentation velocity ultracentrifugation (SV-AUC) studies, that the BTN3A1 B30.2 domain and the BTN2A1 B30.2 domain do not associate in the absence of a modulator. Furthermore, even if a small molecule is added, if the small molecule can only bind to the BTN3A1 B30.2 domain, it cannot activate Vy9V52 T cells; only when the B30.2 domains of both proteins are attached to each other by a small molecule (such as one disclosed in the present application) can Vy9V52 T cell activation be promoted.

[0008] The compounds provided by the present disclosure have the ability to promote 3A1-2A1 binding and activate Vγ9Vδ2 T cells. Furthermore, some compounds provided by the present disclosure have good stability, low clearance rates, and low plasma protein binding rates. This is advantageous for generating more free active drug in the blood. Furthermore, some compounds provided by the present disclosure have comprehensive properties favorable for druggability, such as longer human liver microsome stability and lower plasma protein binding rates, in addition to good cytocidal activity. [Means for solving the problem]

[0009] In one aspect, the present disclosure provides a compound of formula (I): [ka] A compound of the formula

[0010] During the ceremony,

[0011] Ring A is C 6-10 aryl or 5-10 membered heteroaryl;

[0012] R a H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR'', NR'', R'', C 2-6 Alkenyl and C 2-6 alkynyl;

[0013] m=1, 2, 3, 4 or 5;

[0014] X is O or CRR';

[0015] R1 is selected from H, F, Cl, CN and methyl, wherein said methyl is optionally substituted with 1 to 3 substituents independently selected from halogen, CN, OH and NH2;

[0016] R2 is 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 to 12-membered heterocyclyl and C 0-6 alkylene-5 to 10-membered heteroaryl; 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 to 12-membered heterocyclyl and C 0-6 Alkylene-5 to 10-membered heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 10-membered cycloalkyl, 4- to 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 to 10-membered cycloalkyl, -C(O)-4 to 10-membered heterocycloalkyl, -C(O)-C 6-10 optionally substituted with one or more substituents selected from aryl, —C(O)-5 to 10-membered heteroaryl, —CN, and oxo groups;

[0017] R3 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl;

[0018] where:

[0019] R and R' are independently selected from H and halogen;

[0020] R'' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 independently selected from aryl and 5- to 10-membered heteroaryl; Provided is a compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph, or isotopic variant thereof.

[0021] In one aspect, the present disclosure provides a compound of formula (I): [ka] A compound of the formula

[0022] During the ceremony,

[0023] Ring A is C 6-10 aryl or 5-10 membered heteroaryl;

[0024] R a H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR'', NR'', R'', C 2-6 Alkenyl and C 2-6 alkynyl;

[0025] m=1, 2, 3, 4 or 5;

[0026] X is O or CRR';

[0027] R1 is selected from H, F, Cl, CN and methyl, wherein said methyl is optionally substituted with 1 to 3 substituents independently selected from halogen, CN, OH and NH2;

[0028] R2 is 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 to 7-membered heterocyclyl, C 0-6 Alkylene-C 6-10 Aryl and C 0-6 alkylene-5 to 10 membered heteroaryl;

[0029] R3 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl;

[0030] where:

[0031] R and R' are independently selected from H and halogen;

[0032] R'' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 independently selected from aryl and 5- to 10-membered heteroaryl; Provided is a compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph, or isotopic variant thereof.

[0033] In another aspect, the present disclosure provides a compound of formula (I): [ka] A compound of the formula

[0034] During the ceremony,

[0035] Ring A is C 6-10 aryl or 5-10 membered heteroaryl;

[0036] R a H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR'', NR'', R'', C 2-6 Alkenyl and C 2-6 alkynyl;

[0037] m=1, 2, 3, 4 or 5;

[0038] X is O or CRR';

[0039] R1 is selected from H, F, Cl, CN, and methyl, wherein said methyl is substituted with 1 to 3 substituents independently selected from halogen, CN, OH, and NH2;

[0040] R2 is 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 to 7-membered heterocyclyl, C 0-6 Alkylene-C 6-10 Aryl and C 0-6 alkylene-5 to 10 membered heteroaryl;

[0041] R3 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl;

[0042] where:

[0043] R and R' are independently selected from H and halogen;

[0044] R'' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 independently selected from aryl and 5- to 10-membered heteroaryl; Provided is a compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph, or isotopic variant thereof.

[0045] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph, or isotopic variant thereof, and a pharmaceutically acceptable excipient.

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

[0047] In another aspect, the present disclosure provides a kit comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph, or isotopic variant thereof, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0048] In another aspect, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph, or isotopic variant thereof, in the manufacture of a medicament for treating and / or preventing a proliferative disease.

[0049] In another aspect, the present disclosure provides a method for treating and / or preventing a proliferative disease in a subject, the method comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, or a composition of the present disclosure.

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

[0051] In certain embodiments, the proliferative diseases 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, cancer includes, but is not limited to, solid tumors and hematological malignancies, such as breast cancer, neuroblastoma, malignant rhabdomyoma, 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, cholangiocarcinoma, 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.

[0052] In another aspect, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, or a composition of the present disclosure, in the manufacture of a medicament for promoting binding of butyrophilin 3A1 / 2A1.

[0053] In another aspect, the present disclosure provides a method for promoting butyrophilin 3A1 / 2A1 binding in a subject, the method comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, or a composition of the present disclosure.

[0054] In another aspect, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, or a composition of the present disclosure, for use in promoting binding of butyrophilin 3A1 / 2A1.

[0055] Other objects and advantages of the present disclosure will become apparent to those skilled in the art from the following detailed description, examples, and claims. [Brief explanation of the drawings]

[0056] [Figure 1] This shows the binding mode of a small molecule compound (compound 7) with BTN3A1 in vivo, demonstrating that the R1 group of the general formula molecule is substantially exposed to the solvent and can be derivatized in various ways without affecting the binding of the small molecule compound with BTN3A1.

[0057] [Figure 2] The simultaneous binding mode of a small molecule compound (compound 7) with BTN3A1 and BTN2A1 in vivo indicates that the R1 structure of the general formula molecule is constrained by a specific cavity, and only R1 with a specific spatial size can simultaneously bind to BTN3A1 and BTN2A1 and exert the corresponding biological effects.

[0058] Figures 1 and 2 show that the requirements for small molecule ligands designed based on the BTN3A1 model (Figure 1) are quite different from those for small molecule ligands designed based on the BTNA1-BTN2A1 model (Figure 2). In the model shown in Figure 2, small molecules can only exert their biological functions if they simultaneously bind to the cavity formed by BTN3A1 and BTN2A1. DETAILED DESCRIPTION OF THE INVENTION

[0059] definition

[0060] chemical definition

[0061] Definitions of certain functional groups and chemical terms are described in more detail below.

[0062] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1-6 "Alkyl" refers to 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 It is intended to include alkyl.

[0063] It should be understood that, as described herein, any of the groups defined below may be substituted with several substituents, and that the corresponding definitions, including the substituted groups, are within the scope of those listed below. Unless otherwise specified, the term "substituted" is as defined below.

[0064] "C 1-10"Alkyl" refers to a group of linear or branched saturated hydrocarbon groups having 1 to 10 carbon atoms. In some embodiments, C 1-8 Alkyl is an option. In some embodiments, C 1-6 Alkyl (also called "lower alkyl") is an option. In some embodiments, C 1-4 Alkyl is a further option. Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3), butyl (C4), pentyl (C5), hexyl (C6), heptyl (C7), octyl (C8), nonyl (C9), and decyl (C10). 10 ), but are not limited to. Alkyl groups include any isomers of the aforementioned 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); etc. Unless otherwise specified, each alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In some embodiments, an alkyl group is an unsubstituted C 1-6 In some embodiments, the alkyl group is a substituted C 1-6 It is an alkyl group.

[0065] "C 2-10 "Alkenyl" refers to a group of straight or branched chain hydrocarbon groups 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 Alkenyl is an option. In some embodiments, C 2-4Alkenyl is an option. The one or more carbon-carbon double bonds can be internal (e.g., in the case of 2-butenyl) or terminal (e.g., in the case of 1-butenyl). Examples of alkenyl groups include, but are not limited to, vinyl (C2), propenyl (C3), butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Alkenyl groups include any isomers of the aforementioned 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 is, 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 with one or more substituents (a "substituted alkenyl"), e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, an alkenyl group is an unsubstituted C 2-6 In some embodiments, the alkenyl group is a substituted C 2-6 It is alkenyl.

[0066] "C 2-10 "Alkynyl" refers to a group of straight-chain or branched-chain hydrocarbon groups having 2 to 10 carbon atoms and 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 2-6Alkynyl is an option. In some embodiments, C 2-4 Alkynyl is an option. In some embodiments, the alkynyl group does not contain a double bond. The one or more carbon-carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), 3-methylbut-1-ynyl (C5), hexynyl (C6), and the like. Unless otherwise specified, each alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In some embodiments, the alkynyl group is an unsubstituted C 2-6 In some embodiments, the alkynyl group is a substituted C 2-6 It is alkynyl.

[0067] "Halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halogen is -F, -Cl, or -Br. In some embodiments, the halogen is -F or -Cl.

[0068] Therefore, "C 1-10 "Haloalkyl" refers to the above "C" substituted with one or more halogens. 1-10 In some embodiments, C 1-6 Haloalkyl or C 1-4 Haloalkyl is an option, and more optionally C 1-2 Exemplary haloalkyl groups include, but are not limited to, -CF, -CHF, -CHFCHF, -CHCHF, -CFCF, -CCl, -CHCl, -CHCl, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like.

[0069] "C 3-12 "Cycloalkyl" refers to a group of non-aromatic cyclic hydrocarbon groups having 3 to 12 ring carbon atoms and no heteroatoms, including fused, bridged, spirocyclic, etc. In some embodiments, C 3-7 Cycloalkyl is the option, C 3-6 Cycloalkyl is an option, and more preferably C 5-6 Exemplary cycloalkyl groups include 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), cyclodecyl (C8), and the like. 10 ), cyclodecenyl (C 10 ), cycloundecyl (C 11 ), cycloundecenyl (C 11 ), cyclododecyl (C 12 ), cyclododecenyl (C 12 ), cyclotridecyl (C 13 ), cyclotridecenyl (C 13 ), adamantyl, and the like.

[0070] "3- to 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- to 7-membered heterocyclyl and 3- to 6-membered heterocyclyl are options, where the 3- to 6-membered heterocyclyl is a 3- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. In some embodiments, 4- to 7-membered heterocyclyl is an option, where the 4- to 7-membered non-aromatic ring system has ring carbon atoms and 1 to 3 ring heteroatoms. In some embodiments, 5- to 6-membered heterocyclyl is an option, where the 5- to 6-membered non-aromatic ring system has ring carbon atoms and 1 to 3 ring heteroatoms. Exemplary 3-membered heterocyclyl groups having one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups having one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups having one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups having two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups having three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups having one heteroatom include, but are not limited to, piperidyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclyl groups having two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups having three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups having one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl.In some embodiments, the 3- to 12-membered heterocyclyl of the present disclosure includes the following: [ka] The group includes:

[0071] "C 6-10 "Aryl" refers to a group of monocyclic or bicyclic 4n+2 aromatic ring systems (e.g., having 6 or 10 shared π electrons in a cyclic arrangement) having 6 to 10 ring carbon atoms and no heteroatoms within the aromatic ring system. In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 Aryl"; for example, naphthyl, e.g., 1-naphthyl and 2-naphthyl). Unless otherwise specified, each aryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted with one or more substituents (a "substituted aryl").

[0072] "5-10-membered heteroaryl" refers to a 5-10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur). In some embodiments, 5-6-membered heteroaryl is an option, which is a 5-6-membered monocyclic 4n+2 aromatic ring system (e.g., having 6 shared π electrons in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur). In some embodiments, 5-membered heteroaryl is an option, which is a 5-membered monocyclic 4n+2 aromatic ring system (e.g., having 6 shared π electrons in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur). In some embodiments, 6-membered heteroaryl is optional and is a 6-membered monocyclic 4n+2 aromatic ring system (e.g., having six shared π electrons in a cyclic arrangement) having ring carbon atoms and 1 to 4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur). Unless otherwise specified, each heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). Exemplary 5-membered heteroaryl groups having one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. Exemplary 5-membered heteroaryl groups having two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups having three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups having four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups having one heteroatom include, but are not limited to, pyridyl.Exemplary 6-membered heteroaryl groups having two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups having three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively.

[0073] "Heteroatom" refers to a non-metallic atom other than carbon atom. Oxygen, nitrogen, phosphorus, sulfur, silicon, and boron atoms are alternatives, and more preferably oxygen, nitrogen, phosphorus, and sulfur atoms.

[0074] "-C 1-6 "Alkylene-" is defined as "C 1-6 Specifically, it refers to a divalent group of "alkyl." 1-6 It refers to a divalent group formed by removing another hydrogen from an alkyl, and can be a substituted or unsubstituted alkylene group. In some embodiments, C 1-4 Alkylene is a further option. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Examples of substituted alkylene groups, e.g., those 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)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0075] "C 0-6 An "alkylene group" is a group consisting of a chemical bond and a "C" as defined above. 1-6 The term "alkylene group" refers to an "alkylene group."

[0076] In a compound, a chemical bond " [ka] " is used, it means that the cis and trans isomers of the compound coexist in any ratio, i.e., it may be the cis isomer, the trans isomer, or a mixture thereof.

[0077] Alkyl, alkenyl, alkynyl, aryl, heteroaryl, and the like, as defined herein, are optionally substituted groups, whether or not previously described as "optionally substituted." In general, the term "substituted," whether or not previously described as "optionally," refers to the replacement of at least one hydrogen atom present in a group (e.g., on a carbon atom or nitrogen atom) with a permissible substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when multiple positions are substituted in any given structure, the substituents at each position are the same or different. The term "substituted" includes substitution with all permissible substituents of organic compounds (any substituents described herein that result in the formation of a stable compound). In the present disclosure, heteroatoms, such as nitrogen, may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0078] Exemplary substituents on carbon atoms include 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(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa, -SC(=O)R aa , -P(=O)2R aa , -OP(=O)2R aa , -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, each of which may be selected from the group consisting of 0, 1, 2, 3, 4, or 5 R dd independently substituted with groups;

[0079] Or two geminal hydrogens on a carbon atom are =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 is replaced by a group;

[0080] R aaeach independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R aa groups combine to form a heterocyclyl or heteroaryl ring, and each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups may have 0, 1, 2, 3, 4, or 5 R dd independently substituted with groups;

[0081] R bb are hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R bb groups combine to form a heterocyclyl or heteroaryl ring, and each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups may have 0, 1, 2, 3, 4, or 5 R dd independently substituted with groups;

[0082] Rcc each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups combine to form a heterocyclyl or heteroaryl ring, and each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups may have 0, 1, 2, 3, 4, or 5 R dd independently substituted with groups;

[0083] R dd Each of the following is a 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, and heteroaryl, each of said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl being independently selected from 0, 1, 2, 3, 4, or 5 R gg groups or two geminal R dd The substituents may combine to form =O or =S;

[0084] R ee each is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl, and each of said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is selected from 0, 1, 2, 3, 4, or 5 R gg independently substituted with groups;

[0085] R ff each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R ffgroups combine to form a heterocyclyl or heteroaryl ring, and each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups may have 0, 1, 2, 3, 4, or 5 R gg independently substituted with groups;

[0086] R gg each independently represents a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(C 1-6 alkyl)3 + X - , -NH(C 1-6 alkyl)2 + X - , -NH2(C 1-6 alkyl) + X - , -NH3 + X - , -N(OC 1-6 Alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6alkyl), -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(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal R gg The substituents may combine to form =O or =S, and X - is the counterion.

[0087] Exemplary substituents on a nitrogen atom include 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)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R bonded to a nitrogen atom cc groups combine to form a heterocyclyl or heteroaryl ring, and each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups may have 0, 1, 2, 3, 4, or 5 R dd groups, and R aa , R bb , R cc and R dd is as described herein.

[0088] When the chemical structure of a compound has a chiral atom, such as a chiral carbon atom or a chiral phosphorus atom, the present disclosure encompasses all isomers associated with the chiral atom, including R isomers, S isomers, (+) isomers, (-) isomers, mixtures thereof, and racemates. At the same time, when a chemical bond "-" is used to connect to a chiral atom rather than a wedge bond, it merely represents the connection relationship between the two atoms and does not designate a specific configuration of the compound, i.e., it represents that all isomers, mixtures thereof, or racemates may be included, and should not be interpreted as representing only a racemate.

[0089] If the chemical structure of a compound contains a double bond, it merely indicates that two atoms are connected by a double bond and that the compound does not have a specific configuration, i.e., it may include (E) isomers, (Z) isomers, and mixtures thereof.

[0090] Other definitions

[0091] The term "pharmaceutically acceptable salt" refers to a salt that is suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and that is commensurate with a reasonable benefit / risk ratio. 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 disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or formed by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and methyl ... + (C 1-4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, as appropriate.

[0092] "Subjects" to which administration is contemplated 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 the elderly)) and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0093] As used herein, and unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions taken while a subject is afflicted with the specified disease, disorder, or condition that reduce the severity of the disease, disorder, or condition or delay or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), and also contemplate actions taken before a subject begins to suffer from the specified disease, disorder, or condition ("prophylactic treatment").

[0094] Generally, the "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response. As will be understood by those skilled in the art, the effective amount of the compound of the present disclosure may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, health and condition of the subject. The effective amount includes both a therapeutically effective amount and a prophylactically effective amount.

[0095] As used herein, 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 means an amount of a therapeutic agent that, alone or in combination with other treatments, provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, an amount that reduces or avoids the symptoms or causes of a disease or condition, or an amount that enhances the therapeutic effectiveness of another therapeutic agent.

[0096] As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or to prevent one or more symptoms associated with the disease, disorder, or condition, or to prevent its recurrence. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent that, alone or in combination with other agents, provides a prophylactic benefit in the prevention of a disease, disorder, or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or an amount that enhances the prophylactic effectiveness of another prophylactic agent.

[0097] compound

[0098] As used herein, "compounds of the disclosure" refer to compounds of the following general formula or subformulas thereof, or pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, hydrates, polymorphs or isotopic variants thereof:

[0099] In one embodiment, the present disclosure provides a compound of formula (I): [ka] A compound of the formula

[0100] During the ceremony,

[0101] Ring A is C 6-10aryl or 5-10 membered heteroaryl;

[0102] R a H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR'', NR'', R'', C 2-6 Alkenyl and C 2-6 alkynyl;

[0103] m=1, 2, 3, 4 or 5;

[0104] X is O or CRR';

[0105] R1 is selected from H, F, Cl, CN and methyl, wherein said methyl is optionally substituted with 1 to 3 substituents independently selected from halogen, CN, OH and NH2;

[0106] R2 is 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 and C 0-6 alkylene-4 to 12-membered heterocyclyl; 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 and C 0-6 Alkylene-4 to 12-membered heterocyclyl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10Aryl, 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 to 10-membered cycloalkyl, -C(O)-4 to 10-membered heterocycloalkyl, -C(O)-C 6-10 optionally substituted with one or more substituents selected from aryl, —C(O)-5 to 10-membered heteroaryl, —CN, and oxo groups;

[0107] R3 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl;

[0108] where:

[0109] R and R' are independently selected from H and halogen;

[0110] R'' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 independently selected from aryl and 5- to 10-membered heteroaryl; The present invention relates to a compound or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

[0111] In one embodiment, the present disclosure provides a compound of formula (I): [ka] A compound of the formula

[0112] During the ceremony,

[0113] Ring A is C 6-10 aryl or 5-10 membered heteroaryl;

[0114] R a H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR'', NR'', R'', C 2-6 Alkenyl and C 2-6 alkynyl;

[0115] m=1, 2, 3, 4 or 5;

[0116] X is O or CRR';

[0117] R1 is selected from H, F, Cl, CN and methyl, wherein said methyl is optionally substituted with 1 to 3 substituents independently selected from halogen, CN, OH and NH2;

[0118] R2 is 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 to 7-membered heterocyclyl, C 0-6 Alkylene-C 6-10 Aryl and C 0-6 alkylene-5 to 10 membered heteroaryl;

[0119] R3 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl;

[0120] where:

[0121] R and R' are independently selected from H and halogen;

[0122] R'' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 independently selected from aryl and 5- to 10-membered heteroaryl; The present invention relates to a compound or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

[0123] In another embodiment, the present disclosure provides a compound of formula (I): [ka] A compound of the formula

[0124] During the ceremony,

[0125] Ring A is C 6-10 aryl or 5-10 membered heteroaryl;

[0126] R a H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR'', NR'', R'', C 2-6 Alkenyl and C 2-6 alkynyl;

[0127] m=1, 2, 3, 4 or 5;

[0128] X is O or CRR';

[0129] R1 is selected from H, F, Cl, CN, and methyl, wherein said methyl is substituted with 1 to 3 substituents independently selected from halogen, CN, OH, and NH2;

[0130] R2 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 0-6 Alkylene-C 3-7 Cycloalkyl, C 0-6 Alkylene-3 to 7-membered heterocyclyl, C 0-6 Alkylene-C 6-10 Aryl and C 0-6 alkylene-5 to 10 membered heteroaryl;

[0131] R3 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl;

[0132] where:

[0133] R and R' are independently selected from H and halogen;

[0134] R'' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 independently selected from aryl and 5- to 10-membered heteroaryl; The invention covers the compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

[0135] Ring A

[0136] In one specific embodiment, ring A is C 6-10 aryl, with phenyl being an option. In another specific embodiment, Ring A is a 5-10 membered heteroaryl.

[0137] R a

[0138] In one specific embodiment, R a is H, and in another specific embodiment, Ra is halogen, and in another specific embodiment, R a C 1-6 In another specific embodiment, R a C 1-6 haloalkyl, and in another specific embodiment, R a is -OR'', and in another specific embodiment, R a is NR"R" and in another specific embodiment, R a C 2-6 alkenyl, and in another specific embodiment, R a C 2-6 It is alkynyl.

[0139] m

[0140] In one specific embodiment, m=1, in another specific embodiment, m=2, in another specific embodiment, m=3, in another specific embodiment, m=4, and in another specific embodiment, m=5.

[0141] X

[0142] In one specific embodiment, X is O; in another specific embodiment, X is CRR'; and in another specific embodiment, X is CH2 or CF2.

[0143] R1

[0144] In one specific embodiment, R1 is H, in another specific embodiment, R1 is F, in another specific embodiment, R1 is Cl, in another specific embodiment, R1 is CN, in another specific embodiment, R1 is methyl substituted with 1 to 3 substituents independently selected from halogen, CN, OH, and NH2, e.g., R1 is CF3 or CH2OH, in another specific embodiment, R1 is methyl, which may be substituted with 1 to 3 substituents independently selected from halogen, CN, OH, and NH2.

[0145] In a more specific embodiment, R1 is H; in another more specific embodiment, R1 is selected from CF3 and CH2OH; in another more specific embodiment, R1 is selected from H and CF3; in another more specific embodiment, R1 is CF3; in another more specific embodiment, R1 is selected from H, F, Cl, CN, CH3, CF3 and CH2OH; in another more specific embodiment, R1 is selected from H, CH3 and CF3; in another more specific embodiment, R1 is selected from CH3 and CF3; in another more specific embodiment, R1 is CH3.

[0146] R2

[0147] In one specific embodiment, R2 is C 1-6 Alkyl, optionally C 1-4 Alkyl, optionally C 5-6 alkyl, optionally isopropyl or 2-ethylbutyl; in another specific embodiment, R2 is C 1-6 haloalkyl, optionally C 1-4 haloalkyl, optionally C 5-6 haloalkyl, and in another specific embodiment, R2 is C 2-6 alkenyl, optionally C 2-4 alkenyl, optionally C 5-6 alkenyl, and in another specific embodiment, R2 is C 2-6 Alkynyl, optionally C 2-4 Alkynyl, optionally C 5-6 In another specific embodiment, R2 is alkynyl. 0-6 Alkylene-C 3-7 cycloalkyl, optionally C 0-6 Alkylene-C 5-6 In another specific embodiment, R2 is C 0-6 alkylene-3 to 7-membered heterocyclyl, optionally C 0-6 Alkylene-4 to 7-membered heterocyclyl, C 0-6 alkylene-5-6 membered heterocyclyl, optionally tetrahydropyranyl; in another specific embodiment, R2 is C 0-6Alkylene-C 6-10 aryl, and in another specific embodiment, R2 is C 0-6 alkylene-5 to 10 membered heteroaryl.

[0148] In more specific embodiments, R2 is C 1-6 Alkyl, C 0-6 Alkylene-C 3-7 Cycloalkyl, C 0-6 Alkylene-3 to 7-membered heterocyclyl, C 0-6 Alkylene-C 6-10 Aryl or C 0-6 alkylene-5 to 10 membered heteroaryl; 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, cyclopentyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, or benzyl; , tetrahydrofuranyl, or benzyl; 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;

[0149] In another more specific embodiment, R2 is a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclyl, wherein the 3- to 12-membered cycloalkyl or the 4- to 12-membered heterocyclyl is selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C2-6 Alkenyl, C 2-6 Alkynyl, 3- to 10-membered cycloalkyl, 4- to 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 to 10-membered cycloalkyl, -C(O)-4 to 10-membered heterocycloalkyl, -C(O)-C 6-10 Optionally, R2 is substituted with one or more substituents selected from aryl, -C(O)-5 to 10 membered heteroaryl, -CN, and oxo groups. 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 and hydroxyalkyl, -C(O)-3- to 10-membered cycloalkyl, -CN, and oxo. More preferably, R2 is a 4- to 7-membered heterocyclyl, the heteroatom of which is an oxygen atom or a nitrogen atom, and the 4- to 7-membered heterocyclyl is C 1-6 and optionally substituted with one or more substituents selected from alkyl and oxo groups. [ka] is selected from.

[0150] R3

[0151] In one specific embodiment, R3 is C, such as methyl or isopropyl. 1-6 alkyl, and in another specific embodiment, R3 is C 1-6 haloalkyl, and in another specific embodiment, R3 is C 2-6 alkenyl, and in another specific embodiment, R3 is C 2-6 It is alkynyl.

[0152] R and R'

[0153] In one specific embodiment, R and R' are H, and in one specific embodiment, R and R' are halogen.

[0154] R''

[0155] In one specific embodiment, R″ is C 1-6 alkyl, and in another specific embodiment, R″ is C 1-6 haloalkyl, and in another specific embodiment, R″ is C 0-6 Alkylene-C 6-10 aryl, and in another specific embodiment, R″ is C 0-6 alkylene-5 to 10 membered heteroaryl.

[0156] Any technical solution or any combination thereof in any one of the above specific embodiments may be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical solution or any combination thereof of X may be combined with any technical solution or any combination thereof of R1 to R3, R, R', and R''. The present disclosure intends to include all combinations of such technical solutions, but to save space, they are not exhaustively listed here.

[0157] In alternative embodiments, the present disclosure relates to the following technical solutions:

[0158] Technical solution 1. Formula (I) [ka] A compound of the formula

[0159] During the ceremony,

[0160] Ring A is C 6-10aryl or 5-10 membered heteroaryl;

[0161] R a H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR'', NR'', R'', C 2-6 Alkenyl and C 2-6 alkynyl;

[0162] m=1, 2, 3, 4 or 5;

[0163] X is O or CRR';

[0164] R1 is selected from H, F, Cl, CN and methyl, wherein said methyl is optionally substituted with 1 to 3 substituents independently selected from halogen, CN, OH and NH2;

[0165] R2 is 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 to 12-membered heterocyclyl and C 0-6 alkylene-5 to 10-membered heteroaryl; 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 to 12-membered heterocyclyl and C 0-6 Alkylene-5 to 10-membered heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, 3- to 10-membered cycloalkyl, 4- to 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 to 10-membered cycloalkyl, -C(O)-4 to 10-membered heterocycloalkyl, -C(O)-C 6-10 optionally substituted with one or more substituents selected from aryl, —C(O)-5 to 10-membered heteroaryl, —CN, and oxo groups;

[0166] R3 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl;

[0167] where:

[0168] R and R' are independently selected from H and halogen;

[0169] R'' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 independently selected from aryl and 5- to 10-membered heteroaryl; The compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

[0170] Technical Solution 2. Formula (I) of Technical Solution 1 [ka] A compound of the formula

[0171] During the ceremony,

[0172] Ring A is C 6-10 aryl or 5-10 membered heteroaryl;

[0173] R a H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR'', NR'', R'', C 2-6 Alkenyl and C 2-6 alkynyl;

[0174] m=1, 2, 3, 4 or 5;

[0175] X is O or CRR';

[0176] R1 is selected from H, F, Cl, CN and methyl, wherein said methyl is optionally substituted with 1 to 3 substituents independently selected from halogen, CN, OH and NH2;

[0177] R2 is 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 to 7-membered heterocyclyl and C 0-6 alkylene-5 to 10 membered heteroaryl;

[0178] R3 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl;

[0179] where:

[0180] R and R' are independently selected from H and halogen;

[0181] R'' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 independently selected from aryl and 5- to 10-membered heteroaryl; The compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

[0182] Technical solution 3. Formula (II) [ka] A compound of the formula

[0183] During the ceremony,

[0184] X is O or CRR';

[0185] R1 is selected from H, F, Cl, CN and methyl, wherein said methyl is optionally substituted with 1 to 3 substituents independently selected from halogen, CN, OH and NH2;

[0186] R2 is 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 and C 0-6 alkylene-4 to 12-membered heterocyclyl; 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 and C 0-6Alkylene-4 to 12-membered heterocyclyl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 10-membered cycloalkyl, 4- to 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 to 10-membered cycloalkyl, -C(O)-4 to 10-membered heterocycloalkyl, -C(O)-C 6-10 optionally substituted with one or more substituents selected from aryl, —C(O)-5 to 10-membered heteroaryl, —CN, and oxo groups;

[0187] R3 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl;

[0188] where:

[0189] R and R' are independently selected from H and halogen; The compound of Technical Solution 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

[0190] Technical solution 4. Formula (II) [ka] A compound of the formula

[0191] During the ceremony,

[0192] X is O or CRR';

[0193] R1 is selected from H, F, Cl, CN and methyl, wherein said methyl is optionally substituted with 1 to 3 substituents independently selected from halogen, CN, OH and NH2;

[0194] R2 is C 5-6 Alkyl, C 5-6 Haloalkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6 Alkylene-C 3-7 Cycloalkyl and C 0-6 alkylene-4 to 7 membered heterocyclyl;

[0195] R3 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl;

[0196] where:

[0197] R and R' are independently selected from H and halogen; The compound of Technical Solution 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

[0198] Technical solution 5. Formula (III) [ka] A compound of the formula

[0199] During the ceremony,

[0200] X is O or CRR';

[0201] Ring A is C 6-10 aryl or 5-10 membered heteroaryl;

[0202] R a H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR'', NR'', R'', C 2-6 Alkenyl and C 2-6 alkynyl;

[0203] R2 is 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 and C 0-6 alkylene-4 to 12-membered heterocyclyl; 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 and C 0-6 Alkylene-4 to 12-membered heterocyclyl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 10-membered cycloalkyl, 4- to 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 to 10-membered cycloalkyl, -C(O)-4 to 10-membered heterocycloalkyl, -C(O)-C 6-10 optionally substituted with one or more substituents selected from aryl, —C(O)-5 to 10-membered heteroaryl, —CN, and oxo groups;

[0204] where:

[0205] R and R' are independently selected from H and halogen; The compound of Technical Solution 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

[0206] Technical Solution 6. A compound of any one of Technical Solutions 1 to 5, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein X is CRR', optionally CH2 or CF2.

[0207] 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 and CH2OH, and even more selectively, R1 is selected from H, CH3, CH2OH and CF3, and even more selectively, R1 is selected from CH3 and CF3, and even more selectively, R1 is CH3.

[0208] Technical Solution 8. The compound of any one of Technical Solutions 1 to 7, wherein R2 is 2-ethylbutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl or tetrahydropyridinyl, and alternatively cyclopentyl, tetrahydrofuranyl, tetrahydrothiophenyl or pyrrolidinyl, and further alternatively cyclopentyl or tetrahydrofuranyl, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

[0209] Technical Solution 9.R3 is C 1-6A 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 R is alkyl and optionally is methyl or isopropyl.

[0210] Technical solution 10. Formula (IV) [ka] A compound of the formula

[0211] In the formula, ring A is C 6-10 aryl or 5-10 membered heteroaryl, for example, a phenyl ring or a naphthalene ring;

[0212] R a H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR'', NR'', R'', C 2-6 Alkenyl and C 2-6 alkynyl;

[0213] m=1, 2, 3, 4 or 5;

[0214] R2 is a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclyl, and the 3- to 12-membered cycloalkyl or the 4- to 12-membered heterocyclyl is selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 10-membered cycloalkyl, 4- to 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 2-6Alkynyl, -C(O)-3 to 10-membered cycloalkyl, -C(O)-4 to 10-membered heterocycloalkyl, -C(O)-C 6-10 optionally substituted with one or more substituents selected from aryl, —C(O)-5 to 10-membered heteroaryl, —CN, and oxo groups; The compound of Technical Solution 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

[0215] Technical solution 11. Formula (V) [ka] A compound of the formula

[0216] In the formula, R2 is a 4- to 12-membered heterocyclyl, and the 4- to 12-membered heterocyclyl is selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 10-membered cycloalkyl, 4- to 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 to 10-membered cycloalkyl, -C(O)-4 to 10-membered heterocycloalkyl, -C(O)-C 6-10 optionally substituted with one or more substituents selected from aryl, —C(O)-5 to 10-membered heteroaryl, —CN, and oxo groups; The compound of technical solution 10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

[0217] Technical Solution 12.R2 is halogen, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 The compound of any one of technical solutions 1 to 11, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, which is a 4- to 10-membered heterocyclyl optionally substituted with one or more substituents selected from hydroxyalkyl, —C(O)-3- to 10-membered cycloalkyl, —CN and oxo group.

[0218] Technical Solution 13. R2 is a 4- to 7-membered heterocyclyl, the heteroatom of which is an oxygen atom or a nitrogen atom, and the above 4- to 7-membered heterocyclyl is C 1-6 A compound of any one of technical solutions 1 to 11, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, optionally substituted with one or more substituents selected from alkyl and oxo groups.

[0219] Technical solution 14.R2 is below: [ka] 12. The compound of any one of technical solutions 1 to 11, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, selected from:

[0220] Technical solution 15. Formula (I) [ka] A compound of the formula

[0221] During the ceremony,

[0222] Ring A is C 6-10 aryl or 5-10 membered heteroaryl;

[0223] Ra H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR'', NR'', R'', C 2-6 Alkenyl and C 2-6 alkynyl;

[0224] m=1, 2, 3, 4 or 5;

[0225] X is O or CRR';

[0226] R1 is selected from H, F, Cl, CN, and methyl, wherein said methyl is substituted with 1 to 3 substituents independently selected from halogen, CN, OH, and NH2;

[0227] R2 is 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 and C 0-6 alkylene-4 to 12-membered heterocyclyl; 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 and C 0-6 Alkylene-4 to 12-membered heterocyclyl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 10-membered cycloalkyl, 4- to 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 to 10-membered cycloalkyl, -C(O)-4 to 10-membered heterocycloalkyl, -C(O)-C 6-10 and optionally substituted with one or more substituents selected from aryl, —C(O)-5 to 10-membered heteroaryl, —CN, and oxo groups; optionally, R2 is 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 to 7-membered heterocyclyl, C 0-6 Alkylene-C 6-10 Aryl and C 0-6 alkylene-5 to 10 membered heteroaryl;

[0228] R3 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl;

[0229] where:

[0230] R and R' are independently selected from H and halogen;

[0231] R'' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 independently selected from aryl and 5- to 10-membered heteroaryl; The compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

[0232] Technical solution 16. Formula (II) [ka] A compound of the formula

[0233] During the ceremony,

[0234] X is O or CRR';

[0235] R1 is selected from H, F, Cl, CN, and methyl, wherein said methyl is substituted with 1 to 3 substituents independently selected from halogen, CN, OH, and NH2;

[0236] R2 is 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 and C 0-6 alkylene-4 to 12-membered heterocyclyl; 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 and C 0-6 Alkylene-4 to 12-membered heterocyclyl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 10-membered cycloalkyl, 4- to 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 to 10-membered cycloalkyl, -C(O)-4 to 10-membered heterocycloalkyl, -C(O)-C 6-10 and optionally substituted with one or more substituents selected from aryl, —C(O)-5 to 10-membered heteroaryl, —CN, and oxo groups; optionally, R2 is 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 to 7-membered heterocyclyl, C 0-6 Alkylene-C 6-10 Aryl and C 0-6 alkylene-5 to 10 membered heteroaryl;

[0237] R3 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl;

[0238] where:

[0239] R and R' are independently selected from H and halogen; The compound of Technical Solution 15, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

[0240] Technical Solution 17. The compound of Technical Solution 15 or Technical Solution 16, wherein X is CRR', optionally CH2 or CF2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

[0241] Technical Solution 18. A 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 and CH2OH, and more selectively R1 is selected from H and CF3, and even more selectively R1 is CF3.

[0242] Technical solution 19.R2 but C 1-6 Alkyl, C 0-6 Alkylene-C 3-7 Cycloalkyl, C 0-6 Alkylene-3 to 7-membered heterocyclyl, C 0-6 Alkylene-C 6-10 Aryl or C 0-6 or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

[0243] Technical Solution 20.R3 is C 1-6 The compound of any one of technical solutions 15 to 19, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein R is alkyl and optionally is methyl or isopropyl.

[0244] Technical Solution 21. R2 is a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclyl, and the 3- to 12-membered cycloalkyl or the 4- to 12-membered heterocyclyl is selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 10-membered cycloalkyl, 4- to 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 to 10-membered cycloalkyl, -C(O)-4 to 10-membered heterocycloalkyl, -C(O)-C 6-10 and optionally R2 is substituted with one or more substituents selected from aryl, -C(O)-5 to 10 membered heteroaryl, -CN and oxo groups; optionally R2 is halogen, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 and R2 is a 4- to 10-membered heterocyclyl optionally substituted with one or more substituents selected from hydroxyalkyl, —C(O)-3- to 10-membered cycloalkyl, —CN, and oxo; more preferably, R2 is a 4- to 7-membered heterocyclyl, the heteroatom of which is an oxygen atom or a nitrogen atom, and the 4- to 7-membered heterocyclyl is C 1-6 and optionally substituted with one or more substituents selected from alkyl and oxo groups, and more preferably R2 is [ka] 20. The compound of any one of technical solutions 15 to 20, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, selected from:

[0245] Technical solution 22. Formula (VI) [ka] A compound of the formula

[0246] During the ceremony,

[0247] Ring A is C 6-12 aryl or 5-12 membered heteroaryl;

[0248] R a is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR'', NR'', R'', C 2-6 Alkenyl and C 2-6 alkynyl;

[0249] m=1, 2, 3, 4 or 5;

[0250] X is O or CRR';

[0251] R1 is selected from H, F, Cl, CN and methyl, wherein said methyl is optionally substituted with 1 to 3 substituents independently selected from halogen, CN, OH and NH2;

[0252] R2 is 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 to 12-membered heterocyclyl and C 0-6 alkylene-5 to 10-membered heteroaryl; 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Haloalkyl, C 5-6 Alkenyl, C 5-6 Alkynyl, C 0-6Alkylene-C 3-12 Cycloalkyl, C 0-6 Alkylene-4 to 12-membered heterocyclyl and C 0-6 Alkylene-5 to 10-membered heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 10-membered cycloalkyl, 4- to 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 to 10-membered cycloalkyl, -C(O)-4 to 10-membered heterocycloalkyl, -C(O)-C 6-10 optionally substituted with one or more substituents selected from aryl, —C(O)-5 to 10-membered heteroaryl, —CN, and oxo groups;

[0253] R3 and R3' are each C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 independently selected from alkynyl;

[0254] where:

[0255] R and R' are independently selected from H and halogen;

[0256] R'' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 independently selected from aryl and 5- to 10-membered heteroaryl; The compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

[0257] Technical solution 23. Formula (VII) [ka] A compound of the formula

[0258] During the ceremony,

[0259] X is O or CRR';

[0260] Ring A is C 6-12 aryl or 5-12 membered heteroaryl;

[0261] R a is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR'', NR'', R'', C 2-6 Alkenyl and C 2-6 alkynyl;

[0262] m=1, 2, 3, 4 or 5;

[0263] X is O or CRR';

[0264] R2 is 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 to 12-membered heterocyclyl and C 0-6 alkylene-5 to 10-membered heteroaryl; 1-6 Hydroxyalkyl, C 5-6 Alkyl, C 5-6 Haloalkyl, C 5-6 Alkenyl, C 5-6Alkynyl, C 0-6 Alkylene-C 3-12 Cycloalkyl, C 0-6 Alkylene-4 to 12-membered heterocyclyl and C 0-6 Alkylene-5 to 10-membered heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 10-membered cycloalkyl, 4- to 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 to 10-membered cycloalkyl, -C(O)-4 to 10-membered heterocycloalkyl, -C(O)-C 6-10 optionally substituted with one or more substituents selected from aryl, —C(O)-5 to 10-membered heteroaryl, —CN, and oxo groups;

[0265] R3 and R3' are each C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 independently selected from alkynyl;

[0266] where:

[0267] R and R' are independently selected from H and halogen;

[0268] R'' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10independently selected from aryl and 5- to 10-membered heteroaryl; The compound of Technical Solution 22, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

[0269] Technical Solution 24. A compound of Technical Solution 22 or Technical Solution 23, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein X is CRR', optionally CH2 or CF2.

[0270] Technical solution 25.R2 but C 1-6 Alkyl, C 0-6 Alkylene-C 3-7 Cycloalkyl, C 0-6 Alkylene-3 to 7-membered heterocyclyl, C 0-6 Alkylene-C 6-10 Aryl or C 0-6 The compound of any one of technical solutions 22 to 24, wherein R2 is alkylene-5 to 10 membered heteroaryl, and optionally R2 is isopropyl, 2-ethylbutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyridinyl, or benzyl, and even more optionally R2 is 2-ethylbutyl, cyclopentyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, or benzyl, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph, or isotopic variant thereof.

[0271] Technical Solution 26.R3 is C 1-6 The compound of any one of technical solutions 22 to 25, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein R is alkyl and optionally is methyl or isopropyl.

[0272] Technical Solution 27. R2 is a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclyl, and the 3- to 12-membered cycloalkyl or the 4- to 12-membered heterocyclyl is selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 10-membered cycloalkyl, 4- to 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 to 10-membered cycloalkyl, -C(O)-4 to 10-membered heterocycloalkyl, -C(O)-C 6-10 and optionally R2 is substituted with one or more substituents selected from aryl, -C(O)-5 to 10 membered heteroaryl, -CN and oxo groups; optionally R2 is halogen, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 and R2 is a 4- to 10-membered heterocyclyl optionally substituted with one or more substituents selected from hydroxyalkyl, —C(O)-3- to 10-membered cycloalkyl, —CN, and oxo; more preferably, R2 is a 4- to 7-membered heterocyclyl, the heteroatom of which is an oxygen atom or a nitrogen atom, and the 4- to 7-membered heterocyclyl is C 1-6 and optionally substituted with one or more substituents selected from alkyl and oxo groups; more preferably, R2 is [ka] 27. The compound of any one of technical solutions 22 to 26, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, selected from:

[0273] Technical solution 28. Below: [ka] [ka] [ka] A compound of any one of technical solutions 1 to 27, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, selected from:

[0274] Technical solution 29. Below: [ka] 29. The compound of any one of technical solutions 1 to 28, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, selected from:

[0275] Technical Solution 30. A pharmaceutical composition comprising any one of the compounds of Technical Solutions 1 to 29, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

[0276] Technical solution 31. Use of a compound of any one of technical solutions 1 to 29, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, or a pharmaceutical composition of technical solution 30, in the manufacture of a medicament for treating a proliferative disease.

[0277] Technical solution 32. A compound of any one of technical solutions 1 to 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.

[0278] Technical solution 33. A method for treating a proliferative disease in a subject, comprising administering to the subject a compound of any one of technical solutions 1 to 29, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, or a pharmaceutical composition of technical solution 14.

[0279] Technical Solution 34. The proliferative disease is selected from cancer, cardiovascular disorders, infectious diseases, chronic inflammatory diseases, autoimmune disorders and other cell proliferative disorders; optionally, the cancer is solid tumors and hematological malignancies, such as breast cancer, neuroblastoma, malignant rhabdomyoma, 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; optionally, said proliferative disease is selected from multiple myeloma, non-Hodgkin's lymphoma, lung cancer, renal cancer and prostate cancer.

[0280] Technical Solution 35. A compound of formula (I) for the preparation of a medicament for promoting the binding of butyrophilin 3A1 / 2A1. [ka] A compound of the formula

[0281] During the ceremony,

[0282] Ring A is C 6-10 aryl or 5-10 membered heteroaryl;

[0283] R a H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR'', NR'', R'', C 2-6 Alkenyl and C 2-6 alkynyl;

[0284] m=1, 2, 3, 4 or 5;

[0285] X is O or CRR';

[0286] R1 is selected from H, F, Cl, CN and methyl, wherein said methyl is optionally substituted with 1 to 3 substituents independently selected from halogen, CN, OH and NH2;

[0287] R2 is 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 to 7-membered heterocyclyl, C 0-6 Alkylene-C 6-10 Aryl and C 0-6 alkylene-5 to 10 membered heteroaryl;

[0288] R3 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl;

[0289] where:

[0290] R and R' are independently selected from H and halogen;

[0291] R'' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 independently selected from aryl and 5- to 10-membered heteroaryl; Use of the compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

[0292] Technical Solution 36. A compound of formula (I) for use in promoting the binding of butyrophilin 3A1 / 2A1 [ka] A compound of the formula

[0293] During the ceremony,

[0294] Ring A is C 6-10 aryl or 5-10 membered heteroaryl;

[0295] R a H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR'', NR'', R'', C 2-6 Alkenyl and C 2-6 alkynyl;

[0296] m=1, 2, 3, 4 or 5;

[0297] X is O or CRR';

[0298] R1 is selected from H, F, Cl, CN and methyl, wherein said methyl is optionally substituted with 1 to 3 substituents independently selected from halogen, CN, OH and NH2;

[0299] R2 is C 1-6 Alkyl, C 1-6 Haloalkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkylene-C 3-7 Cycloalkyl, C 0-6 Alkylene-3 to 7-membered heterocyclyl, C 0-6 Alkylene-C 6-10 Aryl and C 0-6 alkylene-5 to 10 membered heteroaryl;

[0300] R3 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl;

[0301] where:

[0302] R and R' are independently selected from H and halogen;

[0303] R'' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 independently selected from aryl and 5- to 10-membered heteroaryl; The compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

[0304] Technical Solution 37. A method for promoting the binding of butyrophilin 3A1 / 2A1 in a subject, comprising administering to a subject an antibody of formula (I) [ka] A compound of the formula

[0305] During the ceremony,

[0306] Ring A is C 6-10 aryl or 5-10 membered heteroaryl;

[0307] R a H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR'', NR'', R'', C 2-6 Alkenyl and C 2-6 alkynyl;

[0308] m=1, 2, 3, 4 or 5;

[0309] X is O or CRR';

[0310] R1 is selected from H, F, Cl, CN and methyl, wherein said methyl is optionally substituted with 1 to 3 substituents independently selected from halogen, CN, OH and NH2;

[0311] R2 is 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 to 7-membered heterocyclyl, C 0-6 Alkylene-C 6-10 Aryl and C 0-6 alkylene-5 to 10 membered heteroaryl;

[0312] R3 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 alkynyl;

[0313] where:

[0314] R and R' are independently selected from H and halogen;

[0315] R'' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 independently selected from aryl and 5- to 10-membered heteroaryl; A method comprising administering to a subject a compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph, or isotopic variant thereof.

[0316] Technical solution 38. Use of technical solution 35, or use of the compound or pharmaceutical composition of technical solution 36, or method of technical solution 37, wherein said compound is selected from the compounds of any one of technical solutions 1 to 29, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

[0317] Technical Solution 39. The above compound is: [ka] [ka] [ka] or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

[0318] The compounds of the present disclosure may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of the present disclosure may be in the form of individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or in the form of mixtures of stereoisomers, such as racemic mixtures and mixtures enriched in one or more stereoisomers. Individual isomers can be separated from mixtures by methods known to those skilled in the art, such as chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts. Alternatively, alternative isomers can be prepared by asymmetric synthesis.

[0319] The present disclosure also includes all suitable isotopic derivatives of the compounds of the present disclosure.The isotopic derivatives of the compounds of the present disclosure are defined as derivatives in which at least one atom is replaced with an atom that has the same atomic number but has an atomic mass that is different from the atomic mass that is usually found in nature.The examples of isotopes that can be incorporated into the compounds of the present disclosure 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 36 Some isotopic derivatives of the compounds of the present disclosure include, for example, 3 H or 14 Those incorporating radioactive isotopes such as C are useful for drug and / or substrate tissue distribution studies. Tritiated (i.e. 3 H) and carbon-14 (i.e. 14 C) isotopes are a further option because they are easy to prepare and detectable. In addition, isotopes (e.g., deuterium, i.e. 2H) may be an option in some circumstances, as it may offer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Isotopic derivatives of the compounds of the present disclosure can generally be prepared by conventional procedures, such as the exemplary methods or preparations described in the Examples below, using appropriate isotopic derivatives of appropriate reagents.

[0320] The compounds of the present disclosure, or their pharmaceutically acceptable salts, may be amorphous or crystalline. Furthermore, the compounds of the present disclosure may exist in one or more crystalline forms. Accordingly, the present disclosure includes within its scope all amorphous or crystalline forms of the compounds of the present disclosure. The term "polymorph" refers to a crystalline form of a compound (or its salts, hydrates, or solvates) in a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms generally have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical properties, electrical properties, stability, and solubility. Factors such as the recrystallization solvent, crystallization rate, and storage temperature may result in one crystalline form predominating. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0321] 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 known as "solvates." When the solvent is water, the complex is known as a "hydrate." The present disclosure encompasses all solvates of the compounds of the present disclosure.

[0322] Pharmaceutical Compositions, Preparations and Kits

[0323] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

[0324] The pharmaceutically acceptable excipient used in the present disclosure refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound that is formulated together.The pharmaceutically acceptable carrier, adjuvant or vehicle that can be used in the compositions of the present disclosure includes but is not limited to ion exchanger, alumina, aluminum stearate, lecithin, serum protein (for example, human serum albumin), buffer substance (for example, phosphate), glycine, sorbic acid, potassium sorbate, mixture of partial glycerides of saturated vegetable fatty acids, water, salt or electrolyte (for example, protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based material, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene block polymer, polyethylene glycol and lanolin.

[0325] The present disclosure also includes kits (e.g., pharmaceutical packs). The provided kits may include a compound disclosed herein, another therapeutic agent, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compound disclosed herein and / or another therapeutic agent. In some embodiments, the provided kits may also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending the compound disclosed herein and / or another therapeutic agent. In some embodiments, the compound disclosed herein provided in a first container and the other therapeutic agent provided in a second container are combined to form a unit dosage form. [Example]

[0326] The following examples are provided to provide those skilled in the art with a complete disclosure and description of how to carry out, prepare, and evaluate the methods and compounds claimed, and are intended to be illustrative only and not limiting of the scope of the disclosure. In this disclosure, the structures of compounds are determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shifts (δ) are 10 ー6 The NMR data were recorded on a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d), deuterated chloroform (CDCl), and deuterated methanol (CDOD) as solvents, with tetramethylsilane (TMS) set to zero as the internal standard.

[0327] Preparation of intermediates

[0328] 4-Dichlorophosphorylbut-1-ene (Int-A)

[0329] The title compound was prepared according to the following scheme. [ka]

[0330] Experimental procedures

[0331] Step 1: Diethyl but-3-en-1-ylphosphonate (Int-A1) [ka]

[0332] Diethyl phosphite (15 g, 108.62 mmol, 14.02 mL, 1 equiv.) was added dropwise to a solution of sodium hydride (5.21 g, 130.34 mmol, 60% w / w, 1.2 equiv.) in anhydrous tetrahydrofuran (300 mL) under nitrogen protection at 0° C., and the mixture was stirred at 20° C. for 1 hour. Next, 4-bromo-1-butene (17.60 g, 130.34 mmol, 13.23 mL, 1.2 equiv.) was added, and the mixture was stirred at 60° C. for 5 hours. After the reaction was completed, the mixture was cooled to room temperature and quenched by adding saturated ammonium chloride solution (300 mL). The mixture was extracted with ethyl acetate (300 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with 0-55% petroleum ether / ethyl acetate to give diethyl 3-butenylphosphonate (18.4 g, 95.74 mmol, 88.14% yield) as a colorless oil.

[0333] 1 H NMR (400 MHz, 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 = 7.2 Hz, 6H);

[0334] 31 P NMR (162 MHz, CDCl3) δ = 31.48.

[0335] Step 2: Bis(trimethylsilyl)but-3-en-1-ylphosphonate (Int-A2) [ka]

[0336] To a solution of diethyl but-3-en-1-ylphosphonate (18.4 g, 95.74 mmol, 1 equiv.) in dichloromethane (600 mL) was added trimethylsilyl bromide (146.48 g, 957.4 mmol, 10 equiv.) dropwise under nitrogen protection at 20° C., and the mixture was stirred for 4 hours at 20° C. After the reaction was completed, the mixture was concentrated under reduced pressure to remove the solvent to give bis(trimethylsilyl)but-3-en-1-ylphosphonate (25 g, 93% yield) as a yellow oil, which was used directly in the next step without further treatment.

[0337] 1 H NMR (400 MHz, 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);

[0338] 31 P NMR (162 MHz, CDCl3) δ = 14.94.

[0339] Step 3: 4-Dichlorophosphorylbut-1-ene (Int-A) [ka]

[0340] Oxalyl chloride (34.0 g, 267.87 mmol, 3 equiv.) 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) at 0° C. under nitrogen protection. The mixture was stirred at 20° C. for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solvent was removed by concentration under reduced pressure to give 4-dichlorophosphorylbut-1-ene (14.5 g, 94% yield) as a yellow oil, which was used directly in the next step without further treatment.

[0341] Isopropyl((but-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Int-B)

[0342] The title compound was prepared according to the following scheme. [ka]

[0343] Experimental procedures

[0344] Step 1: Isopropyl((but-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Int-B) [ka]

[0345] To a solution of 4-dichlorophosphorylbut-1-ene (5.0 g, 28.9 mmol, 1 equiv.) in dichloromethane (200 mL) was added isopropyl L-alaninate hydrochloride (4.85 g, 28.9 mmol, 1 equiv.) and triethylamine (5.85 g, 57.8 mmol, 2 equiv.) under nitrogen protection at −78° C. After stirring for 5 minutes at −78° C., phenol (2.72 g, 28.9 mmol, 1 equiv.) was added to the reaction solution. After stirring at −78° C. for 0.5 hours, the mixture was stirred at 20° C. for 16 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with 0-60% petroleum ether / ethyl acetate to give isopropyl((but-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (4.5 g, 13.83 mmol, 47.8% yield) as a colorless oil.

[0346] MS (ESI) m / z: calcd. 326.1 [M + H] + , found 326.0 [M + H] + .

[0347] (Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-ol (Int-C)

[0348] The title compound was prepared according to the following scheme. [ka]

[0349] Experimental procedures

[0350] Step 1: 3-(benzyloxy)-1,1,1-trifluoropropan-2-ol (Int-C1) [ka]

[0351] To a reaction solution of benzyl alcohol (19.11 g, 176.71 mmol, 1 equiv.) and boron trifluoride diethyl etherate (501.63 mg, 3.53 mmol, 0.02 equiv.) was added 1,1,1-trifluoro-2,3-epoxypropane (19.8 g, 176.71 mmol, 1 equiv.) at room temperature, and the mixture was stirred at 40 °C for 16 h. After the reaction was completed, the reaction mixture was cooled to room temperature and quenched by adding an appropriate amount of water. The mixture was extracted with dichloromethane (30 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 column chromatography on silica gel eluting with 20–40% petroleum ether / ethyl acetate to obtain 3-(benzyloxy)-1,1,1-trifluoropropan-2-ol (30 g, 136.25 mmol, 77.1% yield) as a yellow oil.

[0352] 1H NMR (400 MHz, 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);

[0353] 19 F NMR (376 MHz, CDCl3) δ = -77.61.

[0354] Step 2: 3-(benzyloxy)-1,1,1-trifluoropropan-2-one (Int-C2) [ka]

[0355] To a solution of 3-(benzyloxy)-1,1,1-trifluoropropan-2-ol (21 g, 95.37 mmol, 1.0 equiv.) in dichloromethane (50 mL) was added Dess-Martin periodinane (DMP) (56.63 g, 133.52 mmol, 1.4 equiv.) dropwise at 20 °C, and the mixture was stirred at 20 °C for 16 h. After the reaction was complete, the mixture was diluted with dichloromethane, and the organic layer was washed with sodium thiosulfate solution and sodium bicarbonate solution, respectively. The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with 20–40% petroleum ether / ethyl acetate to give the desired 3-(benzyloxy)-1,1,1-trifluoropropan-2-one (11.0 g, 50.42 mmol, 52.8% yield) as a colorless oil.

[0356] 1 H NMR (400 MHz, CDCl3) δ = 7.42 - 7.32 (m, 5H), 4.70 (s, 2H), 3.69 (s, 2H);

[0357] 19F NMR (376 MHz, CDCl3) δ = -85.13.

[0358] Step 3: Ethyl (Z)-3-((benzyloxy)methyl)-4,4,4-trifluorobut-2-enoate (Int-C3) [ka]

[0359] 3-(Benzyloxy)-1,1,1-trifluoropropan-2-one (9.0 g, 41.26 mmol, 1 equiv.) was dissolved in an appropriate amount of benzene under nitrogen protection, and water was removed from the system by reflux. The reaction solution was cooled to 25 °C, and ethoxyformylmethyltriphenylphosphonium bromide (21.26 g, 49.51 mmol, 1.2 equiv.) and triethylamine (9.59 g, 94.90 mmol, 2.3 equiv.) were added to the reaction system, followed by stirring at 25 °C for 16 h. After completion of the reaction, the reaction was quenched by adding an appropriate amount of water, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography on silica gel eluting with 20-30% petroleum ether / ethyl acetate to give ethyl (Z)-3-((benzyloxy)methyl)-4,4,4-trifluorobut-2-enoate (4.8 g, 16.65 mmol, 40.3% yield) as a colorless oil.

[0360] 1 H NMR (400 MHz, CDCl3) δ = 7.36 - 7.34 (m, 5H), 6.53 (s, 1H), 4.62 (s, 2H), 4.57 (s, 2H), 4.23 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H);

[0361] 19 F NMR (376 MHz, CDCl3) δ = -67.23.

[0362] Step 4: Ethyl (Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-enoate (Int-C4) [ka]

[0363] To a solution of ethyl (Z)-3-((benzyloxy)methyl)-4,4,4-trifluorobut-2-enoate (4.8 g, 16.64 mmol, 1 equiv.) in dichloromethane (80 mL) was added boron trichloride (1.0 M, 94.36 mL, 8.0 equiv.) dropwise under nitrogen protection at 0°C, and the mixture was stirred at -78°C for 5 hours. After the reaction was completed, the mixture was diluted with an appropriate amount of dichloromethane, and the organic layer was washed with saturated sodium chloride solution. The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography on silica gel eluting with 40-60% petroleum ether / ethyl acetate 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.

[0364] 1 H NMR (400 MHz, CDCl3) δ = 6.47 (t, J = 1.6 Hz, 1H), 5.01 (s, 1H), 4.35 (d, J = 0.8 Hz, 2H), 4.26 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H);

[0365] 19 F NMR (377 MHz, CDCl3) δ = -63.15, -65.07.

[0366] Step 5: Ethyl (Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-enoate (Int-C5) [ka]

[0367] To a mixed solution of ethyl (Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-enoate (2.1 g, 10.60 mmol, 1 equivalent) and imidazole (1.08 g, 15.90 mmol, 1.5 equivalents) in dichloromethane (25 mL), tert-butyldimethylsilyl chloride (2.08 g, 13.78 mmol, 1.3 equivalents) was added dropwise under nitrogen protection at 0° C., and the mixture was stirred for 16 hours at 20° C. After the reaction was completed, the reaction mixture was diluted with a suitable amount of dichloromethane, and the organic layer was washed with saturated sodium chloride solution. The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography on silica gel eluting with 40-60% petroleum ether / ethyl acetate to give ethyl (Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-enoate (2.4 g, 7.69 mmol, 72.53% yield) as a colorless oil.

[0368] 1 H NMR (400 MHz, CDCl3) δ = 6.44 (t, J = 2.4 Hz, 1H), 4.32 (s, 2H), 4.26 (q, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H), 0.93 (s, 9H), 0.12 (s, 6H);

[0369] 19 F NMR (376 MHz, CDCl3) δ = -63.16.

[0370] Step 6: (Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-ol (Int-C) [ka]

[0371] To a solution of ethyl (Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-enoate (2.1 g, 6.73 mmol, 1 equivalent) in tetrahydrofuran (30 mL) was added red-Al (1.0 M in toluene, 13.46 mL, 2.0 equivalents) dropwise under nitrogen protection at −78° C., and the mixture was stirred at 0° C. for 5 hours. After the reaction was completed, the mixture was diluted with a suitable amount of dichloromethane, and the organic layer was washed with saturated sodium chloride solution, then the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography on silica gel 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.

[0372] 1 H NMR (400 MHz, 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);

[0373] 19 F NMR (376 MHz, CDCl3) δ = -60.92, -61.00.

[0374] (Trimethylsilyl)(E)-(4-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pent-3-en-1-yl)phosphonate (Int-D)

[0375] The title compound was prepared according to the following scheme. [ka]

[0376] Experimental procedures Step 1-1: Diethyl (4-methyl-3-en-1-yl)phosphonate (Int-D1) [ka]

[0377] To triethyl phosphite (500 mL) was added 5-bromo-2-methyl-2-pentene (50 g, 0.31 mol) at room temperature, and the mixture was refluxed and stirred at 150° C. for 26 hours. After the reaction was completed, the mixture was distilled at 150° C. under atmospheric pressure, then cooled to 100° C. and distilled under reduced pressure (0.1 MPa), gradually increasing the temperature to 140° C. until the solvent no longer evaporated. The residue was obtained as a yellow oily product (38 g, 0.17 mol, 55.72% yield).

[0378] MS (ESI) m / z: calcd. 221.1 [M + H] + , found 221.1 [M + H] + .

[0379] Step 2: Diethyl (E)-(5-hydroxy-4-methylpent-3-en-1-yl)phosphonate (Int-D2) [ka]

[0380] To a solution of diethyl (4-methyl-3-en-1-yl)phosphonate (10 g, 52.05 mmol, 1 equiv.) in dichloromethane (100 mL) was added selenium dioxide (2.89 g, 26.03 mmol, 0.5 equiv.), 4-hydroxybenzoic acid (0.72 g, 5.21 mmol, 0.1 equiv.), and tert-butyl hydroperoxide (5.5 M aqueous solution, 37.82 mL, 208.20 mmol, 4 equiv.) under nitrogen protection at 20 °C. The mixture was stirred at 20 °C for 16 h. After completion of the reaction, the reaction was quenched by adding saturated aqueous sodium bicarbonate (50 mL). The mixture was extracted with dichloromethane (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 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 equiv.) was added in portions at 0°C under nitrogen protection. The mixture was stirred at 0°C for 2 hours. After the reaction was completed, saturated ammonium chloride solution (200 mL) was added to the mixture and extracted with ethyl acetate (200 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with 0-10% dichloromethane / methanol and concentrated under reduced pressure to give crude diethyl (E)-(5-hydroxy-4-methylpent-3-en-1-yl)phosphonate (2.8 g, 11.86 mmol, 22.82% yield) as a yellow oil.

[0381] MS (ESI) m / z: calcd. 237.1 [M + H] + , found 219.2 [M + H-H2O] + .

[0382] Step 3: Diethyl (E)-(4-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pent-3-en-1-yl)phosphonate (Int-D3) [ka]

[0383] To a solution of diethyl (E)-(5-hydroxy-4-methylpent-3-en-1-yl)phosphonate (3 g, 12.70 mmol, 1 equiv.) and p-toluenesulfonic acid pyridine salt (0.34 g, 1.27 mmol, 0.1 equiv.) in tetrahydrofuran (30 mL) was added 3,4-dihydropyran (3.21 g, 38.10 mmol, 3 equiv.) at 20 °C, and the reaction mixture was stirred at 20 °C for 5 h. After the reaction was complete by TLC detection, the reaction was quenched by adding water (20 mL), and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with 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 pale yellow oil.

[0384] MS (ESI) m / z: calcd. 321.2 [M+H] + , found 219.1 [M+H-102] + .

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

[0386] To a solution of (E)-5-diethoxyphosphoryl-2-methyl-2-pent-1-yloctanoate (2.5 g, 7.81 mmol, 1 equiv.) in dichloromethane (25 mL), trimethylsilyl bromide (11.76 g, 78.10 mmol, 10 equiv.) was added dropwise at 0 °C under nitrogen protection, and the mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC spot plate (PE:EA = 1:5). After the disappearance of the raw materials, the mixture was concentrated under reduced pressure to give (trimethylsilyl)(E)-(4-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pent-3-en-1-yl)phosphonate (crude product) (2.5 g, 6.12 mmol, 78.56% yield) as a yellow oil, which was used directly in the next step.

[0387] MS (ESI) m / z: calcd. 409.2 [M + H] + , found 181.1 [M + H-228] + .

[0388] Control Compound 1:

[0389] Isopropyl (((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Reference compound 1)

[0390] The title compound was prepared according to the following scheme. [ka]

[0391] Experimental procedures

[0392] Step 1: Isopropyl (((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Reference Compound 1) [ka]

[0393] To a solution of isopropyl ((but-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (300.00 mg, 922.12 μmol, 1 equiv.), 2-methylallyl alcohol (134.97 mg, 1.87 mmol, 2 equiv.), and p-benzoquinone (12.00 mg, 111.01 μmol, 0.12 equiv.) in dichloromethane (20 mL) was added Hoveyda-Grubbs second-generation catalyst (43.35 mg, 69.15 μmol, 0.075 equiv.). The catalyst was added in three equal portions (14.45 mg, 23.05 μmol, 0.025 equiv. each portion) at t=0, 2, and 4 hours during the reaction. The solution was then heated to reflux at 45° C. for 18 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (FA conditions) to give the target product, isopropyl (((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (127.6 mg, 345.43 μmol, 37.4% yield) as a colorless oil.

[0394] 1 H NMR (400 MHz, 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 - 3.94 (m, 3H), 3.50 - 3.29 (m, 1H), 2.48 - 2.44 (m, 2H), 2.00 - 1.93 (m, 2H), 1.70 (d, J = 4.4 Hz, 3H), 1.30 - 1.29 (m, 3H), 1.23 - 1.19 (m, 6H);

[0395] 31 P NMR (162 MHz, CDCl3) δ = 31.34, 30.98;

[0396] MS (ESI) m / z: calcd. 370.2 [M+H] +, found 352.1 [M+H-H2O] + .

[0397] Example 1:

[0398] Isopropyl((5-hydroxy-4-(hydroxymethyl)pent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 1)

[0399] The title compound was prepared according to the following scheme. [ka]

[0400] Operation process:

[0401] Isopropyl((5-hydroxy-4-(hydroxymethyl)pent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 1) [ka]

[0402] To a solution of isopropyl ((but-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (1 g, 3.36 mmol, 1 equiv.), 2-methylene-1,3-propanediol (541.62 mg, 6.15 mmol, 2 equiv.), and p-benzoquinone (39.87 mg, 368.85 μmol, 0.12 equiv.) in dichloromethane (30 mL) was added Hoveyda-Grubbs second-generation catalyst (144.45 mg, 230.52 μmol, 0.075 equiv.). The catalyst was added in three equal portions (48.15 mg, 76.84 μmol, 0.025 equiv. each portion) at t=0, 2, and 4 hours during the reaction. The solution was then heated to reflux at 45° C. for 18 hours under nitrogen. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (FA conditions) to give the target product, isopropyl((5-hydroxy-4-(hydroxymethyl)pent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (0.04 g, 117.19 μmol, 3.48% yield) as a colorless oil.

[0403] 1 H NMR (400 MHz, 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);

[0404] 31 P NMR (162 MHz, CDCl3) δ = 32.08, 31.86;

[0405] MS (ESI) m / z: calcd. 386.2 [M + H] +, found 368.2 [M + H -H2O] + .

[0406] Example 2:

[0407] 2-Ethylbutyl(((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 2)

[0408] The title compound was prepared according to the following scheme. [ka]

[0409] Experimental procedures

[0410] Step 1: 2-Ethylbutyl(tert-butyloxycarbonyl)-L-alaninate (Compound 2-1) [ka]

[0411] To a mixture of N-tert-butyloxycarbonyl-L-alanine (2.22 g, 11.74 mmol, 1.2 equiv.) and 2-ethyl-1-butanol (1.0 g, 9.79 mmol, 1 equiv.) in dichloromethane (50 mL) was added 4-dimethylaminopyridine (1.79 g, 14.68 mmol, 1.5 equiv.), triethylamine (1.19 g, 11.74 mmol, 1.2 equiv.), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.97 g, 10.28 mmol, 1.05 equiv.) at 25 °C. The mixture was stirred at 25 °C for 16 h. After completion of the reaction, the reaction was quenched by adding an appropriate amount of water. The mixture was extracted with dichloromethane (20 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with 0-40% petroleum ether / ethyl acetate to give 2-ethylbutyl(tert-butyloxycarbonyl)-L-alaninate (1.6 g, 5.85 mmol, 59.80% yield) as a colorless oil.

[0412] MS (ESI) m / z: calcd. 274.2 [M+H] + , found 296.0 [M+Na] + .

[0413] Step 2: 2-Ethylbutyl L-alaninate hydrochloride (Compound 2-2) [ka]

[0414] To a solution of hydrogen chloride in 1,4-dioxane (4 M, 15 mL) at 25° C. was added (tert-butyloxycarbonyl)-L-alanine 2-ethylbutyl ester (1.6 g, 5.85 mmol, 1.0 equiv.), and the mixture was stirred for 1 hour at 25° C. After the reaction was complete, the solvent was removed by concentration under reduced pressure to give 2-ethylbutyl L-alaninate hydrochloride (1.2 g, 98% yield) as a white solid, which was used directly in the next step without further treatment.

[0415] MS (ESI) m / z: calcd. 174.2 [M+H] + , found 174.2 [M+H] + .

[0416] Step 3: 2-Ethylbutyl((but-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 2-3) [ka]

[0417] To a solution of 4-dichlorophosphorylbut-1-ene (1 g, 5.78 mmol, 1 equivalent) in dichloromethane (50 mL) was added triethylamine (1.17 g, 11.56 mmol, 2 equivalents) at −78° C. under nitrogen protection, and the mixture was stirred at −78° C. for 5 minutes. Next, to the mixture was added 2-ethylbutyl L-alaninate hydrochloride (1.20 g, 5.78 mmol, 1 equivalent) and phenol (0.54 g, 5.78 mmol, 1 equivalent) under nitrogen protection at −78° C., and the mixture was stirred at 20° C. for 16 hours. After the reaction was completed, 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 column chromatography on silica gel eluting with 10-30% petroleum ether / ethyl acetate to give 2-ethylbutyl((but-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (210 mg, 0.57 mmol, 9.89% yield) as a colorless oil.

[0418] MS (ESI) m / z: calcd. 368.2 [M + H] + , found 368.2 [M + H] + .

[0419] Step 4: 2-Ethylbutyl(((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 2) [ka]

[0420] To a solution of 2-ethylbutyl((but-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (0.15 g, 408.25 μmol, 1 equiv.), 2-methylallyl alcohol (58.87 mg, 816.51 μmol, 2 equiv.), and p-benzoquinone (5.30 mg, 48.99 μmol, 0.12 equiv.) in dichloromethane (50 mL) was added Hoveyda-Grubbs second-generation catalyst (19.17 mg, 30.63 μmol, 0.075 equiv.). The catalyst was added in three equal portions (6.39 mg, 10.21 μmol, 0.025 equiv. each portion) at t=0, 2, and 4 hours during the reaction. The solution was then heated to reflux at 45° C. for 18 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under vacuum to give a residue, which was purified by preparative HPLC (FA conditions) to give the target product, 2-ethylbutyl(((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (8.8 mg, 21.40 μmol, 5.24% yield) as a colorless oil.

[0421] 1 H NMR (400 MHz, CDCl3) δ = 7.33 - 7.31 (m, 2H), 7.30 - 7.29 (m, 2H), 7.22 - 7.14 (m, 1H), 5.48 (q, J = 7.2 Hz, 1H), 4.15 - 3.98 (m, 5H), 3.48 - 3.28 (m, 1H), 2.50 - 2.46 (m, 2H), 2.06 - 1.89 (m, 2H), 1.71 (d, J = 4.4 Hz, 3H), 1.54 - 1.44 (m, 1H), 1.35 - 1.20 (m, 7H), 0.88 (t, J = 7.2 Hz, 6H);

[0422] 31 P NMR (162 MHz, CDCl3) δ = 31.53, 31.15;

[0423] MS (ESI) m / z: calcd. 412.2 [M+H] + , found 412.2 [M+H] + .

[0424] Example 3:

[0425] Isopropyl((phenoxy)(((Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-en-1-yl)oxy)phosphoryl)-L-alaninate (Compound 3)

[0426] The title compound was prepared according to the following scheme. [ka]

[0427] Experimental procedures

[0428] Step 1: Isopropyl ((((Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-yl)oxy)(phenoxy)phosphoryl)-L-alaninate (Compound 3-1) [ka]

[0429] To a solution of phenyl dichlorophosphate (300 mg, 1.43 mmol, 1 equiv.) in dichloromethane (5 mL) was added triethylamine (289.20 mg, 2.86 mmol, 2 equiv.) under nitrogen protection at −78° C., and the mixture was stirred at −78° C. for 5 minutes. Next, isopropyl L-alaninate hydrochloride (238.91 mg, 1.43 mmol, 1 equiv.) and (Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-ol (386.29 mg, 1.43 mmol, 1 equiv.) were added, and the mixture was stirred at 20° C. for 16 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (NH4HCO3 condition) to give isopropyl ((((Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-yl)oxy)(phenoxy)phosphoryl)-L-alaninate (21.8 mg, 40.43 μmol, yield 2.83%) as a colorless oil.

[0430] 1 H NMR (400 MHz, CDCl3) δ = 7.35 - 7.31 (m, 2H), 7.24 - 7.16 (m, 3H), 6.20 (q, J = 6.0 Hz, 1H), 5.05 - 4.98 (m, 1H), 4.91 - 4.90 (m, 2H), 4.24 (s, 2H), 4.01 - 3.96 (m, 1H), 3.60 (t, J = 10.4 Hz, 1H), 1.38 (dd, J = 6.8, 4.4 Hz, 3H), 1.26 - 1.21 (m, 6H), 0.92 (s, 9H), 0.09 (s, 6H);

[0431] 31 P NMR (162 MHz, CDCl3) δ = 2.38;

[0432] 19 F NMR (376 MHz, CDCl3) δ = -61.40;

[0433] MS (ESI) m / z: calcd. 540.1 [M+H] + , found 540.1 [M+H] + .

[0434] Step 2: Isopropyl((phenoxy)(((Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-en-1-yl)oxy)phosphoryl)-L-alaninate (Compound 3) [ka]

[0435] To a solution of isopropyl ((((Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-yl)oxy)(phenoxy)phosphoryl)-L-alaninate (10.0 mg, 18.53 μmol, 1.0 equiv) in acetonitrile (3 mL) was added p-toluenesulfonic acid (6.38 mg, 37.06 μmol, 2.0 equiv), and the mixture was stirred at 25° C. for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (NHHCO condition) to give the desired product isopropyl((phenoxy)(((Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-en-1-yl)oxy)phosphoryl)-L-alaninate (2.7 mg, 6.35 μmol, 34.27% yield) as a colorless oil.

[0436] 1 H NMR (400 MHz, 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 = 7.2 Hz, 3H), 1.25 - 1.22 (m, 6H);

[0437] 31 P NMR (162 MHz, CDCl3) δ = 2.56, 2.38;

[0438] 19 F NMR (376 MHz, CDCl3) δ = 61.20;

[0439] MS (ESI) m / z: calcd. 426.1 [M + H] + , found 426.0 [M + H] + .

[0440] Example 4:

[0441] Isopropyl (((E)-5-hydroxy-4-ethylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 4)

[0442] The title compound was prepared according to the following scheme. [ka]

[0443] Experimental procedures

[0444] Step 1: Isopropyl (((E)-5-hydroxy-4-ethylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 4) [ka]

[0445] To a solution of isopropyl(but-3-en-1-yl(phenoxy)phosphoryl)-L-alaninate (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 Hoveyda-Grubbs second-generation catalyst (43.2 mg, 69 μmol, 0.075 eq.). The catalyst was added in three equal portions (14.4 mg, 23 μmol, 0.025 eq. each) at t=0, 2, and 4 hours during the reaction. The solution was then heated to reflux at 45° C. for 18 hours under a nitrogen atmosphere. After the reaction was complete, 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 target product isopropyl(((E)-5-hydroxy-4-ethylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (2.8 mg, 7.30 μmol, 7.93% yield) as a colorless oil.

[0446] 1 H NMR (400 MHz, CDCl3) δ = 7.34 - 7.30 (m, 2H), 7.22 (d, J = 7.6 Hz, 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);

[0447] 31 P NMR (162 MHz, CDCl3): δ 31.40, 30.99;

[0448] MS (ESI) m / z: calcd. 384.2 [M+H] +, found 384.2 [M+H] + .

[0449] Example 5:

[0450] Isopropyl (((E)-5-hydroxypent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 5)

[0451] The title compound was prepared according to the following scheme. [ka]

[0452] Experimental procedures

[0453] Step 1: Isopropyl (((E)-5-hydroxypent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 5) [ka]

[0454] To a solution of isopropyl ((but-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (200 mg, 0.62 mmol, 1 equiv.), allyl alcohol (83.90 mg, 1.45 mmol, 2.35 equiv.), and p-benzoquinone (8.04 mg, 0.74 mmol, 0.12 equiv.) in dichloromethane (10 mL) was added Hoveyda-Grubbs second-generation catalyst (29.16 mg, 46.5 μmol, 0.075 equiv.). The catalyst was added in three equal portions (9.72 mg, 15.5 μmol, 0.025 equiv. each portion) at t=0, 2, and 4 hours during the reaction. The solution was then heated to reflux at 45° C. for 18 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA conditions) to give the target product isopropyl(((E)-5-hydroxypent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (16.8 mg, 47.30 μmol, 7.63% yield) as a colorless oil.

[0455] 1 H NMR (400 MHz, CDCl3) δ = 7.34 - 7.30 (m, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.28 - 7.14 (m, 1H), 5.77 - 5.75 (m, 2H), 4.98 (dt, J = 12.4, 6.4 Hz, 1H), 4.12 (d, J = 2.4 Hz, 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);

[0456] 31 P NMR (162 MHz, CDCl3) δ = 30.73;

[0457] MS (ESI) m / z: calcd. 356.1 [M+H] + , found 338.1 [M+H-H2O]+ .

[0458] Example 6:

[0459] Cyclopentyl (((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 6) [ka]

[0460] Example 6 was synthesized in the same manner as in Example 2, using benzyloxycarbonyl-L-alanine and cyclopentanol as raw materials.

[0461] 1 H NMR (400 MHz, CDCl3) δ = 7.34 - 7.30 (m, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.16 - 7.12 (m, 1H), 5.47 (t, J = 7.2 Hz, 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), 1.89 - 1.79 (m, 2H), 1.73 - 1.70 (m, 3H), 1.68 - 1.64 (m, 6H), 1.31-1.18 (m, 3H);

[0462] 31 P NMR (162 MHz, CDCl3) δ = 31.51, 31.11;

[0463] MS (ESI) m / z: calcd. 396.2 [M+H] + , found 396.4 [M+H] + .

[0464] Example 7:

[0465] (R)-Tetrahydrofuran-3-yl(((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 7) [ka]

[0466] Example 7 was synthesized in the same manner as in Example 2, using benzyloxycarbonyl-L-alanine and (R)-tetrahydrofuran-3-ol as raw materials.

[0467] 1 H NMR (400 MHz, 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);

[0468] 31 P NMR (162 MHz, CDCl3) δ = 31.40, 31.00;

[0469] MS (ESI) m / z: calcd. 398.1 [M+H] + , found 380.1 [M+H-H2O] + .

[0470] Example 8:

[0471] (S)-Tetrahydrofuran-3-yl(((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 8) [ka]

[0472] Example 8 was synthesized in the same manner as in Example 2, using benzyloxycarbonyl-L-alanine and (S)-tetrahydrofuran-3-ol as starting materials.

[0473] 1 H NMR (400 MHz, 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 = 5.2 Hz, 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, 7.6 Hz, 2H), 2.22 - 2.12 (m, 1H), 2.01 - 1.91 (m, 3H), 1.70 (d, J = 4.0 Hz, 3H), 1.33 - 1.21 (m, 3H);

[0474] 31 P NMR (162 MHz, CDCl3) δ = 31.40, 31.00;

[0475] MS (ESI) m / z: calcd. 398.1 [M+H] + , found 380.1 [M+H-H2O] + .

[0476] Example 9:

[0477] Cyclopropylmethyl((phenoxy)(((Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-en-1-yl)oxy)phosphoryl)-L-alaninate (Compound 9)

[0478] The title compound was prepared according to the following scheme. [ka]

[0479] Experimental procedures

[0480] Step 1: Cyclopropylmethyl(tert-butyloxycarbonyl)-L-alaninate (Compound 9-1) [ka]

[0481] To a solution of N-tert-butyloxycarbonyl-L-alanine (5.00 g, 26.43 mmol, 1 equiv.) and hydroxymethylcyclopropane (2.29 g, 31.72 mmol, 1.2 equiv.) in acetonitrile (50 mL) was added 4-dimethylaminopyridine (4.84 g, 39.65 mmol, 1.5 equiv.) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.32 g, 27.75 mmol, 1.05 equiv.) at 0 °C, and the mixture was stirred at 25 °C for 3 h. After completion of the reaction, the reaction was quenched by adding an appropriate amount of water. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with 0-20% petroleum ether / ethyl acetate to give cyclopropylmethyl(tert-butoxycarbonyl)-L-alaninate (3.5 g, 14.39 mmol, 54.45% yield) as a colorless oil.

[0482] 1H NMR (400 MHz, CDCl3) δ = 5.07 (d, J = 2.4 Hz, 1H), 4.35 - 4.31 (m, 1H), 4.02 - 3.95 (m, 2H), 1.46 (s, 9H), 1.40 (d, J = 7.2 Hz, 3H), 1.16 - 1.12 (m, 1H), 0.59 - 0.57 (m, 2H), 0.31 - 0.27 (m, 2H).

[0483] Step 2: Cyclopropylmethyl L-alaninate trifluoroacetate (Compound 9-2) [ka]

[0484] To a solution of cyclopropylmethyl(tert-butyloxycarbonyl)-L-alaninate (0.5 g, 2.06 mmol, 1 equiv.) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) at 25° C., and the mixture was stirred for 1 hour at 25° C. After the reaction was completed, the solvent was removed by concentration under reduced pressure to give cyclopropylmethyl L-alaninate trifluoroacetate (0.46 g, 92.7% yield) as a light yellow oil, which was used directly in the next step without further treatment.

[0485] 1H NMR (400 MHz, CDCl3) δ = 9.85 (s, 2H), 4.15 - 4.13 (m, 1H), 4.07 - 4.01 (m, 2H), 1.63 (d, J = 7.2 Hz, 3H), 1.16 - 1.12 (m, 1H), 0.64 - 0.60 (m, 2H), 0.30 (q, J = 4.8 Hz, 2H).

[0486] Step 3: Cyclopropylmethyl((((Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-yl)oxy)(phenoxy)phosphoryl)-L-alaninate (Compound 9-3) [ka]

[0487] To a solution of phenyl dichlorophosphate (300 mg, 1.43 mmol, 1 equiv.) in dichloromethane (10 mL) was added triethylamine (718.2 mg, 7.1 mmol, 5 equiv.) under nitrogen protection at −78°C, and the mixture was stirred at −78°C for 5 minutes. Next, cyclopropylmethyl L-alaninate trifluoroacetate (365.11 mg, 1.42 mmol, 1 equiv.) and (Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-ol (383.78 mg, 1.42 mmol, 1 equiv.) were added. The mixture was stirred at 25°C for 16 hours. After completion of the reaction, the reaction was quenched by adding an appropriate amount of water. The mixture was extracted with dichloromethane (20 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with 0-55% petroleum ether / ethyl acetate to give cyclopropylmethyl((((Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-yl)oxy)(phenoxy)phosphoryl)-L-alaninate (70 mg, 126.90 μmol, 8.94% yield) as a yellow oil.

[0488] MS (ESI) m / z: calcd. 552.2 [M+H] + , found 552.2 [M+H] + .

[0489] Step 4: Cyclopropylmethyl((phenoxy)(((Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-en-1-yl)oxy)phosphoryl)-L-alaninate (Compound 9) [ka]

[0490] To a solution of cyclopropylmethyl((((Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-yl)oxy)(phenoxy)phosphoryl)-L-alaninate (70 mg, 126.90 μmol, 1 equivalent) in acetonitrile (3 mL) was added p-toluenesulfonic acid (43.69 mg, 253.8 μmol, 2 equivalents), and the mixture was stirred at 25° C. for 16 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (NHHCO) to give the target product cyclopropylmethyl((phenoxy)(((Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-en-1-yl)oxy)phosphoryl)-L-alaninate (0.5 mg, 1.14 μmol, 0.90% yield) as a colorless oil.

[0491] 1 H NMR (400 MHz, CDCl3) δ = 7.36 - 7.33 (m, 2H), 7.24 - 7.18 (m, 3H), 6.23 (dt, J = 11.6, 5.6 Hz, 1H), 4.92 - 4.90 (m, 2H), 4.25 (s, 2H), 4.11 - 4.00 (m, 1H), 3.99 - 3.94 (m, 2H), 3.74 (q, J = 7.2 Hz, 1H), 3.72 - 3.57 (m, 1H), 1.41 (t, J = 7.2 Hz, 3H), 1.25 (t, J = 7.2 Hz, 1H) 1.13 - 1.11 (m, 1H), 0.60 - 0.56 (m, 2H), 0.30 - 0.27 (m, 2H);

[0492] 31 P NMR (162 MHz, CDCl3) δ = 2.29;

[0493] 19 F NMR (376 MHz, CDCl3) δ = -61.19;

[0494] MS (ESI) m / z: calcd. 438.1 [M+H] + , found 438.1 [M+H] + .

[0495] Example 10:

[0496] 2-Ethylbutyl((phenoxy)(((Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-en-1-yl)oxy)phosphoryl)-L-alaninate (Compound 10) [ka]

[0497] Example 10 was synthesized in the same manner as in Example 9, using N-tert-butyloxycarbonyl-L-alanine and 2-ethyl-1-butanol as raw materials.

[0498] 1 H NMR (400 MHz, CDCl3) δ = 7.37 - 7.33 (m, 2H), 7.25 - 7.19 (m, 3H), 6.25 (dt, J = 11.6, 5.6 Hz, 1H), 4.91 (dd, J = 4.4, 2.0 Hz, 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);

[0499] 31 P NMR (162 MHz, CDCl3) δ = 2.51;

[0500] 19 F NMR (376 MHz, CDCl3) δ = -61.24;

[0501] MS (ESI) m / z: calcd. 468.2 [M+H] +, found 468.2 [M+H] + .

[0502] Example 11:

[0503] Cyclopentyl((phenoxy)(((Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-en-1-yl)oxy)phosphoryl)-L-alaninate (Compound 11) [ka]

[0504] Example 11 was synthesized in the same manner as in Example 9, using N-benzyloxycarbonyl-L-alanine and cyclopentanol as raw materials.

[0505] 1 H NMR (400 MHz, 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 = 7.6 Hz, 3H);

[0506] 31 P NMR (162 MHz, CDCl3) δ = 2.35;

[0507] 19 F NMR (376 MHz, CDCl3) δ = -61.24;

[0508] MS (ESI) m / z: calcd. 452.1 [M+H] + , found 452.1 [M+H] + .

[0509] Example 12:

[0510] (S)-Tetrahydrofuran-3-yl((phenoxy)(((Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-en-1-yl)oxy)phosphoryl)-L-alaninate (Compound 12) [ka]

[0511] Example 12 was synthesized in the same manner as in Example 9, using N-benzyloxycarbonyl-L-alanine and (S)-3-hydroxytetrahydrofuran as starting materials.

[0512] 1 H NMR (400 MHz, 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, 2H), 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);

[0513] 31 P NMR (162 MHz, CDCl3) δ = 2.38, 2.15;

[0514] 19 F NMR (376 MHz, CDCl3) δ = -61.18, -61.19;

[0515] MS (ESI) m / z: calcd. 454.1 [M+H] + , found 454.0 [M+H] +.

[0516] Example 13: Compound 13 [ka]

[0517] Example 13 was synthesized in the same manner as in Example 9 using N-benzyloxycarbonyl-L-alanine and (R)-3-hydroxytetrahydrofuran as starting materials.

[0518] 1 H NMR (400 MHz, 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, 3.6 Hz, 3H);

[0519] 31 P NMR (162 MHz, CDCl3) δ = 2.40, 1.95;

[0520] 19 F NMR (376 MHz, CDCl3) δ = -61.19, -61.27;

[0521] MS (ESI) m / z: calcd. 454.1 [M+H] + , found 454.2 [M+H] + .

[0522] Example 14: Compound 14

[0523] The title compound was prepared according to the following scheme. [ka]

[0524] Experimental procedures

[0525] Step 1: 1-Naphthyl dichlorophosphate (Compound 14-1) [ka]

[0526] To a solution of 1-naphthol (1 g, 6.94 mmol, 1 equiv.) in tetrahydrofuran (40 mL) was added phosphorus oxychloride (1.06 g, 6.94 mmol, 1 equiv.) under nitrogen protection at −78° C. Then, to the mixture was added triethylamine (701.87 mg, 6.94 mmol, 1 equiv.) dropwise under nitrogen protection at −78° C. The mixture was stirred at 25° C. for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent to give 1-naphthyl dichlorophosphate (1.2 g, 66.7% yield) as a colorless oil, which was used directly in the next step without further treatment.

[0527] Step 2: Isopropyl ((((Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-yl)oxy)(naphthyloxy)phosphoryl)-L-alaninate (Compound 14-2) [ka]

[0528] To a solution of 1-naphthyl dichlorophosphate (300 mg, 1.15 mmol, 1 equiv.) in dichloromethane (5 mL) was added triethylamine (465.31 mg, 4.6 mmol, 4 equiv.) under nitrogen protection at −78°C, and the mixture was stirred at −78°C for 5 minutes. Next, isopropyl L-alaninate hydrochloride (192.72 mg, 1.15 mmol, 1 equiv.) and (Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-ol (310.81 mg, 1.15 mmol, 1 equiv.) were added. The mixture was stirred at 25°C for 16 hours. After completion of the reaction, the reaction was quenched by adding an appropriate amount of water. The mixture was extracted with dichloromethane (20 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with 0-50% petroleum ether / ethyl acetate to give isopropyl ((((Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-yl)oxy)(naphthyloxy)phosphoryl)-L-alaninate (25 mg, 42.4 μmol, 3.69% yield) as a colorless oil.

[0529] MS (EI) m / z: calcd. 590.2 [M+H] + , found 590.2 [M+H] + .

[0530] Step 3: Isopropyl((naphthyloxy)(((Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-en-1-yl)oxy)phosphoryl)-L-alaninate (Compound 14) [ka]

[0531] To a solution of isopropyl ((((Z)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4,4,4-trifluorobut-2-en-1-yl)oxy)(naphthyloxy)phosphoryl)-L-alaninate (20 mg, 33.92 μmol, 1 equivalent) in acetonitrile (2 mL) was added p-toluenesulfonic acid (11.68 mg, 67.84 μmol, 2.0 equivalents), and the mixture was stirred at 25° C. for 16 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (NH.HO condition) to give the target product isopropyl((naphthyloxy)(((Z)-4,4,4-trifluoro-3-(hydroxymethyl)but-2-en-1-yl)oxy)phosphoryl)-L-alaninate (1.4 mg, 2.94 μmol, yield 8.67%) as a colorless oil.

[0532] 1 H NMR (400 MHz, CDCl3) δ = 8.11 (dd, J = 6.4, 3.2 Hz, 1H), 7.86 - 7.84 (m, 1H), 7.67 (dd, J = 8.4, 1.6 Hz, 1H), 7.54 - 7.52 (m, 3H), 7.41 (td, J = 8.0, 3.2 Hz, 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, 3.2 Hz, 3H), 1.23 (dt, J = 6.4, 3.2 Hz, 3H), 1.18 (td, J = 6.4, 3.2 Hz, 3H);

[0533] 31 P NMR (162 MHz, CDCl3) δ = 2.82;

[0534] 19 F NMR (376 MHz, CDCl3) δ = -61.21;

[0535] MS (ESI) m / z: calcd. 476.1 [M+H] + , found 476.1 [M+H] + .

[0536] Example 15:

[0537] (R)-Tetrahydrofuran-3-yl((4-chlorophenoxy)(E)-5-hydroxy-4-methylpent-3-en-1-yl)phosphoryl)-L-alaninate (Compound 15)

[0538] The title compound was prepared according to the following scheme. [ka]

[0539] Example 15 was synthesized in the same manner as in Example 2, except that benzyloxycarbonyl-L-alanine and (R)-3-hydroxytetrahydrofuran were used as starting materials and p-chlorophenol was used instead of phenol in step 3 of Example 2.

[0540] 1 H NMR (400 MHz, 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);

[0541] 31 P NMR (162 MHz, CDCl3) δ = 31.57, 31.49

[0542] MS (ESI) m / z: calcd. 432.1 [M ( 35 Cl) + H] + , 434.1 [M ( 37 Cl) + H] + , found 432.1 [M ( 35 Cl) + H] + , 434.1 [M ( 37 Cl) + H] +

[0543] Example 16:

[0544] (R)-Tetrahydrofuran-3-yl((E)-5-hydroxy-4-methylpent-3-en-1-yl)(p-methoxy)phosphoryl)-L-alaninate (Compound 16)

[0545] The title compound was prepared according to the following scheme. [ka]

[0546] Example 16 was synthesized in the same manner as in Example 2, except that benzyloxycarbonyl-L-alanine and (R)-3-hydroxytetrahydrofuran were used as starting materials and p-methylphenol was used instead of phenol in step 3 of Example 2.

[0547] 1H NMR (400 MHz, 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);

[0548] 31 P NMR (162 MHz, CDCl3) δ = 30.86, 30.82

[0549] MS (ESI) m / z: calcd. 412.2 [M + H] + , found 394.2 [M + H - HO] + .

[0550] Example 17:

[0551] (R)-Tetrahydrofuran-3-yl((E)-5-hydroxy-4-methylpent-3-en-1-yl)(naphthalen-1-yloxy)phosphoryl)-L-alaninate (Compound 17)

[0552] The title compound was prepared according to the following scheme. [ka]

[0553] Example 17 was synthesized in the same manner as in Example 2, except that benzyloxycarbonyl-L-alanine and (R)-3-hydroxytetrahydrofuran were used as starting materials and 1-naphthol was used instead of phenol in Step 3 of Example 2.

[0554] 1 H NMR (400 MHz, CDCl3) δ = 8.08 - 8.06 (m, 1H), 7.86 - 7.84 (m, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 7.6 Hz, 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), 2.55 - 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);

[0555] 31 P NMR (162 MHz, CDCl3) δ = 31.44, 31.39;

[0556] MS (ESI) m / z: calcd. 448.2 [M + H] + , found 470.0 [M + Na] + .

[0557] Example 18:

[0558] (R)-Tetrahydrofuran-3-yl((S)-((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 18) and (R)-Tetrahydrofuran-3-yl((S)-((R)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 19)

[0559] The title compound was prepared according to the following scheme.

[0560] Compound 7 of Example 7 was resolved by SFC. [ka]

[0561] (R)-Tetrahydrofuran-3-yl((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (600 mg, 1.51 mmol, 1 equiv.) 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 product to elute was compound 18 (305.56 mg, 768.90 μmol, 50.92% yield), and the second product to elute was compound 19 (137.6 mg, 346.25 μmol, 22.93% yield), both of which were the target products as colorless oils.

[0562] The characterization data for compound 18 are as follows:

[0563] 1 H NMR (400 MHz, CDCl3) δ = 7.34 - 7.30 (m, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.17 - 7.15 (m, 1H), 5.47 (t, J = 6.8 Hz, 1H), 5.27 - 5.24 (m, 1H), 4.07 - 4.05 (m, 1H), 4.02 (s, 2H), 3.90 - 3.84 (m, 3H), 3.73 (d, J = 10.4 Hz, 1H), 3.35 (t, J = 10.4 Hz, 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 = 7.2 Hz, 3H);

[0564] 31P NMR (162 MHz, CDCl3) δ = 30.88;

[0565] MS (EI) m / z: calcd. 398.2 [M + H] + , found 398.1 [M + H] + .

[0566] The characterization data for compound 19 are as follows:

[0567] 1 H NMR (400 MHz, CDCl3) δ = 7.35 - 7.31 (m, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.17 - 7.15 (m, 1H), 5.49 (t, J = 6.8 Hz, 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 = 10.4 Hz, 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 = 7.2 Hz, 3H);

[0568] 31 P NMR (162 MHz, CDCl3) δ = 31.31;

[0569] MS (EI) m / z: calcd. 398.2 [M + H] + , found 398.1 [M + H] + .

[0570] Example 20:

[0571] Tetrahydro-2H-pyran-4-yl((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 20) [ka]

[0572] This product was synthesized in the same manner as described in Example 2 using benzyloxycarbonyl-L-alanine and tetrahydro-2H-pyran-4-ol as starting materials.

[0573] 1 H NMR (400 MHz, CDCl3) δ = 7.33 - 7.31 (m, 2H), 7.23 - 7.20 (m, 2H), 7.15 - 7.13 (m, 1H), 5.51 - 5.43 (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 - 3.49 (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);

[0574] 31 P NMR (162 MHz, CDCl3) δ = 31.42, 31.04;

[0575] MS (ESI) m / z: calcd. 412.2 [M + H] + , found 394.2 [M+H-H2O] + , 434.1 [M + Na] + ;

[0576] Example 21 and Example 22:

[0577] Tetrahydro-2H-pyran-4-yl((S)-((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine (Compound 21) and tetrahydro-2H-pyran-4-yl((R)-((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alanine (Compound 22)

[0578] The title compound was prepared according to the following scheme. [ka]

[0579] Compound 20 (90 mg, 218.75 μmol, 1 equiv.) 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% to 47% B in 10 min). The first compound obtained was compound 21 (10 mg, 24.31 μmol, 11.11% yield), and the second compound obtained was compound 22 (5 mg, 12.15 μmol, 5.55% yield). Both were the target products as colorless oils.

[0580] The characteristics of compound 21 are as follows.

[0581] 1H NMR (400 MHz, CDCl3) δ = 7.33 - 7.29 (m, 2H), 7.23 - 7.20 (m, 2H), 7.16 - 7.14 (m, 1H), 5.49 - 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 = 10.4 Hz, 1H), 2.46 (dq, J = 14.8, 7.2 Hz, 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 = 7.2 Hz, 3H);

[0582] 31 P NMR (162 MHz, CDCl3) δ = 31.02;

[0583] MS (ESI) m / z: calcd. 412.2 [M + H] + Found 394.2 [M + H-H2O] + .

[0584] The properties of compound 22 are evaluated as follows.

[0585] 1H NMR (400 MHz, CDCl3) δ = 7.34 - 7.30 (m, 2H), 7.22 - 7.20 (m, 2H), 7.17 - 7.13 (m, 1H), 5.49 (t, J = 6.8 Hz, 1H), 4.94 - 4.90 (m, 1H), 4.13 - 4.10 (m, 1H), 4.01 (s, 2H), 3.90 - 3.86 (m, 2H), 3.55 - 3.50 (m, 2H), 3.29 (t, J = 10.8 Hz, 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 = 7.2 Hz, 3H);

[0586] 31 P NMR (162 MHz, CDCl3) δ = 31.42;

[0587] MS (ESI) m / z: calcd. 412.2 [M + H] + , found 394.2 [M + H-H2O] + .

[0588] Example 23:

[0589] Isopropyl(((Z)-4-fluoro-5-hydroxy-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 23)

[0590] The title compound was prepared according to the following scheme. [ka]

[0591] Experimental procedures

[0592] Step 1: Isopropyl (((E)-5-oxo-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 23-1) [ka]

[0593] To a solution of isopropyl(but-3-en-1-yl(phenoxy)phosphoryl)-L-alaninate (13 g, 39.96 mmol, 1 equiv.), acrolein (9.81 g, 319.68 mmol, 8 equiv.), and 1,4-benzoquinone (367.54 mg, 3.40 mmol, 0.1 equiv.) in dichloromethane (150 mL) was added Hoveyda-Grubbs second-generation catalyst (2.13 g, 3.40 mmol, 0.1 equiv.). The catalyst was added in three equal portions (710 mg, 1.13 mmol per portion) at t=0, 2, and 4 hours during the reaction. The solution was then heated to reflux at 45° C. for 18 hours under a nitrogen atmosphere. LCMS showed that the starting material was completely consumed and the product was detected. The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel eluting with 10% ethyl acetate / methanol to give the target product isopropyl(((E)-5-oxo-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (7.5 g, 21.23 mmol, 53.13% yield) as a brown oil.

[0594] MS (ESI) m / z: calcd. 354.2 [M + H] + , found 354.1 [M + H] + .

[0595] Step 2: Isopropyl (((Z)-4-fluoro-5-oxo-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 23-2) [ka]

[0596] To a solution of isopropyl (((E)-5-oxo-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (6 g, 16.98 mmol, 1 equiv.), L-proline (1.95 g, 16.98 mmol, 1 equiv.), sodium acetate (1.39 g, 16.98 mmol, 1 equiv.), and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanedi(tetrafluoroborate) salt (12.03 g, 33.96 mmol, 2 equiv.) in methanol (60 mL) was added nitromethane (57.23 g, 937.58 mmol, 55.2 equiv.) under a nitrogen atmosphere. The solution was then stirred at 65° C. under a nitrogen atmosphere for 16 hours. LCMS showed complete consumption of the starting material and detection of the product. The mixture was cooled to room temperature and quenched by adding 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 give a residue. The residue was purified by column chromatography on silica gel eluting with 10% ethyl acetate / methanol to give the target product isopropyl(((Z)-4-fluoro-5-oxo-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (720 mg, 1.94 mmol, 11.42% yield) as a brown oil.

[0597] MS (ESI) m / z: calcd. 372.1 [M + H] + , found 372.1 [M + H] + .

[0598] Step 7: Isopropyl(((Z)-4-fluoro-5-hydroxy-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 23) [ka]

[0599] To a solution of isopropyl (((Z)-4-fluoro-5-oxo-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (360 mg, 969.46 μmol, 1 equiv.) in methanol (5 mL) was added sodium borohydride (73.39 mg, 1.94 mmol, 2 equiv.) slowly under a nitrogen atmosphere at 0° C. The solution was then stirred at 0° C. for 1 hour under a nitrogen atmosphere. LCMS showed that the starting material was completely consumed and the product was detected. The mixture was quenched by adding saturated ammonium chloride solution (10 mL). 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 give a residue. The residue was purified by column chromatography on silica gel eluting with 10% ethyl acetate / methanol, followed by preparative HPLC (Phenomenex Synergi C18 150 × 25 mm × 10 μm; mobile phase: [water (0.1% FA)-ACN]; B%: 40%-50%, 2 min) to give the target product isopropyl(((Z)-4-fluoro-5-hydroxy-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (3.08 mg, 8.25 μmol, 0.85% yield) as a colorless oil.

[0600] 1 H NMR (400 MHz, 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 (162 MHz, CDCl3) δ = 30.64, 30.39; 19 F NMR (376 MHz, CDCl3) δ = -118.43, -118.49; MS (ESI) m / z: calcd. 374.2 [M + H] +, found 374.1 [M + H] + .

[0601] Example 24:

[0602] Isopropyl(((Z)-4-fluoro-5-hydroxy-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 24)

[0603] The title compound was prepared according to the following scheme. [ka]

[0604] Experimental procedures

[0605] Step 1: 3-(benzyloxy)-1,1,1-trifluoropropan-2-ol (compound 24-2) [ka]

[0606] To a reaction solution of benzyl alcohol (30 g, 267.70 mmol, 1 equiv.) and boron trifluoride etherate (3.8 g, 26.77 mmol, 0.1 equiv.) was added 1,1,1-trifluoro-2,3-epoxypropane (29 g, 267.70 mmol, 1 equiv.) at room temperature, and the mixture was stirred at 40 °C for 16 h. After the reaction was completed, the reaction mixture was cooled to room temperature and quenched by adding an appropriate amount of water. The mixture was extracted with dichloromethane (300 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 column chromatography on silica gel eluting with 20–40% petroleum ether / ethyl acetate to obtain 3-(benzyloxy)-1,1,1-trifluoropropan-2-ol (35 g, 206.20 mmol, 57.08% yield) as a yellow oil.

[0607] 1H NMR (400 MHz, 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 = 4.0 Hz, 1H).

[0608] Step 2: 3-(benzyloxy)-1,1,1-trifluoropropan-2-one (compound 24-3) [ka]

[0609] To a solution of 3-(benzyloxy)-1,1,1-trifluoropropan-2-ol (24 g, 116.40 mmol, 1.0 equiv.) in dichloromethane (500 mL) was added Dess-Martin periodinane (DMP) (64.18 g, 151.32 mmol, 1.3 equiv.) dropwise at 20 °C, and the mixture was stirred at 20 °C for 16 h. After the reaction was complete, the mixture was diluted with dichloromethane, and the organic layer was washed with sodium thiosulfate solution and sodium bicarbonate solution, respectively. The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with 20–40% petroleum ether / ethyl acetate to give the desired 3-(benzyloxy)-1,1,1-trifluoropropan-2-one (15 g, 66.10 mmol, 56.79% yield) as a colorless oil.

[0610] 1 H NMR (400 MHz, CDCl3) δ = 7.39 - 7.37 (m, 5H), 4.70 (s, 2H), 3.68 (s, 2H).

[0611] Step 3: Ethyl 3-((benzyloxy)methyl)-4,4,4-trifluorobut-2-enoate (Compound 24-5) [ka]

[0612] 3-(Benzyloxy)-1,1,1-trifluoropropan-2-one (20 g, 91.70 mmol, 1 equiv.) was dissolved in an appropriate amount of benzene under nitrogen protection, and water was removed from the system by refluxing. The reaction solution was cooled to 25 °C, and ethoxyformylmethyltriphenylphosphonium bromide (47.18 g, 109.92 mmol, 1.2 equiv.) and triethylamine (10.66 g, 210.68 mmol, 2.3 equiv.) were added to the reaction system, followed by stirring at 25 °C for 16 h. After completion of the reaction, the reaction was quenched by adding an appropriate amount of water, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography on silica gel eluting with 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.

[0613] 1 H NMR (400 MHz, 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).

[0614] Step 4: 3-((benzyloxy)methyl)-4,4,4-trifluorobut-2-en-1-ol (Compound 24-6) [ka]

[0615] To a solution of ethyl 3-((benzyloxy)methyl)-4,4,4-trifluorobut-2-enoate (6 g, 20.80 mmol, 1 equiv.) in tetrahydrofuran (50 mL) was added DIBALH (1.0 M, 41.60 mL, 2.0 equiv.) dropwise at -60 °C under nitrogen protection. After the addition was complete, the mixture was slowly warmed to room temperature and stirred at room temperature for 15 hours. After the reaction was complete, the mixture was diluted with dichloromethane (100 mL). The organic layer was washed with saturated sodium chloride solution (20 mL × 3). The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with 10–20% petroleum ether / ethyl acetate to give 3-((benzyloxy)methyl)-4,4,4-trifluorobut-2-en-1-ol (3.8 g, 13.90 mmol, 66.8% yield) as a colorless oil.

[0616] 1 H NMR (400 MHz, 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).

[0617] Step 5: (((4-bromo-2-(trifluoromethyl)but-2-en-1-yl)oxy)methyl)benzene (Compound 24-7) [ka]

[0618] To a solution of 3-((benzyloxy)methyl)-4,4,4-trifluorobut-2-en-1-ol (3.5 g, 14.20 mmol, 1 equiv.) in dichloromethane (20 mL) was added triphenylphosphine (4.47 g, 17.04 mmol, 1.2 equiv.) and carbon tetrabromide (5.18 g, 15.62 mmol, 1.1 equiv.) under nitrogen protection at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. After the reaction was completed, the reaction mixture was diluted with an appropriate amount of dichloromethane, and the organic layer was washed with saturated sodium chloride solution. The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with 40–60% petroleum ether / ethyl acetate to give 24-7 (3.6 g, 32.65 mmol, 98.02% yield) as a colorless oil.

[0619] 1 H NMR (400 MHz, 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).

[0620] 19 F NMR (376 MHz, CDCl3) δ = -60.38, -67.68.

[0621] Step 6: 4-Bromo-2-(trifluoromethyl)but-2-en-1-ol (Compound 24-8) [ka]

[0622] To a solution of (((4-bromo-2-(trifluoromethyl)but-2-en-1-yl)oxy)methyl)benzene (2.9 g, 52.03 mmol, 1 equiv.) in dichloromethane (150 mL) was added boron trichloride (1.0 M, 75.20 mL, 8.0 equiv.) dropwise at −78 °C under nitrogen protection. The resulting mixture was gradually heated to 20 °C and stirred for another 5 h. After the reaction was completed, the mixture was diluted with dichloromethane (150 mL). The organic layer was washed with saturated sodium chloride solution (50 mL × 3). The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with 40–60% petroleum ether / ethyl acetate to give 24-8 (1.20 g, 4.90 mmol, 52.13% yield) as a colorless oil.

[0623] 1 H NMR (400 MHz, 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).

[0624] Step 7: 2-((4-bromo-2-(trifluoromethyl)but-2-en-1-yl)oxy)tetrahydro-2H-pyran (Compound 24-9) [ka]

[0625] To a solution of 4-bromo-2-(trifluoromethyl)but-2-en-1-ol (1.50 g, 6.80 mmol, 1 equiv.) and p-toluenesulfonic acid pyridine salt (0.17 g, 0.06 mmol, 0.1 equiv.) in tetrahydrofuran (40 mL) was added 3,4-dihydropyran (1.71 g, 20.30 mmol, 3 equiv.) at 20 °C, and the reaction mixture was stirred at 20 °C for 2 hours. After completion of the reaction, the reaction was quenched by adding water (20 mL), and the mixture was extracted with dichloromethane (50 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel 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.

[0626] 1 H NMR (400 MHz, 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), 3.87-3.80 (m, 1H), 3.58-3.53 (m, 1H), 1.82 -1.69 (m, 3H), 1.67-1.54 (m, 3H).

[0627] Step 8: Dimethyl (5,5,5-trifluoro-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pent-3-en-1-yl)phosphonate (Compound 24-12) [ka]

[0628] To a solution of dimethyl methylphosphonate (135 mg, 1.08 mmol, 1 equiv.) in tetrahydrofuran (15 mL), 2.4 M n-butyllithium / n-hexane solution (0.50 mL, 1.30 mmol, 1.2 equiv.) was added dropwise at −78° C. under nitrogen protection, and the reaction solution was stirred at −78° C. for 0.5 hours. Next, a solution of 2-((4-bromo-2-(trifluoromethyl)but-2-en-1-yl)oxy)tetrahydro-2H-pyran (330 mg, 1.08 mmol, 1.0 equiv.) in tetrahydrofuran (1 mL) was added dropwise, and the reaction mixture was slowly heated and stirred at 20° C. for 16 hours. After completion of the reaction, the mixture was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with 0-10% ethyl acetate / methanol to give 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.

[0629] MS (ESI) m / z: calcd. 347.3 [M+H] + , found 263.0 [M-THP+H] + .

[0630] 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) [ka]

[0631] To a solution of (E)-5-diethoxyphosphoryl-2-methyl-2-pent-1-yloctanoate (1.13 g, 3.12 mmol, 1 equiv.) in dichloromethane (500 mL) was added TMSBr (4.77 g, 31.20 mmol, 10 equiv.) dropwise at 0 °C, and the mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC spot plate (PE:EA = 1:5). After completion, the mixture was concentrated under reduced pressure. 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) was obtained as a yellow oil, which was used directly in the next step.

[0632] Step 10: Isopropyl(phenoxy(-5,5,5-trifluoro-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pent-3-en-1-yl)phosphoryl)-L-alaninate (Compound 24-16) [ka]

[0633] 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 equiv.) in pyridine (5 mL) was added isopropyl (2S)-2-aminopropionate (26 mg, 0.19 mmol, 1 equiv.), phenol (110 mg, 1.16 mmol, 6 equiv.), triethylamine (295 mg, 2.92 mmol, 15 equiv.), triphenylphosphine (306 mg, 1.17 mmol, 6 equiv.), and 1,2-di(pyridin-2-yl)disulfane (257 mg, 1.17 mmol, 6 equiv.) under nitrogen protection, and the mixture was stirred at 50° C. for 16 hours. After the reaction was completed, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC to give the target product isopropyl(phenoxy((Z)-5,5,5-trifluoro-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pent-3-en-1-yl)phosphoryl)-L-alaninate (10 mg, 0.02 mmol, 8.65% yield) as a white solid.

[0634] MS (ESI) m / z: calcd. 508.2 [M+H] + , found 508.1 [M+H] + .

[0635] Step 11: Isopropyl(phenoxy((Z)-5,5,5-trifluoro-4-(hydroxymethyl)pent-3-en-1-yl)phosphoryl)-L-alaninate (Compound 24) [ka]

[0636] To a solution of isopropyl(phenoxy(-5,5,5-trifluoro-4-(hydroxymethyl)pent-3-en-1-yl)phosphoryl)-L-alaninate (10 mg, 0.02 mmol, 1 equiv.) in water (2 mL), 1N hydrochloric acid solution was added dropwise until the pH reached 4-5, and the mixture was stirred at 25 °C for 2 h. After the reaction was completed, the reaction solution was purified by preparative HPLC (column: Gemini-C18 150 × 21.2 mm, 5 μm, mobile phase: ACN / HO, 25% to 50% in 40 min) to obtain isopropyl(phenoxy((Z)-5,5,5-trifluoro-4-(hydroxymethyl)pent-3-en-1-yl)phosphoryl)-L-alaninate (3.1 mg, 37.16% yield).

[0637] 1 H NMR (400 MHz, 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), 4.06 - 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);

[0638] 31 P NMR (162 MHz, CDCl3) δ = 29.94, 29.75;

[0639] 19 F NMR (376 MHz, CDCl3) δ = -60.09, -59.98;

[0640] MS (ESI) m / z: calcd. 424.1 [M+H] + , found 424.1 [M+H] + .

[0641] Example 25:

[0642] 2-Hydroxyethyl (((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 25)

[0643] The title compound was prepared according to the following scheme. [ka]

[0644] Experimental procedures

[0645] Step 1: 2-((4-methoxybenzyl)oxy)ethan-1-ol (Compound 25-2) [ka]

[0646] To a solution of ethylene glycol (5.94 g, 95.78 mmol, 1 equiv.) in tetrahydrofuran (60 mL) was added sodium hydride (3.84 g, 95.78 mmol, 60% w / w, 1 equiv.) in portions at 0 °C under nitrogen protection, and the mixture was stirred at 20 °C for 0.5 h. p-Methoxybenzyl chloride (15.0 g, 95.78 mmol, 1 equiv.) and tetrabutylammonium iodide (3.54 g, 9.58 mmol, 0.1 equiv.) were added to the reaction solution under nitrogen protection at 20 °C, and the mixture was stirred at 60 °C for 5 h. TLC (PE:EA = 1:1) showed the reaction was complete, and a new, less polar spot was observed. The mixture was cooled to room temperature and quenched by adding saturated ammonium chloride solution (100 mL). The mixture was extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel 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.

[0647] 1 H NMR (400 MHz, 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).

[0648] Step 2: 2-((4-methoxybenzyl)oxy)ethyl(tert-butoxycarbonyl)-L-alaninate (Compound 25-4) [ka]

[0649] To a solution of 2-((4-methoxybenzyl)oxy)ethan-1-ol (12.0 g, 65.85 mmol, 1 equiv.) in acetonitrile (100 mL) was added BOC-L-alanine (14.95 g, 79.02 mmol, 1.2 equiv.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (13.89 g, 72.44 mmol, 1.1 equiv.), and 4-dimethylaminopyridine (8.85 g, 72.44 mmol, 1.1 equiv.) under nitrogen protection at 20 °C, and the mixture was stirred at 20 °C for 16 h. TLC (PE:EA = 1:1) showed 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 give a residue. The residue was purified by column chromatography on silica gel eluting with 0-60% petroleum ether / ethyl acetate to give 2-((4-methoxybenzyl)oxy)ethyl(tert-butoxycarbonyl)-L-alaninate (12.4 g, 35.09 mmol, 53.29% yield) as a yellow oil.

[0650] 1H NMR (400 MHz, 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 = 4.8 Hz, 2H), 1.39 - 1.38 (m, 9H), 1.33 (d, J = 7.2 Hz, 3H).

[0651] Step 3: 2-((4-methoxybenzyl)oxy)ethyl L-alaninate (Compound 25-5) [ka]

[0652] To a solution of 2-((4-methoxybenzyl)oxy)ethyl (tert-butyloxycarbonyl)-L-alaninate (5.0 g, 14.15 mmol, 1 equiv.) in tetrahydrofuran (40 mL) was added p-toluenesulfonic acid monohydrate (9.75 g, 56.60 mmol, 4 equiv.) under nitrogen protection at 20° C., and the mixture was stirred at 60° C. for 4 hours. LCMS showed that the starting material was completely consumed and the product was detected. 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 give a residue. The residue was purified by preparative HPLC (Waters Xbridge C18 150 × 50 mm × 10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 30% to 45% B in 5 min) to give 2-((4-methoxybenzyl)oxy)ethyl L-alaninate (0.6 g, 2.37 mmol, 16.75% yield) as a colorless oil.

[0653] MS (ESI) m / z: calcd. 254.1 [M + H] + , found 254.1 [M + H] + .

[0654] Step 4: Diphenylbutyl-3-en-1-ylphosphonate (Compound 25-6) [ka]

[0655] To a solution of 4-dichlorophosphorylbut-1-ene (20 g, 115.62 mmol, 1 equiv.) in dichloromethane (200 mL), triethylamine (23.40 g, 231.24 mmol, 2 equiv.) was added under nitrogen protection at −78° C., and the mixture was stirred at −78° C. for 5 minutes. To the mixture, a solution of phenol (23.94 g, 254.37 mmol, 2.2 equiv.) in dichloromethane (200 mL) was slowly added dropwise under nitrogen protection at −78° C. Then, the mixture was stirred at 20° C. for 16 hours. LCMS showed that the starting material was completely consumed and the product was detected. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography on silica gel eluting with 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.

[0656] MS (ESI) m / z: calcd. 289.1 [M + H] + , found 289.0 [M + H] + .

[0657] Step 5: Phenyl hydrogen but-3-en-1-yl phosphonate (compound 25-7) [ka]

[0658] To a solution of diphenylbutyl-3-en-1-ylphosphonate (28.0 g, 97.13 mmol, 1 equiv.) in acetonitrile (300 mL) was added aqueous sodium hydroxide (2 M, 485.65 mL, 10 equiv.) under nitrogen protection at 0 °C, and the mixture was stirred at 20 °C for 16 h. LCMS showed complete consumption of the starting material and detection of the product. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Waters Xbridge C18 150 × 50 mm × 10 μm; mobile phase: [water (NH₃·HO)-ACN]; gradient: 20% to 30% B in 5 min) to give phenyl hydrogen but-3-en-1-ylphosphonate (13.0 g, 61.27 mmol, 63.08% yield) as a colorless oil.

[0659] MS (ESI) m / z: calcd. 213.1 [M + H] + , found 213.0 [M + H] + .

[0660] Step 6: Phenylbut-3-en-1-ylphosphonochloridate (Compound 25-8) [ka]

[0661] To a solution of phenyl hydrogen but-3-en-1-ylphosphonate (7.0 g, 32.99 mmol, 1 equiv.) in toluene (50 mL) was added thionyl chloride (19.62 g, 164.95 mmol, 5 equiv.) under nitrogen protection. The mixture was stirred at 75° C. for 2 hours. LCMS showed that the starting material was completely consumed and the product was detected. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent to give phenyl but-3-en-1-yl phosphonochloridate (7.0 g, crude) as a yellow oil, which was used directly in the next step without further treatment.

[0662] Step 7: 2-((4-methoxybenzyl)oxy)ethyl (but-3-en-1-yl(phenoxy)phosphoryl)-L-alaninate (Compound 25-9) [ka]

[0663] To a solution of phenylbut-3-en-1-ylphosphonochloridate (500 mg, 2.17 mmol, 1 equiv.) in dichloromethane (10 mL), triethylamine (438.76 mg, 4.34 mmol, 2 equiv.) was added under nitrogen protection at 0° C., and the mixture was stirred at 0° C. for 5 minutes. To the mixture, a solution of ethyl 2-((4-methoxybenzyl)oxy)L-alaninate (549.14 mg, 2.17 mmol, 1 equiv.) in dichloromethane (2 mL) was slowly added dropwise under nitrogen protection at 0° C. Then, the mixture was stirred at 20° C. for 16 hours. LCMS showed that the starting material was completely consumed and the product was detected. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with 50-80% petroleum ether / ethyl acetate to give 2-((4-methoxybenzyl)oxy)ethyl (but-3-en-1-yl(phenoxy)phosphoryl)-L-alaninate (300 mg, 670.45 μmol, 30.92% yield) as a colorless oil.

[0664] MS (ESI) m / z: calcd. 448.2 [M + H] + , found 448.2 [M + H] + .

[0665] Step 8: 2-((4-Methoxybenzyl)oxy)ethyl ((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 25-10) [ka]

[0666] To a solution of 2-((4-methoxybenzyl)oxy)ethyl (but-3-en-1-yl(phenoxy)phosphoryl)-L-alaninate (300 mg, 670.45 μmol, 1 equiv.), 2-methylprop-2-en-1-ol (386.75 mg, 5.36 mmol, 8 equiv.), and 1,4-benzoquinone (7.25 mg, 67.05 μmol, 0.1 equiv.) in dichloromethane (6 mL) was added Hoveyda-Grubbs second-generation catalyst (84.02 mg, 134.09 μmol, 0.2 equiv.). The catalyst was added in three equal portions (28.01 mg, 44.70 μmol each) at t=0, 2, and 4 hours during the reaction. The solution was then heated to reflux at 45° C. for 18 hours under a nitrogen atmosphere. LCMS showed complete consumption of the starting material and detection of the product. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with 0-10% ethyl acetate / methanol to give the target product, 2-((4-methoxybenzyl)oxy)ethyl ((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (160 mg, 325.52 μmol, 48.55% yield) as a colorless oil.

[0667] MS (ESI) m / z: calcd. 492.2 [M + H] + , found 492.2 [M + H] + .

[0668] Step 9: 2-Hydroxyethyl (((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate [ka]

[0669] To a solution of 2-((4-methoxybenzyl)oxy)ethyl ((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (130 mg, 264.49 μmol, 1 equiv.) in dichloromethane (4 mL) and water (0.4 mL) was added dichlorodicyanobenzoquinone (72.05 mg, 317.39 μmol, 1.2 equiv.) under nitrogen protection at 0°C, and the mixture was stirred at 0°C for 1 hour. LCMS showed that the starting material was completely consumed and the 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 give a residue. The residue was purified by preparative HPLC (Phenomenex Synergi C18 150 × 25 mm × 10 μm; mobile phase: [water (0.1% FA)-ACN]; B%: 30%-45%, 2 min) to give the target product 2-hydroxyethyl (((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (12.79 mg, 34.46 μmol, 13.03% yield) as a colorless oil.

[0670] 1 H NMR (400 MHz, 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);

[0671] 31 P NMR (162 MHz, CDCl3) δ = 32.89, 32.35;

[0672] MS (ESI) m / z: calcd. 372.2 [M + H] +, found 394.1 [M + Na] + ;

[0673] Example 26:

[0674] (R)-Tetrahydrofuran-3-yl 2-((((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)amino)-2-methylpropanoate (Compound 26)

[0675] The title compound was prepared according to the following scheme. [ka]

[0676] Experimental procedures

[0677] Step (R)-Tetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate (26-1) [ka]

[0678] To a solution of 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (5 g, 22.5 mmol, 1.0 equiv.) in tetrahydrofuran (50 mL) was added 4-dimethylaminopyridine (3.01 g, 2.46 mmol, 1.0 equiv.) and carbodiimide hydrochloride (9.35 g, 24.6 mmol, 1.0 equiv.) under nitrogen protection at 0° C. The resulting mixture was stirred under nitrogen protection at 0° C. for 0.5 hours, and then (R)-tetrahydrofuran-3-ol (2.38 g, 27.0 mmol, 1.1 equiv.) was added to the reaction system. The reaction solution was stirred for 16 hours. After completion of the reaction, the reaction was quenched by adding water (100 mL). The mixture was extracted with dichloromethane (100 mL × 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The resulting residue was purified by silica gel chromatography eluting with 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 pale yellow oil.

[0679] MS (ESI) m / z: calcd. 274.2 [M+H] + , found 174.2 [M+H-100] + .

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

[0681] (R)-Tetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate (5 g, 18.2 mmol) was dissolved in hydrochloric acid / ethyl acetate (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, the reaction was quenched by adding saturated aqueous sodium bicarbonate solution (10 mL). The mixture was extracted with ethyl acetate (50 mL × 2), and the combined organic layer was 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) as a white solid.

[0682] MS (ESI) m / z: calcd. 174.2 [M + H] + , found 174.2 [M + H] + .

[0683] Step 1: (R)-Tetrahydrofuran-3-yl 2-((but-3-en-1-yl(phenoxy)phosphoryl)amino)-2-methylpropanoate (26-3) [ka]

[0684] To a solution of but-3-en-1-ylphosphine dichloride (500 mg, 2.89 mmol, 1 equiv.) in dichloromethane (10 mL) was added dropwise (R)-tetrahydrofuran-3-yl 2-amino-2-methylpropanoate (500 mg, 2.89 mmol, 1 equiv.) and triethylamine (584 mg, 5.78 mmol, 2 equiv.) under nitrogen protection at -78 °C. The resulting mixture was stirred at room temperature for 6 hours under nitrogen protection. The reaction solution was then cooled to -78 °C, and phenol (109 mg, 1.16 mmol, 1 equiv.) and triethylamine (584 mg, 5.78 mmol, 2 equiv.) were added. The resulting mixture was stirred at room temperature for 16 hours under nitrogen protection. After completion of the reaction, the reaction was quenched by adding water (20 mL). The mixture was extracted with dichloromethane (20 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that 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.

[0685] MS (ESI) m / z: calcd. 368.2 [M + H] + , found 368.2 [M + H] + .

[0686] Step 2: (R)-Tetrahydrofuran-3-yl 2-((((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)amino)-2-methylpropanoate (Compound 26) [ka]

[0687] 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 equiv.) in dichloromethane (5 mL), 2-methylprop-2-en-1-ol (58.9 mg, 0.82 mmol, 2 equiv.), Hoveyda-Grubbs catalyst (25.6 mg, 0.04 mmol, 0.1 equiv.), and p-benzoquinone (1 mg, 0.01 mmol, 0.1 equiv.) were added under nitrogen protection at 20° C., and the resulting mixture was stirred at 40° C. for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by HPLC (column: Gemini-C18 150 × 21.2 mm, 5 μm, mobile phase: ACN-HO, gradient: 27%-95%, flow rate: 20 ml / min, ACN (%): 45, retention time: 13 min) to give the title compound (12.7 mg, 0.03 mmol, yield: 7.5%) as a colorless oil.

[0688] 1 H NMR (400 MHz, CDCl3) δ 7.34 - 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).

[0689] 31 P NMR (162 MHz, CDCl3) δ = 30.51;

[0690] MS (ESI) m / z: calcd. 412.2 [M+H] + , found 412.1 [M+H] + .

[0691] Example 27:

[0692] (R)-Tetrahydrofuran-3-yl(phenoxy((Z)-5,5,5-trifluoro-4-(hydroxymethyl)pent-3-en-1-yl)phosphoryl)-L-alaninate (Compound 27)

[0693] Example 27 was synthesized according to the method of Example 24 using benzyloxycarbonyl-L-alanine and (R)-3-hydroxytetrahydrofuran as starting materials. [ka]

[0694] 1 H NMR (400 MHz, CDCl3) δ 7.34-7.30 (m, 2H), 7.21 - 7.13 (m, 3H), 6.17 - 6.14 (m, 1H), 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).

[0695] 31 P NMR (162 MHz, CDCl3) δ = 29.72, 29.42;

[0696] 19 F NMR (376.5 MHz, CDCl3) δ = -60.00, -60.10;

[0697] MS (ESI) m / z: calcd. 452.1 [M+H] + , found 452.1 [M+H]+ .

[0698] Example 28:

[0699] 1,1-Dioxotetrahydro-2H-thiopyran-4-yl(((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 28) [ka]

[0700] Example 28 was synthesized according to the method of Example 2 using benzyloxycarbonyl-L-alanine and 4-hydroxytetrahydro-2H-thiopyran-1,1-dioxide as starting materials.

[0701] 1 H NMR (400 MHz, CDCl3) δ 7.34-7.28 (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).

[0702] 31 P NMR (162 MHz, CDCl3) δ = 32.03, 31.73;

[0703] MS (ESI) m / z: calcd. 460.2 [M+H] + , found 460.2 [M+H]+ .

[0704] Example 29:

[0705] compound 29

[0706] Example 29 was synthesized according to the method of Example 2 using benzyloxycarbonyl-L-alanine and 4-hydroxypiperidine as starting materials. [ka]

[0707] 1 H NMR (400 MHz, CDCl3) δ 7.32 - 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).

[0708] 31 P NMR (162 MHz, CDCl3) δ = 32.05, 31.98, 31.66, 31.62;

[0709] MS (ESI) m / z: calcd. 453.2 [M+H] + , found 453.2 [M+H] + .

[0710] Example 30:

[0711] 2-Oxaspiro[3.3]heptan-6-yl(((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 30)

[0712] Example 30 was synthesized according to the method of Example 2 using benzyloxycarbonyl-L-alanine and 2-oxaspiro[3.3]heptan-6-ol as starting materials. [ka]

[0713] 1 H NMR (400 MHz, CDCl3) δ 7.32 - 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 - 1.83 (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).

[0714] 31 P NMR (162 MHz, CDCl3) δ = 31.98, 31.56;

[0715] MS (ESI) m / z: calcd. 424.2 [M+H] + , found 424.0 [M+H] + .

[0716] Example 31:

[0717] compound 31

[0718] Example 31 was synthesized according to the method of Example 2 using benzyloxycarbonyl-L-alanine and 4-hydroxypiperidine as starting materials. [ka]

[0719] 1 H NMR (400 MHz, CDCl3) δ 7.34 - 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 = 10.4 Hz, 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), 1.80 - 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).

[0720] 31 P NMR (162 MHz, CDCl3) δ = 31.44, 31.10;

[0721] MS (ESI) m / z: calcd. 493.2 [M+H] + , found 493.1 [M+H] + .

[0722] Example 32:

[0723] (3R,3aS,6aR)-Hexahydrofuran[2,3-b]furan-3-yl(((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 32)

[0724] Example 32 was synthesized according to the method of Example 2 using benzyloxycarbonyl-L-alanine and (3R,3aS,6aR)-hexahydrofurano[2,3-b]furan-3-ol as starting materials. [ka]

[0725] 1 H NMR (400 MHz, CDCl3) δ 7.30 - 7.29 (m, 2H), 7.20 -7.19 (m, 2H), 7.16-7.14 (t, J = 6.7 Hz, 1H), 5.71 (d, J = 4.8 Hz, 1H), 5.52 - 5.35 (m, 1H), 5.13 (p, J = 6.6 Hz, 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, 7.7 Hz, 1H), 3.77 - 3.67 (m, 1H), 3.58 (d, J = 9.7 Hz, 0.5H), 3.43 (d, J = 9.8 Hz, 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 = 6.9 Hz, 1.5H), 1.24 (d, J = 6.6 Hz, 1.5H).

[0726] 31 P NMR (162 MHz, CDCl3) δ = 31.48, 31.16;

[0727] MS (ESI) m / z: calcd. 440.2 [M+H] + , found 422.2 [M+H-H2O] + .

[0728] Example 33:

[0729] compound 33

[0730] Example 33 was synthesized according to the method of Example 2 using benzyloxycarbonyl-L-alanine and (2R,4R)-2-methyloxan-4-ol as starting materials. [ka]

[0731] 1 H NMR (400 MHz, CDCl3) δ 7.31 - 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 = 7.0 Hz, 1.5H), 1.28 - 1.21 (m, 1H), 1.20 - 1.16 (m, 4.5H).

[0732] 31 P NMR (162 MHz, CDCl3) δ = 31.99, 31.59;

[0733] MS (ESI) m / z: calcd. 426.2 [M+H] + , found 408.1 [M+H-H2O] + .

[0734] Example 34:

[0735] (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)

[0736] The title compound was prepared according to the following scheme. [ka]

[0737] Experimental procedures

[0738] Step 1-1: (2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-ol (34-2) [ka]

[0739] To a solution of 2,6-dimethyl-4H-pyran-4-one (4.00 g, 32.2 mmol, 1 equiv.) in ethanol (40 mL) was added 10% Pd(OH)2 / C (3.39 g, 6.45 mmol, 0.1 equiv.) at room temperature, and the resulting mixture was placed in a hydrogen reactor at 50 psi. The reaction was stirred at 35 °C for 19 h. After the reaction was complete, the mixture was filtered and concentrated under reduced pressure to give 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.

[0740] 1H NMR (400 MHz, CDCl3) δ 3.68 - 3.77 (m, 1H), 3.37-3.45 (m, 2H), 2.11 (s, 1H), 1.87 (dd, J = 12.1, J=4.7 Hz, 2H),1.18 (d, J = 6.2 Hz, 6H), 1.05 - 1.15 (m, 2H).

[0741] Step 1: (2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl((benzyloxy)carbonyl)-L-alaninate (34-3) [ka]

[0742] To a solution of ((benzyloxy)carbonyl)-L-alanine (2.00 g, 8.97 mmol, 1 equiv.) and (2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-ol (1.28 g, 9.87 mmol, 1.1 equiv.) in dichloromethane (20 mL), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.70 g, 13.46 mmol, 1.5 equiv.) and 4-dimethylaminopyridine (0.22 g, 1.79 mmol, 0.2 equiv.) were added under nitrogen protection at room temperature, and the resulting mixture was stirred for 16 hours under nitrogen protection at room temperature. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 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.

[0743] MS (ESI) m / z: calcd. 336.2 [M + H] + , found 336.0 [M + H] + .

[0744] Step 2: (2R,4R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl L-alaninate (34-4) [ka]

[0745] 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 equiv.) in tetrahydrofuran (20 mL) was added 20% palladium hydroxide on carbon (0.75 g, 1.34 mmol, 0.25 equiv.) at room temperature, and the system was purged with hydrogen gas three times. The resulting mixture was stirred under hydrogen protection at 35°C for 3 hours. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure to give (2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl L-alaninate (0.91 g, 4.50 mmol, 83.89% yield) as a colorless oil.

[0746] MS (ESI) m / z: calcd. 202.1 [M + H] + , found 202.2 [M + H] + .

[0747] 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) [ka]

[0748] A solution of (trimethylsilyl)(E)-(4-methyl-5-((tetrahydro-2H-pyran-2-yl)oxy)pent-3-en-1-yl)phosphonate (500 mg, 1.22 mmol, 1 equiv.) in pyridine (5 mL) was treated with (2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl L-alaninate (248.46 mg, 1.23 mmol) under nitrogen protection. mol, 1 equiv), phenol (691 mg, 7.35 mmol, 6 equiv), triethylamine (1.86 g, 18.38 mmol, 15 equiv), triphenylphosphine (1.93 mg, 7.35 mmol, 6 equiv), and 1,2-di(pyridin-2-yl)disulfane (1.62 g, 7.35 mmol, 6 equiv) were added, and the resulting mixture was stirred at 50° C. for 16 hours. After the reaction was complete, the reaction was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel eluting with 50-100% petroleum ether / ethyl acetate to give crude product (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 pale yellow oil.

[0749] MS (ESI) m / z: calcd. 524.3 [M+H] + , found 546.2 [M+Na] + .

[0750] 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) [ka]

[0751] 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 / 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 (column: Gemini-C18 150 × 21.2 mm, flow rate: 20 ml / min, mobile phase: ACN / HO, 0% to 60% in 7 min) 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, yield 43.18%) as a colorless oil.

[0752] 1 H NMR (400 MHz, CDCl3) δ 7.33 - 7.27 (m, 2H), 7.21 (d, J = 8.7 Hz, 2H), 7.14 (td, J = 7.5, J=3.2 Hz, 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 = 10.6 Hz, 0.5H), 3.27 (t, J = 10.6 Hz, 0.5H), 2.51-2.40 (m, 2H), 2.01 - 1.93 (m, 2H), 1.91 - 1.85 (m, 2H), 1.71 (d, J = 5.4 Hz, 3H), 1.31 (d, J = 7.0 Hz, 1.5H), 1.23 - 1.14 (m, 9.5H).

[0753] 31 P NMR (162 MHz, CDCl3) δ = 31.35, 30.97;

[0754] MS (ESI) m / z: calcd. 440.2 [M+H] + , found 440.3 [M+H] + .

[0755] Example 35:

[0756] (R)-2-Piperidon-4-yl(((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 35)

[0757] Example 35 was synthesized according to the method of Example 34 using benzyloxycarbonyl-L-alanine and (R)-4-hydroxypiperidin-2-one as starting materials. [ka]

[0758] 1 H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 7.8 Hz, 2H), 7.25 - 7.18 (m, 2H), 7.15 (t, J = 7.3 Hz, 1H), 6.64 (s, 1H), 5.52 - 5.39 (m, 1H), 5.17-5.15 (m, 1H), 4.15 - 3.95 (m, 3H), 3.67 (t, J = 10.2 Hz, 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 = 5.2 Hz, 0.4H), 2.63 (d, J = 4.8 Hz, 0.4H), , 2.49 - 2.39 (m, 3H), 2.02 - 1.84 (m, 4H), 1.70 (s, 1.2H), 1.68 (s, 1.8H), 1.30 (d, J = 7.0 Hz, 1.8H), 1.24 (d, J = 7.1 Hz, 1.2H).

[0759] 31 P NMR (162 MHz, CDCl3) δ = 31.51, 31.12;

[0760] MS (ESI) m / z: calcd. 425.2 [M+H] + , found 424.8 [M+H] + .

[0761] Example 36:

[0762] 1-Cyanocyclopentyl(((E)-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 36)

[0763] Example 36 was synthesized according to the method of Example 34 using benzyloxycarbonyl-L-alanine and 1-hydroxycyclopentane-1-carbonitrile as starting materials. [ka]

[0764] 1 H NMR (400 MHz, CDCl3) δ 7.32 - 7.27 (m, 2H), 7.19 - 7.17 (m, 2H), 7.14 - 7.10 (m, 1H), 5.45 (q, J = 7.8, 7.4 Hz, 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 = 7.1 Hz, 1.5H), 1.20 (d, J = 7.2 Hz, 1.5H).

[0765] 31 P NMR (162 MHz, CDCl3) δ = 32.00, 31.58;

[0766] MS (ESI) m / z: calcd. 421.2 [M+H] + , found 403.1 [M+H-H2O] + .

[0767] Example 37:

[0768] Tetrahydro-2H-pyran-4-yl(((E)-1,1-difluoro-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 37)

[0769] The title compound was prepared according to the following scheme. [ka]

[0770] Step 1: Diethyl (1,1-difluorobut-3-en-1-yl)phosphonate (Compound 37-1) [ka]

[0771] To a solution of activated zinc powder (1.22 g, 18.7 mmol) in anhydrous N,N-dimethylformamide (9.5 mL) was added diethyl bromofluoromethylphosphonate (3.3 mL, 18.6 mmol) dropwise under nitrogen protection. The resulting mixture was stirred at room temperature for 3 hours under nitrogen protection, and then cuprous bromide (2.66 g, 18.5 mmol) was added. After stirring at room temperature, allyl bromide (2.26 g, 18.5 mmol) was slowly added dropwise to the reaction mixture. The resulting mixture was stirred at room temperature for 16 hours, filtered, and the filtrate was rotary evaporated to dryness. The crude product was purified by column chromatography on silica gel eluting with 60-70% petroleum ether / ethyl acetate to give diethyl (1,1-difluorobut-3-en-1-yl)phosphonate (1.70 g, 7.46 mmol, 40.09% yield) as a yellow oil.

[0772] 1 H NMR (400 MHz, CDCl3) δ 5.86 - 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).

[0773] 31 P NMR (400 MHz, CDCl3) δ = -111.12, -111.40;

[0774] MS (ESI) m / z: calcd. 229.1 [M + H] + , found 229.1 [M + H] + .

[0775] Step 2 and Step 3: (1,1-difluorobut-3-en-1-yl)phosphonic acid dichloride (compound 37-3) [ka]

[0776] To a solution of diethyl (1,1-difluorobut-3-en-1-yl)phosphonate (4.00 g, 17.54 mmol, 1 equiv.) in dichloromethane (15 mL), TMSBr (26.84 g, 175.44 mmol, 10 equiv.) was added dropwise at 0°C under nitrogen protection. The resulting mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The mixture was dissolved in anhydrous dichloromethane (50 mL), the reaction solution was cooled to 0°C, and then 2 drops of DMF and oxalyl chloride (6.68 g, 52.62 mmol, 3 equiv.) were added to the reaction mixture under nitrogen protection and stirred at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to give 3.6 g of crude product (1,1-difluorobut-3-en-1-yl)phosphonic acid dichloride as a tan oil / solid mixture.

[0777] Step 4: (R)-Tetrahydrofuran-3-yl((1,1-difluorobut-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 37-4) [ka]

[0778] To a solution of (1,1-difluorobut-3-en-1-yl)phosphonic acid dichloride (2.30 g, 11.06 mmol, 1 equiv.) in dichloromethane (40 mL) was added dropwise (R)-tetrahydrofuran-3-yl L-alaninate (1.76 g, 11.06 mmol, 1 equiv.) and triethylamine (2.23 g, 22.12 mmol, 2 equiv.) under nitrogen protection at -78 °C, and the resulting mixture was stirred at room temperature for 6 hours. The mixture was then cooled to -78 °C, and phenol (1.048 g, 11.06 mmol, 1 equiv.) and triethylamine (2.23 g, 22.12 mmol, 2 equiv.) were added, and the resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction was quenched by adding water (30 mL). The mixture was extracted with dichloromethane (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel 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.

[0779] MS (ESI) m / z: calcd. 390.1 [M+H] + , found 390.1 [M+H] + .

[0780] Step 5: (R)-Tetrahydrofuran-3-yl(((E)-1,1-difluoro-5-hydroxy-4-methylpent-3-en-1-yl)(phenoxy)phosphoryl)-L-alaninate (Compound 37) [ka]

[0781] 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 equiv.) and 2-methylprop-2-en-1-ol (387 mg, 6.68 mmol, 2 equiv.) in dichloromethane (40 mL), Hoveyda-Grubbs catalyst (232.12 mg, 0.33 mmol, 0.1 equiv.) and p-benzoquinone (80.35 mg, 0.668 mmol, 0.2 equiv.) were added dropwise under nitrogen protection, and the resulting mixture was stirred at 45° C. for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with 40-100% petroleum ether / ethyl acetate, and the resulting crude product was purified by preparative HPLC (chromatography column: Gemini-C18 150 × 21.2 mm, 5 μm; mobile phase: ACN-HO; gradient: 30%-95%, flow rate: 20 mL / min, retention time: 10.5 min) to give (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) as a colorless oil / solid mixture.

[0782] 1H NMR (400 MHz, DMSO-d6) δ 7.39 - 7.34 (m, 2H), 7.25 - 7.17 (m, 3H), 6.64-6.57 (m, 1H), 5.45 (t, J = 7.1 Hz, 1H), 5.16-5.12 (m, 1H), 4.83 (td, J = 5.5, 2.0 Hz, 1H), 3.94-3.86 (m, 1H), 3.80 (d, J = 8.0 Hz, 2H), 3.78 - 3.62 (m, 3H), 3.55 (d, J = 10.4 Hz, 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 = 7.2 Hz, 1.5H), 1.18 (d, J = 7.2 Hz, 1.5H).

[0783] 31 P NMR (400 MHz, DMSO-d6) δ = 11.22, 10.76, 10.57, 10.13, 9.92, 9.47;

[0784] MS (ESI) m / z: calcd. 434.1 [M+H] + , found 416.0 [M+H-H2O] + .

[0785] Example 38: Compound 38

[0786] Example 38 was synthesized according to the method of Example 37 using benzyloxycarbonyl-L-alanine and 4-hydroxytetrahydropyran as starting materials. [ka]

[0787] 1H NMR (400 MHz, CDCl3) δ 7.35 - 7.31 (m, 2H), 7.27 - 7.18 (m, 3H), 5.56 - 5.54 (m, 1H), 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, 7.2 Hz, 1.5H), 1.34 (d, J = 6.8, 1.5H).

[0788] 31 P NMR (162 MHz, CDCl3) δ 9.79, 9.21, 9.15, 9.09, 8.59, 8.51, 8.45, 7.89;

[0789] MS (ESI) m / z: calcd. 448.2 [M+H] + , found 470.2 [M+Na] + .

[0790] Example 39: Control Compound 2

[0791] Example 39 was synthesized according to the method of Example 2 using benzyloxycarbonyl-L-alanine and benzyl alcohol as starting materials. [ka]

[0792] 1H NMR (400 MHz, 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 = 6.8 Hz, 1.5H), 1.21 (d, J = 7.2 Hz, 1.5H);

[0793] 31 P NMR (162 MHz, CDCl3) δ = 31.36, 30.94;

[0794] MS (ESI) m / z: calcd. 418.2 [M+H] + , found 418.2 [M+H] +

[0795] Biological Examples

[0796] Test Example 1: EC of small molecule-activated γδ T cells on tumor cell killing 50 Assay

[0797] γδ T cells and MIApaca / FG2 tumor cell line were expanded in vitro. MIApaca / FG2 cells were digested, counted, and resuspended in DMEM complete medium. The density of the cell suspension was adjusted to 5 × 10 3 Cells were added to a 96-well plate at 50 μL / well and incubated overnight. The next day, test compounds and control compounds were diluted 10-fold with γδT complete medium. 50 μL of the diluted compounds were transferred to the corresponding wells where tumor cells were seeded. The actual detection concentration was 10 -12 ~10 -5 The γδT cells were resuspended in γδT complete medium, and the density of the cell suspension was adjusted according to an effector-target ratio of E:T = 2:1, before cells were added at 1 × 104 50 μL of cells / well was added to the corresponding wells. After 20 hours of co-culture at 37°C and 5% CO2, the cells were centrifuged. The supernatant was removed, and 50 μL of cell lysate containing luciferin substrate was added to each well. After 18 minutes in the dark, the chemiluminescent signal was detected. EC 50 The values ​​were calculated by four-parameter fitting, with the corresponding signal value of the well containing only tumor cells as the minimum killing value and the corresponding signal value of the well without tumor cells as the maximum killing value. The killing data for MIApaca / FG2 cells are as follows: [Table 1]

[0798] γδ T cells and MIApaca / FG2 tumor cell line were expanded in vitro. MIApaca / FG2 cells were digested, counted, and resuspended in DMEM complete medium. The density of the cell suspension was adjusted to 5 × 10 3 100 μL of cells / well were added to a 96-well plate and incubated overnight. The next day, test and control compounds were diluted 3-fold with DMSO, and 4 μL of the diluted compound was added to 96 μL of culture medium to make a 25-fold dilution. 5 μL of the 25-fold diluted compound was transferred to the corresponding wells seeded with tumor cells. The actual detection concentration ranged from 0.05 to 100 nM. γδT cells were resuspended in γδT complete medium, and the density of the cell suspension was adjusted according to an effector-target ratio of E:T = 2:1, and then the cells were added at a concentration of 1 × 10 4 Cells were added to the corresponding wells at 100 μL per well. After 20 hours of co-culture at 37°C and 5% CO2, the cells were centrifuged. The supernatant was removed, and 50 μL of cell lysate containing fluorescein substrate was added to each well. After 18 minutes in the dark, the chemiluminescent signal was detected. EC 50 The values ​​were calculated by four-parameter fitting, with the corresponding signal value of the well containing only tumor cells as the minimum killing value and the corresponding value of the well without tumor cells as the maximum killing value. The killing data for MIApaca / FG2 cells are as follows: [Table 2]

[0799] γδ T cells and Huh7 / FG2 tumor cell line were expanded in vitro. Huh7 / FG2 cells were digested, counted, and resuspended in DMEM complete medium. The density of the cell suspension was adjusted to 5 × 10 3 100 μL of cells / well were added to a 96-well plate and incubated overnight. The next day, test and control compounds were diluted 3-fold with DMSO, and 4 μL of the diluted compound was added to 96 μL of culture medium to obtain a 25-fold dilution. 5 μL of the 25-fold diluted compound was transferred to the corresponding wells seeded with tumor cells. The actual detection concentration ranged from 0.05 to 100 nM. γδT cells were resuspended in complete γδT medium, and the density of the cell suspension was adjusted according to an effector-target ratio of E:T = 5:1, and then the cells were added at a concentration of 2.5 × 10 4 Cells were added to the corresponding wells at 100 μL per well. After 20 hours of co-culture at 37°C and 5% CO2, the cells were centrifuged. The supernatant was removed, and 50 μL of cell lysate containing fluorescein substrate was added to each well. After 18 minutes in the dark, the chemiluminescent signal was detected. EC 50 Values ​​were calculated by four-parameter fitting, with the corresponding signal value of wells containing only tumor cells taken as the minimum killing value and the corresponding value of wells without tumor cells taken as the maximum killing value.

[0800] The killing data for Huh7 cells is as follows: [Table 3]

[0801] γδ T cells and SKOV3 / ELP tumor cell lines were expanded in vitro. SKOV3 / ELP cells were digested, counted, and resuspended in MC5A complete medium. The density of the cell suspension was adjusted to 5 × 10 3100 μL of cells / well were added to a 96-well plate and incubated overnight. The next day, test and control compounds were diluted 3-fold with DMSO, and 4 μL of the diluted compound was added to 96 μL of culture medium to make a 25-fold dilution. 5 μL of the 25-fold diluted compound was transferred to the corresponding wells seeded with tumor cells. The actual detection concentration ranged from 0.05 to 100 nM. γδT cells were resuspended in γδT complete medium, and the density of the cell suspension was adjusted according to an effector-target ratio of E:T = 2:1, and then the cells were added at a concentration of 1 × 10 4 Cells were added to the corresponding wells at 100 μL per well. After 20 hours of co-culture at 37°C and 5% CO2, the cells were centrifuged. The supernatant was removed, and 50 μL of cell lysate containing fluorescein substrate was added to each well. After 18 minutes in the dark, the chemiluminescent signal was detected. EC 50 Values ​​were calculated by four-parameter fitting, with the corresponding signal value of wells containing only tumor cells taken as the minimum killing value and the corresponding value of wells without tumor cells taken as the maximum killing value.

[0802] The killing data for SKOV3 cells is as follows: [Table 4]

[0803] γδ T cells and the MV4-11-luc tumor cell line were expanded in vitro. MV4-11-luc cells were digested, counted, and resuspended in IMDM complete medium. The cell suspension density was adjusted to 5 × 10. 3 100 μL of cells / well were added to a 96-well plate and incubated overnight. The next day, test and control compounds were diluted 3-fold with DMSO, and 4 μL of the diluted compound was added to 96 μL of culture medium to make a 25-fold dilution. 5 μL of the 25-fold diluted compound was transferred to the corresponding wells seeded with tumor cells. The actual detection concentration ranged from 0.05 to 100 nM. γδT cells were resuspended in γδT complete medium, and the density of the cell suspension was adjusted according to an effector-target ratio of E:T = 2:1, and then the cells were added at a concentration of 1 × 10 4Cells were added to the corresponding wells at 100 μL per well. After 20 hours of co-culture at 37°C and 5% CO2, the cells were centrifuged. The supernatant was removed, and 50 μL of cell lysate containing fluorescein substrate was added to each well. After 18 minutes in the dark, the chemiluminescent signal was detected. EC 50 Values ​​were calculated by four-parameter fitting, with the corresponding signal value of wells containing only tumor cells taken as the minimum killing value and the corresponding value of wells without tumor cells taken as the maximum killing value.

[0804] The killing data for MV4-11 cells are as follows: [Table 5]

[0805] Test Example 2: Stability test of the compound in human plasma

[0806] Human plasma stored in a freezer was thawed in a 37°C water bath. After centrifugation at 4000 rpm for 5 minutes, the solution was collected. Each sample was run in duplicate and the plasma was added to a 96-well plate at 98 μL / well using an Apricot automated workstation. Next, 2 μL of a 100 μM small molecule solution was added. After incubation for 0, 10, 30, 60, 120 minutes, 6 hours, and 24 hours, 500 μL of quenching solution was added to the plate to precipitate proteins. The plate was shaken for 20 minutes and centrifuged at 4000 rpm for 20 minutes at 4°C. The resulting supernatant was analyzed by LC-MS / MS.

[0807] Test Example 3: Compound stability test in human whole blood

[0808] (1) An appropriate amount of blank whole blood was added to an EP tube containing sodium heparin, and then a working solution of the test substance was added to a final concentration of 1 μM and mixed by vortexing.

[0809] (2) In two parallel experiments, samples were placed in a 37°C water bath. In one experiment, the time points were 0, 0.5, 1, 2, and 4 hours. A separate experiment was performed to obtain an absolute zero point, which was compared with the zero time point.

[0810] (3) An appropriate amount of sample was taken from the incubation system, and 300 μL of the internal standard precipitant was added thereto to precipitate the protein. (4) All samples were centrifuged (15,700 × g) at 6 °C for 10 minutes.

[0811] (5) 150 μL of the supernatant was collected, 150 μL of water was added thereto, and the mixture was mixed by vortexing and analyzed by LC-MS / MS. The stability data of the compound in human whole blood is as follows: [Table 6]

[0812] Test Example 4: Stability experiment of the compound in human liver microsomes

[0813] Compounds were prepared as 10 mM stock solutions in DMSO and then diluted to a 100 μM working solution in 80% acetonitrile-water for use. Human liver microsomes were obtained from BIOIVT.

[0814] (1) Liver microsomes were taken out of the freezer and placed in a water bath thermostatic shaker at 37°C, pre-incubated for 5 minutes, and then thawed for use.

[0815] (2) A certain amount of NADPH was weighed out and dissolved in an appropriate amount of magnesium chloride solution to prepare a 2 mM solution for use.

[0816] (3) The mixed solution for the heated incubation system (without β-NADPH) was prepared according to the ratios in the above “Composition of the experimental heated incubation system” and dispensed at 165 μL per tube (45 μL per tube for the negative control group and 120 μL per tube for the positive control group).

[0817] (4) For the 0 min sample: 200 μL of internal standard working precipitant was added, followed by 30 μL of NADPH solution.

[0818] (5) For other samples, 135 μL of NADPH solution was added to start the reaction (45 μL of magnesium chloride solution was added for the negative control group), and the samples were incubated in a 37°C water bath for 5, 15, 30, and 60 minutes (60 minutes for the negative control group). 60 μL of the samples were then sampled and added to 200 μL of precipitant containing the internal standard.

[0819] (6) For the positive control group: 90 μL of NADPH solution was added to start the reaction, and the mixture was incubated in a water bath at 37°C for 5 to 15 minutes. After that, 60 μL of the mixture was sampled and added to 200 μL of precipitant containing the internal standard.

[0820] (7) For neat samples: 297 μL of water was pipetted into the tube, 1000 μL of the internal standard working solution was added, and 3 μL of the test compound working solution was added.

[0821] (8) All samples were vortexed and centrifuged.

[0822] (9) 150 μL of the supernatant was sampled and added to 150 μL of water, mixed uniformly by vortexing, and analyzed by LC-MS / MS. The half-life stability data for human liver microsomes are as follows: [Table 7]

[0823] Test Example 5: Test of binding rate between compound and human plasma protein

[0824] (1) The dried dialysis membrane was immersed in ultrapure water for at least 20 minutes, then immersed in 20% ethanol for 30 minutes to 1 hour, and then rinsed with ultrapure water 2 to 3 times. Finally, the membrane was immersed in ultrapure water for 20 minutes before use.

[0825] (2) Frozen plasma was thawed in a water bath at 37°C.

[0826] (3) Test compounds were diluted to a final concentration of 1 μM in plasma preheated to 37° C. The final concentration of the control compound warfarin in plasma was 2 μM.

[0827] (4) The pretreated dialysis membrane was assembled into a dialysis plate according to the product specifications, and 120 μL of receptor solution (100 mM phosphate buffer supplemented with 0.002% Tween 80) was added to one side of the permeable membrane of each dialysis well.

[0828] (5) 20 μL of each final solution of the test compound and control compound was added in duplicate to a 96-well sample plate to obtain TO samples, which were stored in a freezer at −20° C. An additional 20 μL of the above final solution was added in duplicate to the opposite side of the membrane in the dialysis device, which was then incubated at 37° C. with shaking for 6 hours at a constant temperature.

[0829] (6) After 6 hours of incubation, 20 μL of the dialyzed receptor solution and the administered plasma were weighed out to obtain samples B and A in duplicate. Corresponding volumes of the corresponding blank plasma or receptor solution were added to samples B and A so that the volume ratio of plasma to buffer in each sample well was 1:1. 300 μL of acetonitrile solution containing the internal standard was added to all sample wells, mixed uniformly, and then centrifuged.

[0830] (7) 200 μL of ultrapure water (150 μL for the control group) was added to the corresponding sample wells of a 96-well sample plate, and 300 μL of the supernatant (150 μL for the control group) was added to the sample wells. The samples were mixed uniformly and then analyzed. The free percentage and recovery rate of the compound in plasma were calculated using the following formula: plasma protein binding rate (%) = 1 - free percentage (where free percentage (%) = C B / C A ).

[0831] In the formula, C B is the concentration of the compound in the receiving solution after equilibrium dialysis, and CA is the concentration of the compound in the plasma after equilibrium dialysis, and CT is the initial concentration of the compound in the plasma. The human plasma protein binding data are as follows: [Table 8]

[0832] Test Example 6: Test of the inhibitory rate of compounds against CYP

[0833] (1) 100× specific inhibitor: The inhibitor working solution with the corresponding concentration was prepared by diluting the corresponding stock solution with 50% acetonitrile-water.

[0834] (2) 200× Compound: Compound stock solution was diluted with acetonitrile to a 2000 μM working solution.

[0835] (3) 200× substrate: Substrate working solutions with the corresponding concentrations were prepared by diluting the corresponding stock solutions with 50% acetonitrile-water.

[0836] (4) A 4 mM NADPH solution was prepared using the PB solution as a solvent.

[0837] (5) Liver microsome substrate solution: A certain amount of PB was added to a centrifuge tube, followed by a certain amount of MgCl2-PB solution, followed by human liver microsome solution, followed by the substrate working solution for each isoform, which was then added and mixed uniformly by vortexing, followed by dispensing at 148 μL per tube.

[0838] (6) 1 μL of inhibitor / test compound working solution / 50% acetonitrile-water was added to each tube, followed by pre-incubation in a water bath at 37°C for 5 minutes. Simultaneously, NADPH was pre-incubated in a water bath at 37°C for 5 minutes.

[0839] (7) 50 μL / well of NADPH working solution was added and incubated for 30 minutes (for 2C19) or 10 minutes (for other isoforms).

[0840] (8) 100 μL of the sample was sampled, and 300 μL / well of ice-cold internal standard working solution was added. After vortexing for 5 minutes, the reaction was stopped and then centrifuged.

[0841] (9) 100 μL of supernatant was sampled and added to 300 μL of water (for 1A2 and 2C8), or 150 μL of supernatant was sampled and added to 150 μL of water (for other isoforms), mixed uniformly by vortexing, and injected for LC-MS / MS analysis. Using Excel, the enzyme inhibition rate was calculated based on the metabolic rate of each specific probe substrate for the test substance and control at the test concentration. The calculation method was: % enzyme inhibition = 100 - average remaining enzyme activity %. % remaining enzyme activity = peak area ratio of the metabolite of the probe substrate after inhibitor addition / peak area ratio of the metabolite of the probe substrate without inhibitor addition × 100%.

[0842] Test Example 7: Kinetic Solubility Assay of Compounds

[0843] Test compounds were prepared in DMSO to a 10 mM stock solution prior to use.

[0844] (1) The test compound stock solution was added to a pH 7.4 buffer solution at a ratio of 1:49.

[0845] (2) The mixture was shaken vigorously for 24 hours.

[0846] (3) After centrifugation (15700 g, 20 min), the clear liquid was removed from the interlayer, diluted 2000 times with 80% acetonitrile-water, mixed homogeneously, and then injected for analysis.

[0847] Test Example 8: Caco2 membrane permeability test

[0848] 1. Test compounds were diluted to 5 μM test solutions in the corresponding transport buffer. The final concentration of organic reagents in the incubation system was less than 1%.

[0849] 2. The transport rate of compounds from the apical to the basolateral end of the substrate was determined. 75 μL of dosing solution was added to each well of the upper compartment (apical end), and 250 μL of receptor solution was added to each well of the lower compartment (basolateral end). The transport rate of compounds from the basolateral to the apical end was determined. 75 μL of receptor solution was added to each well of the upper compartment (apical end), and 250 μL of dosing solution was added to each well of the lower compartment (basolateral end). The plate was sealed and placed in a 37°C incubator and incubated for 120 minutes.

[0850] 3. After the incubation was complete, the incubation was sampled and all samples were mixed, followed by the addition of 600 μL of stop solution containing the internal standard.

[0851] 4. This was mixed on a plate shaker and centrifuged. Finally, 200 μL of supernatant was taken from all samples, 200 μL of water was added, and the mixture was mixed by vortexing and injected for LC-MS / MS analysis.

[0852] After 5.2 hours of incubation, the integrity of the cell monolayer was assessed by leakage of fluorescent yellow. The fluorescent yellow stock solution was diluted to a final concentration of 100 μM in transport buffer. 75 μL of fluorescent yellow solution was added to each well of the upper Transwell insert plate, and 250 μL of transport buffer was added to each well of the lower receiver plate. After 120 minutes of incubation, 10 μL of the solution aspirated from the upper well and 90 μL of transport buffer were added to a new 96-well plate, and 100 μL of the solution aspirated from the lower well was added to a new 96-well plate. Fluorescence assays were performed using a microplate reader with an excitation wavelength of 428 nm and an emission wavelength of 528 nm.

[0853] Apparent permeability coefficient (P app, unit: cm / s 10 -6 was calculated by the following formula:

[0854] P app =(dCr / dt)×Vr / (A×C0)

[0855] where dCr / dt is the cumulative concentration of compound in the receptor compartment as a function of time (μM / s), Vr is the volume of solution at the receptor end (0.075 mL at the apical end and 0.25 mL at the basal end), and A is the surface area, i.e., 0.0804 cm 2 is the cell monolayer area, and C0 is the initial concentration (μM) at the administration edge.

[0856] The emission rate was calculated using the following formula:

[0857] Efflux Ratio=P app (BA) / P app (AB)

[0858] The recovery rate was calculated using the following formula:

[0859] %Recovery=100×[(Vr×Cr)+(Vd×Cd)] / (Vd×C0)

[0860] where Vd is the volume of the dosing end (0.075 mL at the apical end and 0.25 mL at the basal end), and Cd and Cr are the final concentrations of the transported compound at the dosing and receiving ends, respectively.

[0861] Test Example 9: Pharmacokinetic study in cynomolgus monkeys

[0862] Control compound 2 and compound 19 were prepared at 1 mg / mL in 10% DMSO / 90% PBS. Cynomolgus monkeys were obtained from Suzhou Leo Biotechnology Co., Ltd. Control compound 2 and compound 19 were each administered intravenously at 2 mg / kg. Blood collected before administration was recorded as time zero. Subsequently, 1 mL of blood was collected at eight time points: 0.083, 0.15, 0.5, 1.0, 2.0, 4.0, 8.0, and 24.0. Each mL of collected whole blood was placed into a labeled EDTA-2K anticoagulant tube. After gently inverting the tube to thoroughly mix the anticoagulant (EDTA-2K) with the blood, the tube was immediately placed in wet ice and centrifuged within 30 minutes to separate the plasma. The centrifugation conditions were set at 4°C, 2200 g, and 6 minutes. The plasma separated by centrifugation was placed in labeled EP tubes, and the contents of Compound 19 and control Compound 2 in the plasma samples at various time points were detected and analyzed. Each group consisted of three male cynomolgus monkeys. [Table 9]

[0863] After intravenous administration, the exposure of unchanged drug for compounds of the present disclosure was more than three times that of the control compound, indicating that compounds of the present disclosure can provide better active agent exposure and therapeutic effect in subjects.

[0864] Test Example 10: Molecular binding experiment

[0865] (A) Potential map of the BTN3A1 B30.2-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 BTN2A1 B30.2-HMBPP-BTN3A1 B30.2 (PDB ID: 7YGJ). BTN3A1 B30.2 is shown as a potential map. Chains A and B of 2A1 B30.2 are shown as cartoon models. HMBPP and amino acids are shown as sphere models.

[0867] Images were exported using Pymol.

Claims

1. Formula (I) 【Chemistry 1】 A compound of the formula During the ceremony, Ring A is C ６－１０ aryl or 5-10 membered heteroaryl; R ａ is H, halogen, C １－６ Alkyl, C １－６ Haloalkyl, -OR'', NR''R'', C ２－６ Alkenyl and C ２－６ alkynyl; m=1, 2, 3, 4 or 5; X is O or CRR'; R １ is selected from H, F, Cl, CN and methyl, wherein methyl is selected from halogen, CN, OH and NH ２ and optionally substituted with 1 to 3 substituents independently selected from: R ２ is 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 to 12-membered heterocyclyl and C ０－６ alkylene-5 to 10-membered heteroaryl; 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 to 12-membered heterocyclyl and C ０－６ Alkylene-5 to 10 membered heteroaryl is selected from the group consisting of halogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl, 5- to 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 to 10-membered cycloalkyl, —C(O)-4 to 10-membered heterocycloalkyl, —C(O)-C ６－１０ optionally substituted with one or more substituents selected from aryl, —C(O)-5 to 10-membered heteroaryl, —CN, and oxo groups; R ３ is C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl and C ２－６ alkynyl; where: R and R' are independently selected from H and halogen; R'' is H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, 3- to 7-membered heterocyclyl, C ６－１０ independently selected from aryl and 5-10 membered heteroaryl; The compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

2. Formula (I) according to claim 1 【Chemistry 2】 A compound of the formula During the ceremony, Ring A is C ６－１０ aryl or 5-10 membered heteroaryl; R ａ is H, halogen, C １－６ Alkyl, C １－６ Haloalkyl, -OR'', NR''R'', C ２－６ Alkenyl and C ２－６ alkynyl; m=1, 2, 3, 4 or 5; X is O or CRR'; R １ is selected from H, F, Cl, CN and methyl, wherein methyl is selected from halogen, CN, OH and NH ２ and optionally substituted with 1 to 3 substituents independently selected from: R ２ is 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 to 7-membered heterocyclyl and C ０－６ alkylene-5 to 10 membered heteroaryl; R ３ is C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl and C ２－６ alkynyl; where: R and R' are independently selected from H and halogen; R'' is H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, 3- to 7-membered heterocyclyl, C ６－１０ independently selected from aryl and 5-10 membered heteroaryl; The compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

3. Formula (II) 【Transformation 3】 A compound of the formula During the ceremony, X is O or CRR'; R １ is selected from H, F, Cl, CN and methyl, wherein methyl is selected from halogen, CN, OH and NH ２ and optionally substituted with 1 to 3 substituents independently selected from: R ２ is 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 and C ０－６ alkylene-4 to 12-membered heterocyclyl; 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 and C ０－６ Alkylene-4 to 12-membered heterocyclyl is selected from the group consisting of halogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl, 5- to 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 to 10-membered cycloalkyl, —C(O)-4 to 10-membered heterocycloalkyl, —C(O)-C ６－１０ optionally substituted with one or more substituents selected from aryl, —C(O)-5 to 10-membered heteroaryl, —CN, and oxo groups; R ３ is C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl and C ２－６ alkynyl; where: R and R' are independently selected from H and halogen; 10. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein the compound is a compound of formula (I).

4. Formula (II) 【Chemistry 4】 A compound of the formula During the ceremony, X is O or CRR'; R １ is selected from H, F, Cl, CN and methyl, wherein methyl is selected from halogen, CN, OH and NH ２ and optionally substituted with 1 to 3 substituents independently selected from: R ２ is C ５－６ Alkyl, C ５－６ Haloalkyl, C ５－６ Alkenyl, C ５－６ Alkynyl, C ０－６ Alkylene-C ３－７ Cycloalkyl and C ０－６ alkylene-4 to 7 membered heterocyclyl; R ３ is C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl and C ２－６ alkynyl; where: R and R' are independently selected from H and halogen; 10. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein the compound is a compound of formula (I).

5. Formula (III) 【Transformation 5】 A compound of the formula During the ceremony, X is O or CRR'; Ring A is C ６－１０ aryl or 5-10 membered heteroaryl; R ａ is H, halogen, C １－６ Alkyl, C １－６ Haloalkyl, -OR'', NR''R'', C ２－６ Alkenyl and C ２－６ alkynyl; R ２ is 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 and C ０－６ alkylene-4 to 12-membered heterocyclyl; 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 and C ０－６ Alkylene-4 to 12-membered heterocyclyl is selected from the group consisting of halogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl, 5- to 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 to 10-membered cycloalkyl, —C(O)-4 to 10-membered heterocycloalkyl, —C(O)-C ６－１０ optionally substituted with one or more substituents selected from aryl, —C(O)-5 to 10-membered heteroaryl, —CN, and oxo groups; where: R and R' are independently selected from H and halogen; 10. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein the compound is a compound of formula (I).

6. X is CRR' and optionally CH ２ or CF ２ 6. The compound of any one of claims 1 to 5, wherein:

7. R １ H, F, Cl, CN, CH ３ , C.F. ３ and C.H. ２ OH, and more preferably R １ But H, CH ３ , C.H. ２ OH and CF ３ and more optionally, R １ But CH ３ and C.F. ３ and more optionally, R １ is CH ３ 7. The compound of any one of claims 1 to 4 and 6, wherein:

8. R ２ is 2-ethylbutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl or tetrahydropyridinyl, and optionally R ２ is cyclopentyl, tetrahydrofuranyl, tetrahydrothiophenyl or pyrrolidinyl, and more optionally, R ２ is cyclopentyl or tetrahydrofuranyl, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

9. R ３ is C １－６ 9. The compound of any one of claims 1 to 4 and 6 to 8, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein R is alkyl and optionally is methyl or isopropyl.

10. Formula (IV) 【Transformation 6】 A compound of the formula In the formula, ring A is C ６－１０ aryl or 5- to 10-membered heteroaryl, for example a phenyl ring or a naphthalene ring; R ａ is H, halogen, C １－６ Alkyl, C １－６ Haloalkyl, -OR'', NR''R'', C ２－６ Alkenyl and C ２－６ alkynyl; m=1, 2, 3, 4 or 5; R ２ is a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclyl, and the 3- to 12-membered cycloalkyl or the 4- to 12-membered heterocyclyl is selected from the group consisting of halogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl, 5- to 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 to 10-membered cycloalkyl, —C(O)-4 to 10-membered heterocycloalkyl, —C(O)-C ６－１０ optionally substituted with one or more substituents selected from aryl, —C(O)-5 to 10-membered heteroaryl, —CN and oxo groups; 10. The compound of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein the compound is a compound of formula (I).

11. Formula (V) 【Transformation 7】 A compound of the formula In the formula, R ２ is a 4- to 12-membered heterocyclyl, and the 4- to 12-membered heterocyclyl is selected from halogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl, 5- to 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 to 10-membered cycloalkyl, —C(O)-4 to 10-membered heterocycloalkyl, —C(O)-C ６－１０ optionally substituted with one or more substituents selected from aryl, —C(O)-5 to 10-membered heteroaryl, —CN and oxo groups; 11. The compound of claim 10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein the compound is a compound of formula (I).

12. R ２ But halogen, C １－６ Alkyl, —C(O)—C １－６ Alkyl, C １－６ Haloalkyl, C １－６ 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, which is a 4- to 10-membered heterocyclyl optionally substituted with one or more substituents selected from hydroxyalkyl, -C(O)-3- to 10-membered cycloalkyl, -CN and oxo groups.

13. R ２ is a 4- to 7-membered heterocyclyl, the heteroatom of which is an oxygen atom or a nitrogen atom, and the 4- to 7-membered heterocyclyl is １－６ 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, optionally substituted with one or more substituents selected from alkyl and oxo groups.

14. R ２ but below: 【Transformation 8】 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, selected from:

15. Formula (I) 【Chemistry 9】 A compound of the formula During the ceremony, Ring A is C ６－１０ aryl or 5-10 membered heteroaryl; R ａ is H, halogen, C １－６ Alkyl, C １－６ Haloalkyl, -OR'', NR''R'', C ２－６ Alkenyl and C ２－６ alkynyl; m=1, 2, 3, 4 or 5; X is O or CRR'; R １ is selected from H, F, Cl, CN and methyl, wherein methyl is selected from halogen, CN, OH and NH ２ substituted with 1 to 3 substituents independently selected from R ２ is 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 and C ０－６ alkylene-4 to 12-membered heterocyclyl; 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 and C ０－６ Alkylene-4 to 12-membered heterocyclyl is selected from the group consisting of halogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl, 5- to 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 to 10-membered cycloalkyl, —C(O)-4 to 10-membered heterocycloalkyl, —C(O)-C ６－１０ optionally substituted with one or more substituents selected from aryl, —C(O)-5 to 10-membered heteroaryl, —CN, and oxo groups; R ３ is C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl and C ２－６ alkynyl; where: R and R' are independently selected from H and halogen; R'' is H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, 3- to 7-membered heterocyclyl, C ６－１０ independently selected from aryl and 5-10 membered heteroaryl; The compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

16. Formula (II) 【Chemistry 10】 A compound of the formula During the ceremony, X is O or CRR'; R １ is selected from H, F, Cl, CN and methyl, wherein methyl is selected from halogen, CN, OH and NH ２ substituted with 1 to 3 substituents independently selected from R ２ is 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 and C ０－６ alkylene-4 to 12-membered heterocyclyl; 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 and C ０－６ Alkylene-4 to 12-membered heterocyclyl is selected from the group consisting of halogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl, 5- to 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 to 10-membered cycloalkyl, —C(O)-4 to 10-membered heterocycloalkyl, —C(O)-C ６－１０ optionally substituted with one or more substituents selected from aryl, —C(O)-5 to 10-membered heteroaryl, —CN, and oxo groups; R ３ is C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl and C ２－６ alkynyl; where: R and R' are independently selected from H and halogen; 16. The compound of claim 15, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein the compound is a compound of formula (I).

17. X is CRR' and optionally CH ２ or CF ２ 17. The compound of claim 15 or 16, wherein:

18. R １ H, F, Cl, CN, CF ３ and C.H. ２ OH, and more preferably R １ H and CF ３ and more optionally, R １ is CF ３ 18. The compound of any one of claims 15 to 17, wherein:

19. R ２ But C １－６ Alkyl, C ０－６ Alkylene-C ３－７ Cycloalkyl, C ０－６ alkylene-3 to 7-membered heterocyclyl, C ０－６ Alkylene-C ６－１０ Aryl or C ０－６ alkylene-5 to 10 membered heteroaryl, optionally R ２ is isopropyl, 2-ethylbutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyridinyl or benzyl, and more optionally, R ２ is 2-ethylbutyl, cyclopentyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl or benzyl, and more optionally, R ２ is cyclopentyl, tetrahydrofuranyl or benzyl, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

20. R ３ is C １－６ 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 R is alkyl and optionally is methyl or isopropyl.

21. R ２ is a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclyl, and the 3- to 12-membered cycloalkyl or the 4- to 12-membered heterocyclyl is selected from the group consisting of halogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl, 5- to 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 to 10-membered cycloalkyl, —C(O)-4 to 10-membered heterocycloalkyl, —C(O)-C ６－１０ and optionally substituted with one or more substituents selected from aryl, —C(O)-5 to 10 membered heteroaryl, —CN, and oxo groups, and optionally R ２ But halogen, C １－６ Alkyl, —C(O)—C １－６ Alkyl, C １－６ Haloalkyl, C １－６ hydroxyalkyl, —C(O)-3- to 10-membered cycloalkyl, —CN, and oxo groups, and optionally R ２ is a 4- to 7-membered heterocyclyl, the heteroatom of which is an oxygen atom or a nitrogen atom, and the 4- to 7-membered heterocyclyl is １－６ and optionally substituted with one or more substituents selected from alkyl and oxo groups, and further optionally R ２ but below: 【Chemistry 11】 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, selected from:

22. Formula (VI) 【Chemistry 12】 A compound of the formula During the ceremony, Ring A is C ６－１２ aryl or 5-12 membered heteroaryl; R ａ is a halogen, C １－６ Alkyl, C １－６ Haloalkyl, -OR'', NR''R'', C ２－６ Alkenyl and C ２－６ alkynyl; m=1, 2, 3, 4 or 5; X is O or CRR'; R １ is selected from H, F, Cl, CN and methyl, wherein methyl is selected from halogen, CN, OH and NH ２ and optionally substituted with 1 to 3 substituents independently selected from: R ２ is 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 to 12-membered heterocyclyl and C ０－６ alkylene-5 to 10-membered heteroaryl; 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 to 12-membered heterocyclyl and C ０－６ Alkylene-5 to 10 membered heteroaryl is selected from the group consisting of halogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl, 5- to 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 to 10-membered cycloalkyl, —C(O)-4 to 10-membered heterocycloalkyl, —C(O)-C ６－１０ optionally substituted with one or more substituents selected from aryl, —C(O)-5 to 10 membered heteroaryl, —CN, and oxo groups; R ３ and R ３ ' are respectively, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl and C ２－６ independently selected from alkynyl; where: R and R' are independently selected from H and halogen; R'' is H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, 3- to 7-membered heterocyclyl, C ６－１０ independently selected from aryl and 5-10 membered heteroaryl; The compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

23. Formula (VII) 【Chemistry 13】 A compound of the formula During the ceremony, X is O or CRR'; Ring A is C ６－１２ aryl or 5-12 membered heteroaryl; R ａ is a halogen, C １－６ Alkyl, C １－６ Haloalkyl, -OR'', NR''R'', C ２－６ Alkenyl and C ２－６ alkynyl; m=1, 2, 3, 4 or 5; X is O or CRR'; R ２ is 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 to 12-membered heterocyclyl and C ０－６ alkylene-5 to 10-membered heteroaryl; 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 to 12-membered heterocyclyl and C ０－６ Alkylene-5 to 10 membered heteroaryl is selected from the group consisting of halogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl, 5- to 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 to 10-membered cycloalkyl, —C(O)-4 to 10-membered heterocycloalkyl, —C(O)-C ６－１０ optionally substituted with one or more substituents selected from aryl, —C(O)-5 to 10 membered heteroaryl, —CN, and oxo groups; R ３ and R ３ ' are respectively, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl and C ２－６ independently selected from alkynyl; where: R and R' are independently selected from H and halogen; R'' is H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, 3- to 7-membered heterocyclyl, C ６－１０ independently selected from aryl and 5-10 membered heteroaryl; 23. The compound of claim 22, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein the compound is a compound of formula (I).

24. X is CRR' and optionally CH ２ or CF ２ 24. The compound of claim 22 or 23, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein:

25. R ２ But C １－６ Alkyl, C ０－６ Alkylene-C ３－７ Cycloalkyl, C ０－６ alkylene-3 to 7-membered heterocyclyl, C ０－６ Alkylene-C ６－１０ Aryl or C ０－６ alkylene-5 to 10 membered heteroaryl, optionally R ２ is isopropyl, 2-ethylbutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyridinyl or benzyl, and more optionally, R ２ is 2-ethylbutyl, cyclopentyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl or benzyl, and more optionally, R ２ is cyclopentyl, tetrahydrofuranyl or benzyl, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

26. R ３ is C １－６ 26. The compound of any one of claims 22 to 25, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, wherein R is alkyl and optionally is methyl or isopropyl.

27. R ２ is a 3- to 12-membered cycloalkyl or a 4- to 12-membered heterocyclyl, and the 3- to 12-membered cycloalkyl or the 4- to 12-membered heterocyclyl is selected from the group consisting of halogen, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６－１０ Aryl, 5- to 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 to 10-membered cycloalkyl, —C(O)-4 to 10-membered heterocycloalkyl, —C(O)-C ６－１０ and optionally substituted with one or more substituents selected from aryl, —C(O)-5 to 10 membered heteroaryl, —CN, and oxo groups, and optionally R ２ But halogen, C １－６ Alkyl, —C(O)—C １－６ Alkyl, C １－６ Haloalkyl, C １－６ hydroxyalkyl, —C(O)-3- to 10-membered cycloalkyl, —CN, and oxo groups, and optionally R ２ is a 4- to 7-membered heterocyclyl, the heteroatom of which is an oxygen atom or a nitrogen atom, and the 4- to 7-membered heterocyclyl is １－６ and optionally substituted with one or more substituents selected from alkyl and oxo groups, and further optionally R ２ but below: 【Chemistry 14】 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, selected from:

28. below: 【Chemistry 15-1】 【Chemistry 15-2】 28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, selected from:

29. below: 【Chemistry 16】 29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof, selected from:

30. 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. 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 manufacture of a medicament for treating a proliferative disease.

32. 31. 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. 30. A method for treating a proliferative disease in a subject, comprising administering to said subject a compound of 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 of claim 14.

34. The proliferative disease is selected from cancer, cardiovascular disorders, infectious diseases, chronic inflammatory diseases, autoimmune disorders and other cell proliferative disorders, and optionally the cancer is a solid tumor and a hematological malignancy, such as breast cancer, neuroblastoma, malignant rhabdomyoma, 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, and optionally the proliferative disease is selected from multiple myeloma, non-Hodgkin's lymphoma, lung cancer, renal cancer and prostate cancer.

35. A compound of formula (I) in the manufacture of a medicament for promoting the binding of butyrophilin 3A1 / 2A1 【Chemistry 17】 A compound of the formula During the ceremony, Ring A is C ６－１０ aryl or 5-10 membered heteroaryl; R ａ is H, halogen, C １－６ Alkyl, C １－６ Haloalkyl, -OR'', NR''R'', C ２－６ Alkenyl and C ２－６ alkynyl; m=1, 2, 3, 4 or 5; X is O or CRR'; R １ is selected from H, F, Cl, CN and methyl, wherein methyl is selected from halogen, CN, OH and NH ２ and optionally substituted with 1 to 3 substituents independently selected from: R ２ is 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 to 7-membered heterocyclyl, C ０－６ Alkylene-C ６－１０ Aryl and C ０－６ alkylene-5 to 10 membered heteroaryl; R ３ is C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl and C ２－６ alkynyl; where: R and R' are independently selected from H and halogen; R'' is H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, 3- to 7-membered heterocyclyl, C ６－１０ independently selected from aryl and 5-10 membered heteroaryl; Use of the compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

36. A compound of formula (I) for use in promoting the binding of butyrophilin 3A1 / 2A1 [Chemistry 18] A compound of the formula During the ceremony, Ring A is C ６－１０ aryl or 5-10 membered heteroaryl; R ａ is H, halogen, C １－６ Alkyl, C １－６ Haloalkyl, -OR'', NR''R'', C ２－６ Alkenyl and C ２－６ alkynyl; m=1, 2, 3, 4 or 5; X is O or CRR'; R １ is selected from H, F, Cl, CN and methyl, wherein methyl is selected from halogen, CN, OH and NH ２ and optionally substituted with 1 to 3 substituents independently selected from: R ２ is 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 to 7-membered heterocyclyl, C ０－６ Alkylene-C ６－１０ Aryl and C ０－６ alkylene-5 to 10 membered heteroaryl; R ３ is C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl and C ２－６ alkynyl; where: R and R' are independently selected from H and halogen; R'' is H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, 3- to 7-membered heterocyclyl, C ６－１０ independently selected from aryl and 5-10 membered heteroaryl; The compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

37. 1. A method for promoting butyrophilin 3A1 / 2A1 binding in a subject, comprising administering to a subject an antibody of formula (I): 【Chemistry 19】 A compound of the formula During the ceremony, Ring A is C ６－１０ aryl or 5-10 membered heteroaryl; R ａ is H, halogen, C １－６ Alkyl, C １－６ Haloalkyl, -OR'', NR''R'', C ２－６ Alkenyl and C ２－６ alkynyl; m=1, 2, 3, 4 or 5; X is O or CRR'; R １ is selected from H, F, Cl, CN and methyl, wherein methyl is selected from halogen, CN, OH and NH ２ and optionally substituted with 1 to 3 substituents independently selected from: R ２ is 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 to 7-membered heterocyclyl, C ０－６ Alkylene-C ６－１０ Aryl and C ０－６ alkylene-5 to 10 membered heteroaryl; R ３ is C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl and C ２－６ alkynyl; where: R and R' are independently selected from H and halogen; R'' is H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ cycloalkyl, 3- to 7-membered heterocyclyl, C ６－１０ independently selected from aryl and 5-10 membered heteroaryl; A method comprising administering to said subject a compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph, or isotopic variant thereof.

38. 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 compound is: 【Chemistry 20-1】 【Chemistry 20-2】 【Chemistry 20-3】 or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, polymorph or isotopic variant thereof.

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